This is a paper that needs to be widely known. I wish every psychiatrist in the country would read it, and I wish that it would be widely discussed in the media too.

Now, Harrow’s study produced findings that belied common wisdom.  He and Jobe followed schizophrenia patients for 20 years, and those who got off antipsychotics, as a group, had much better outcomes. Over the long term, they were much more likely to be recovered, much more likely to work; they were much less likely to be experiencing psychotic symptoms; and they had better cognitive function and they were much less anxious. So how can you square that finding with research showing that when patients are withdrawn from antipsychotic medications, they relapse at a much higher rate? That is the evidence for long-term use of antipsychotics, and here is what Harrow and Jobe write:  “We view the results from these discontinuation studies as involving a paradox.”

Within six to 10 months following discontinuation, they write, 25% to 55% of schizophrenia patients withdrawn from their medications relapse. But, they note, “relapse rates are considerably lower subsequently in discontinued schizophrenia patients who remain stable during these 6-10 months,” and that “patients with schizophrenia not on antipsychotics for a prolonged period do not show this tendency to relapse when they remain unmedicated.”

So the puzzle is this: Why is there such a high relapse rate in the immediate months following withdrawal, compared to the relapse rate when patients “remain unmedicated” after this initial discontinuation period?

The common perspective, they note, is that the high rate of relapse on discontinuation provides “evidence of the importance of antipsychotic medications in maintaining clinical stability by blocking dopamine receptors.” But there is another perspective to consider:

“From an alternative perspective, the reduction in relapses and low relapse rate, after 6-10 months, could indicate a medicine-generated psychosis in the first 6-10 months, which then recedes. Using this perspective, the first 6-10 month increase in relapses after withdrawal may be influenced by biological conditions generated by the previous continuous use of antipsychotics, with this interacting with schizophrenia patients’ underlying greater vulnerability to psychopathology. The discontinuation effect includes the potential of medication-generated buildup, prior to discontinuation, of supersensitive dopamine receptors, or the buildup of excess dopamine receptors, or supersensitive psychosis, as indicated by multiple studies by Seeman and others of dopamine-blocking agents using animal models.”

This is key. Harrow and Jobe are stating that the high relapse rate that occurs in the drug-withdrawal studies may be an artifact of the patients having been on the drugs in the first place. The drugs induce a dopamine supersensitivity, which puts the patients at high risk of a “medicine-generated psychosis” upon drug withdrawal. And if this is so, then the entire evidence base for long-term use is based on a delusion: mistaking the high relapse rate for a sign that the “disease” is returning, when in truth it is related to prior drug exposure.

Next, Harrow and Jobe ask, what happens if people remain continuously on the drugs? “Well designed studies of dopamine blocking agents using animal models provide strong evidence that ‘breakthrough supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy,’ ” they write. In other words, even if people stay on the drugs, the drugs may stop working, and the reason is that the drugs make the patients more biologically vulnerable to psychosis.

This raises the next question: What do longitudinal studies tell us about outcomes for schizophrenia patients who, shortly after an acute episode, get off antipsychotics? These studies, they write,  “could suggest that, long-term, schizophrenia patients with less or no antipsychotic use after the acute phase may show better outcomes and more periods of recovery.”

In their own research they write, those who stayed continuously on antipsychotics over 15-year and 20-year periods experienced “considerable psychopathology and few sustained periods of recovery.” While some continuously medicated patients had a low level of psychotic symptoms, for most patients so treated “the psychotic symptoms were frequent and, while not intense, were at least of moderate severity, usually with some disruption of functioning.” In contrast, the schizophrenia patients “who were untreated for many years showed significantly better outcomes than those on antipsychotics.”

Now, when Harrow and Jobe reported their 15-year outcomes, Harrow and Jobe noted that it was the good prognosis patients who were most likely to go off, and so many readers took that as the explanation for the better outcomes for those who got off the drugs: the difference in outcomes could be explained by a difference in prognostic status.  But in their 15-year paper, Harrow and Jobe also observed that the good prognosis patients who got off antipsychotics did better than the good prognosis patients who stayed on, and that the bad prognosis patients who got off the drugs did better than those who stayed on. And in their new paper, in the Schizophrenia Bulletin, they directly address this fact:

“Many patients who left treatment for multiyear periods and had favorable outcomes were good prognostic schizophrenia patients, giving some confirmation to earlier views about the importance of prognostic factors. However, some patients treated for many years with antipsychotics also were good prognostic patients who did not show favorable outcomes.”

Furthermore, they note, other longitudinal studies have “found similar results.” They cite studies by Courtney Harding, the Chestnut Lodge study, the Alberta Hospital Studies in Canada, and those of M. Bleuler in Europe. Finally, Harrow and Jobe note that in the studies by the World Health Organization, researchers “found better outcomes in many developing countries where only a small percentage of schizophrenia patients were treated with antipsychotics.”

Thus, in this review, they sum up the big puzzle regarding the evidence base for antipsychotics. Do they show efficacy over the short term? Yes. Do patients withdrawn from the drugs relapse at higher rates than those maintained on the medications? Yes. But is there evidence that over the long term, the drugs may worsen outcomes? Yes.

“How unique among medical treatments is it that the apparent efficacy of antipsychotics could diminish over time or become ineffective or harmful?” they write. “There are many examples for other medications of similar long-term effects, with this often occurring as the body readjusts, biologically, to the medications.”

The conclusion they draw is a straightforward one: our current paradigm for treating schizophrenia, which emphasizes continual lifelong use of antipsychotics, needs to be fundamentally rethought.

“Overall, the longitudinal studies cited do not provide conclusive proof of a causal relationship between being off medications and being psychosis free. They do clearly indicate that not all schizophrenia patients need continuous antipsychotics for a prolonged period, providing extensive evidence of samples of medication-free schizophrenia patients with favorable outcomes . . . The longitudinal studies indicate the importance of further research on how many schizophrenia patients profit from continuous administration of antipsychotics over a prolonged period, what factors identify and separate schizophrenia patients who do not need prolonged antipsychotic treatment, and whether or not prolonged use of antipsychotics is harmful for some or many patients.”

This is a manifesto for change, and much to my amazement, it will be published in the Schizophrenia Bulletin. This is a mainstream journal, and its editors surely wouldn’t publish this discussion unless they knew that the scientific evidence warranted it.

This is a hopeful moment, and an opportunity to be seized. I would urge Madinamerica readers to help seize that opportunity. We can ask those who prescribe antipsychotics and providers of service to read this article in Schizophrenia Bulletin and consider its implications. I hope that E. Fuller Torrey will read it, and that other prominent defenders of the common wisdom will read it too. I hope that Thomas Insel, director of the National Institute of Mental Health, will read it and blog about it. In this way, perhaps this article can trigger a serious discussion, within mainstream psychiatry, about the wealth of evidence showing that our current paradigm of care, regarding the use of antipsychotics, needs to be fundamentally rethought. And that it needs to be rethought with this question in mind: we need to assess, as Harrow and Jobe wrote, whether “prolonged use of antipsychotics is harmful for some or many patients.”

That is a societal discussion we have needed to have for a long, long time.

The post Do Antipsychotics Worsen Long-term Schizophrenia Outcomes? Martin Harrow Explores the Question. appeared first on Mad In America.

I have thought much about David these past two weeks, for of course it is a time like this that you realize anew how much you appreciate a person.

Personally, I owe David a great deal, as it was an interview I did with him in 1998 that propelled me to write more in-depth about psychiatry. At that time, I was co-writing a series for the Boston Globe about abuses of psychiatric patients in research settings, and one of the “abuses” we wrote about were studies in which antipsychotics had been withdrawn from schizophrenia patients. My understanding at that time was that antipsychotics fixed a chemical imbalance in the brains of people so diagnosed, and thus, we reasoned, it was clearly unethical for researchers to have withdrawn antipsychotics from schizophrenia patients.

Having framed the withdrawal studies in that way, I called David, expecting him to voice outrage. I thought he would say something about how only people diagnosed with a mental illness would be treated in such a poor way. Instead, he said that there were good reasons to help people withdraw from such drugs. They could damage the brain, he said. And then he challenged me: Check out the research for yourself, he said. See what the evidence shows.

After the series in the Boston Globe ran, I began to do what David urged me to do. That eventually led me to write Mad in America, my first book on the history of psychiatry.

After that book was published, David invited me to speak several times at MindFreedom events, and our paths also crossed at numerous other events. Several years ago, when I  was in Eugene, Oregon, he took me on a beautiful walk in the old forests east of that city. And during these past ten years, I came to admire him greatly, and for so many reasons.

Smart, funny, and energetic, David could have pursued many career paths, many of which might have offered more financial rewards. But instead, he has devoted his life, for more than 30 years, to fighting a system that he believes can do so much harm. As he liked to say, it was time for “a non-violent revolution.” That is a long time to remain devoted to fighting the good fight. It takes real doggedness and commitment to social change to do that.

He also has put this struggle into a larger social context, that of a fight for civil rights. He is, of course, right in doing so. When the struggle raises questions about discrimination, forced hospitalization, forced treatment, and informed consent about the nature of those treatments, then it is raising questions about the basic rights of American citizens. That is a context that our society needs to think more deeply about, and David’s work has helped prompt such thought.

I also so appreciate that he has seemed to wage this struggle, year after year, with good cheer and even optimism. It is not an easy struggle to wage, and yet, at least when I have encountered David, he has never seemed to be discouraged. I am not sure why that is so, but I can speculate about one possible reason: He knows that he leads a meaningful life, and that sustains him.

I could go on, but no need. I was moved to write this post for a simple reason: when I heard of his fall, and how seriously he was injured, I was, to tell the truth, stunned by how hard I took the news. He changed my life; he has waged a noble struggle for decades; and his efforts have led to social change. And realizing that, I just wanted to publicly say, David, please get well soon.

The post Thoughts About David Oaks appeared first on Mad In America.

As usual, Dr. Torrey has lied to make his criticisms, stating that I wrote things I never did, or completely mischaracterizing the context in which they were written. Thus, my public plea now to Dr. Torrey: Please, stop the lies. Your writings are libelous and slanderous, and–given your prominent public presence–they make it exceedingly difficult for our society to have an honest discussion about the merits of psychiatric medications, and their place in our society.

Here is what you write about me in your latest article.

1. Lie number one. “Whitaker is dead wrong in alleging that schizophrenia is caused by the antipsychotic drugs used to treat it (see Anatomy of an Epidemic.)”

I, of course, don’t allege any such thing. Here is what I wrote in Anatomy of an Epidemic. In chapter six, I reviewed the scientific literature regarding how antipsychotic drugs affect the long-term course of those diagnosed with schizophrenia. In the course of doing so, I wrote about research done in the 1970s and early 1980s that revealed that antipsychotics worked by blocking D2 receptors in the brain, and that in compensatory response to that dopamine blockade, the postsynaptic neurons increase their density of D2 receptors. Two Canadian investigators, Guy Chouinard and Barry Jones, then wrote that this drug-induced increase in D2 receptors made the brain “supersensitive” to dopamine, and thus potentially made patients more biologically vulnerable to psychosis.

This is what Chouinard and Jones wrote:

“Neuroleptics can produce a dopamine supersensitivity that leads to both dyskinetic and psychotic symptoms. An implication is that the tendency toward psychotic relapse in a patient who has developed such a supersensitivity is determined by more than just the normal course of the illness.”

So what am I doing in this passage? I am quoting what researchers concluded from their biological investigations into how antipsychotics affect the brain. So, Dr. Torrey, here is my challenge: Please point to where I wrote in Anatomy of an Epidemic that schizophrenia is caused by the antipsychotic drugs used to treat it.

2. Lie number two: You write that in Mad in America, I described schizophrenia as a term “loosely applied to people with widely disparate emotional problems.”

Once again, let’s go the source.  In chapter seven of Mad in America, I write about the evolution of this diagnosis over the past century, and noted that in the 1960s and 1970s, American psychiatrists—in a form of lousy diagnostic practice—were applying that term to a wide range of patients. I was reporting on criticism of diagnostic practices that had been made by people within the field.  Thus, I concluded at the end of this passage about diagnostic practices at that time, that “people with widely disparate emotional and behavior problems—some anxious, some morbidly depressed, some hostile, and some afflicted with odd notions and bizarre thoughts—were regularly funneled into a single diagnostic category, schizophrenia, and then treated with neuroleptics.” (p. 174, of 2002 paperback edition of Mad in America.)

I was writing in that passage about poor diagnostic practices in the past. Then, in the epilogue of Mad in America, I wrote about the diagnosis of schizophrenia today. (p. 285):

“There remains today great uncertainty over what schizophrenia is, or isn’t. The public has been led to think of schizophrenia as a discrete disorder, one characterized by abnormal brain chemistry. In truth, the biological underpinnings of madness remain as mysterious as ever. In fact, schizophrenia is a diagnosis applied to people who behave or think strangely in a variety of different ways. Some people so diagnosed are withdrawn. Some are manic. Some act very “silly.” Others are paranoid. In some people, the crazy behaviors appear gradually. In others, psychosis descends abruptly. Any well-reasoned concept of ‘madness’ would require teasing apart all these different types and would also require an understanding of how outcomes for the different types—in the absence of neuroleptics—might differ. Yet there is little research in American circles devoted to seeing this more complex picture.”

Again, Dr. Torrey, I urge you to consult your attorney on this. Read him what you claimed I wrote in  Mad in America, that I described schizophrenia as a term “loosely applied to people with widely disparate emotional problems,” and then read him this passage. See if he congratulates you for your accuracy in your summing up—with quotes—of what I wrote.

3. Lie number three: “For the treatment of schizophrenia, Whitaker recommends ‘love and food and understanding, not drugs.’ “

This quote comes from chapter nine in Mad in America, titled “Shame of a Nation.” (Page 214.) In this section of the chapter, I am writing about the history of forced treatment with neuroleptics, and how patient groups in the 1970s organized against it, arguing that it was a form of “psychiatric assault.” I noted that one of their rallying cries was, “We need love and food and understanding, not drugs.” (That quote, if I remember correctly, was taken from a sign at one of their protests.)

Dr. Torrey, I am quite certain that you can see that I am not, in that paragraph, writing about what I recommend as treatment. So, once again, here is my advice: Take what you wrote to your lawyer, have him read this passage, and ask him about the legal ramifications of your obvious dishonesty here.

In an earlier post, I noted that you used this same dishonest, straw-man tactic—misrepresenting what I wrote and then criticizing me for those “writings”—in your scathing review of Anatomy of an Epidemic, also published on the TAC website. Thus, as you meet with your attorney, ask what the law thinks about repeated libel and slander.

There are two other aspects of your latest post that need a response.

First, you write that madinamerica.com is an “antipsychiatry” website. We are not an “antipsychiatry” website. I turned madinamerica.com into a website where people with a variety of backgrounds—psychiatrists, psychologists, family members, social workers, counselors, people with lived experience, etc.—can write about our current paradigm of psychiatric care, and how it might be improved.

The site does give voice to a number of people who are sharply critical of the system, and particularly to people who have been “patients” in the system. Some of those writers are indeed “antipsychiatry.” But if our society is going to have a discussion about how we can build a better system of care, we surely need to hear from the many who feel they have been horribly abused, betrayed, and harmed by our current form of care.

More to the point, though, we also urge our bloggers to write about new treatments and programs that, one hopes, will lead to a more humane and effective paradigm of care in the future. Those writings aren’t “antipsychiatry” tomes; they are writings intent on creating a better psychiatry.

Finally, you criticized Dr. Steingard for writing on our website. In my opinion, her writings are among the most important that appear on madinamerica.com. She writes in a humble, thoughtful, informed fashion about improving psychiatric care, and she does so from the perspective of a physician who works within the system. But in your article—and ultimately this is what is so indecent about it—you try to discredit her through guilt by association.

Honestly, it made me think of the McCarthy hearings in 1954, when Army counsel Joseph Welch asked Senator Joseph McCarthy this ringing question: “Have you no sense of decency, sir?”

The post Dear Dr. Torrey: Please, Stop The Lies! appeared first on Mad In America.

Let’s follow this story from its start.

In 2004, the FDA concluded that in randomized trials, SSRI antidepressants doubled the risk of suicidal thoughts and behaviors in children and young adults, compared to placebo. That finding led the FDA to issue a  “black-box warning” that these drugs could increase the risk of suicide in children and adolescents.

Gibbons was a member of the FDA panel that voted in favor of the black box warning, fifteen to eight. However, he was one of the dissenting eight, and, as he recently recalled in an interview, he felt that the warning was not warranted. Ever since then, he has published a number of articles that dispute the FDA’s finding that SSRIs increase the risk of suicidal thoughts and behaviors.

As his most recent articles disclose, he has also served as an expert witness for Wyeth and Pfizer Pharmaceuticals in cases related to antidepressants and suicide. His findings, it is fair to say, help make him a valuable witness for the makers of SSRIs.

One of his first such papers, which attracted a great deal of media attention, was published in the American Journal of Psychiatry in 2007. He reported that in the wake of the black box warning (and a similar warning by European regulatory authorities), the prescribing of SSRIs to children and adolescents decreased in the U.S. and Europe, and that when this happened, there was a dramatic increase in suicides in the two countries he studied, the U.S. and the Netherlands. The black box warnings, he concluded, apparently led to an increase in pediatric suicides.

Critics quickly pointed out the dishonest science that Gibbons had employed to make this case. He reported that SSRI prescriptions to youth declined by 22% in the U.S. from 2003 to 2005, and that suicide rates in youth rose 14% between 2003 and 2004. But since he had only the suicide rates for the U.S. through 2004, he should have focused on prescribing rates during that same period of time.

In fact, there had only been a very small decrease in the prescribing of SSRIs to youth between 2003 and 2004, when the number of suicides rose. It was between 2004 and 2005 that the there was a significant decrease in the prescribing of SSRIs to youth, and–as the critics noted–once the suicide data for that period became available, it showed that during that time, the number of suicides for persons ages 5 to 24 declined.

In other words, the data showed that as the number of prescriptions to children and youth declined, the number of suicides in this age group declined too. But Gibbons reported that the opposite was true. He did so by matching the increase in suicides in 2003-2004 to the decline in prescribing in 2004-2005. This is not the sort of error a scientist “accidentally makes.” This is the sort of presentation of data one makes when he or she is trying to deliberately tell a story that fits a preconceived end.

In the Netherlands, Dutch academics were incensed with Gibbons and his statistical antics. In the Dutch Drug Bulletin, they noted that the increase in suicides in the Netherlands was so small that it was “not statistically significant.” They described his conclusions as “astonishing” and “misleading,” and stated that Gibbons and his co-authors had been “reckless” to publish such claims.

But how did the U.S. media treat Gibbons’ article? Newspapers took his conclusion at face value. Gibbons, the Chicago Tribune reported, had “documented a close correlation between declining use of the antidepressants known as SSRIs and rising suicide rates among young people up to age 19.” And given that “fact,” Gibbons told the paper that the FDA’s black box warning had a “horrible and unintended effect” and should be withdrawn.

All told, Gibbons published at least eight papers between 2005 and 2011 challenging the FDA’s black box warning (and it would be possible to critique those papers as well.) Then, in February and March of this year, the Archives of General Psychiatry published in its online edition two more of Gibbons’ articles on this topic. These two articles have now appeared in the journal’s June print edition.

In one article, “Suicidal Thoughts and Behavior With Antidepressant Treatment,”  Gibbons reported that he had done a “reanalysis” of the randomized placebo-controlled studies of fluoxetine and venlafaxine, and found “no evidence of increased suicide risk in youths receiving active medication.” In the second article, “Benefits from Antidepressants,” he reported that these drugs were highly effective in reducing depressive symptoms in youths too.

His reports, starting with their online publication, attracted considerable media attention. In an interview with the LA Times, Gibbons again sounded the theme that the black box warning issued in 2004 was a mistake. “The greatest cause of suicide is untreated or undiagnosed depression,” he said. “It’s very important that this condition be recognized and appropriately treated and not discarded because doctors are afraid to be sued.”

On NPR, it was more of the same. When the FDA issued its black box warning, Gibbons said,  “I worried that what we might end up with was a real epidemic of suicide. And the data suggests that this is exactly what happened. Rather than the black-box warnings leading to decreases in child suicide rates, they were followed by some of the largest increases in child suicide rates both here in America and around the world.”

More recently, with the publication of the two articles in the June print edition of the Archives of General Psychiatry, Medscape reported that his findings indicated there might be a “need to revaluate” the black box warning.

Back in February, when Gibbons’ “Suicidal Thoughts” article first appeared online, David Healy wrote a blog detailing—as he said—the many “tricks” that Gibbons had employed to make the case that fluoxetine and velafaxine didn’t increase suicidal thoughts in youth. In a similar vein, Mickey Nardo, a retired psychoanalyst who writes the blog 1boringoldman, wrote a series of posts on the two articles, describing the “inappropriate data selection,” “opaque methodology,” “obvious arithmetic errors” and “deceitful presentation” to be found in the two studies. Such flaws, he noted, rendered the studies incapable of “supporting any broad conclusions about the safety or efficacy of antidepressants in youth.”

Intent on making his criticisms part of the scientific discussion, Nardo sent a “letter to the editor” of the Archives of General Psychiatry with these criticisms. He did so with the expectation that his letter would be published in the print journal. If so, his criticism would then become part of the scientific record that is archived by PubMed.

The AGP editors neatly kept that from happening. They decided to publish his criticism as a “readers reply,” and only online. As a result, they informed Nardo, “like other online posts, your reply will not be indexed in PubMed.”

As such, his criticism of Gibbons’ report is not part of the “evidence base” on this topic.

More recently, Matthew Miller, an associate professor at the Harvard School of Public Health, whose research focuses on suicide, took a critical look at Gibbons’ newly published suicide article. (Disclosure: Matthew Miller is a friend of mine.)  He and his colleagues who collaborated on this review also concluded that Gibbons’ finding—that fluoxetine and venlafaxine didn’t increase the suicide risk in youth—was unwarranted. Instead, as they detailed in a letter to the editor of the Archives of General Psychiatry, Gibbons had committed methodological errors and misinterpreted data to draw “misleading conclusions.” In fact, Miller and his colleagues concluded that the very data that Gibbons presented in his study, when properly analyzed, “align with the FDA findings,” which is that the effect of antidepressants on suicidality in youth “appears harmful.”

The AGP editors treated their “letter to the editor” in the same way they had treated Nardo’s submission. They published it as a “reader’s reply,” but not as a letter to the editor. Once again, in this way, they kept this criticism from being archived in PubMed, and thus part of the searchable record.

In response, Miller wrote to the journal’s editor, Joseph Coyle, urging that their criticism appear in the print edition. Coyle didn’t respond.

Miller also sent an email to Medscape, protesting its touting of the Gibbons’ article as evidence that the two antidepressants didn’t increase suicidal behavior in youth. Medscape didn’t respond to him either. 

In this brief review of Gibbons’ work—and a review of how critiques of his work were handled by the Archives of General Psychiatry–we can see the triumph of bad science. In randomized trials, SSRIs were shown to double the risk of suicidal thoughts and behavior in children and adolescents. This led the FDA to issue its black box warning. But since then Robert Gibbons has sought to tell a different story, both in the medical journals and in the media, and he has succeeded in doing so.

Critics may have revealed the bad science involved in his reports, but that criticism doesn’t substantially affect the bottom-line conclusion that shows up in PubMed and in the media: Researchers have found that SSRIs do not increase the risk of suicidal thoughts and behaviors in children and adolescents, and the real tragedy is that an unwarranted black box warning may be keeping some depressed youth from getting the drug treatment they need.

As such, this story can help us understand why we, as a society, may end up deluded about the merits of psychiatric medications. The evidence base is massaged in a way that protects the image of the drugs.  Dishonest science gets published in the Archives of General Psychiatry and is archived in PubMed, while in-depth criticisms of that bad science are relegated to the “readers’ reply” corner of the journal’s online website, and thus excluded from the PubMed archives. Meanwhile, the media tells of Gibbons’ “findings,” but omits the part about the scientific dishonesty at the heart of those reports.

And voila, you have a process for creating a societal delusion.

The post The Triumph of Bad Science appeared first on Mad In America.

This was a story about high school students abusing stimulants in order to perform better on academic tests, and so, in this case, the article highlighted the harm these drugs can do. Here is the key paragraph: “Abuse of prescription stimulants can lead to depression and mood swings (from sleep deprivation), heart irregularities and acute exhaustion or psychosis during withdrawal, doctors say. Little is known about the long-term effects of abuse of stimulants among the young. Drug counselors say that for some teenagers, the pills eventually become an entry to the abuse of painkillers and sleep aids.”

All of this is quite true. But—and this is the key point—these happen to be the very side effects that show up in trials of stimulants prescribed for ADHD. There, in the scientific literature, you will find reports of the drugs causing mood swings (and thus leading to diagnoses of bipolar), psychotic episodes, hallucinations, depression, heart irregularities, and withdrawal symptoms. While the literature regarding whether stimulants lead to substance abuse in adulthood is mixed, there certainly are a lot of anecdotal stories about youth initially prescribed stimulants for ADHD ending up with a drug addiction problem.

However, in newspaper articles about the prescribing of stimulants for ADHD,  those side effects are never featured prominently. Instead, in those instances, the drugs are presented as being effective and safe. Thus, in this story, the New York Times obviously had a dilemma: How could it reconcile those dueling images of stimulants as both helpful and bad?

The reconciliation comes in two paragraphs.  First, the New York Times writes: “While these medicines tend to calm people with A.D.H.D., those without the disorders find that just one pill can jolt them with the energy and focus to push through all-night homework binges and stay awake during exams afterward.”

In other words, youth with ADHD respond differently to the drugs. Stimulants calm them but keep non-ADHD youth awake.

Then, it quotes Paul L. Hokemeyer, a family therapist at Caron Treatment Centers in Manhattan, who says: “Children have prefrontal cortexes that are not fully developed, and we’re changing the chemistry of the brain. That’s what these drugs do. It’s one thing if you have a real deficiency—the medicine is really important to those people—but not if your deficiency is not getting into Brown.”

And thus, in this quote, readers are told the reason that youth with ADHD respond differently to stimulants — such youth have a “real deficiency.” They  have a “chemical imbalance” (and given that stimulants up dopamine levels, the implication here is that youth with ADHD have low dopamine levels.)

So is this true? Do youth diagnosed with ADHD respond in a fundamentally different way to the drugs than “normal kids” do? Do they suffer from a known “deficiency?”

The literature shows that they experience the same harmful side effects that non-ADHD youth do. Youth diagnosed with ADHD who take stimulants, rather than feeling “calmed,”  may suffer from insomnia, just the same way that “normal” kids do. Youth diagnosed with ADHD who take stimulants may tell of being able to “focus” better on school tests, just as “normal” kids do. As for research into the “biology” of ADHD, it  certainly has not been shown that such youth suffer from low dopamine levels, or that they have a “real” chemical deficiency of any kind.

This was an article intent on exploring how high school students abuse stimulants in order to get better grades. But, unwittingly, it also perfectly revealed our society’s cognitive dissonance around the prescribing of stimulants to youth diagnosed with ADHD. Indeed, we can see our societal mindset vividly on display; how we turn a blind eye to the many side effects these drugs can cause, and how, when we explain to ourselves why stimulants are good for youth so diagnosed, we tell false stories about how they respond differently to the drugs than “normal” kids do and what is known to be “wrong” with them.

Stimulants may help youth—whether diagnosed with ADHD or not—focus better on tests, and thus do better academically over the short term. But it would be helpful, I think, if the prescribing of these drugs did not rely on this sort of cognitive dissonance, but instead was done with medical eyes wide open regarding the harm they can cause too.

Related MiA Blogs:
Stimulants for Good Grades: A Legitimate or an Abuse?
Better Living Through Chemistry?

The post The NY Times: When Stimulants Are Bad appeared first on Mad In America.

As these legal actions have been settled, the manufacturers have paid large fines. I haven’t kept track of all the settlements, but even a quick Google search tells of Astra Zeneca paying a $500 million fine for its illegal marketing of Seroquel; Bristol Myers Squibb paying $515 million for its illegal marketing of Ability; Pfizer paying $301 million for its illegal marketing of Geodon; and Eli Lilly paying $1.4 billion for its illegal marketing of Zyprexa.

It should be noted, of course, that this illegal marketing of atypicals caused considerable harm. It resulted in millions of Americans, young and old, being prescribed powerful drugs that could cause diabetes and other harmful side effects, even though there was an absence of scientific reason to believe the drugs—when prescribed off-label—would provide a benefit.

However, while the companies have paid these fines for their illegal actions, the executives of these firms have gone unscathed. Instead, during the past 15 years, they were rewarded with stock options and bonuses worth billions of dollars. For instance, when I was researching Anatomy of an Epidemic, I reviewed the profits earned by Eli Lilly executives and employees on stock options from 1987 to 2000 (when the company brought Prozac and then Zyprexa to market), and determined that they netted around $3.1 billion during that period.

Thus, from a financial standpoint, the moral of the atypical story appears to be this: crime pays. The executives at the pharmaceutical companies prospered, and so too the companies. Their illegal marketing of the atypicals turned these drugs into the top revenue-generating class of drugs in the country in 2009, with prescription sales totaling $14.6 billion. The fines could be seen as just a cost of doing business, and actually, as money well spent given that the illegal marketing worked so well.

Now consider the financial bottom line for Jim Gottstein, an Alaska attorney who blogs on this site, and, at one point, released sealed court documents to the public related to Eli Lilly’s illegal marketing of Zyprexa. His financial travails—thanks to a recent IRS decision— continue to get worse.

Here is a little background to this story.

In 2002, when Gottstein founded his non-profit organization, PsychRights, he set his sights on two goals.   The first was to file a lawsuit challenging the state’s rights to medicate patients forcibly, with the goal of making it more difficult for the state to do so. The second was to lobby Alaska’s Mental Health Trust Authority to fund a Soteria-like home, where psychotic patients who didn’t want to take neuroleptics could get residential care and help.

He succeeded in achieving both goals.

State laws governing the forced treatment of psychiatric patients date back to the late 1970s. Typically, courts have ruled that while patients have a right to refuse treatment, antipsychotics are understood to be a “medically sound treatment of mental disease,” and thus hospitals can apply to a court to sanction forced treatment. At such hearings, hospitals regularly argue that if the patient were “competent,” he or she would readily agree to take this “medically sound treatment,” and courts consistently order patients to be medicated for that reason. Thus, patients may have a theoretical right to refuse treatment, but in practice it can be very different.

Gottstein, in his challenge of Alaska state law, made a different argument. In a case known as Myers v. Alaska Psychiatric Institute, he argued that the state could not show, through a review of the scientific literature, that antipsychotics were necessarily helpful, particularly over the long run. Thus, a person might have very good reason to refuse the medication;  refusal should not necessarily be seen as a sign of incompetence.

In 2006, the Alaska Supreme Court agreed. “Psychotropic medication can have profound and lasting negative effects on a patient’s mind and body,” the court wrote in its Myers decision. The drugs “are known to cause a number of potentially devastating side effects.” As such, the court ruled, a psychiatric patient could be forcibly medicated only if a court “expressly finds by clear and convincing evidence that the proposed treatment is in the patient’s best interest and that no less intrusive alternative is available.”

In Alaska case law, antipsychotics are no longer viewed as a treatment that will necessarily help psychotic people.

As for the Soteria project, Gottstein spent years pushing Alaska’s Mental Health Trust Authority to fund such a home in Anchorage. His hope was that it could offer psychotic patients the type of care that Loren Mosher’s Soteria Project did in the 1970s. The Soteria model involved using neuroleptics on a cautious, selective basis, and as Gottstein lobbied Alaska’s Mental Health Trust Authority for support, he once again relied on the scientific literature to carry his argument that there was a sound medical reason to provide such care. In the summer of 2009, a seven-bedroom Soteria home opened a few miles south of downtown Anchorage.

Over the past decade, Gottstein and his Law Project for Psychiatric Rights have waged other battles as well. For instance, the Law Project for Psychiatric Rights filed  a whistleblower lawsuit in Alaska federal court, arguing that Alaska physicians, healthcare providers, and pharmacies committed Medicaid fraud when they billed Medicaid for prescriptions of psychiatric drugs to children for non-approved uses. According to Medicaid rules, the federal government is supposed to provide Medicaid reimbursement only for outpatient drugs prescribed for an FDA-approved use, or for a use supported by a drug compendium (a text that will assess off-label uses of a drug as well.)

Thus, Gottstein argued that healthcare providers commit Medicaid fraud when they bill for drugs that don’t meet this standard. While that legal action has so far failed — the trial court ruled, in essence, that the government is aware of this billing practice re psychiatric drugs already, and thus Gottstein lacked whistleblower status — the case is an example of the many ways that Gottstein has tried to curb the improper prescribing of antipsychotics and other psychiatric drugs to children.

His fight with Eli Lilly erupted in 2006. At that time, while representing a client in a forced medication case, Gottstein subpoenaed documents from Dr. David Egilman, an expert witness in the federal case against Eli Lilly for its illegal marketing of Zyprexa. After Egilman produced those documents, which were under seal in the federal case, Gottstein released them to the public, including the New York Times. (He argued that he could legally do so because Eli Lilly had not objected in a timely way to his subpoena.)

The documents, which federal judge Jack Weinstein later unsealed, detailed some of Eli Lilly’s marketing misdeeds. A little more than two years later, Eli Lilly pled guilty to the federal charges, and agreed to pay a $1.415 billion fine. That fine included a criminal penalty of $515 million, which the Department of Justice announced was “the largest criminal fine for an individual corporation ever imposed in a United States criminal prosecution of any kind.”

The New York Times, in its reporting on Eli Lilly’s guilty plea, observed that the federal investigation had “gained momentum” after Gottstein released the documents in December 2006.

However, by this time Gottstein was fighting a legal battle of his own. Judge Weinstein rejected Gottstein’s argument that he had a right to release the documents, and censured Gottstein for having done so. Eli Lilly then sued Gottstein for having made the documents public, arguing that it had been damaged by his actions.

To defend against that lawsuit, Gottstein has run up a legal bill of more than $270,000. His non-profit, PsychRights, has paid $10,000 of this (since it is under the auspices of PsychRights that Gottstein defends clients in forced medication cases). Gottstein  personally paid $125,000 to the attorneys. Finally, the International Center for the Study of Psychiatry and Psychology, where Gottstein was a board member, set up a legal defense fund for Gottstein, and in 2009 and 2010, paid $16,761.50 to his attorneys.

At this moment, Gottstein still owes his attorneys another $130,000.

But now the IRS has come calling. For unknown reasons, the IRS decided to investigate the Center’s defense fund for Gottstein, and it recently determined that the Center’s fundraising for this purpose was not in keeping with its stated mission. It also determined that it was improper because Gottstein was on the board. For those reasons, the IRS concluded that Gottstein was a “disqualified” person under IRS law, unable to receive such financial help, and thus the $16,761.50 the Center paid to his attorneys was an “excess benefit” to him personally.

As such, the IRS is now demanding that he pay an excise tax of $16,761.50, plus a penalty of $558.30. If he fails to do so within an allotted time, the IRS will double the tax to $33,523. Gottstein is fighting the IRS’s decision in court.

Such is the story of two contrasting financial outcomes, and when I heard from Jim Gottstein of this latest financial setback, I could not help myself from writing a blog that, as my high school English teachers might have advised, sought to “compare and contrast.”

The post Black Hats, White Hats, and Financial Reckonings appeared first on Mad In America.

The logic behind outpatient commitment laws is that antipsychotic medication is a necessary good for people with a diagnosis of severe mental illness. The medications are known to be helpful, but—or so the argument goes—people with “severe mental illness” lack insight into their disease and this is why they reject the medication.

However, if the history of science presented in Anatomy of an Epidemic is correct, antipsychotic medications, over the long term, worsen long-term outcomes in the aggregate, and thus a person refusing to take antipsychotic medications may, in fact, have good medical reason for doing so. And if that is so, the logic for forced treatment collapses.

We need to go over Torrey’s review, step by step. This may be a bit exhausting, but since his critical review can ultimately be seen as a defense of his advocacy of forced treatment, I think it will be worthwhile. In the end, we will be able to judge whether his is an honest review, or dishonest in kind, and if it is the latter, that—by itself—will reveal much about the scientific merits of outpatient commitment laws.

Part One: Diagnostic Criteria and Schizophrenia Outcomes

In my foreword to Anatomy of an Epidemic, I told of how, when co-writing a series for the Boston Globe in 1998 on abuses of psychiatric patients in research settings, I stumbled upon two outcome studies that I found difficult to understand.  Dr. Torrey opens his review by setting out to show that my curiosity about those studies was misplaced, and that my subsequent reporting on those studies was in error.

The first such study was by Harvard researchers, who reported in 1994 that outcomes for schizophrenia patients had worsened during the past two decades and were now no better than they had been a century earlier. This outcome belied what I understood to be true at that time, which was that psychiatry had made great progress in treating schizophrenia.

This is the only context for my citing this study in Anatomy of an Epidemic, as a finding that piqued my curiosity. I do not mention the study again in the book, and thus do not cite it in the chapter examining the evidence base for antipsychotics. However, Dr. Torrey claims that I do, writing that after I summarized the findings from this study in the preface, I “later added that the worsened outcomes (in recent decades) were due to the use of antipsychotic drugs.”

Since Dr. Torrey has focused attention on this study, let’s look at what the researchers found and their discussion of their findings.

In a survey of outcome studies over the past century, which were conducted around the world, the researchers reported that from 1895 to 1955, 35.4% of schizophrenia patients “improved;” that this improvement rate increased from 1956 to the 1970s to 48.5%; and then it declined. They concluded that since 1986 the “likelihood of a favorable outcome has diminished to only 36.4%, or a level that is statistically indistinguishable from that found in the first half of the century.”

In their discussion, the researchers reasoned that improved outcomes in the middle part of the century were due to both a change in diagnostic criteria that broadened the definition to include patients who were less ill at disease onset and then to the introduction of neuroleptics. They attribute the decline in outcomes, which began to show up in the late 1970s, to a decline in social services and, starting in 1980 with the publication of DSM-III, a narrowing of the diagnostic criteria for schizophrenia.

So the study has two parts: One tells of how outcomes have deteriorated  in recent times, and are now no better than they were in the first half of the 20^th century, before the arrival of antipsychotics, which seems to belie the common wisdom that the arrival of the drugs “revolutionized” the treatment of schizophrenia. At the same time, in their discussion, the researcher write that that neuroleptics helped improve outcomes, at least when they were first introduced.

As I wrote above, I mentioned this study in my foreword to explain how I got interested in this subject. The deterioration in modern outcomes, such that they were now no better than in the pre-antipsychotic era, surprised me. But I didn’t discuss this study at any length, precisely because I don’t think it provides evidence regarding the long-term efficacy of neuroleptics, one way or another.

However, there is a non-drug explanation for the improvement of outcomes in the 1950s. In the first half of the century, up until the end of World War II, eugenic attitudes toward the mentally ill in the United States, which were also seen in Britain and other European countries, dramatically affected the outcomes of people hospitalized with a diagnosis of schizophrenia. Eugenicists argued that people with schizophrenia were genetically defective, and thus they needed to be segregated from the population—i.e. kept in mental hospitals—to keep them from breeding. This idea began to take hold in the late 1890s, and once it did, discharge rates plunged. Those low discharge rates in the eugenics era would be seen as evidence that patients didn’t improve, and thus the low improvement rate up until 1945 was in large part due to this social policy.

After World War II, eugenics came to be associated with Nazi Germany and the “science” that led to the Holocaust, and thus seen as a discredited, even shameful science. The need to keep schizophrenia patients in mental hospitals for eugenic reasons began to evaporate, and that led, in the wake of World War II, to new discussions within psychiatry and our society about providing care to patients in the community. Discharge rates for first-episode schizophrenia patients immediately began to climb. For instance, a study of first-episode psychotic patients admitted to Warren State Hospital in Pennsylvania from 1946 to 1950 found that 62 percent were discharged within 12 months, and that by the end of three years, 73% were living out of the hospital. Similarly, a study of 216 schizophrenia patients admitted to Delaware State Hospital from 1948 to 1950 found that six years later, 70% were successfully living in the community. These are very high “improvement” rates, and they predate the arrival of the first antipsychotic, Thorazine, in asylum medicine.

Moreover, once Thorazine was introduced in the mid 1950s, there was one large study that looked at how the new antipsychotics affected discharge rates for first-episode patients, and it did not find that the drugs were helpful in this regard. In 1961, the California Department of Mental Hygiene reported on the discharge rates for 1,413 first-episode schizophrenia patients hospitalized in 1956, and it found that 88% of those who weren’t prescribed a neuroleptics—about half of the 1,413 patients—were discharged within 18 months. Those treated with a neuroleptic had a lower discharge rate; only 74 percent were discharged within 18 months.

Thus, if we look closely at changing discharge rates during the middle part of the century, we see that they rose for first-episode patients following World War II, when eugenic attitudes became discredited, and that the arrival of neuroleptics in asylum medicine did not increase this rate. This change in social attitude, along with broadened diagnostic criteria, is what led to the improvement in outcomes following World War II. This change in social attitude grew in the 1950s and 1960s. Deinstitutionalization, as a social policy, took hold and that led to improved discharge rates in those decades.

As anyone can see, the study does raise a question. Why are outcomes today no better than they were in the first half of the century? Doesn’t this finding belie the common wisdom that antipsychotics kicked off a psychopharmacological revolution, a great advance in care. This was a study that understandably piqued my curiosity, which is how I presented it in my book, and yet Dr. Torrey, eager to discredit Anatomy of an Epidemic, states that I cited it as evidence that antipsychotics worsen long-term outcomes.

Call this dishonesty moment number one in his review.

Next, in my foreword to to Anatomy of an Epidemic, I also wrote of how my curiosity about the merits of our drug-based paradigm of care was triggered by studies conducted by the World Health Organization, which twice found that outcomes in three developing countries, India, Columbia, and Nigeria were “considerably better” than in the United States and other developed countries. That also seemed odd—why should outcomes in poor countries like India and Nigeria be better than in the U.S. and other rich countries?

In Anatomy of an Epidemic, I then reported on the WHO findings in the chapter on antipsychotics. This, I noted, was data from a cross-cultural study, in which medication use varied. I presented the WHO data as one piece in a larger body of evidence regarding the long-term merits of antipsychotics.

Here are the findings from the WHO study that included, as part of its reporting on outcomes, the patients’ use of antipsychotics.

• Outcomes were best in the three developing countries, where only 16% of patients were regularly maintained on antipsychotics (versus 61% of patients in the developed countries.)

• The best outcomes of all were seen in Agra, India, where only 3% of patients were maintained on the drugs. The worse outcomes of all—in terms of the highest percentage of patients who were constantly ill—were reported in Moscow, and it was there that medication usage was highest.

• In a 1997 followup (15 to 25 years after the initial study), the patients in the developing countries were still faring much better. “The outcome differential” held up for “general clinical state, symptomatology, disability, and social functioning,” the researchers noted.

In his review, Dr. Torrey seeks to discredit this finding. First, he notes that he and others have argued that the difference in outcomes was due to a difference in the type of schizophrenia suffered by people in the developing countries. Second, and this is more important, he implies that the authors of the WHO studies, in response to such criticism, in 2008 backed away from their initial findings.

The WHO authors, he says, wrote that “we do not argue that the prognosis of schizophrenia in developing countries is groupwise uniformly milder.” The WHO investigators admitted, he says, that “the proportions of continuous unremitting illness . . . did not different significantly across the two types [developed and developing) of settings.”

When you read that sentence, you are led to understand that the authors of the WHO study no longer believe that outcomes in the developing countries were truly better. It seems that they now agree with their critics, which is that the better outcomes were an artifact of diagnostic differences. If that is true, it would mean that this cross-cultural study should not be seen as an instance in which patients, who were treated in settings where antipsychotics were less frequently used, had better outcomes. That is how I presented the study, and so if the researchers did indeed conclude what Dr. Torrey said they did, my presentation of that study would be in error.

So let’s look at what the authors, Jablensky and Sartorius, actually wrote in their 2008 article.

There were two WHO studies that compared outcomes in developing and developed countries, they noted. The first was known as the WHO International Pilot Study of schizophrenia, which found “markedly better outcomes of schizophrenia patients in India and Nigeria at 2-year and 5-year follow-ups.” However, at that time, the researchers concluded that the divergent outcomes—in this first study—might be the result of a difference in patient groups. Thus, they mounted a rigorous second study, known as the DOSMeD study, to investigate that possibility. This study followed all new onset cases of psychosis within a geographical area for two years.

In 1992, the WHO investigators reported their findings, and as part of their report, they divided patients into schizophrenia subtypes and compared outcomes in the subgroups. But it didn’t matter. No matter how the data were cut ande sliced, outcomes in the developing countries were much better. “The findings of a better outcome in developing countries was confirmed,” they wrote.

Now, in their recent 2008 paper,  Sartorius and Jablensky,  rather than back away from their 1992 findings,  vigorously defended them.

They noted the following results from the DOSMeD study:

• High rates of complete clinical remission were significantly more common in developing country areas (37%) than in developed countries (15.5%).

• Patients in developing countries experienced significantly longer periods of unimpaired functioning in the community, although only 16% of them were on continuous antipsychotic medications (compared with 61% in the developed countries.)

• In the study, one of the best predictors of outcome was “type of setting (developed vs. developing country.)”

• Elevated rates of early death (standardized mortality ratios) are more common in developed countries than developing ones.

So, where did Torrey’s misleading quote come from? In their 2008 report, Sartorius and Jablensky did observe that the percentage of patients with a “continuous unremitting illness” in the poor countries was 11.1 %, which was not significantly less than the percentage with this course in the rich countries (17.4%). In other words, there was a small percentage of patients in both settings that had a very bad course, but this did not reflect overall outcomes.

Dr. Torrey, in his review, was intent on discrediting the findings from this WHO study, which reported superior outcomes in poor countries where only a small percentage of patients were regularly maintained on antipsychotics. To do so, he implied that the WHO investigators now agreed with the critics of the study, when that is not true.

Call this dishonesty moment number two in his review.

Part Two:  Schizophrenia Outcomes and Medication

In this part of his review, Dr. Torrey takes aim at two longer-term studies (Courtenay Harding’s and Martin Harrow’s) and my reporting on those studies. He also takes aim at  the results reported for patients treated with open-dialogue therapy in Western Lapland, Finland, and my reporting of that program.

Courtenay Harding’s Vermont Longitudinal Study

I wrote one paragraph on this study in Anatomy of an Epidemic. Here it is:

In the late 1950s and early 1960s, Vermont State Hospital discharged 269 chronic schizophrenics, most of whom were middle-aged, into the community. Twenty years later, Courtenay Harding interviewed 168 patients from this cohort (those who were still alive), and found that 34 percent were recovered, which meant they were “asymptomatic and living independently, had close relationships, were employed or otherwise productive citizens, were able to care for themselves and led full lives in general.” This was a startling good outcome for patients who had been seen as hopeless in the 1950s, and those who had recovered, Harding told the APA Monitor, had one thing in common: They all “had long since stopped taking medications.” She concluded that it was a “myth” that schizophrenia patients “must be on medications all their lives,” and that, in fact, “it may be a small percentage who need medication indefinitely.”

Now here is what Dr. Torrey writes. “As Whitaker describes it . . . ‘34 percent were recovered’ which he claims is a ‘startling good outcome.’ Whitaker attributes this outcome (emphasis added) to the fact that ‘they had all long since stopped taking their medications.’ ”

We can call this dishonesty moment number three in his review. I did not attribute the 34% recovery rate to the fact that they had “all long since stopped taking their medications,” as that would indicate that I had drawn that conclusion. Instead, I repeated what Dr. Harding had said in an interview with the APA Monitor about the recovered patients. Equally revealing is what he omits from his discussion of Dr. Harding’s study: he does not mention her conclusion that the conventional wisdom regarding the need for schizophrenia patients to stay on antipsychotics all their life is a “myth.”

Martin Harrow’s Longitudinal Study

As Dr. Torrey correctly notes (for once), I do consider Martin Harrow’s report on the long-term outcomes of people diagnosed with schizophrenia and milder psychotic disorders to be of great importance. His was a prospective study of 200 psychotic patients, whom he followed for 20 years, and it is the only such study in the scientific literature.

Dr. Torrey dismisses the study as “completely unremarkable,” and so let’s take a close look at it to see if that is a fair assessment of his findings.

In the study, everyone was treated conventionally in the hospital with antipsychotics and then discharged.  Harrow then periodically assessed how they were doing over the next 20 years. At each followup, he looked at whether they were symptomatic, whether they were working, and a variety of other outcome measures. He also charted their use of antipsychotics and other psychiatric medications. At the end of 15 years, he still had 145 patients in his study (64 with schizophrenia and 81 with milder disorders. In one of his article, he also reported outcomes for a schizophrenia-spectrum group, which included the schizophrenia patients and a few others with schizoaffective disorder.)

Here is a summary of Harrow’s findings, taken from both his 2007 report on their 15-year outcomes, and  his 2012 report on their 20-year outcomes. (See slides for a graphic presentation of this data.)

1. Recovery rates in the schizophrenia group

At the end of two years, the schizophrenia patients who had stopped taking antipsychotics were doing slightly better on a “global assessment scale” than those taking an antipsychotic. Then, over the next 30 months, the collective fates of the two groups began to dramatically diverge. The off-med group began to improve significantly, and by the end of 4.5 years, 39% were in recovery. In contrast, outcomes for the medicated group worsened during this 30-month period. As a group, their global functioning declined slightly, and at the 4.5-year mark, only six percent were in recovery, and few were working.

That stark divergence in outcomes remained for the next ten years. At the 15-year followup, 40 percent of the schizophrenia patients off antipsychotics (25 of the 64 patients) were in recovery, compared to five percent of those taking antipsychotics. (To be in recovery, a person had to have no positive or negative symptoms; couldn’t have been hospitalized in the previous year; and adequate work and social functioning.)

2. Spectrum of outcomes in the schizophrenia group

Harrow divided long-term outcomes for the 64 schizophrenia patients into three categories: recovered, fair, and uniformly poor. Of the 25 patients who stopped taking antipsychotics, 10 recovered (40%), 11 had fair outcomes (44%), and 4 (16%) had uniformly poor outcomes. In contrast, only 2 of the 39 patients who stayed on antipsychotics recovered (5%); 18 had fair outcomes (46%), and 19 (49%) had uniformly pair outcomes. In sum, medicated patients had one-eighth the recovery rate of unmedicated patients, and a threefold higher rate of faring miserably over the long term.

3. Global outcomes for schizophrenia patients by prognostic type.

At the start of the study, Harrow grouped his schizophrenia patients into two subgroups: those with a good prognosis and those with a bad prognosis. Although he didn’t provide the global data for these two subtypes, he did report this finding: “In addition, global outcome for the group of patients with schizophrenia who were on antipsychotics were compared with the off-medication schizophrenia patients with similar prognostic status. Starting with the 4.5-year followup and extending to the 15-year follow-up, the off-medication subgroup tended to show better global outcomes at each follow-up.”

In other words, in every subgroup of patients (by prognostic type), those off medication had better long-term outcomes (in the aggregate).

4. Psychotic symptoms in the schizophrenia-spectrum and schizophrenia-only group

At the two-year follow-up, about 35% of the “schizophrenia spectrum” group were off antipsychotics, and that percentage remained fairly stable throughout the next 15 years. There was no significant differences in severity of psychotic symptoms between the on-med and off-med groups at two years, but starting with the 4.5-year followup and continuing through year 20, those “who were not on antipsychotic medications were significantly less psychotic than those on antipsychotics.

Among the schizophrenia patients, at the 10-year follow-up, 23% off antipsychotics were experiencing psychotic symptoms, versus 79% of those still on the drugs. At the 15-year followup, 28% of those off antipsychotics had psychotic symptoms, versus 64% of those on the medications.

5. Anxiety symptoms in the schizophrenia-spectrum group

At the two-year followup, about 50% of those on antipsychotics and a similar percentage of those off medications were experiencing “high anxiety.” However, over the next 30 months, high anxiety symptoms soared in the on-antipsychotics group, such that nearly 75% were experiencing this distress by year 4.5, whereas anxiety markedly declined for those off antipsychotics, such that only about 20% were experiencing this distress by year 4.5.  This dramatic difference in anxiety symptoms remained throughout the study, with more than half of those on antipsychotics still suffering from high anxiety at the end of 20 years.

6. Cognitive function in the schizophrenia-spectrum group

The researchers assessed cognitive function at each followup, with one test assessing ability to access general information, and the other abstract thinking. At three of the six follow-ups, those off antipsychotics showed significantly better cognitive functioning, and in the other three follow-ups, there was a general trend favoring those off antipsychotics.

7. Sustained periods of recovery in the schizophrenia-spectrum group.

Of the 24 schizophrenia patients who remained continuously on antipsychotics throughout the 20 years, only 4 (17%) “ever entered into a period meeting the operational definition of recovery during any of the six follow-ups.” The reasons they failed to do so was either because they were psychotic or not working, Harrow noted. In contrast, there were 15 in the group of 70 who were off antipsychotics by the two-year follow-up and remained off the drugs throughout the remaining 18 years. Thirteen of these 15 patients (87%) “experienced two or more periods of recovery,” which meant they were both asymptomatic and working more than 50% of the time.

8. Global outcomes of all 145 patients

Harrow provided global adjustment data for all four groups in his study: schizophrenia on meds, schizophrenia off psychiatric medications, milder disorders on psychiatric meds, milder disorders off. At the end of 15 years, the global outcomes for the four groups lined up like this, from best to worst: Milder disorders off meds, schizophrenia off meds, milder disorders on meds, and schizophrenia on meds.

As could be expected, Dr. Torrey does not report of any of these outcomes in detail. I’ll let readers of this blog decide whether such findings are—as Dr. Torrey writes— “completely unremarkable.”

In his discussion of the Harrow study, Dr. Torrey also makes this claim:  “Whitaker . . . using tortured logic, asserts that the Harrow study proves that long-term antipsychotic use causes brain damage and is responsible for many of the symptoms of schizophrenia, when in fact the study does nothing of the kind.”

Here is my challenge to Dr. Torrey. I wrote about the Harrow study on pages 115 to 118 of Anatomy of An Epidemic.  He should point to the passage on those pages where I asserted that the Harrow study “proves that long-term antipsychotic use causes brain damage and is responsible for many of the symptoms of schizophrenia.” If he can not point to such an assertion, then he should print this correction on his Treatment for Advocacy web page: “I lied about what Robert Whitaker wrote about the Harrow study.” He could then explain to his readers why he felt motivated to lie in this way.

But for our purposes, we can chalk this up as dishonesty moment number four in his review.

The Open Dialogue Program in Finland

In the solutions section of Anatomy of an Epidemic, I wrote about the good outcomes for psychotic patients in Western Lapland, a region in Finland, that—since 1992—has used antipsychotic drugs in a selective manner. Two-thirds of their first-episode patients have not been exposed to antipsychotics five years after initial diagnosis, and 80% are either working or back in school. These are extraordinarily good results, but Dr. Torrey dismisses them out of hand: “Most revealing and remarkable, however, is the fact that more than 40 years after the treatment program began, there are almost no publications describing its results and nobody in Finland or elsewhere has tried to replicate it. Robert Whitaker appears to be the person most impressed by it.

If Dr. Torrey had checked the notes section of my book, he would have found a number of citations documenting the good outcomes in Western Lapland since 1992, when that district began using antipsychotics in a selective manner. Here are five such published reports, and if Dr. Torrey likes, I can point him to others:

1. V. Lehtinen, “Two-year outcome in first-episode psychosis treated according to an integrated model,” European Psychiatry 15 (2000):312-20.

2. J. Seikkula. “Five year experience of first-episode non-affective psychosis in open-dialogue approach,” Psychotherapy Research 16 (2006): 214-28.

3. J. Seikkula. “A two-year follow-up on open dialogue treatment in first episode psychosis,” Society of Clinical Psychology 10 (2000):20-29.

4. J. Seikkula. “Open dialogue, good and poor outcome,” J of Constructivist Psychology 14 (2002):267-86.

5. J. Seikkula. “Open dialogue approach: treatment principles and preliminary results of a two-year follow-up on first episode schizophrenia.” Ethical Human Sciences Services 5 (2003):163-82.

There are also now groups in the United States and elsewhere seeking to "replicate" the open-dialogue model, and if Dr. Torrey likes, I could point him to a conference that will be held in Finland in late August devoted to this topic. Many others, who have read the published articles, apparently are "impressed" by the success of Open Dialogue Therapy.

Part Three: What SSI and SSDI Rates Say

In this part of his review, Dr. Torrey states that while the number of individuals on disability for SSI and SSDI has “indeed increased alarmingly,” he argues that this is because these programs “have become alternatives to welfare for poor and unemployed individuals who have any kind of psychiatric problem.”

I agree this is partly true. But, as I detail in Anatomy of an Epidemic, our drug-based paradigm of care is fueling this epidemic too. One, the widespread use of stimulants and antidepressants has helped create a “bipolar boom” and  the disability numbers are soaring, in large part, because of an extraordinary influx of bipolar patients. Two, a review of the long-term outcomes data for antipsychotics, anti-anxiety agents, and antidepressants reveals that these drugs, in the aggregate, increase the risk of long-term disability.

Part Four: The Dopamine Receptor Story

This section of Dr. Torrey’s review has its interesting moments. He writes that if antipsychotics do indeed cause an increase in dopamine receptors (as I report in Anatomy of an Epidemic,) then “Whitaker is correct that this could potentially be a serious problem, but at this point in time the reality of the problem in humans is unknown.” Although antipsychotics have been shown to cause an increase in dopamine receptors in rats, he writes, it “still is not clear whether or not this also occurs in humans.”

But as Dr. Torrey well knows, there is in fact good evidence that it does indeed occur in humans.

As Philip Seeman first reported in Nature in 1978, the brains of schizophrenia patients at autopsy have 50 percent more dopamine receptors than controls. But at that time, Seeman and his collaborators were uncertain whether this increase in dopamine receptors was due to the disease, or caused by the antipsychotics. During the next decade, investigators in the United States, England and Germany investigated this question, and all determined that neuroleptics led to an increase in brain dopamine receptors.

“From our data,” German investigators wrote in 1989, “we conclude that changes in [receptor density] values in schizophrenics are entirely iatrogenic [drug caused.]”

Finally, in 2002, Seeman reported that, in a study that utilized positron emission tomography, he had documented this increase in dopamine receptors in living patients. This study, he reported, “demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans.”

Here is why this is so important. This increase in D2 receptors is thought to make patients more biologically vulnerable to psychosis. The increase may lead to severe relapses when patients abruptly withdraw from antipsychotics, and the worry is that it also leads to tardive psychosis—a deepening of psychotic symptoms—over the long term (when patients stay on the drugs.) In his 2002 paper, Seeman also found that those patients that had the “highest degree of D2 receptor upregulation” subsequently developed “severe and persistent tardive dyskinesia.”

So, in this instance, give Dr. Torrey credit for acknowledging that a drug-induced increase in dopamine receptors could be a troubling thing indeed. But when he writes that it is “not clear whether or not this occurs in humans,” we have a new moment of dishonesty in his review to tally up.

Miscellany:

I could point to many other instances from Dr. Torrey’s review in which he hasn’t accurately represented what I wrote in the book, or has misrepresented the research literature. But detailing all such problems would take several thousand words more, and so I will let those pass.

However, there is one final bit of miscellany in his review that I want to address, and it has to do with Loren Mosher’s ouster from the NIMH.

Dr. Torrey states that Loren Mosher was not ousted from his position at NIMH as head of the Center for Schizophrenia Studies because he had led the Soteria experiment, but because the field “was moving strongly in a biological direction” and thus Mosher held views of schizophrenia that were at odds with this new wave in psychiatry. Dr. Torrey then writes this of my reporting on Dr. Mosher’s ouster from the NIMH:

“What is perhaps most surprising in Whitaker’s book, given his past career as a respected journalist, is his willingness to uncritically accept anything he has been told as long as it fits his thesis and his wish to blame antipsychotics for everything except global warming.”

The story of Dr. Mosher’s fall from grace at the NIMH is, in fact, easily documented, and it indeed is associated with the Soteria project. As internal written records reveal, the psychiatric establishment began attacking Dr. Mosher the minute he reported good outcomes for his Soteria patients. The study had “serious flaws,” the NIMH review committee snapped. “The credibility of the pilot study is very low,” it wrote. Evidence of superior outcomes for the Soteria patients is “not compelling.” And so on, and then, after the initial reports appeared  the committee hit Mosher with the lowest blow of all: It would approve further funding for the Soteria project only if he was replaced by another  investigator, who would then work with the committee to redesign the experiment.

“The message was clear,” Mosher said, when I interviewed him years later about the Soteria project. “If we were getting outcomes this good, then I must not be an honest scientist.”

When I reported this story in Mad in America, I obtained the written documents that detailed this response to Loren Mosher’s Soteria experiment. Those documents laid bare the hostility of the biological faction within psychiatry toward his study, and toward Mosher personally because of it. So rather than accept this story “uncritically,” as Dr. Torrey suggests, I dotted my I’s and crossed by T’s. In fact, this was the same reporting path–a reliance on documents–that led me to write Mad in America and Anatomy of an Epidemic. If I had been willing to “uncritically accept anything had been told,” then I would have written about the wonders of the “psychopharmacological revolution.” 

Dr. Torrey’s Review as a Foil for Assessing the Merits of  Outpatient Commitment Laws 

The fact that Dr. Torrey has written a scathing review of Anatomy of an Epidemic, asserting that I “made so many errors it is difficult to know where to begin,” is—in its guise as a book review–of little import. I had exchanged a couple of emails with him before his review appeared, and I knew this was coming. You cannot write a book like Anatomy of an Epidemic, which so directly challenges conventional beliefs, and not expect to be attacked, and it should not be surprising when the attacker misrepresents what you wrote, or twists things in order to try to publicly discredit you. Indeed, in the two years since my book was published, I have gotten quite used to reviews of this type, with defenders of the faith eager to inform readers that all is well in the world of psychiatric medications.

But here is why the review could be considered important to us as a society. We are embracing the increased use of outpatient commitment laws that force people to take antipsychotic medications, and we do so under the belief that these drugs are a necessary good for those people. This is an extraordinary thing for a society to do, to force people to take medications that alter their minds and experience of the world.

Yet, here is the story told in Anatomy of an Epidemic: If we look closely at Harrow’s study and a long list of other research, there is good reason to believe that these medications increase psychotic symptoms over the long-term, increase feelings of anxiety, impair cognitive function, cause tardive dyskinesia with some frequency, and dramatically reduce the likelihood that people will fully recover and be able to work. If this is so, how can we, as a society, defend our increasing embrace of forced treatment laws?

We can now ask this key question about Dr. Torrey’s review of Anatomy of an Epidemic. Given that he is a foremost proponent of outpatient commitment laws, what are we—as a society—to make of the fact that, in order to attack the book, he had to do so in a dishonest way?

The post E. Fuller Torrey’s Review of Anatomy of an Epidemic: What Does It Reveal About the Rationale for Forced Treatment? appeared first on Mad In America.

This is a big subject, one that I think should command the attention of our entire society, given how profoundly psychiatry shapes our society today. I wanted to have people with lived experience writing here, social workers, psychologists, providers of services, journalists, ethicists, psychiatrists and other physicians.

We are slowly working toward that goal. And as we do, I have become more convinced than ever that it is important that this site invite and welcome bloggers who may have quite differing opinions about current practices and how to make things better. That is the only way to stir a robust “dialogue” about this subject.

Posted comments by readers are an important, essential part of that discussion. In fact, it is an aspect of this site that I particularly like. I very much enjoy reading what people have to say in response to a blog, and in response to other people making comments.

At the outset, I decided to not screen comments. People could post their comments and they would appear instantaneously. One reason for that is that I believe in free-wheeling discussions, and, second, I hadn’t figured out, in my own mind, what sort of comments might hinder, or shut down, the discussion.

But now I think I do. We encourage readers, if they disagree with the content of a blog, to say so and to express their reasons for why they disagree. Readers should make an argument, point to facts, and tell of personal experiences (and hopefully in a calm, measured way.) All that is good. However, what shuts down discussion is when a comment attacks the person (rather than what the person has written), or seeks to personally discredit the person. This is true whether the comments are directed toward the blogger, or toward someone else commenting on the site. People commenting on the site shouldn’t worry that they will be personally attacked for their views.

And thus my conclusion: The comments’ section has a very simple goal, which is to further discussion,  and if comments distract from that goal, and instead serve to stifle discussion, then they are not helpful.

So this will be our new policy. Comments will still appear instantaneously. But if we find a comment that is attacking the blogger personally, or another commenter personally, we will pull that comment, and we will do so for an easily understood reason: the comment is not serving the purpose of adding to the discussion, but rather shutting it down. And when that happens, all readers of this site lose.

The post Guidelines for a Thoughtful Discussion appeared first on Mad In America.

The same dramatic difference in outcomes was seen in patients diagnosed with a mood disorder with psychotic features:  those who stayed on antipsychotics fared markedly worse over the long-term.

The psychiatric establishment mostly ignored Harrow’s 2007 report, or tried to explain away his findings. But with the publication of the 20-year results, I think the time has come for psychiatry—and our society—to take a close look at his research, and to try to honestly assess what is going on. A full-bodied inquiry is essential for another reason too: We are now prescribing antipsychotics to an ever larger number of children, and to many non-psychotic adults as well, and if antipsychotics are worsening the long-term outcomes of people with a psychotic disorder, which is the obvious concern raised by Harrow’s findings, then we really need to rethink the use of these medications in those other populations.

Here is a review of the study’s design, and the findings from the two papers.

Study Design

From 1975 to 1983, Harrow, who is a psychologist at the University of Illinois, enrolled 200 people with a diagnosis of schizophrenia or a milder psychotic disorder into his NIMH-funded study, recruiting the patients from two Chicago hospitals. One was private and the other public, as this ensured that the patient group would be economically and ethnically diverse. The enrolled patients had a median age of 22.9 years, and for 46%, this was their first hospitalization. Another 21% of the patients had had one previous hospitalization. Thus, this study largely charted long-term outcomes in patients newly diagnosed, or recently diagnosed, with a psychotic disorder. (See chart).

All of the patients were treated conventionally in the hospital, and then Harrow followed them as their lives unfolded, periodically assessing how well they were doing.  Were they symptomatic? In recovery? Employed? Were they taking antipsychotic medications? Or other psychotic medications? He conducted such reviews at 2 years, 4.5 years, 7.5 years, 10 years, 15 years, and 20 years. At the end of 15 years, he had successfully followed 145 of the 200 patients enrolled into the study, and at the end of 20 years, he had outcomes data for 139 patients. For a long-term study, this is a very good retention rate.

The 15-Year Results

In 2007, Harrow published the 15-year results for the 145 people in the study. Of the 145, 64 were diagnosed with schizophrenia, and the remaining 81 with milder psychotic disorders (schizoaffective disorder, bipolar with psychotic features, and unipolar depression with psychotic features.) Here were his findings:

1. Recovery rates in schizophrenia group

At the end of two years, those who had stopped taking antipsychotics were doing slightly better  on a “global assessment scale” than those taking an antipsychotic. Then, over the next 30 months, the collective fates of the two groups began to dramatically diverge. The off-med group began to improve significantly, and by the end of 4.5 years, 39% were in recovery. In contrast, outcomes for the medicated group worsened during this 30-month period. As a group, their global functioning declined slightly, and at the 4.5-year mark, only six percent were in recovery, and few were working.

That stark divergence in outcomes remained for the next ten years. At the 15-year followup, 40 percent of those off antipsychotics (25 of the 64 patients) were in recovery, compared to five percent of those taking antipsychotics. (To be in recovery, a person had to have no positive or negative symptoms; couldn’t have been hospitalized in the previous year; and adequate work and social functioning.) See charts for recovery rates and for global adjustment.

2. Spectrum of outcomes in schizophrenia group

Harrow divided long-term outcomes for the 64 schizophrenia patients into three categories: recovered, fair, and uniformly poor. Of the 25 patients who stopped taking antipsychotics, 10 recovered (40%), 11 had fair outcomes (44%), and 4 (16%) had uniformly poor outcomes. In contrast, only 2 of the 39 patients who stayed on antipsychotics recovered (5%); 18 had fair outcomes (46%), and 19 (49%) had uniformly pair outcomes. (See chart.)  In sum, medicated patients had one-eighth the recovery rate of unmedicated patients, and a threefold higher rate of faring miserably over the long term.

3. Psychotic symptoms in the schizophrenia group

At the 10-year follow-up, 23% of the patients off antipsychotics were experiencing psychotic symptoms, versus 79% of those still on the drugs. At the 15-year followup, 28% of those off antipsychotics had psychotic symptoms, versus 64% of those on the medications. (See chart).

4. Global adjustment of those with milder psychotic disorders

At the end of two years, those with milder psychotic disorders who got off antipsychotics were doing somewhat better than those on the drugs. This difference in global outcomes became pronounced by the end of 4.5 years, with those off medications doing markedly better, and remained so throughout the 15 years. (See chart.)

5. Global outcomes of all 145 patients

Harrow provided global adjustment data for all four groups in his study: schizophrenia on meds, schizophrenia off psychiatric medications, milder disorders on psychiatric meds, milder disorders off. At the end of 15 years, the global outcomes for the four groups lined up like this, from best to worst: Milder disorders off meds, schizophrenia off meds, milder disorders on meds, and schizophrenia on meds. (See chart.)

6. Global outcomes for schizophrenia patients by prognostic type.

At the start of the study, Harrow grouped his schizophrenia patients into two subgroups: those with a good prognosis and those with a bad prognosis. Although he didn’t provide the global data for these two subtypes, he did report this finding: “In addition, global outcome for the group of patients with schizophrenia who were on antipsychotics were compared with the off-medication schizophrenia patients with similar prognostic status. Starting with the 4.5-year followup and extending to the 15-year follow-up, the off-medication subgroup tended to show better global outcomes at each follow-up.”

Interpreting the 15-year findings: Harrow’s explanation

In his discussion, Harrow noted that it was those with a good prognosis (which was characterized by a stronger internal sense of self,) who were more likely to stop taking antipsychotics, and thus stated that his study had simply identified a subset of schizophrenia patients who could fare well off medication. He did not attribute the poor outcomes in the medicated patients to possible iatrogenic effects of antipsychotics.

Another possibility: The drugs are to blame.

In order to explore whether the antipsychotics may be to blame for the poor outcomes, these questions need to be examined:

a) Is there evidence in the scientific literature that antipsychotics might increase a person’s biological vulnerability to psychosis over the long-term? (The dopamine supersensitivity theory.) If so, is this problem seen in the data that shows the medicated patients were much more likely to still be psychotic at the 10-year and 15-year follow-ups?

b) Nancy Andreasen has reported that antipsychotic usage is associated with a decrease in brain volumes over time, and that this decrease in brain volumes is associated with an increase in negative symptoms and cognitive impairment. Is this effect of antipsychotics showing up in the poor recovery rates for the medicated patients over the long-term? Is this why so few worked?

c) Those with milder psychotic disorders could be expected to have a better long-term course than those diagnosed with schizophrenia. Yet, the schizophrenia patients off meds fared better over the long-term than those with milder disorders on the medications.  If the drugs have long-term iatrogenic effects, wouldn’t that explain this surprising outcome?

d) In the study, there are several subsets of patients that can be identified, including good-prognosis and bad-prognosis schizophrenia patients. Why, in every case, did the off-med group have better global outcomes over the 15-year followup?

The 20-Year  Results

In his current paper in Psychological Medicine (published online), Harrow has grouped his patients in a slightly different manner. He grouped those with a schizoaffective diagnosis, who in the 15-year study had been in the “other psychotic disorders category,” with the schizophrenia patients. There are 70 in this SZ (schizophrenia spectrum) category in his new paper, and 69 now in a “mood disorders with psychotic features” diagnostic group.

Here are the relevant findings from his 20-year report:

1. Psychotic symptoms in SZ group

At the two-year follow-up, about 35% of the SZ group were off antipsychotics, and that percentage remained fairly stable throughout the next 15 years. There was no significant differences in severity of psychotic symptoms between the on-med and off-med groups at two years, but starting with the 4.5-year followup and continuing through year 20, those “who were not on antipsychotic medications were significantly less psychotic than those on antipsychotics.”

2. High anxiety in SZ group

At the two-year followup, about 50% of those on antipsychotics and a similar percentage of those off medications were experiencing “high anxiety.” However, over the next 30 months, high anxiety symptoms soared in the on-antipsychotics group, such that nearly 75% were experiencing this disress by year 4.5%, whereas anxiety markedly declined for those off antipsychotics, such that only about 20% were experiencing this distress by year 4.5.  This dramatic difference in anxiety symptoms remained throughout the 15 years, with more than half of those on antipsychotics still suffering from high anxiety at the end of 20 years.

3) Cognitive function in the SZ group

The researchers assessed cognitive function at each followup, with one test assessing ability to access general information, and the other abstract thinking. At three of the six follow-ups, those off antipsychotics showed significantly better cognitive functioning, and in the other three follow-ups, there was a general trend favoring those off antipsychotics.

 4)  Relapse rates in the SZ group

Harrow and his colleagues assessed whether patients who were not psychotic at a followup then relapsed in the next study interval. The relapse rate was much higher in each instance for the medicated patients. Between the 7.5 and 10-year assessments, the relapse rate was 33% for those on medications, 0% for those off the drugs.  Between 10 and 15 years, the relapse rate was 67% for the medicated group and 0% for those off medication. Between 15 and 20 years, it was 25% for those on antipsychotics and 11% for those off medication. This finding revealed that those who remitted off medication were very likely to stay well.

5) Sustained periods of recovery in the SZ group

Of the 70 SZ patients, 24 remained continuously on antipsychotics throughout the 20 years. This was the patient group that were fully medication compliant, yet only 4 of the 24 patients (17%) “ever entered into a period meeting the operational definition of recovery during any of the six follow-ups.” The reasons they failed to do so was either because they were psychotic or not working, Harrow noted.

In contrast, there were 15 in the group of 70 who were off antipsychotics by the two-year follow-up and remained off the drugs throughout the remaining 18 years. Thirteen of these 15 patients (87%) “experienced two or more periods of recovery,” which meant they were both asymptomatic and working more than 50% of the time.

Outcomes in the mood disorders group

At every follow-up, significantly more of the unmedicated patients than those on antipsychotics experienced a period of recovery. Those with mood disorders who stayed on antipsychotics had poor long-term functioning, which was “consistent with the data on the poorer long-term functioning of the schizophrenia (group) who were on antipsychotic medications,” Harrow wrote.

Is it the Drugs?

Thus, we see in these two reports, which arise from the best longitudinal study we have today of long-term outcomes of schizophrenia patients, a consistent story: At every turn, those on medications—as a group–have worse long-term results. They suffer more psychotic symptoms, they are more anxious, they relapse more, they don’t do as well on cognitive tests, and very few enjoy a period of recovery (when the definition of recovery includes returning to work at least part-time.)

This is outcomes data that needs to be closely examined. As we do so, we need to ask whether we should continue with our current paradigm of care, which emphasizes continual use of antipsychotics, or whether that paradigm of care needs to be rethought. Indeed, in this new paper, Harrow and his co-authors do broach the essential question: “Is very long-term treatment with antipsychotic medications undesirable?”

To address that question, we need to look at other research that bears on this question. Is there reason to believe that antipsychotics induce a dopamine supersensitivity, that leads to more chronic symptoms over the long-term? If antipsychotics are associated with a shrinkage of brain volumes, and if studies have shown that as this shrinkage occurs, there is an increase in negative symptoms and cognitive impairment, does this explain why patients on the drugs have poor long-term functional outcomes? We need to assess whether this larger body science tells us that Harrow’s findings are to be expected, as they are consistent with what we have learned about the long-term effects of antipsychotics, or whether there is another plausible explanation—other than the drugs are to blame—for the markedly worse outcomes in the medicated patients.

And I would think that this is a question, given our society’s current widespread use of antipsychotics, of extreme moral urgency.

The post Interpreting Harrow’s 20-Year Results: Are the Drugs to Blame? appeared first on Mad In America.

But in Healy’s blog, there was a reference to new data from the NIMH’s Treatment for Adolescents with Depression Study (TADS), and therein lies a much more important story.

In his blog, Healy published a table on suicidal events from the NIMH’s TADS study of antidepressants in youth, which had been prepared by a Swedish correspondent, Göran Högberg. That table put the suicidal risk associated with fluoxetine in a different light than had been presented in the published articles about the TADS study, and I thus asked Högberg where he had obtained this “updated data.” He pointed me to a 2009 article authored by Benedetto Vitiello, titled “Suicidal Events in the Treatment for Adolescents with Depression Study (TADS),” which was published in the Journal of Clinical Psychiatry. In particular, Högberg pointed me to a table titled “Timing of First Suicidal Event.”  And there, hidden in plain sight,  was the real suicide data from the TADS study.

The Background to the TADS Study

When the TADS results were first published, the practice of prescribing SSRIs to children was taking an evidence-based beating. First, in 2004 the FDA held a hearing on the increased risk of suicide with SSRIs in children, which led to a black box warning. In addition, the FDA’s Thomas Laughren reported at that meeting that these drugs—with the exception of fluoxetine—didn’t work in children either. Twelve of the 15 pediatric trials that had been conducted prior to that date had failed, as the SSRI had not bested placebo. The FDA, in fact, had rejected the application of six manufacturers seeking approval to sell their SSRIs to children.

Fluoxetine (Prozac) was the one SSRI that the FDA had approved for pediatric use. Two of the three positive studies reviewed by Laughren had come from trials of this drug. But as many critics pointed out, there was no reason to think that fluoxetine was any more effective in children than the other SSRIs. The percentage of children who responded to Prozac in the two positive trials was similar to the response rate in the twelve failed trials; Eli Lilly had simply been better at using biased trial designs to knock down the placebo response rate and thus make it appear that its drug worked. Indeed, Australian investigators who reviewed the trial data wrote in the British Medical Journal that the evidence for fluoxetine’s efficacy in children “is not convincing.” As such, they concluded, “recommending [any antidepressant] as a treatment option, let alone as first line treatment, would be inappropriate.”

The editors at Lancet came to a similar conclusion at that time: The truth, they wrote, was that SSRI antidepressants “were both ineffective and harmful in children.”

Such was the embattled status of SSRIs as a treatment for pediatric depression when the TADS investigators, in 2004, first announced their efficacy results. In the study, 439 youth, ages 12 to 17 years old, were randomized either to placebo, fluoxetine, cognitive behavior therapy (CBT), or a combination of CBT plus fluoxetine. At the end of 12 weeks, the response rate was highest for the combination group (71%), and lowest for the placebo group (35%). Although industry-funded trials hadn’t provided good evidence for the use of SSRIs in youth, this NIMH-funded study had done so, at least for fluoxetine.

At that time, several academic critics, including Jon Jureidini from Australia, noted that the two cognitive therapy groups in the TADS study were unblinded, and that in the only blinded comparison from the study, between fluoxetine and placebo, fluoxetine did not provide a statistically significant advantage over placebo on the primary endpoint, the children’s rating scale. As such, Jureidini concluded that the TADS studied showed “that fluoxetine, like all other antidepressants, is of doubtful clinical importance for children.” But this criticism was mostly ignored, and psychiatry now had its efficacy data for an SSRI in youth.

However, a safety problem did show up in the TADS study. There was an increased risk of suicidal events seen in the fluoxetine group compared to placebo, and the question of that risk hovered for a while over the trial, until it was basically dismissed in subsequent reports. However, with the publication of Vitiello’s 2009 report, and Göran Högberg’s alert reading of that study, we can see how the NIMH-funded investigators  finessed this risk, keeping its true scope hidden from the public.

The Suicide Data, Step by Step

The 12-Week Results: Then and Now

In 2006, Graham Emslie and the other TADS’ investigators published the 12-week “safety results” in the Journal of the American Academy of Child and Adolescent Psychiatry. They reported that in the 109 youth treated with fluoxetine, there were 10 suicidal events (9.2%), which was defined as either suicidal ideation or suicidal behavior/attempts. There were three such events in the 112 youth given a placebo (2.7%.) Two in the fluoxetine group attempted suicide, versus none in the placebo group.

Although this data clearly raised a concern, the investigators wrote that suicidal ideation rates had improved in all four groups during the trial, compared to baseline rates, and that nobody in the trial had actually committed suicide. Thus, the excess risk in the fluoxetine group was not seen as unduly alarming.

In Vitiello’s 2009 paper, we find slightly different data. In the 12-week study, there had actually been 12 suicidal events—rather than 10—in the 109 fluoxetine patients. There were three attempted suicides in the fluoxetine group, rather than two. Moreover, in the group of 112 placebo patients, there were 8 that were put on fluoxetine during the 12 weeks, and 2 of these 8 then suffered a suicidal event. But these 2 suicidal events in fluoxetine-treated patients were not included in Emslie’s 2006 report.

Thus, in Vitiello’s paper, we find this additional data: two more suicidal events among the 109 youth randomized to fluoxetine, one additional suicide attempt in the fluoxetine group, and two suicidal events among fluoxetine-treated patients in the placebo group.

The 36-Week Results: The Initial Report by the TADS Team

After the initial 12-week period, the study was unblinded (in the placebo and fluoxetine-only arms), and those in the placebo group who hadn’t done well were offered the choice of choosing one of the three active treatments—fluoxetine, CBT, or a combination of the two—during the 24-week followup.

In 2007, the “TADs Team” published the 36-week results for the three “active treatment” groups, but not for placebo, in the Archives of General Psychiatry.  They reported the following “suicidal events” at the end of 36 weeks:  16 of the 109 fluoxetine patients (14.7%) had such an event; 9 of 107 in the CBT-plus-fluoxetine group (8.4%); and 7 of 111 in the CBT-alone group (6.3%).

The researchers did not break down the suicidal events into their two components (suicidal ideation and suicidal attempts), and thus there is no data, in this article, on the number of youth in the study who attempted suicide. And while suicidal events were notably higher in the fluoxetine-only group, the researchers explained it away. They reasoned that CBT likely mitigated suicidal thoughts (as opposed to fluoxetine triggering such thoughts), and thus they concluded in the abstract, “adding CBT to medication enhances the safety of the medication.” (Emphasis added.)

Yet, once again, in Vitiello’s 2009 paper, we find additional suicidal data in the chart titled “Timing of First Suicidal Event,” and when it is included in the data analysis, we see that the risk of suicide, during the followup phase, was found only in fluoxetine-exposed patients.  There were no suicidal events in the CBT-alone group who didn’t take fluoxetine during this period. However,  some of the patients in the CBT-alone group were in fact exposed to fluoxetine during the 12-week-to-36-week period (we don’t know how many), and there  were two suicidal attempts in those fluoxetine-exposed patients.

Here is the bottom line: at the end of 36 weeks, of the 12 suicide attempts in the three groups, 11 were by youth taking fluoxetine.

The TADS Report on the 36-Week Results of the Placebo Group

In March of 2009, the TADS investigators, led by lead author Betsy Kennard, reported the 36-week safety data for all four groups in the American Journal of Psychiatry. As noted earlier, the 112 youth initially randomized to placebo were given the option, at the end of 12 weeks, to opt for one of the three active treatments.

The TADS reported that of the 112 youth assigned to the placebo/open group, 12 (10.7%) had a suicidal event between week 12 and week 36, compared with 32 of the 327 (9.8%) from the three active treatment groups. The researchers wrote that they had also compared suicidal events in the placebo/open group to those taking SSRIs, and the results were the same. There was no excess risk of suicide in those prescribed fluoxetine, compared to the placebo/open group.

In this article, it appeared that 15 of the 112 youth in the placebo/open group had a suicidal event during the 36 weeks (3 in the initial 12 weeks, and 12 in the 24-week followup). It was unclear how many of these events were suicidal ideation and how many involved suicide attempts, as this distinction was not reported. Then, in the discussion part of the paper, the researchers muddied things a bit more, writing that 15 of the 112 in the placebo/open group made “suicide attempts.”

Thus, the impression from this report was that there had been a fair number of suicidal events–and suicide attempts–in youth not exposed to fluoxetine. And having presented the 36-week safety data in this way, the TADS investigators drew this conclusion: Assignment to placebo during the initial treatment period “does not increase harm-related events, including suicidality.” Since placebo didn’t lead to increased suicidality, the use of placebo in research settings was “acceptable,” although “delaying the onset of meaningful treatment in non-research settings is not ethical or clinically appropriate.” Fluoxetine was safe, and in normal clinical care, pediatricians and psychiatrists should prescribe the drug as a first-line therapy (and ideally in combination with CBT.)

Now let’s return to the Vitiello paper and his table, which can tell us the real story about the placebo/open group, from start of the trial to the end of 36 weeks.

Here is the data:

Of the 112 youth randomized to placebo, 103 stayed on placebo during the initial 12 weeks, and three showed suicidal ideation during this period. There were eight in the placebo group who were put on fluoxetine during the initial 12 weeks, and two of these fluoxetine-taking youth developed suicidal ideation.

In the 12-week to 36-week followup, no youth in the placebo/open group who stayed off medication had a suicidal event. However, seven in the placebo/open group who went on fluoxetine suffered a suicidal event, including six who attempted suicide.

During the 36 weeks, no youth randomized into the placebo group attempted suicide while on placebo.

In Vitiello’s table of “first suicidal events,” there are 18 suicide attempts listed for all four groups. Of the 18, 17 occurred in youth on fluoxetine (94%). The one non-drug suicide attempt during the 36 weeks occurred in the CBT alone group, roughly at week five of the study.

In Vitiello’s table, there are 44 total suicidal events listed. Of the 44, 36 were in fluoxetine-treated patients (82%).

Here is a graphic that shows this data.

The Scandal

The TADS study has been used to justify the prescribing of Prozac—and really, by extension—other SSRIs to children and adolescents. The TADS researchers reported that the drug treatment was effective and didn’t increase the risk for suicidal events, as compared to placebo. Adding CBT to medication “enhances the safety of medication,” the TADS researchers wrote.

All the while, the real suicide data was being hidden. The TADS investigators weren’t disclosing the number of suicide attempts, and they weren’t reporting that all but one of the suicide attempts were in fluoxetine-treated youth. Instead, they made it appear that a similar number of suicidal events had been seen in the placebo group, and, at one point, even wrote that 15 in this group had attempted suicide.  The real suicide data didn’t appear until Vitiello’s 2009 article, and even then it had to be dug out from a table, which Göran Högberg did.

This, of course, is a hiding of data that puts the lives of children at risk. Maria Bradshaw is blogging on this site, and she has written how her son Toran committed suicide 15 days after being prescribed Prozac. Now imagine if the suicide data from the TADS study had been properly published.  Seventeen of the 18 suicide attempts in the study had been in youth on Prozac. Wouldn’t that have served as a warning signal to psychiatrists in New Zealand? Wouldn’t it have served as a warning signal to Maria Bradshaw? Wouldn’t it have served as a warning signal to her son, when he became agitated and aggressive?

And so we can ask: Would Toran be alive today if not for this scandal? And how many other youth have lost their lives in this way, unaware of the real suicide data in the TADS trial?

The post The Real Suicide Data from the TADS Study Comes to Light appeared first on Mad In America.

“This has been a year of exciting discoveries and scientific progress . . . Here are 10 breakthroughs and events of 2011 that are changing the landscape of mental health research.”

His words fit neatly into a larger narrative in psychiatry, which is that of science on the march. For the past 30 years (or even longer), leaders in the field have regularly told of “great advances,” and of how “extraordinary” new research is leading to “tremendous advances” in care, and Insel’s list is the latest addition to that narrative. And yet—and this is the puzzling part of this modern tale of scientific progress—the burden of mental illness in our society keeps going up and up, and clinical outcomes have, in anything, worsened in the past 30 years (at least for affective disorders.)

So, in the hope of gaining some insight into this mystery, let’s take a closer look at Insel’s list of “exciting discoveries” and “breakthroughs” from the past year. Here are the titles for the top five:

Complexity: Discovering New Sources of Genetic Variance.
Transcriptome: Developing Brains Have Unique Molecular Signatures.
Induced Pluripotent Stem Cells: Disease in a Dish.
De Novo Genetic Variants.
Epigenomics: How Experience Alters Behavior.

If your initial response is like mine, you may be tempted to say: what a bunch of molecular gobbledygook. But then I took a deep breath and sought to identify, in a more clear-headed way, why this list is so disappointing.

The first reason is a practical one. Researchers have spent the last 30 years trying to identify molecular and genetic explanations for psychiatric disorders, but this effort has not led to any therapeutic advance. In fact, it is proving so barren that many drug companies are shutting down their efforts to develop new psychiatric drugs, precisely because such research has failed to identify promising new molecular targets. So why keep on pursuing this tack? Might it be time to put our federal dollars into research more likely to produce a therapeutic benefit?

But the second reason for disappointment is the more important one. Insel’s list tells of a research enterprise devoted to identifying what is genetically wrong with the “mentally ill.” As the history of eugenics reminds us, that is a pursuit, unless it is handled with great care, that can engender bad social policy and a great deal of harm.

In 1869, Sir Francis Galton, cousin to Charles Darwin, gave birth to eugenics when he published a book titled Hereditary Genius. In it, he concluded that it was nature, rather than nurture, that made the superior man. Thus, he argued, humans were decidedly unequal. Democratic ideals that men were of “equal value,” he wrote, were simply “undeniably wrong and cannot last.”

This was a sentiment that rang true to one group in American society: the ruling elite with a White Anglo Saxon Protestant heritage. Many believed that a large influx of non-WASP immigrants was weakening the country. Soon, American eugenicists were busily ranking ethnic groups along a “more fit and less fit” spectrum, and the “insane” were put at the bottom of the list. Eugenicists then argued that in order to keep America strong, it was necessary to encourage those with “good germ plasm” to have lots of children, and to prevent those with “bad germ plasm” from breeding.

In 1896, Connecticut became the first state to prohibit the “insane” from marrying. Other states followed suit, and by 1933, there were no states left where the insane could legally tie the knot. However, the problem with such laws, eugenicists lamented, was that few people seeking a marriage license declared themselves insane. The insane, one eugenicist noted, are “biased” in their own favor.

Thus, since that social policy didn’t do the trick, eugenicists began arguing that the insane needed to be segregated from society in mental hospitals. They needed to be locked up and kept there until their breeding years passed. This belief—that the “insane” needed to be removed from society—led to a rapid buildup in the number of hospitalized mentally ill, which increased from 31,973 in 1880 to 272,527 in 1929.

At that time, a Journal of Hereditary editorial concluded that “segregation of the insane is fairly complete.” But eugenicists had also been advocating for a more permanent solution to the “breeding” problem, and now they got their wish. In 1907, Indiana had become  the first state to authorize forced sterilization of people with “hereditary defects,” and in 1927, the U.S. Supreme Court declared such state laws constitutional. By the end of 1945, more than 45,127 Americans had been sterilized under such laws, 21,311 of whom were patients in state mental hospitals.

As such social policies took hold, a number of scientists at top colleges promoted eugenics as a science. By 1914, 44 colleges in America had introduced eugenics into their curriculums, and such courses were particularly popular at such elite schools as Harvard, Columbia, Cornell and Brown. By 1924, more than 9,000 research papers on eugenics had been published, and the Eugenics Research Association could boast that a third of its 383 members were fellows of the American Association for the Advancement of Science, the national’s most prestigious scientific group.

The physician who took the lead in proving that insanity was an inherited disease was Aaron Rosanoff, a physician at Kings Park State. He charted the family histories of 72 insane patients, but initially he did not find the results he expected. Among the 1,097 relatives of the 72 patients, only 43 had ever been hospitalized for a mental illness, a number far too low to show a causal genetic link. But Rosanoff was determined to prove there was one, and so he decided that he had defined mental illness too narrowly. If he expanded the definition of what could be considered abnormal behavior, and thus could include people who were “high strung, excitable, dictatorial, or abnormally selfish” as mentally ill, he determined that the 72 patients had 351 relatives who were mentally unwell. This was very close to the precise number he needed to conclude that insanity was a single gene recessive disorder, transmitted much like blue eyes. If a child inherited a copy of the normalcy gene from one parent and the insanity gene from another, he or she would grow up to be normal but would be a “carrier” of insanity. A child who got the insanity gene from both parents was doomed to be insane as an adult, he wrote.

This “finding,” and other such findings said to prove that mental illness was a genetic illness, naturally led the public to fear the hospitalized mentally ill. Their genes were a threat to society’s collective gene pool. Meanwhile, in their writings, eugenicists described the mentally ill  as “social wastage” and as “unfit” human beings, and talked about the need to remove this “social cancer” from American society. With such declarations influencing the American mind, 66% of the public said in 1937 that they favored sterilizing the “defectives” in society.

This disparagement of the mentally ill naturally led to a drop in public funding for state mental hospitals, and many fell into total disrepair. In addition, it set the stage for psychiatry, in the 1930s and 1940s, to embrace a quartet of medical therapies that were understood to “work” by damaging the brain. The therapeutic reasoning was easy to understand: If the mentally ill had little value, and were generally “unfit” human beings, then therapies that quieted them and made them easier to manage—even if they seemed to knock the patients down to a lower level of being—could be embraced as helpful. The first three such therapies were insulin coma therapy, metrazole convulsive therapy, and repetitious electroshock therapy. The fourth was frontal lobotomy, which at the time was hailed as a miracle brain surgery.

Today, as a society, we would never conclude that we hold “eugenic” ideas about the “mentally ill.” Eugenics became a discredited science at the end of World War II, when it became evident that Hitler had risen to power on a eugenics agenda, and that this grading of humans—into the fit and unfit—had led to the Holocaust. Yet, it is easy to see today that our modern research agenda has encouraged eugenic conceptions of the mentally ill and encouraged the adoption of policies that rob people so diagnosed of their basic rights.

In 1980, when American psychiatry published its third edition of its Diagnostic and Statistical Manual, it informed the public that mental disorders were now to be thought of as “diseases of the brain,” much like diabetes or some other physical illness. The mentally ill were said to have “broken brains,” characterized by faulty “brain chemistry.” Trauma, environmental stressors, difficult family relationships, and other problems were no longer to be seen as primary causes of psychiatric distress. The root cause was an internal biological flaw with the person. With this conception in mind, NIMH-funded researchers renewed a quest, first born in the eugenics era, to identify a genetic basis for psychiatric disorders.

There is, of course, an understandable therapeutic rationale for such research. If a biological pathology, arising from a genetic defect, can be identified, then it would provide a target for drug development. But—and this is important to recognize—this research has not proceeded in an ideologically neutral manner. In 1980, with the publication of DSM-III, the field became ideologically committed to telling a certain story, which is that mental disorders are brain diseases. As such, the field became committed to proving that this was so, and we can see this ideological impulse in many of the published findings. You find it in particular in the MRI studies, in which researchers may announce that some abnormality or another has been found in a group of patients, without making an effort to distinguish whether the abnormality is medication induced. When that happens, ideology is trumping honest inquiry and science, and it is impossible, as such moments, to not be reminded of Aaron Rosanoff, and his desire to report that insanity was a single gene recessive disorder.

In terms of shaping public opinion about mental illness, what has this modern genetics research wrought?  When we hear of how people diagnosed with schizophrenia or bipolar disorder have “broken brains,” or that these disorders have a genetic basis and run in families, we are being encouraged, as a society, to think of people so diagnosed as not quite “right,” or that they are “unfit.” As such, we shouldn’t be surprised that recent studies have found that as the public comes to understand that mental disorders are “biological” in kind, stigma toward the “mentally ill” increases.

In short, thirty years of NIMH-funded research into the possible genetic causes of mental disorders has proven to be both a therapeutically barren enterprise and one that has encouraged eugenic conceptions of the mentally ill. Those eugenic conceptions are now showing up in our social polices, and this can be clearly seen in our society’s embrace of “outpatient commitment” orders. The public has been encouraged to “fear” the mentally ill, and to conceive of them as driven in their behaviors by their faulty brain chemistry and genes, which they can’t control, and thus society embraces the idea that “they”—i.e. the other in our midst—need to be kept under state control.

A century ago, such societal beliefs led to the segregation of the mentally ill in hospitals. Today, people may get released from hospitals, but if they are under an outpatient commitment order, they certainly are not “free” and enjoying the rights of full citizenship. They may be forced to take medications that they do not want to take, and if they complain that the drugs make them feel like “zombies” and rob them of their capacity to feel the world, such complaints are dismissed. They don’t know what is good for them, we say.

This state control of the “mentally ill” extends beyond those under an outpatient order to many who receive government services. Such people may not be under a legal order, but still feel coerced. They may have to take medications they don’t like in order to continue to receive services, and such coercion surely is an impingement on their self-autonomy.

This, of course, is true regardless of the merits of the medications. If a person living in society is being forced to take a medication he or she does not want to take,  that is impinging on his or her usual rights as a citizen. Their right to liberty has been compromised.

Now, let’s return to Insel’s list for a second look. Only this time, instead of focusing on what is named on the list, let’s look at what is missing. See if you can find even one item that tells of research designed to help living, breathing human beings get well and stay well. See if you can find anything  that tells of research designed to identify the strengths that can be found in people struggling with their minds, and all the ways that, in fact, such struggles can be an ordinary part of human experience.

Once again, history can tell us why it is tragic that such research is missing from the NIMH list.

In the last years of the 18^th century, Quakers in York, England, acting in rebellion against the harsh ministrations of English mad doctors, developed a form of care known as “moral therapy.” The medical wisdom at the time was that the mad, by virtue of having lost their reason, had descended to the level of “brutes, but the Quakers in York thought differently: They declared that the “mad” were “brethren” and should be treated as such.  The Quakers in York built a small retreat in the countryside, where the mad were given shelter and food, and treated with gentleness and kindness. In this manner, the Quakers hoped to “assist nature” in helping the mad get well. They believed that their mad brethren had a God-given inner capacity for regaining self-control and reason, and thus their therapeutic challenge was to provide a gentle environment that could best promote such healing.

In fairly short order, the Quakers in York reported that this care was proving to be quite successful, and in the first decades of the 19^th century, Quakers in the United States built a number of such small retreats, in the countryside outside Boston, Philadelphia, Hartford and other cities. The patients were encouraged to garden, exercise, take long walks, and engage in social activities. And this therapy worked. Modern historians who have reviewed the records of these retreats have determined that more than half of the newly insane would be discharged within three years.  Moreover, a long-term study of 984 patients discharged from Worcester Asylum in this period found that 58% remained well throughout their lives.

Today, we often hear of how our society is discovering that some people can “recover” from mental illness, as if this is an extraordinary finding. If the Quakers from the early 19^th century could hear such pronouncements, they would undoubtedly furrow their brows and wonder, this is considered new?

Imagine if the NIMH revisited this history and funded studies mindful of the lessons to be gleaned from it. NIMH-funded investigators, rather than seeing people with a psychiatric diagnosis as having an innate defect, would see them instead as “brethren,” and thus as human beings having an inner resilience and an inner capacity for getting better.  The investigators could then focus their efforts on developing therapeutic approaches that help nurture such inner strengths. The Quakers found that diet, exercise, meaningful work and social engagement were a recipe that could help many disturbed people get better, and I imagine that if the NIMH invested in this idea today, researchers would discover anew their benefits.

Yet—and I know this well—that is a wish-list thought. The NIMH has published a list of its “Top Ten Research Advances of 2011,” and pronounced them to be “exciting discoveries” and “breakthroughs,” and so undoubtedly we will see much more of this type of research, which unfortunately encourages us, as a society, to think of people who may struggle with their minds not as “brethren,” but as fundamentally “unfit.”  Even well-meaning research can have unintended consequences, and I think, if we look at our ongoing genetics research within a historical light, we can see why that is so.

The post The Taint of Eugenics In NIMH-Funded Research Today appeared first on Mad In America.

But this research, funded by the National Institute of Health, doesn’t pass that simple test. As a result, we now have yet another research study funded by American taxpayers, that, in my opinion, is essentially worthless, or even worse than worthless. By assigning the abnormality to the disease, without having assessed whether it may in fact be due to the drug exposure, the study may be presenting a “finding” that is fundamentally misleading.

And so I offer a modest proposal: I think it is time for federally funded brain research in psychiatry to move in a new direction.

First, let’s look at this particular study. The researchers studied 82 “postmortem human brain samples.” Thirty-four were from “normal subjects,” 32 were from schizophrenia subjects, and 16 from subjects with bipolar disorder. The investigators did report that none of the subjects had a record of treatment with valproic acid.  They did so because this is a drug thought to be protective against the deficiency in gene expression they were going to be assessing. However, the researchers didn’t report on other medication use by the schizophrenia and bipolar subjects, and obviously most of those diagnosed with schizophrenia would have spent years taking neuroleptics.

In the December issue of Translational Psychiatry, the researchers announced that, based on their study of the 82 brain samples, DNA “stays too tightly wound” in the brain cells of schizophrenia subjects. This can lead to certain genes in the cells being “turned off,” and thus the cells won’t manufacture proteins essential to normal functioning. In a press release, Scripps’ neuroscientist Elizabeth Thomas said that her group was “excited by the findings,” which could lead to the development of new drugs to treat schizophrenia.

That is the usual concluding pronouncement from such studies. An abnormality is discovered, it is attributed to the disease and not the medications used to treat the disease, and then the researchers say this could lead to new drug development.

Now let’s turn to a 1996 paper by Steve Hyman titled “Initiation and Adaptation: A Paradigm for Understanding Psychotropic Drug Action.” A neuroscientist, Hyman was director of the NIMH when he authored that paper. He told of how psychotropic drugs perturb neurotransmitter function, and how in response to that perturbation, the brain goes through a series of compensatory adaptations in order to maintain its normal functioning.   However, after a time  these compensatory adaptations break down, and the “chronic administration” of the drugs causes “substantial and long-lasting alterations in neural function,” Hyman wrote. As part of this adaptive process, there are changes in intracellular pathways and “gene expression.”

Focus on those last words. The drugs alter gene expression in brain cells. And what is this finding by Elizabeth Thomas and the Scripps’ scientists? There is evidence of abnormal gene expression in the brain cells of schizophrenia patients.

That begs an obvious question: If  DNA is too “tightly wound” in the brain cells of schizophrenia patients, is that due to the “disease” or the drugs?

There is a fairly easy way to at least partly investigate that question. The Scripps’ researchers could have administered neuroleptics to healthy rats for an extended period of time, at clinically relevant dosages, and assessed whether the same “brain cell malfunction” showed up in the rats. But their paper does not tell of that simple step having being done.

This study is emblematic of the many problems with the brain research literature in psychiatry. The confounding factor of drug exposure is often ignored. While there have been a number of first-episode studies, or studies in “medication naïve” patients, that seemingly avoid this problem, those studies—upon closer examination—are often not what they seem.   Many of the subjects—even in the “medication naive” studies—may in fact have been exposed to psychiatric drugs, at least for a short period of time (with the researchers then discounting this exposure because of its relative short duration.) Another problem with this literature is that the studies regularly present “composite” findings. The researchers use MRIs or some other technology to put together a picture of the “schizophrenic” brain in comparison to a “normal” brain, and while that composite comparison may lead to an identified “abnormality” in the schizophrenia group, many individuals in the schizophrenia group don’t actually exhibit the identified abnormality, while some in the “normal” group do. When this overlap happens, it is a bit of a leap to conclude that you have identified a pathology that is a defining characteristic of a disease, and yet that is how the findings are often presented to the public.

But even more to the point, decades of such brain research has not produced any notable therapeutic payoff. As is now clear, the second-generation psychiatric drugs are no more effective than the first-generation psychiatric drugs. Nor is there a promising “third-generation” of psychiatric drugs coming down the pipeline. In fact, new drug development in psychiatry is stymied precisely because decades of  brain research has failed to provide pharmaceutical companies with promising new molecular targets.

Thus, a modest proposal:  Rather than continue putting so much money into a line of inquiry that has proven rather futile, the NIMH should concentrate on funding research into the effects of psychiatric drugs on brain morphology and brain function The purpose of this research would be to flesh out the many possible harmful effects of psychiatric drugs, a pursuit, it should be noted, that is consistent with the Hippocratic Oath to “Do No Harm.” It is also one certain to be therapeutically useful. It would provide both physicians and the general public with information needed to better evaluate a drug’s risks and benefits, particularly over the long term.

I can think of many questions that desperately need to be investigated. In the U.S. today, one is six babies is born to a mother who took a psychiatric drug during her pregnancy. How might that in-utero drug exposure affect brain development? The organizing of cell structures in the brain? And how will any brain abnormality arising from that in-utero exposure affect the child over the long-term? There is research in rats that suggests in-utero exposure to an SSRI leads to a clumsy adult rat; is the same thing occurring in humans?

Next, we are prescribing stimulants, antidepressants, antipsychotics and mood stabilizers to our children today on a regular basis. This has often been described as one big “experiment.” The kids are the guinea pigs in this experiment, and so shouldn’t we at least  try to answer a few fundamental questions? What effect do the various drugs have on brain development? The maturation of the frontal lobes? Hormonal systems? Sexual development? Cognitive function? Metabolic function? Physical skills? Will the drugs cause lasting changes in gene expression? Will neuroleptics cause the teenage brain to shrink? And so on. The daily taking of a psychiatric drug modifies the child’s brain, and I would think that both parent and child would like to see such questions answered.

With adults, many of the same questions apply. NIMH-funded studies could investigate a drug’s long-term effect on brain morphology, gene expression, the functioning of neurotransmitter pathways, cognition,  behavior, and physical health.

Finally, here is the one pressing question that I am regularly asked when I give a talk about Anatomy of an Epidemic. In response to a psychiatric drug, the brain goes through a series of compensatory adaptations. If you then withdraw from the drug, does the brain return to its normal functioning? For instance, in response to an SSRI, which blocks the normal reuptake of serotonin from the synaptic cleft, the postsynaptic neurons decrease the density of their serotonergic receptors. Upon withdrawal from the SSRI, will the density of serotonergic receptors return to normal?

Unfortunately, nobody knows the answer to that question.

This is why I think it is  time for the NIMH to reallocate its research dollars. We have had decades of research seeking to discover the biological causes of mental disorders, but that research has failed to produce any notable therapeutic benefit. The NIMH should alter its focus, or at least expand it,  and provide financial support to brain research of a kind that is certain to benefit society. It should fund animal and human studies that would give us a better understanding of what we are doing to our newborns, our children, and our adult selves when we take these medications on a regular basis.

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In particular, we will want to make this assessment: Is Dr. Glazer able to point to research findings that show that psychiatric medications improve the long-term outcomes of major mental disorders? And is his rebuttal intellectually honest?

Dr. Glazer’s Industry Ties

In his Behavioral Healthcare rebuttal, Dr. Glazer notes that he has “had a longstanding collaborative relationship with the pharmaceutical and insurance industries,” and that he receives funding from Eli Lilly and Merck. In the past, he has also been a consultant to Johnson & Johnson, Bristol-Myers Squibb, and Astra Zeneca. He also is owner of Glazer Medical Solutions, which promotes continuing medical education programs (which often are funded by pharmaceutical companies.)

Dr. Glazer’s “Argument Number One.”

In Anatomy of an Epidemic, I detail how there has been a dramatic rise in the number of “disabled” mentally ill since the beginning of the “psychopharmacological revolution,” and that this has been particularly true since the arrival of Prozac and the other second-generation drugs. I then note that this data raises a question: Is it possible that our drug-centered paradigm of care is fueling this epidemic? And to answer that question, I then spent several hundred pages reviewing the outcomes literature for major mental disorders to see whether this history of science tells of drugs that improve long-term outcomes, or worsen them.

Although Dr. Glazer’s opening argument is, in my opinion, rather confused, he basically states this: Although it is true that there has been a sharp rise in the number of people on disability due mental illness, there is no “evidence available to suggest that the increase in psychiatric disability claims was caused by the use of psychiatric medications.” Instead, he argues that the rise is due to the inadequacy of funding for community-based services, the growing disparity in wealth in the United States, and changes in disability rules that have made it easier for people to qualify for a disability payment. He also states that epidemiological surveys conducted in 1990 to 2003 did not find any dramatic increase in the prevalence of mental disorders, and thus, there is no “epidemic.”

Now, the interesting part of this argument is that, if we are to accept Dr. Glazer’s statement that there is “no available evidence” to assess whether psychiatric medications are fueling an epidemic of disabling mental illness, then it shows that psychiatry has an utter lack of evidence on how medications shape long-term outcomes. Indeed, Dr. Glazer states that it would be worthwhile to study whether the drugs are causing the surge in the number of disabled mentally ill. “This is a “hypothesis in need of testing, not a fact. A properly designed study to test this hypothesis would have to rule out many possible confounding factors. And no such study has been proposed or conducted.”

I would think that the American people, faced with the mounting cost of the disability epidemic, would indeed welcome such a study. But, in fact, one could argue that the prevalence and treatment figures cited by Dr. Glazer for the years between 1990 and 2003 provide the raw data for such a study.

Here is the data. The prevalence of psychiatric disorders was 29.4% in 1990-1992 and 30.5% in 2001-2003. Thus, the percentage of adults in the population experiencing psychiatric distress remained the same during these two periods. However, what changed during this period was that the percentage of people with a psychiatric disorder who were treated for it rose from 20.3% to 32.7%.

Thus, this is the hypothesis that can now be tested: If treatment increases the likelihood that a person struggling with psychiatric distress will end up on disability, then the total number of people on disability should have climbed sharply during that 13-year period.

Let’s do the math. If you then look up census data for the number of adults in 1990 and 2003, and do the relevant calculations, you find that the number of people treated rose from 11.16 million adults in 1990 to 21.77 million in 2003. And what happened as more people got treated? The number of people receiving SSI or SSDI due to mental illness during this period more than doubled, from 1.47 million people in 1990 to 3.25 million people in 2003.

So here is the bottom line: The prevalence remained the same between 1990 and 2003, but the percentage of people treated for the disorder rose, and as that happened, the number of people on disability soared.

There is one other way we can parse this data. In 1990, there were 55 million adult Americans with a “psychiatric disorder” (based on the prevalence data cited by Dr. Glazer.) There were 1.47 million adults who collected a federal disability check that year due to mental illness. Thus, one in every 37 adults (2.7%) with a psychiatric disorder in 1990 was on long-term disability. By 2003, the adult population had increased, and thus although the prevalence of psychiatric disorders had remained the same as in 1990, the number with a psychiatric disorder had risen to 66 million. There were 3.25 million adults who were collecting a federal disability payment that year due to mental illness, or one in every 20 with a psychiatric disorder (5%).

Thus, during this period of increased treatment, the percentage of those with a psychiatric disorder who ended up on long-term disability rose from 2.7% to 5%.

In sum, we already have data that can be used to test the hypothesis that Dr. Glazer thinks is worthy of investigation. Unfortunately, the results are exactly what you would expect if psychiatric drugs are indeed fueling an “epidemic” of disabling mental illness. And I should note that this epidemic of disabling mental illness is showing up in country after country that has adopted this paradigm of care.

Dr. Glazer’s “Argument Number Two”

In the second part of his rebuttal, Dr. Glazer discusses several of the scientific studies I cited in Anatomy of an Epidemic.

1. Supersensitvity psychosis

In Anatomy, I detail how, by the end of the 1970s, various studies had raised the worry that antipsychotics might be making people diagnosed with schizophrenia more biologically vulnerable to psychosis over the long run. This is how the NIMH’s William Carpenter framed this worry:

“There is no question that, once patients are placed on medication, they are less vulnerable to relapse if maintained on neuroleptics. But what if these patients had never been treated to drugs to begin with? We raise the possibility that antipsychotic medication may make some schizophrenic patients more vulnerable to future relapse than would be the case in the natural course of the illness.”

Two Canadian investigators, Guy Chouinard and Barry Jones, then proposed an explanation for why this might be so. The first-generation antipsychotics had been found to block dopamine receptors in the brain, particularly a subtype known as D2 receptors.  In an effort to compensate for this response, the brain increased the density of its D2 receptors. This made the brain “supersensitive” to dopamine, Chouinard and Jones argued, and this in turn made patients more likely to relapse when they withdrew from antipsychotics. At the same time, when patients stayed on the drugs long-term, this process could lead to a “tardive psychosis,” and when this happened, the illness “appears worse than ever,” they wrote.

In his review, Dr. Glazer states that there is no need to worry about this any longer. He writes that “an authoritative review of the literature concluded in the early 1990s that ‘research has not established that neuroleptics caused the proposed effect, and considerations of mechanism have not been separated from those of causation.’ . . . This idea did not bear out. ”

So let’s see if that is indeed true. The 1992 study cited by Dr. Glazer was titled “The concept of supersensitivity psychosis.” Dr. Glazer has quoted part of the abstract correctly, but he has left off the key concluding line, in which the authors state that more research is needed on this subject. “The focus of research in this area should be the establishment of a causal relationship between chronic neuroleptic use and psychotic relapse.”

In other words, this paper, which Dr. Glazer has cited as reason to think the concern had been put to rest, actually stated that more research was needed. That was in 1992, and fortunately there has been further research on “supersensitivity psychosis” by Philip Seeman, at the University of Toronto.

First, in 2005, Seeman reported that agents that triggers psychotic-like behavior in animals—amphetamines, angel dust, lesions to the hippocampus, and gene-knockout manipulations—all cause an increase in D2 receptors that have a “high” affinity for dopamine (meaning that they are very sensitive to the neurotransmitter.) These results “imply that there may be many pathways to psychosis, including multiple gene mutations, drug abuse, or brain injury, all of which may converge via D2 HIGH to elicit psychotic symptoms,” Seeman wrote.

However, in this same report, Seeman found that haloperidol and olanzapine both doubled the density of D2 HIGH receptors. Thus, the drugs cause the very biological abnormality that in animal models had been identified as a final pathway to psychosis.

This finding set up an obvious experiment. Seeman could induce psychosis in rats, and then see how the drugs affected their behavior.  Since the drugs blocked D2 receptors, at first the drugs should be effective. But then, over time, since they also caused a doubling of D2 HIGH receptors, that should lead to supersensitivity psychosis and “relapse.”

Seeman did that study, and here is what he reported in 2007: “We show that during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy . . . the loss of efficacy is linked to an increase in D2 receptor number and sensitivity. These results are the first to demonstrate that ‘breakthrough’ supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy.”

I am sure that Dr. Glazer knows of Philip Seeman’s work, as I wrote about it in Anatomy of an Epidemic and on this blog. So we see in this quick review of “supersensitivity psychosis” that the worry arose in the 1970s, and that in recent years, Philip Seeman has shown, in animal studies, that the drugs do cause this effect.

So now we can ask: Given Philip Seeman’s work, was it intellectually honest for Dr. Glazer to tell readers of Behavioral Healthcare that worry about supersensitivity psychosis had been put to rest two decades ago?

2. Martin Harrow’s 15-year outcomes study

If readers of this blog want to know what I actually wrote about this study, instead of what Dr. Glazer claims I wrote, I urge them to read pages 115 to 118 of Anatomy of an Epidemic. But let’s visit the actual findings from that prospective study (yet again.)

From 1975 to 1983, Harrow enrolled sixty-four young people diagnosed with schizophrenia into his study, recruiting them from two Chicago hospitals. One was private and the other public, as this ensured that the group would be economically diverse. He also enrolled 81 young people with milder psychotic disorders. All of these patients were treated conventionally with medications in the hospital, and then Harrow tracked their long-term outcomes, periodically assessing how they were doing. Were they symptomatic? In recovery? Employed? Were they taking antipsychotic medications? And here is what his data shows:

• The 25 schizophrenia patients who got off antipsychotic medications had much better long-term outcomes than those who stayed on the drugs. The off-antipsychotic patients had an eight-fold higher recovery rate; their aggregate global outcomes were much better; they were much less likely to have a “uniformly poor outcome;” and they were much less likely to still have psychotic symptoms at the 10-year and 15-year follow-up assessments.

• Among the 81 patients with milder psychotic disorders, those who stopped taking antipsychotics and other psychiatric medications (nearly half of the cohort) had markedly better global outcomes than those who stayed on the medications.

• The collective outcomes for all of the psychotic patients stacked up like this, from best to worse: milder psychotic disorders off meds, schizophrenia off meds, milder psychotic disorders on meds, and schizophrenia on meds. In other words, those with a milder disorder at the beginning who stayed on antipsychotics did worse long-term than the schizophrenia patients who got off the medications.

• Finally, Harrow grouped his schizophrenia patients into good-prognosis and bad-prognosis patients. While he didn’t provide the specific outcomes data for each group, he did observe that in each of these two sub-groups, it was those who got off antipsychotics who had better long-term outcomes.

Now this is the only study of its type in the outcomes literature, in which a researcher has followed a large cohort of patients over a long period of time, and assessed both their medication usage and outcomes. As Martin Harrow concluded, the results belie the common wisdom that all people diagnosed with schizophrenia and other psychotic disorders need to be on antipsychotics all their lives.  At the very least, it shows that there is a subset of patients that can do well off the medications long-term.

However, Dr. Glazer presents none of this data in his discussion of the study. He doesn’t mention that every subset of patients who got off antipsychotics, including those with a bad prognosis, had better outcomes. Instead, he simply claims that this is just a matter of those with a better prognosis getting off the meds doing better. “Standard clinical logic would conclude that poor outcomes in the antipsychotic treated patients were a function of their illness, not of their treatment.”

As readers of this blog know, I presented at a Grand Rounds at Massachusetts General Hospital last January, and in response Dr. Andrew Nierenberg presented a “rebuttal” of my book. In this rebuttal, Dr. Glazer follows Dr. Nierenberg’s lead time and again, and he ends his dismissal of the Harrow study with this line, which he borrowed from Dr. Nierenberg: “Mr. Whitaker needs a basic course on principles of epidemiologic research, specifically on the concept of susceptibility bias.”

So readers can now ask this question: Why didn’t Dr. Nierenberg and Dr. Glazer discuss the actual data, which showed that every subset of patients off medications did better? Why didn’t they discuss the dramatic differences between every subset of patients? And what does it say about the integrity of their argument that, having failed to discuss the actual data, they conclude that I, a journalist who reported the actual data, should be considered a dunce, in need of remedial education?

3. Nancy Andreasen’s MRI study on brain volumes

Next, we turn to the issue of whether antipsychotics shrink the brain, and in particular, studies on this subject by Nancy Andreasen, who was the editor in chief of the American Journal of Psychiatry from 1993 to 2005.

Here’s a quick review of the relevant literature. First, animal studies have found that antipsychotics do indeed shrink the brain. For instance, in a study in macaque monkeys, researchers reported in 2005 that treatment with either haloperidol or olanzapine for 17 to 27 months led to an “8 – 11% reduction in mean fresh brain weights” compared to controls. The differences in brain weights and brain volumes “were observed across all major brain regions, but appeared most robust in the frontal and parietal regions.”

Nancy Andreasen began her large study of schizophrenia patients in 1989. She periodically used MRI technology to measure their brain volumes, and in 2003 she reported that their brains shrunk over time. At that point in her research, she blamed the shrinkage on the disease.  She reported that schizophrenia was a “progressive neurodevelopmental disorder” characterized by “progressive reduction in frontal white matter volume.”  Next, in 2003 and 2005, she reported that this brain shrinkage was associated with a worsening of negative symptoms, increased functional impairment, and, after five years, cognitive decline.

But there was an obvious question for Andreasen to address, given the animal studies: Was this shrinkage due, at least in part, to the drugs? In February 2011, she reported that this shrinkage was indeed drug-related. Use of the old neuroleptics, the atypical antipsychotics, and clozapine were all “associated with smaller brain tissue volumes,” with decreases in both white and grey matter. The severity of illness and substance abuse had “minimal or no effect” on brain volumes.

Here is what she told the New York Times: “What exactly do these drugs do? They block basal ganglia activity. The prefrontal cortex doesn’t get the input it needs and is being shut down by drugs. That reduces psychotic symptoms. It also causes the prefrontal cortex to slowly atrophy.”

That’s the story told by Andreasen. However, in his rebuttal, Dr. Glazer doesn’t report her conclusions, or mention the animal research. Instead, he writes that  “it must be noted that these brains were compared to those of normal control subjects, not to those of untreated schizophrenia patients. Thus, it is impossible to examine whether it is the medications or the illness that lead to the smaller brain size.”

That is not what Andreasen concluded.  She stated that the drugs cause “the prefrontal cortex to slowly atrophy.” And so, once again, we have the same question to ask: why didn’t Dr. Glazer honestly present her research findings?

4. Evidence that antipsychotics improve long-term outcomes

When Dr. Nierenberg and now Dr. Glazer sought to rebut Anatomy of an Epidemic, the obvious thing for them to do would be to cite studies that show that psychiatric medications improve long-term outcomes. Both claimed that they had identified studies that did just that.

In regards to antipsychotics, Dr. Nierenberg turned to an obscure study of older patients diagnosed with schizophrenia in China who weren’t treated with antipsychotics. I have written about how he misrepresented that study and its findings, and so won’t repeat that explication here.

For his part, Dr. Glazer didn’t try to point to that Chinese study in his rebuttal (likely seeing it as ridiculous in kind), and so he sought a different one. He cited a study of 104 patients treated at Hillside Hospital in Queens during the late 1980s for a first episode of schizophrenia or schizoaffective disorder, who were then followed for five years. He reported that those treated with “antipsychotics were five times less likely to relapse than were patients who stopped such medication,” and thus this study “is one of the best demonstrations of the beneficial impact of long-term antipsychotic therapy.”

I looked up that study, and I have to confess that I gasped. I had written about this research in 1998, when I co-wrote a series for the Boston Globe on abuse of patients in psychiatric research settings.

Here’s the background to the study. Starting in the 1970s, researchers investigating the “dopamine hypothesis” of schizophrenia reasoned that if too much dopamine could cause psychosis, then a drug that caused brain neurons to release dopamine—amphetamine, methylphenidate, L-dopa—should make psychotic patients much worse. They began running experiments to see if that was so, and in the 1970s, David Janowsky, a physician at the University of California at San Diego School of Medicine, reported that dopamine-releasing drugs did indeed make psychotic patients much worse. Methylphenidate, which caused a doubling in the severity of symptoms, was the most potent of the dopamine-releasing agents when it came to making patients more psychotic.

In the late 1980s, psychiatrists at Hillside Hospital in Queens decided to repeat this experiment in first-episode patients who came stumbling into the hospital’s emergency room for help. Rather than treat them with neuroleptics, they gave them methylphenidate, expecting this drug would make them worse. In studies published in 1993, the researchers reported that methylphenidate caused 59 percent of them to temporarily become “much worse” or “very much worse.” The patients were then placed on neuroleptics, but they took longer than usual to stabilize. “We were surprised by the length of time required for patients to recover,” the investigators reported.

The researchers then followed that patient group for another five years. Eighty-two percent relapsed at least once during the five years (after recovering from their initial episode), and a significant percentage suffered several relapses during that period. Those patients who discontinued their medications and remained in the study—the study doesn’t state how many patients were in this category—relapsed at a five-fold higher rate than those who continued on the drugs. However, there were also 13 stable patients off medication who dropped out of the study, and researchers don’t know whether this group subsequently relapsed, or stayed well off medication. (In his study, Martin Harrow discovered that the off-med group that stayed well dropped out of treatment, and thus their success remained hidden to clinicians.)

Researchers have been studying neuroleptics for 50 years, and this is the study that Dr. Glazer cites as one of the “best demonstrations of the beneficial impact of long-term antipsychotic therapy.” And quite apart from its egregious ethical nature, the fact that patients who eventually stabilized on the drugs and then went off them relapsed at high rates is not surprising either; there is a long line of evidence that once patients are exposed to antipsychotics they are at great risk of relapse when withdrawing from them. That, in fact, is the whole point of the dopamine supersensitivity problem: the drugs induce changes in the brain that increase the risk of relapse upon drug withdrawal.

Let us now weigh the respective evidence reviewed by Dr. Glazer, and his assessment of it. The 15-year study by Martin Harrow that found that patients off antipsychotics had much better long-term outcomes is to be dismissed. Worries about drug-induced supersensitivity psychosis are to be dismissed, in spite of the recent findings by Philip Seeman. The fact that Nancy Andreasen reported that antipsychotics shrink the brain is to be dismissed. Instead, if our society wants to know whether antipsychotics improve long-term outcomes, it should look to a study of 104 first-episode patients that, once you investigate its design, involved deliberately making them worse by giving them methylphenidate when they arrived at the emergency room. That study then found after the patients had gotten worse on that drug, they took a longer time than normal to stabilize on neuroleptics. The group as a whole had high relapse rates over five years, with the highest relapse rate seen in those patients who went off the drugs and stayed in the study. We don’t know what happened to 13 off-med patients who were stable and then dropped out of the study. The study also doesn’t tell us anything about how well the on-med patients functioned during that five-year period.

So, after 50 years of neuroleptics, this study of first-episode patients at Hillside Hospital in Queens, in which researchers initially gave the patients a drug expected to make them worse, is—according to Dr. Glazer—some of the “best” evidence there is that antipsychotics provide a long-term benefit.

5. Evidence that antidepressants improve the long-term course of depression.

Here, Dr. Glazer turns to the same NIMH study that Dr. Nierenberg did in his “refutation” of Anatomy of an Epidemic. He tells readers that in a 20-year study by Leon, “vigorous (antidepressant) treatment resulted in better short-term and long-term outcomes than did suboptimal treatments or no treatment at all.”

Here’s the context for the study. From 1978 to 1981, the NIMH Collaborative Depression Study recruited 955 subjects who sought treatment at a hospital for one of the major affective disorders. Over the next two decades, NIMH-funded researchers conducted many studies of this population. In the Leon study cited by Dr. Nierenberg and Dr. Glazer, researchers were studying 285 patients with major depressive disorder who, at some point during the 20 years, suffered a recurrence of depression. These 285 patients had been treated with antidepressants, and many were taking antidepressants when they suffered a relapse. And what the researchers studied in this particular study was whether those who had suffered a relapse should be treated with a high dose of an antidepressant, a medium dose, or a low dose. They found that the recovery rate from that recurrent episode, over a short period of time, was higher for those given a high dose, and that apparently a medium dose was also better than no somatic treatment (although the study doesn’t provide any information about that no-treatment group, and so it is unclear how that comparison was made.)

Thus, the Leon study doesn’t provide any information on the long-term outcomes of depressed patients who take antidepressants versus those who eschew such treatment. However, and this is the important point, NIMH investigators leading the Collaborative Depression research effort did conduct a well-designed study that made such a comparison. Coryell and his colleagues studied 547 people who suffered a bout of depression, and they found that over the course of six years, those who were treated for the illness were three times more likely than the untreated group to suffer a “cessation” of their “principal social role,” and nearly seven times more likely to become “incapacitated.” Moreover, while many of the treated patients saw their economic status markedly decline during the six years, only 17 percent of the unmedicated group saw their incomes drop, and 59 percent saw their incomes rise. “The untreated individuals described here had milder and shorter-lived illnesses [than those who were treated], and, despite the absence of treatment, did not show significant changes in socioeconomic status in the long term,” the researchers wrote in their 1995 report.

In short, Dr. Nierenberg picked a short-term dosage study from this larger NIMH research effort to assert that antidepressants improve the long-term outcomes of depressed patients. He ignored the actual study from that same research program that assessed six-year outcomes of treated and untreated patients, and had found that the untreated patients fared remarkably better. Now here is what I find remarkable: I had already written about this on my blog, which Dr. Glazer clearly read. And yet still Dr. Glazer chose to follow Dr. Nierenberg’s lead, and present the Leon study in the same disingenuous way that he did.

I should note that if Dr. Glazer is looking for evidence that treatment increases the risk that a depressed patient will become disabled, he might want to read the Coryell study. There, the “treated” group was seven times more likely to become “incapacitated.”

Dr. Glazer’s Argument Number Three

In the last section of his rebuttal, Dr. Glazer argues that the psychiatric establishment has been an honest broker of information, and that, for the most part, those who serve as consultants and advisors to pharmaceutical companies, as he and Dr. Nierenberg do, have not been corrupted by that financial influence. They remain devoted to science, unbiased, and honest in their statements to the public, and thus I am wrong to suggest otherwise.

All I can say is that, having parsed the “rebuttal” made by Dr. Nierenberg back in January, and again here in this two-part rebuttal by Dr. Glazer, I think I can “rest my case” on this particular topic

The post Answering the Critics: William Glazer, in Behavioral Healthcare Magazine appeared first on Mad In America.

In the first study, researchers in the United Kingdom tested cognitive therapy in patients with schizophrenia spectrum disorders who refused antipsychotic medication and had been off the drugs for six months. Twenty patients were provided with a maximum of 26 CT sessions over nine months, and then were followed for an additional six months.

In a paper published in Psychological Medicine, the U.K. researchers reported that  35%  of the patients had at least a 50% reduction in their psychiatric symptoms at the end of nine months (as measured by the Positive and Negative Syndromes Scale), and that an even higher percentage of patients — 50% — had reached this level of improvement by the end of the followup period.

No patient significantly deteriorated during the study, and only one dropped out during the nine-month treatment period.

The researchers concluded that cognitive therapy for psychotic disorders “is an acceptable treatment and is associated with a clinically significant reduction in psychiatric symptoms at both end of treatment and follow-up, in a group that are assumed to deteriorate without total adherence to medication.” In addition, cognitive therapy was “associated with improved functioning and self-rated recovery, with significant increases shown at follow-up for both.”

An obvious question, but one unaddressed by the study, is how these results would compare with outcomes from drug treatment over a 15-month period. It also would be helpful to run a study in which  unmedicated psychotic patients were randomized to CT or to a “placebo” form of psychotherapy, and thus determine if CT beat placebo.

The second CT study was led by Aaron Beck, the father of cognitive therapy in the United States, and his colleagues at the University of Pennsylvania. Their goal was to help low-functioning schizophenia patients with severe negative symptoms — a loss of motivation and emotional engagement — identify and pursue concrete goals for improving their quality of life and reintegrating into society.

In the study, 60 were randomized either to a combination of cognitive therapy and standard therapy (which included antipsychotic medication), or to standard therapy alone. Those in the cognitive therapy group got weekly outpatient CT sessions for 18 months, with each session typically lasting 50 minutes. At the end of 18 months, the CT patients had better functioning and greater improvement on their negative and positive symptoms relative to those who received standard treatment only. The researchers concluded:

“The [CT] treatment encourages the patients to set goals related to their everyday functioning, and they become motivated to engage in tasks (initially simple pleasurable, social, and constructive activities) that move them out of their withdrawn state. This increase in activity and motivation puts the patients more in touch with reality and reduces hallucinations, delusions, and disorganization. Reduced positive symptoms allow for further engagement in activity, leading to better functional outcomes and enhancement of motivation, which in turn facilitate a further amelioration of positive symptoms.”

In this case, one wonders what outcomes might have been if cognitive therapy had been paired with a medication tapering protocol, given that antipsychotics can induce emotional lethargy in patients. But together, the two studies tell of a non-drug therapy that needs to be further tested and explored.

In other news:

Antipsychotics and brain shrinkage

In February of 2011, Nancy Andreasen reported that the brain shrinkage seen in schizophrenia patients was associated with use of the older neuroleptics, the newer atypical antipsychotics and clozapine. In a recent follow-up  paper, Andreasen provides new details about the nature of that shrinkage, but downplays her earlier findings that antipsychotics cause such shrinkage. Instead, she mostly attributes it to the disease, even while acknowledging that she previously found that “neuroleptic treatment” contributes “significantly and independently to the tissue volume reductions, while other possible confounders such as substance misuse do not.”

In this new article, Andreasen reports that tissue loss in schizophrenia patients is seen in multiple gray matter regions of the brain (total cerebral, frontal lobes, and thalamus), and in multiple white matter regions (total cerebral, frontal, temporal, and parietal.)This tissue loss appears to be most severe during the early stages of illness, and occurs “at severe levels” in only a subset of patients. The tissue loss is strongly associated with cognitive decline, and more weakly associated with an increase in symptoms (negative symptoms, psychotic symptoms, and disorganized thinking.)

However, it is unclear why Andreasen is confident that the shrinkage is due at least in part to a disease process, given the recent review of this topic by Joanna Moncrieff and Jonathan Leo. They scoured the literature for MRI studies of schizophrenia patients who had been ill for an extended period of time and had never been medicated, and they found three such studies. Yet, in all three, the researchers concluded that there were “no major differences” between the schizophrenia patients and normal controls “in global cerebral, grey-matter, ventricular, or CSF (cerebrospinal fluid) volumes.”

Andreasen doesn’t cite that finding in her new paper. Instead, she sums up the disease/medication question in this way: “While neuroprogression may be partially accounted for by a medication effect, it also reflects an intrinsic and progressive disease process.”

In other words, if her interpretation is correct, antipsychotics could be said to exacerbate a disease process that characterizes schizophrenia.

 More Evidence of Harm To Children

Recently, there has been a steady stream of evidence detailing the increasing burden of mental illness in our society. The latest report, published in the December issue of Archives of General Psychiatry, tells of a sharp rise in the number of children and adolescents hospitalized for psychiatric problems between 1996 and 2007.

Joseph Blader, from Stony Brook University School of Medicine, found that the number of children ages five to 13 years old hospitalized for psychiatric reasons rose from 155 per 100,000 children in 1996 to 283 per 100,000 in 2007. Total inpatient days for children of this age soared from 1,845 days per 100,000 in 1996 to 4,370 per 100,000 children in 2007.

In adolescents ages 14 to 19, the number hospitalized for psychiatric reasons rose from 683 per 100,000 to 969 per 100,000 between 1996 and 2007. Total inpatient days for adolescents increased from 5,882 to 8,247 days per 100,000 population in that period.

As is well documented, the prescribing of psychiatric drugs to children and adolescents has increased notably in the past 15 years. Thus, once again, we see the same correlation: As the prescribing of psychiatric drugs to a population increases, there is an increase in psychiatric distress in that population. This data tells of that happening— and one might conclude tragically so — to our nation’s youngest population.

 Please, no more STAR*D lies

When the NIMH announced the results of its STAR*D trial, it claimed that two-thirds of the patients who entered the trial remitted. The trial design was such that if a first antidepressant didn’t work, patients could be put on a second one, and so forth, through four tries, and this result suggested that if depressed people would just keep on trying one pill after another, they would likely eventually find a drug that would work.

Unfortunately, that 67% recovery rate is a made-up number. Ed Pigott has published a number of articles detailing all of the scientific chicanery that went on during that trial, all of which served to inflate the remission rate. As best as I can tell, fewer than 40% of the protocol-eligible patients ever remitted, even for a brief period. More to the point, only 3% of the 4,041 patients remitted and then stayed well and in the trial during the year-long followup.

However, go to a recent blog written by Thomas Insel, director of the NIMH. In a piece that discusses the long-term effectiveness of antidepressants, he points to the STAR*D trial as possible evidence of that sort. He writes that “65 percent” of the patients remitted at six months, which makes it seem as though two-thirds of the patients were depression free at the end of that longer period. So the public is being fed the spin, rather than the real results, and this is being used to promote the notion that antidepressants provide a long-term benefit.

One does wish that this sort of government propaganda would come to a stop.

The post Cognitive Therapy Found Effective in Unmedicated Psychotic Patients . . . And Other News appeared first on Mad In America.

In particular, we will want to make this assessment: Is Dr. Glazer able to point to research findings that show that psychiatric medications improve the long-term outcomes of major mental disorders? And is his rebuttal intellectually honest?

Dr. Glazer’s Industry Ties

In his Behavioral Healthcare rebuttal, Dr. Glazer notes that he has “had a longstanding collaborative relationship with the pharmaceutical and insurance industries,” and that he receives funding from Eli Lilly and Merck. In the past, he has also been a consultant to Johnson & Johnson, Bristol-Myers Squibb, and Astra Zeneca. He also is owner of Glazer Medical Solutions, which promotes continuing medical education programs (which often are funded by pharmaceutical companies.)

Dr. Glazer’s “Argument Number One.”

In Anatomy of an Epidemic, I detail how there has been a dramatic rise in the number of “disabled” mentally ill since the beginning of the “psychopharmacological revolution,” and that this has been particularly true since the arrival of Prozac and the other second-generation drugs. I then note that this data raises a question: Is it possible that our drug-centered paradigm of care is fueling this epidemic? And to answer that question, I then spent several hundred pages reviewing the outcomes literature for major mental disorders, to see whether this history of science tells of drugs that improve long-term outcomes, or worsen them.

Although Dr. Glazer’s opening argument is, in my opinion, rather confused, he basically states this: Although it is true that there has been a sharp rise in the number of people on disability due mental illness, there is no “evidence available to suggest that the increase in psychiatric disability claims was caused by the use of psychiatric medications.” Instead, he argues that the rise is due to the inadequacy of funding for community-based services, the growing disparity in wealth in the United States, and changes in disability rules that have made it easier for people to qualify for a disability payment. He also states that epidemiological surveys conducted in 1990 to 2003 did not find any dramatic increase in the prevalence of mental disorders, and thus, there is no “epidemic.”

Now, the interesting part of this argument is that, if we are to accept Dr. Glazer’s statement that there is “no available evidence” to assess whether psychiatric medications are fueling an epidemic of disabling mental illness, then it shows that psychiatry has an utter lack of evidence on how medications shape long-term outcomes. Indeed, Dr. Glazer states that it would be worthwhile to study whether the drugs are causing the surge in the number of disabled mentally ill. “This is a “hypothesis in need of testing, not a fact. A properly designed study to test this hypothesis would have to rule out many possible confounding factors. And no such study has been proposed or conducted.”

I would think that the American people, faced with the mounting cost of the disability epidemic, would indeed welcome such a study. And, in fact, one could argue that the prevalence and treatment figures cited by Dr. Glazer for the years between 1990 and 2003 provide the raw data for such a study.

Here is the data. The prevalence of psychiatric disorders was 29.4% in 1990-1992 and 30.5% in 2001-2003. Thus, the percentage of adults in the population experiencing psychiatric distress remained the same during these two periods. However, what changed during this period was that the percentage of people treated rose from 20.3% to 32.7%.

Thus, this is the hypothesis that can now be tested: If treatment increases the likelihood that a person struggling with psychiatric distress will end up on disability, then the total number of people on disability should have climbed sharply during that 13-year period, and the percentage of people with a psychiatric problem who are on disability should also be greater in 2003 than in 1992.

Let’s do the math. If you then look up census data for the number of adults in 1990 and 2003, and do the relevant calculations, you find that the number of people treated rose from 11.16 million adults in 1990 to 21.77 million in 2003. And what happened as more people got treated? The number of people receiving SSI or SSDI due to mental during this period more than doubled, from 1.47 million people in 1990 to 3.25 million people in 2003.

Next, if you look at the percentage of people with a psychiatric disorder who are on disability, here is what you find. In 1990, there were 55 million adult Americans with a “psychiatric disorder” (based on the prevalence data cited by Dr. Glazer.) There were 1.47 million adults who collected a federal disability check that year due to mental illness. Thus, one in every 37 adults (2.7%) with a psychiatric disorder in 1990 was on long-term disability. By 2003, the adult population had increased, and thus although the prevalence of psychiatric disorders had remained the same as in 1990, the number with a psychiatric disorder had risen to 66 million. There were 3.25 million adults who were collecting a federal disability payment that year due to mental illness, or one in every 20 with a psychiatric disorder (5%).

In sum, during this period of increased treatment, the percentage of those with a psychiatric disorder who ended up on long-term disability rose from 2.7% to 5%.

Thus, we already have data that can be used to test the hypothesis that Dr. Glazer thinks is worthy of investigation. Unfortunately, the results are exactly what you would expect if psychiatric drugs are indeed fueling an “epidemic” of disabling mental illness.

Dr. Glazer’s “Argument Number Two”

In the second part of his rebuttal, Dr. Glazer discusses several of the scientific studies I cited in Anatomy of an Epidemic.

1. Supersensitvity psychosis

In Anatomy, I detail how, by the end of the 1970s, various studies had raised the worry that antipsychotics might be making people diagnosed with schizophrenia more biologically vulnerable to psychosis over the long run. This is how the NIMH’s William Carpenter framed this worry:

“There is no question that, once patients are placed on medication, they are less vulnerable to relapse if maintained on neuroleptics. But what if these patients had never been treated to drugs to begin with? We raise the possibility that antipsychotic medication may make some schizophrenic patients more vulnerable to future relapse than would be the case in the natural course of the illness.”

Two Canadian investigators, Guy Chouinard and Barry Jones, then proposed an explanation for why this might be so. The first-generation antipsychotics had been found to block dopamine receptors in the brain, particularly a subtype known as D2 receptors.  In an effort to compensate for this response, the brain increased the density of its D2 receptors. This made the brain “supersensitive” to dopamine, Chouinard and Jones argued, and this in turn made patients more likely to relapse when they withdrew from antipsychotics. At the same time, when patients stayed on the drugs long-term, this process could lead to a “tardive psychosis,” and when this happened, the illness “appears worse than ever,” they wrote.

In his review, Dr. Glazer states that there is no need to worry about this any longer. He writes that “an authoritative review of the literature concluded in the early 1990s that ‘research has not established that neuroleptics caused the proposed effect, and considerations of mechanism have not been separated from those of causation.’ . . . This idea did not bear out. ”

So let’s see if that is indeed true. The 1992 study cited by Dr. Glazer was titled “The concept of supersensitivity psychosis.” Dr. Glazer has quoted part of the abstract correctly, but he has left off the key concluding line, in which the authors state that more research is needed on this subject. “The focus of research in this area should be the establishment of a causal relationship between chronic neuroleptic use and psychotic relapse.”

In other words, this paper, which Dr. Glazer has cited as reason to think the concern had been put to rest, actually stated that more research was needed. That was in 1992, and fortunately there has been further research on “supersensitivity psychosis” by Philip Seeman, at the University of Toronto.

First, in 2005, Seeman reported that agents that triggers psychotic-like behavior in animals—amphetamines, angel dust, lesions to the hippocampus, and gene-knockout manipulations—all cause an increase in D2 receptors that have a “high” affinity for dopamine (meaning that they are very sensitive to the neurotransmitter.) These results “imply that there may be many pathways to psychosis, including multiple gene mutations, drug abuse, or brain injury, all of which may converge via D2 HIGH to elicit psychotic symptoms.”

However, in this same report, Seeman found that haloperidol and olanzapine both doubled the density of D2 HIGH receptors. Thus, the drugs cause the very biological abnormality that in animal models had been identified as a final pathway to psychosis.

This finding set up an obvious experiment. Seeman could induce psychosis in rats, and then see how the drugs affected their behavior.  Since the drugs blocked D2 receptors, at first the drugs should be effective. But then, over time, since they also caused a doubling of D2 HIGH receptors, that should lead to supersensitivity psychosis and “relapse.”

Seeman did that study, and here is what he reported in 2007: “We show that during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy . . . the loss of efficacy is linked to an increase in D2 receptor number and sensitivity. These results are the first to demonstrate that ‘breakthrough’ supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy.”

I am sure that Dr. Glazer knows of Philip Seeman’s work, as I wrote about it in Anatomy of an Epidemic and on this blog. So we see in this quick review of “supersensitivity psychosis” that the worry arose in the 1970s, and that in recent years, Philip Seeman has shown, in animal studies, that the drugs do cause this effect.

So now we can ask: Given Philip Seeman’s work, was it intellectually honest for Dr. Glazer to tell readers of Behavioral Healthcare that worry about supersensitivity psychosis had been put to rest two decades ago?

2. Martin Harrow’s 15-year outcomes study

If readers of this blog want to know what I actually wrote about this study, instead of what Dr. Glazer claims I wrote, I urge them to read pages 115 to 118 of Anatomy of an Epidemic. But let’s visit the actual findings from that prospective study (yet again.)

From 1975 to 1983, Harrow enrolled sixty-four young people diagnosed with schizophrenia into his study, recruiting them from two Chicago hospitals. One was private and the other public, as this ensured that the group would be economically diverse. He also enrolled 81 young people with milder psychotic disorders. All of these patients were treated conventionally with medications in the hospital, and then Harrow tracked their long-term outcomes, periodically assessing how they were doing. Were they symptomatic? In recovery? Employed? Were they taking antipsychotic medications? And here is what his data shows:

    • The 25 schizophrenia patients who got off antipsychotic medications had much better long-term outcomes than those who stayed on the drugs. The off-antipsychotic patients had an eight-fold higher recovery rate; their aggregate global outcomes were much better; they were much less likely to have a “uniformly poor outcome;” and they were much less likely to still have psychotic symptoms at the 10-year and 15-year follow-up assessments.

    • Among the 81 patients with milder psychotic disorders, those who stopped taking antipsychotics and other psychiatric medications (nearly half of the cohort) had markedly better global outcomes than those who stayed on the medications.

    • The collective outcomes for all of the psychotic patients stacked up like this, from best to worse: milder psychotic disorders off meds, schizophrenia off meds, milder psychotic disorders on meds, and schizophrenia on meds. In other words, those with a milder disorder at the beginning who stayed on antipsychotics did worse long-term than the schizophrenia patients who got off the medications.

    • Finally, Harrow grouped his schizophrenia patients into good-prognosis and bad-prognosis patients. While he didn’t provide the specific outcomes data for each group, he did observe that in each of these two sub-groups, it was those who got off antipsychotics who had better long-term outcomes.

Now this is the only study of its type in the outcomes literature, in which a researcher has followed a large cohort of patients over a long period of time, and assessed both their medication usage and outcomes. As Martin Harrow concluded, the results belie the common wisdom that all people diagnosed with schizophrenia and other psychotic disorders need to be on antipsychotics all their lives.  At the very least, it shows that there is a subset of patients that can do well off the medications long-term.

However, Dr. Glazer presents none of this data in his discussion of the study. He doesn’t mention that every subset of patients who got off antipsychotics, including those with a bad prognosis, had better outcomes. Instead, he simply claims that this is just a matter of those with a better prognosis getting off the meds doing better. “Standard clinical logic would conclude that poor outcomes in the antipsychotic treated patients were a function of their illness, not of their treatment.”

As readers of this blog know, I presented at a Grand Rounds at Massachusetts General Hospital last January, and in response Dr. Andrew Nierenberg presented a “rebuttal” of my book. In this rebuttal, Dr. Glazer follows Dr. Nierenberg’s lead time and again, and he ends his dismissal of the Harrow study with this line, which he borrowed from Dr. Nierenberg: “Mr. Whitaker needs a basic course on principles of epidemiologic research, specifically on the concept of susceptibility bias.”

So readers can now ask this question: Why didn’t Dr. Nierenberg and Dr. Glazer discuss the actual data, which showed that every subset of patients off medications did better? Why didn’t they discuss the dramatic differences between every subset of patients? And what does it say about the integrity of their argument that, having failed to discuss the actual data, they conclude that I, a journalist who reported the actual data, should be considered a dunce, in need of remedial education?

3. Nancy Andreasen’s MRI study on brain volumes

Next, we turn to the issue of whether antipsychotics shrink the brain, and in particular, studies on this subject by Nancy Andreasen, who was the editor in chief of the American Journal of Psychiatry from 1993 to 2005.  

Here’s a quick review of the relevant literature. First, animal studies have found that antipsychotics do indeed shrink the brain. For instance, in a study in macaque monkeys, researchers reported in 2005 that treatment with either haloperidol or olanzapine for 17 to 27 months led to an “8 – 11% reduction in mean fresh brain weights” compared to controls. The differences in brain weights and brain volumes “were observed across all major brain regions, but appeared most robust in the frontal and parietal regions.”

Nancy Andreasen began her large study of schizophrenia patients in 1989. She periodically used MRI technology to measure their brain volumes, and in 2003 she reported that their brains shrunk over time. At that point in her research, she blamed the shrinkage on the disease.  She reported that schizophrenia was a “progressive neurodevelopmental disorder” characterized by “progressive reduction in frontal white matter volume.”  Next, in 2003 and 2005, she reported that this brain shrinkage was associated with a worsening of negative symptoms, increased functional impairment, and, after five years, cognitive decline.

But there was an obvious question for Andreasen to address, given the animal studies: Was this shrinkage due, at least in part, to the drugs? In February 2011, she reported that this shrinkage was indeed drug-related. Use of the old neuroleptics, the atypical antipsychotics, and clozapine were all “associated with smaller brain tissue volumes,” with decreases in both white and grey matter. The severity of illness and substance abuse had “minimal or no effect” on brain volumes.

Here is what she told the New York Times: “What exactly do these drugs do? They block basal ganglia activity. The prefrontal cortex doesn’t get the input it needs and is being shut down by drugs. That reduces psychotic symptoms. It also causes the prefrontal cortex to slowly atrophy.”

That’s the story told by Andreasen. However, in his rebuttal, Dr. Glazer doesn’t report her conclusions, or mention the animal research. Instead, he writes that  “it must be noted that these brains were compared to those of normal control subjects, not to those of untreated schizophrenia patients. Thus, it is impossible to examine whether it is the medications or the illness that lead to the smaller brain size.”

That is not what Andreasen concluded.  She stated that the drugs cause “the prefrontal cortex to slowly atrophy.” And so, once again, we have the same question to ask: why didn’t Dr. Glazer honestly present her research findings?

3. Evidence that antipsychotics improve long-term outcomes

When Dr. Nierenberg and now Dr. Glazer sought to rebut Anatomy of an Epidemic, the obvious thing for them to do would be to cite studies that show that psychiatric medications improve long-term outcomes. Both claimed that they had identified studies that did just that.

In regards to antipsychotics, Dr. Nierenberg turned to an obscure study of older patients diagnosed with schizophrenia in China who weren’t treated with antipsychotics. I have written about how he misrepresented that study and its findings, and so won’t repeat that explication here.

For his part, Dr. Glazer didn’t try to point to that Chinese study in his rebuttal (likely seeing it as ridiculous in kind), and so he sought a different one. He cited a study of 106 patients treated at Hillside Hospital in Queens during the late 1980s for a first episode of schizophrenia or schizoaffective disorder, who were then followed for five years. He reported that those treated with “antipsychotics were five times less likely to relapse than were patients who stopped such medication,” and thus this study “is one of the best demonstrations of the beneficial impact of long-term antipsychotic therapy.”

I looked up that study, and I have to confess that I gasped. I had written about this research in 1998, when I co-wrote a series for the Boston Globe on abuse of patients in psychiatric research settings.

Here’s the background to the study. Starting in the 1970s, researchers investigating the “dopamine hypothesis” of schizophrenia reasoned that if too much dopamine could cause psychosis, then a drug that caused brain neurons to release dopamine—amphetamine, methylphenidate, L-dopa—should make psychotic patients much worse. They began running experiments to see if that was so, and in the 1970s, David Janowsky, a physician at the University of California at San Diego School of Medicine, reported that dopamine-releasing drugs did indeed make psychotic patients much worse. Methylphenidate, which caused a doubling in the severity of symptoms, was the most potent of the dopamine-releasing agents when it came to making patients more psychotic.

In the late 1980s, psychiatrists at Hillside Hospital in Queens decided to repeat this experiment in first-episode patients who came stumbling into the hospital’s emergency room for help. Rather than treat them with neuroleptics, they gave them methylphenidate, expecting this drug would make them worse. In studies published in 1993, the researchers reported that methylphenidate caused 59 percent of them to temporarily become “much worse” or “very much worse.” The patients were then placed on neuroleptics, but they took longer than usual to stabilize. “We were surprised by the length of time required for patients to recover,” the investigators reported.

The researchers then followed that patient group for another five years. Eighty-two percent relapsed at least once during the five years (after recovering from their initial episode), and a significant percentage suffered several relapses during that period. Those patients who discontinued their medications and remained in the study—the study doesn’t state how many patients were in this category—relapsed at a five-fold higher rate than those who continued on the drugs. However, there were also 13 stable off-med patients off medication who dropped out of the study, and researchers don’t know whether this group subsequently relapsed, or stayed well off medication. (In his study, Martin Harrow discovered that the off-med group that stayed well dropped out of treatment, and thus their success remained hidden to clinicians.)

Researchers have been studying neuroleptics for 50 years, and this is the study that Dr. Glazer cites as one of the “best demonstrations of the beneficial impact of long-term antipsychotic therapy.” And quite apart from its egregious ethical nature, the fact that patients who eventually stabilized on the drugs and then went off them relapsed at high rates is not surprising either; there is a long line of evidence that once patients are exposed to antipsychotics they are at great risk of relapse when withdrawing from them. That, in fact, is the whole point of the dopamine supersensitivity problem: the drugs induce changes in the brain that increas

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However, the story didn’t clearly detail the role of medications in her life, and as Keris can attest, the published article seems to serve as something of a Rorschach test for readers. Those inclined to think of medications as essential to recovery may read the article and conclude that must be true in her case. Those who think of psychiatric medications in a more critical light may read the story and conclude that she probably uses the medication very infrequently. I ran into Keris last weekend, where I asked about this Rorschach aspect of the story, and she thought it would be important to publicly clear up the details of her medication use, since she has now been presented, in this very visible newspaper venue, as a model for what is possible.

In the Times story, her treatment regimen is said to consist of a “combination of medication as needed and personal supports, including an intuitive pet dog, the occasional weekend stay at a luxury hotel — and, not least, a strong alliance with a local psychiatrist.” Then, a little further along in the story, she is said to have started on her journey to recovery in 2006, when her psychiatrist got her to “try certain antipsychosis medications.” Finally, readers learn that researchers in southern California are studying a small number of people with a diagnosis of schizophrenia or schizoaffective disorder who are thriving, with Keri one of those in the study, and that the researchers state that most in the study, like Keris, “adhere to a medication regimen.”

Add those bits of information together, and some readers conclude that Keris, in one manner or another, must take antipsychotics — and perhaps other psychiatric medications as well —  on a regular basis. Keris told me that many doctors and other readers called her psychiatrist, asking for information on the specific drugs, or drug combination, that she takes. However, other readers focus on the line that she takes “medication as needed,” and concluded that she probably takes them fairly infrequently.

Here is the detailed story of Keris’s use of psychiatric medications. From 2000 to 2006, she regularly suffered from thoughts of suicide and hallucinations, and it was toward the end of that time that her psychiatrist, Timothy Pylko, convinced her to take antipsychotic medications on a daily basis. She did so for about six months, but it has been at least five years since she used antipsychotics or any other psychiatric medication in that regular way.

Once she stopped taking psychiatric medications daily, she began to use them on an as-needed basis “when all of the [non-drug] techniques I usually use do not work and I am truly unable to work, hang out with my friends or participate in life.” For a time, she found that she would need to take an antipsychotic on the “very rare occasions” when “the voices are very distracting and any kind of stimuli (light, noise and touch) cannot be tolerated.” She would take the antipsychotic for two weeks or so, “while also engaging as much as possible in life.”

However, she found that even this occasional use of an antipsychotic had its drawbacks. “Truly, what I have found in returning to work is that this approach is not as successful, as the meds usually make me too tired and ‘cognitively slow’ to work effectively. It has been a while since I used this approach, and the last time I did, I more than likely took time off while on the meds until the side effects diminished, and then I came back to work and tapered off.” She has not used any antipsychotic medication for more than a year now.

She still does use an anti-anxiety medication on “rare occasions.” She’ll turn to this class of drugs when “I have so much anxiety that I am incessantly pacing, cannot physically keep still and the type of OCD that I have kicks into overdrive.” She says such moments are now “incredibly rare,” and that when she does take an anti-anxiety med, she does so “mainly at night.”

Keris is fortunate to have a psychiatrist who has supported her use of medications in this way, on an as-needed basis for those rare occasions today when her anxiety or her voices flare up to intolerable levels. She consults with him on the dosage and for how long to take the drug, and “he provides instructions on how to taper [from the drug] as well.” As a result, she has a therapeutic relationship with her psychiatrist that works very well and is an essential part of her recovery.

The reason that is it important to know this aspect of Keris’s story is that, in her use of medications on “rare” occasions, she is not following the model of “medication adherence” that is usually promoted to the public-and to patients-as essential and necessary. If you look at her story of recovery, hers is one of using antipsychotics on a daily basis for a relatively short period of time, and then developing “personal supports” and finding meaningful work as a foundation for a more lasting wellness. And once she stopped taking psychiatric medications on a daily basis, she used them only as temporary aids when her symptoms flared up. In essence, she was “non-compliant” with the usual model of drug treatment for someone with a schizoaffective diagnosis, and today, given her very infrequent use of any psychiatric medications, she would be best described as “off meds.”

There may be many paths to robust recovery, but what is clear from the research literature — and from stories like Keris’s — is that one possible path involves being “off meds,” or using them in the selective, occasional manner that she does. In Martin Harrow’s 15-year study of schizophrenia patients and patients with milder psychotic disorders, the off-med patients had much better long-term outcomes, and for those with milder psychotic disorders, those who got off psychiatric medications — as a group — had good long-term outcomes.

It is refreshing to see the New York Times publish Keris’s story, for it presents a vision of recovery that our society needs to know and embrace. We can read such stories and then ask, okay, so what do we, as a society, need to do to help make such recovery commonplace? But as we ask ourselves that question, it is important to know the details of Keris’s story in terms of her medication use, because such clarity can help us reconceptualize what is possible. Her story, together with a close look at what the research literature tells us about long-term outcomes, can ultimately help us imagine a radically different paradigm of care.

Wednesday, November 2, 2011

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And so I am now starting to look at disability numbers in those countries, and as might be expected, they are all telling a similar story.

In the United States, the number of adults on government disability due to mental illness rose from 1.25 million in 1987 to 3.97 million in 2007. On a per-capita basis, the disability rate rose from 1 in every 184 Americans in 1987 to 1 in every 76 Americans  over that 20-year period. (Total population divided by number of working-age adults on disability.) At the same time, societal spending on psychiatric drugs soared, from less than $1 billion in 1987 to more than $40 billion annually today.

Now, I recently spent a week in New Zealand speaking on this topic. The United States and New Zealand are the only two Western countries that allow pharmaceutical companies to directly market their products to consumers, and perhaps not surprisingly, the prescribing of antidepressants in that country has soared over the past 15 years. And now here is its disability data.

New Zealand’s Numbers

In 2000, there were 23,142 adults 18 to 64 years old on government disability (sickness or invalid benefits) in New Zealand due to psychiatric conditions. In 2010, there were 48,899 adults on government disability due to psychiatric disorders. On a per capita basis (total population divided by number of working-age adults on disability), that is an increase in disability from 1 in every 168 to 1 in every 90.

It is also notable that in 2000, disability due to psychiatric conditions represented 26% of the total disability pie, and that by 2010, this percentage had jumped to 34%. In other words, it is mental illness that is driving the country’s disability numbers upward. Between 2000 and 2010, the total disability count rose by 56,161 adults in New Zealand, and 46% of that increase was due to psychiatric conditions.

Finally, World Health Organization researchers recently published their findings on the prevalence of “bipolar spectrum disorder” in eleven countries. The United States led the list, while New Zealand was second. In the United States, the WHO investigators reported, the lifetime prevalence of bipolar spectrum disorder is 4.4% of the population; in New Zealand, it is 3.9%. At the bottom of the 11-country list were India, at .1%, and Bulgaria, .3%. Although I don’t have the prescribing data for antidepressants in those latter two countries, I feel confident in stating that antidepressant usage in those two countries much be much less than it is in the United States and New Zealand.

You might conclude, from this report, that a dramatic increase in the prevalance of bipolar disorder is one of the societal costs of allowing direct-to-consumer advertising of prescription drugs.

Australia

While Australia doesn’t allow direct-to-consumer advertising, use of antidepressants and other psychotropics is quite popular in that country. Psychiatry in that country has adopted a drug-based paradigm of care similar to ours. There, the number of adults on disability due a psychiatric disorder rose from 140,965 in 2001 to 227,420 in 2010. That is an increase in the disability rate from 1 in every 137 to 1 in every 98 (Total population divided by adults of working age on disability.)

Moreover, as is the case in New Zealand, psychiatric disorders are composing an ever-greater percentage of the disability pie in Australia, increasing from 22.6% in 2001 to 28.7% in 2010.   Between 2001 and 2010, 51% of the increase in total number of disability beneficiaries in Australia was due to psychiatric disorders.

Iceland

Researchers in Iceland, which also has embraced the use of antidepressants, recently provided an update on disability numbers in that country. There, the number of new cases of disability annually due to mental and behavioral disorders rose from 84 per 100,000 population in 1992 to 217 per 100,000 population in 2007.

Where there’s smoke . . .

One common criticism of Anatomy of an Epidemic has been that I mistake “correlation for causation.” The fact that disability numbers have soared during a time of sharply increased usage of psychiatric drugs doesn’t prove that the drugs are causing the rise in disability, the critcs say. I agree, but in fact, in my book, I used the disability data  merely as a starting point for questioning our drug-based paradigm of care. However, as I now find the same correlation occurring in country after country, I would say this is a case of more and more “smoke” appearing, and at some point, you have to ask when such correlational data provides evidence of a “fire.”

The drug-based paradigm of care that we have adopted in the United States, which took off in 1987 with the arrival of Prozac on the market, has taken hold in many Western countries. I wish that a researcher could take the time to chart usage of psychiatric drugs in fifteen “developed” countries over the past 20 years, and chart the number of people on government disability due to mental illness during that period (and the prevalence of bipolar spectrum disorder in those countries.) If that could be done, I think that the pattern that shows up in the United States, Australia, New Zealand, and Iceland woul, quite unfortunately, be found again and again.

And if  that fact were documented, I wonder whether the defenders of our current paradigm of care would once again shout: Correlation is not causation! Or would it be taken as evidence that something is quite amiss with this paradigm of care?

Sep 16, 2011

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Dr. Angell’s essay, which reviewed three books (one of which was mine, Anatomy of an Epidemic), raised fundamental questions about psychiatry’s diagnostics and its treatments. As could be expected, it stirred a response from leaders in American psychiatry. The New York Times provided Peter Kramer with an extraordinary forum—the front page of its Sunday Review section—to pen an essay “In Defense of Antidepressants.” Now, in the current issue of the New York Review of Books, there are a number of letters-to-the-editor from prominent psychiatrists, with a reply by Dr. Angell. 

In a previous post, I wrote about how Dr. Kramer, in his defense of antidepressants, misrepresented the research findings by Irving Kirsch and Robert DeRubeis, and of course that is revealing in its own way.  The letters published by the New York Review of Books are also quite revealing, and that is particularly true of two comments made by Richard Friedman and Andrew Nierenberg in their joint letter. Dr. Friedman is director of the psychopharmacology clinic at Weill Cornell Medical College, while Dr. Nierenberg is  director of the bipolar clinic and research program at Massachusetts General Hospital.

Here are the two salient points.

A. The chemical imbalance theory of mental disorders is “outdated and disproven.”

In her essay, Dr. Angell noted that, after reviewing the three books, it appeared that there was little scientific merit to the chemical imbalance theory of mental disorders. In their letter, Friedman and Nierenberg criticize Angell for making it seem as though this is news: “Angell uses an outdated and disproven chemical imbalance theory of depression (i.e., serotonin deficiency) as a straw man to deny that depression has any biological basis at all.”

Now, as Dr. Angell notes in her able–and I must say, vigorous–reply, she didn’t write in her essay that depression doesn’t have a biological basis. She simply wrote that the chemical imbalance story didn’t appear to have merit. But forget about that back and forth, for here’s the critical point: In their letter, Dr. Friedman and Dr. Nierenberg  acknowledged that the chemical imbalance theory of mental disorders was disproven long ago.

That, in fact, is true. But of course it begs a question. Why then has the American public regularly been told for the past two decades that psychiatric medications fix chemical imbalances in the brain, like “insulin for diabetes?” Why was it okay for the profession to tell society that false story?

This is a question, I think,  that the psychiatric establishment should address, and as it does so, it needs to mull over this thought: Is it possible to imagine cardiologists or oncologists telling their patients that they have a known biological deficiency, which requires lifelong treatment, when research hadn’t shown that to be true?

B. The prevalence of mood disorders has not increased, but treatment of those disorders has.

In their letter, Dr. Friedman and Dr. Nierenberg make this argument: “What about the inflammatory claim that psychiatric drugs increase the rates of psychiatric disorders? If so, one would expect to see a steady increase in the prevalence of mental disorders in the population. But the epidemiologic evidence shows otherwise.”

Here, they are misstating the nature of the “mystery” I investigate in my book, Anatomy of an Epidemic. I ask this question: Why has the number of people on government disability due to mental illness soared in the past thirty years? Could psychiatric drugs be fueling that epidemic of people disabledby mental disorders?  And the key point here is this: in their presentation of prevalence and treatment data, Dr. Friedman and Dr. Nierenberg have unwittingly provided compelling evidence that the drugs are doing just that.

In their letter, they note that the prevalence of anxiety, mood and substance disorders has been stable in the American population: 29.4% in 1991 and 30.5% in 2003. What went up during this period was the percentage of people receiving treatment, from 20 percent in 1991 to 32.7 percent in 2003.

Now, if psychiatric medications help people with mood disorders function well over the long term, then one would expect that as more people with a mood disorder got treated, then the number of people on government disability due to mental illness would decline (or at least stabilize.) However, if psychiatric medications increase the risk of long-term disability, then you would expect disability numbers to increase.

So let’s do the math. If you look up census data for the number of adults in 1990 and 2003, and then do the relevant prevalance-and-treatment calculations, you find that the number of people treated for mood disorders and substance abuse rose from 11.16 million adults in 1990 to 21.77 million in 2003. At the same time, the number of people receiving SSI or SSDI due to mental illness more than doubled, from 1.47 million people in 1990 to 3.25 million in 2003.

In short, as more people were treated for mood disorders, more people ended up disabled by mental illness. I wish that I had had this information when I wrote Anatomy of an Epidemic, for it provides information important for society to consider.

There is a third revealing point to be found in the letters-to-the-editor published by the New York Review of Books. In her essay, Dr. Angell questioned whether there was good evidence that psychiatric medications do more good than harm (particularly over the long term.) The obvious way for psychiatry to answer that question would be to cite studies that show that psychiatric medications improve the long-term course of major mental disorders. But none of the letter writers refer to any such long-term studies, and Dr. Angell, in her reply, points that out. “All three of these letters simply assume that psychoactive drugs are highly beneficial, but none of them provides references that would substantiate that belief,” she wrote. “Our differences stem from the fact that I make no such assumption.”

Her words here neatly focus on the issue that our society desperately needs to address. We have been using these drugs now for more than 50 years, and so one might expect that, after all this time, there would be good evidence that the medications are helpful over the long-term. But where is that evidence?

Tuesday, August 2, 2011

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Today, the New York Times published an op-ed essay by Peter Kramer titled “In Defense of Antidepressants” on the front page of its Sunday Review section.

In Anatomy of an Epidemic, I wrote about the need for our society to have an honest discussion about the merits of psychiatric medications, and in his essay, Dr. Kramer suggests that he took up his pen in response to recent “debunkings” of the drugs. In particular, he noted the “especially high-profile debunking” that occurred last month in the New York Review of Books when “Marcia Angell, former editor in chief of the New England Journal of Medicine, favorably entertained the premise that ‘psychoactive drugs are useless.’ ” My book Anatomy of an Epidemic was one of three reviewed by Dr. Angell, and as I wrote in Anatomy, I think what our society desperately needs is an honest discussion about what science is telling us about the merits of psychiatric medications. As such, it seems worthwhile to look at Dr. Kramer’s essay in that light.

Here is the question that we need to ask ourselves: Does the essay further public understanding of what science is telling us about the merits of antidepressants? Or does it rely on a misrepresentation of the science in order to protect the image of the drugs?

In his essay, Dr. Kramer writes specifically about research conducted by Irving Kirsch, a psychologist at the University of Hull in the United Kingdom, who detailed his findings in his book The Emperor’s New Drugs (which was also reviewed by Dr. Angell.) He also writes about a study by Robert DeRubeis, a psychologist at the University of Penn, which was published in JAMA in 2010.

First, Kirsch’s work and Dr. Kramer’s review of it.

The Emperor’s New Drugs

In his  research, Kirsch analyzed the results of industry-funded trials submitted to the Food and Drug Administration for four antidepressants: Prozac, Effexor, Serzone, and Paxil. As Kirsch noted, these trials — with one exception — were conducted in patients who, at study entry, were severely depressed. In 34 of the 35 trials Kirsch reviewed, the mean baseline score for the patients was 23 or greater on the Hamilton Depression Rating Scale (HDRS), which is a score characteristic of “very severe depression.”

One reason that pharmaceutical companies seek to enroll people who are very depressed into their clinical trials is because they know that it is in this patient group that their drugs are mostly likely to show a benefit over placebo. Once the FDA has approved their drugs, the pharmaceutical companies can then market them to people with mild depression, regardless of whether the medications are effective in that population. In most of the industry-funded trials of SSRIs, the patients had to have a baseline score of at least 20 on the HDRS, which meant that those with mild to moderate depression were explicitly excluded.

In his review of the FDA data for the four drugs, Kirsch found that symptoms in the medicated patients dropped 9.6 points on the HDRS, versus 7.8 points for the placebo group. This was a difference of only 1.8 points, and the National Institute for Clinical Excellence in Britain had previously determined that a three-point drug-placebo difference was needed on the Hamilton scale to demonstrate a “clinically significant benefit.” Kirsch found that it was only in the very severely depressed patients — basically those with a baseline HDRS score over 28 — that the drugs provided a clinically significant benefit.

On page 31 of his book, Kirsch writes: “In examining baseline depression scores (that is, measures of how depressed the patients were before the clinical trial began), the first thing we noticed was that all but one of the trials had been conducted with patients whose scores put them in the ‘very severe’ category of depression . . . in other words, our findings of a clinically insignificant difference between drug and placebo was based primarily on data from those patients who are the most severely depressed according to the APA and NICE classification scheme.”

So how does Dr. Kramer, in his essay, “defend” antidepressants in the light of Kirsch’s report? Let’s go over this point-by-point.

First, he writes that Kirsch “found that while the drugs outperformed the placebos for mild and moderate depression, the benefits were small.” This, of course, is not what Kirsch found at all. The studies didn’t involve patients with mild to moderate depression (except for the one study.) What Kirsch found was that in the FDA trials, the antidepressants didn’t outperform placebo, in a clinical meaningful way, for patients with severe depression.

That, of course, is a finding that would cause readers to seriously wonder about the merits of the drugs. But rather than write about Kirsch’s actual findings, Dr. Kramer crafted a sentence that tells of how the drugs provide a small benefit even in mild to moderate patients. As such, he is reassuring readers — even though falsely so — that antidepressants provide a benefit to the larger universe of patients that take these drugs. And the implication is that the benefit must be quite marked for the severely depressed.

Having misrepresented Kirsch’s findings, Dr. Kramer then writes that “the problem with the Kirsch analysis — and none of the major press reports considered this shortcoming — is that the FDA material is ill suited to answer questions about mild depression.” The reason, Dr. Kramer explains, is that “companies rushing to get medications to market have had an incentive to run quick, sloppy trials,” and in their haste, they “often [enroll] subjects who don’t really have depression.” It is these non-depressed patients who then become counted in the trial results as placebo responders, because, Dr. Kramer writes, “no surprise — weeks down the road they are not depressed.”

I have to confess that this is a paragraph that took my breath away. Dr. Kramer makes it seem that Kirsch’s review focuses on mild to moderate depression (it doesn’t);  then he explains that the reason that Kirsch found that the drugs provide only a slight benefit to those patients in the FDA trials is that the drug companies enroll patients who aren’t really depressed at all (when in fact the study criteria required patients to be severely ill); and finally he concludes that when those non-depressed patients end up in the placebo arm of the study, they  show up as improved and thus as placebo responders. The “improvement” of the placebo group, Dr. Kramer writes, “may have nothing to do with faith in the dummy pills; it is an artifact of the recruitment process.”

So, readers of the New York Times piece can only conclude this: The industry-funded trials used for  FDA approval were in large part conducted in patients with mild depression, or in patients who weren’t depressed at all, and that is why the drugs only slightly beat placebo. The results would  have been markedly different in patients who were really depressed. Plus, even in these flawed trials, antidepressants produced a small benefit in the mild-to-moderate group. 

Placebo Washouts and Biased Trial Designs

Now let’s go to Dr. Kramer’s analysis of the study by Robert DeRubeis and his collaborators.

As might be expected, the drug companies in fact design their trials in a manner expected to suppress the placebo response rate. This is done through what is known as a placebo washout period, which may last a few days to two weeks. All patients enrolled into the study — who may have to be taken off an antidepressant they might have been on — are given a placebo in single-blind fashion (the investigators know it is a placebo; the patients do not.) Those who get better on placebo in this washout phase are then excluded from the study. Only those who don’t respond to a placebo are randomized into the trial. As such, trials with this design might be better described as “drug versus initial non-responders to placebo,” and of course this is a design that is supposed to reduce the number of placebo responders in the final results.

In his investigation, DeRubeis searched the published literature for trials of patients with a broad range of symptom severity (and thus not just severely ill patients), and also for trials that didn’t use a placebo-washout phase to suppress the placebo response. He found six studies that met that criteria, and analyzed the collective results. Here is what he and his collaborators concluded: “True drug effects — an advantage of antidepressant medication over placebo — were nonexistent to negligible among depressed patients with mild, moderate, and even severe baseline symptoms, whereas they were large for patients with very severe symptoms.”

So how does Dr. Kramer “defend antidepressants” in light of this study? Again, let’s go point by point.

First, Dr. Kramer launches what might best be described as an ad hominem attack. He states that critics have questioned “aspects of DeRubeis’s math,” which is a subtle suggestion that DeRubeis fudged his figures to get the results he wanted. But Dr. Kramer doesn’t provide any information about who has actually raised such criticism, nor does he provide any evidence that there is a problem with DeRubeis’s math skills.

Second, Dr. Kramer writes that DeRubeis concluded that “medications looked best for very severe depression and had only slight benefits for mild depression.” As was the case with his review of Kirsch’s work, Dr. Kramer here isn’t accurately summing up DeRubeis’s findings. DeRubeis found “true drug effects were nonexistent to negligible among depressed patients with mild, moderate, and even severe baseline symptoms.” Dr. Kramer’s sentence instead tells of a finding that drugs help all patients along a spectrum — slight benefit for mild depression, marked benefit for more severe forms.

Third, Dr. Kramer writes that DeRubeis analyzed studies that “intentionally maximized placebo effects.” Here, Dr. Kramer is turning the biased design of the industry-funded trials, which employed a placebo washout to suppress the placebo effect, into an example of good design, and he is asserting that the six studies that didn’t employ a placebo washout were, in essence, biased against the antidepressants.

Together, Kirsch’s review of the FDA data and DeRubeis’s meta-analysis of studies published in medical journals tell a similar story. In clinical studies, antidepressants regularly fail to provide a clinically significant benefit over placebo for patients with mild, moderate, and even severe depression. But these drugs do provide a significant benefit for patients who are very severely ill. Their findings arise from an exhaustive review of the research, both published and unpublished, and thus can be seen as an in-depth look at what science has to say about the short-term efficacy of antidepressants.

But readers of “In Defense of Antidepressants” learned nothing of that. Instead, Dr. Kramer misrepresented their work, and then having done so, dismisses its relevance in this cavalier way: “In the end, the much heralded overview analyses look to be editorials with numbers attached.”

Turning a Blind Eye to Long-term Outcomes

Dr. Angell’s comment that psychiatric drugs might be “worse than useless” was in reference to Anatomy of an Epidemic, and to my review, in my book, of the long-term outcomes literature for antidepressants and other psychiatric drugs. The evidence for long-term outcomes may be very different thanfindings from short-term studies, and thus if the profession wants to “defend” its use of antidepressants, it needs to do more than  show that the drugs are better than placebo  in six-week trials. The profession needs to show that the drugs improve long-term outcomes, and that they do so in “real-world” patients.

There are two notable studies that Dr. Kramer could have reviewed to shed light on this question.

In 2004, John Rush, a prominent psychiatrist at Southwestern Medical Center in Dallas, observed that industry-funded trials of antidepressants were conducted in a group of patients that weren’t representative of larger patient populations because study criteria regularly excluded patients with comorbidities. In addition, the industry-funded trials were short term, and together these two factors led to a notable deficiency in the evidence base. “Longer-term clinical outcomes of representative outpatients with nonpsychotic major depressive disorder treated in daily practice in either the private or public sectors are yet to be well defined,” Rush wrote.

To remedy this deficiency, Rush and his colleagues conducted a study of antidepressants in “real-world” patients, and followed them for a year. During this period, they provided their patients with a wealth of emotional and clinical support “specifically designed to maximize clinical outcomes.” This was the best care that modern psychiatry could provide.

Here were their real-world results: Only 26% of the patients in their study even responded to the antidepressant (meaning that their symptoms decreased at least 50% on a rating scale), and only about half of those who responded stayed better for any length of time. Most startling of all, only six percent of the patients saw their depression fully remit and stay away during the yearlong trial. These “findings reveal remarkably low response and remission rates,” Rush said.

Dr. Kramer might also have discussed the findings from the STAR*D trial funded by the National Institute of Mental Health. This was the “largest antidepressant trial” ever conducted, and the one-year results are now known. Only 108 of the 4,041 patients who entered the trial remitted and then stayed well and in the trial throughout the follow-up period. The remaining patients — 97% of the total – either failed to remit, relapsed or dropped out of the trial.

But there was no discussion of these longer-term results in Dr. Kramer’s op-ed, which became the most-emailed New York Times article on Sunday. As a result, the Internet buzzed on Sunday with a prominent story from arguably the leading newspaper in the United States, which assured readers that all is well in the land of antidepressants. These drugs “work — ordinarily well, on a par with other medications doctors prescribe,” Dr. Kramer wrote.

As I noted in Anatomy of An Epidemic, the real problem we have in this field of medicine is that academic psychiatry hasn’t been honest in what it tells the public about psychiatric medications. If the medications are to be used wisely, and in an evidence-based manner, we need to have an honest discussion about what science is telling us about the drugs. But on Sunday, in this essay “In Defense of Antidepressants,” the American public has been treated to yet another dose of misinformation.

The post The New York Times’ Defense of Antidepressants appeared first on Mad In America.

Although this concern first surfaced in the late 1960s and early 1970s, when a handful of psychiatrists expressed concern that antidepressants were causing a “chronification” of the disorder, it was in 1994 that Italian psychiatrist Giovanni Fava, editor of Psychotherapy and Psychosomatics, urged the field to directly confront this possibility. He wrote: “Within the field of psychopharmacology, practitioners have been cautious, if not fearful, of opening a debate on whether the treatment is more damaging [than helpful] . . . I wonder if the time has come for debating and initiating research into the likelihood that psychotropic drugs actually worsen, at least in some cases, the progression of the illness which they are supposed to treat.”

In subsequent papers, Fava set forth a biological explanation for why this may be so. Psychiatric drugs perturb neurotransmitter pathways in the brain, and in response to that perturbation, the brain undergoes a series of compensatory adaptations in an effort to maintain normal functioning of those systems. In scientific terms, the brain is trying restore its “homeostatic equilibrium.” Fava has dubbed this compensatory response to a psychiatric drug “oppositional tolerance.”

For instance, a selective serotonin reuptake inhibitor (SSRI) blocks the normal reuptake of serotonin from the synaptic cleft, which is the tiny gap between neurons. Serotonin now stays in the cleft longer than normal, and feedback mechanisms immediately kick into gear. The presynaptic neurons begin putting out less serotonin than usual, while the postsynaptic neurons—the neurons receiving the message—decrease the density of their receptors for serotonin. The drug is acting as an accelerator of serotonergic activity; the brain responds by putting down the brake.

When Fava first raised this issue in the 1990s, several American researchers wrote that this was a valid concern, which needed to be investigated. One who did so was Rif El-Mallakh at the University of Louisville School of Medicine. He has periodically revisited this issue, and in a paper published in the June issue of Medical Hypotheses, he provides an overview of “emerging evidence that, in some individuals, persistent use of antidepressants may be pro-depressant.”

El-Mallakh’s Overview

In the early 1990s, El-Mallakh notes, only about 10% to 15% of patients with major depressive illness had treatment-resistant depression (and thus were chronically ill.) In 2006, researchers reported that nearly 40% of patients were now treatment-resistant. In a period when use of SSRI antidepressants exploded, refractory depression went on the march.

This condition, El-Mallakh writes, often develops in people who had a good initial response to an antidepressant, and then continue taking the drug. However, up to 80% of patients maintained on an antidepressant suffer a recurrence of symptoms,  and once that “initial treatment response is lost,” continued efforts to treat the relapsed patient with antidepressants frequently results in “poor response and the rise of treatment-resistant depression.” Ultimately, this process—the continual prescribing of antidepressants to someone who has become treatment resistant—may “make the chronic depression permanent,” he writes.

In his discussion, El-Mallakh notes that people without any history of depression who are prescribed an antidepressant for other reasons—anxiety, panic disorder, or because they are serving as “normal controls” in a study—may become depressed, with that depression at times persisting for a fairly long period of time after the antidepressant is withdrawn. The reason that antidepressants may have a “prodepressant effect,” El-Mallakh writes, is that “continued drug treatment may induce processes that are the opposite of what the medication originally produced.” This is the “oppositional tolerance” that Fava has written about, and this process may  “cause a worsening of the illness, continue for a period of time after discontinuation of the medication, and may not be reversible.”

This same basic mechanism—oppositional tolerance to a psychiatric drug—has been proposed to be a cause of tardive dyskinesia (TD), which develops with some frequency in long-term users of antipsychotic medications. TD is characterized by repetitive, purposeless movements, such as a constant licking of the lips, which is evidence that the basal ganglia has been damaged by the drugs. Although various explanations for TD have been put forth, one thought is that it is caused by drug-induced dopamine supersensitivity. Antipsychotics block dopamine receptors (and in particular, a subtype known as the D2 receptor), and in compensatory response, the brain’s neurons increase the density of their D2 receptors, and thus become “supersensitive” to this neurotransmitter. That may lead to the constant firing of neurons controlling motor movement (such as tongue movement), and even when the offending antipsychotic is withdrawn, TD symptoms often remain, which suggests that the brain is unable to renormalize its dopaminergic pathways.

With antidepressants, the problem may be that patients, because of the “oppositional tolerance” process, end up with a depleted serotonergic system. The postsynaptic neurons end up with a reduced density of receptors for serotonin; in rat studies, long-term treatment with an SSRI led to markedly reduced levels of serotonin in “nine areas of the brain.”  El-Mallakh, in his paper, details several other ways that exposure to an SSRI may deplete serotonergic function, and notes that in experiments with young animals, such impairments are “associated with increased depressive and anxious behaviors.”

In conclusion, El-Mallakh writes that “a chronic and treatment-resistant depressive state is proposed to occur in indivudals who are exposed to potent antagonists of serotonin reuptake pumps (i.e. SSRIs) for prolonged time periods. Due to the delay in the onset of this chronic depressive state, it is labeled tardive dysphoria. Tardive dysphoria manifests as a chronic dysphoric state that is initially transiently relieved by — but ultimately becomes unresponsive to  – antidepressant medication. Serotonergic antidepressants may be of particular importance in the development of tardive dysphoria.”

Another Side of Oppositional Tolerance

El-Mallakh detailed how tardive dysphoria may develop in patients who initially respond to an antidepressant and then stay on antidepressants long term. But what if patients respond well to an antidepressant and then stop taking the drug?  Their brains have been modified by exposure to the antidepressant (i.e. oppositional tolerance has developed), and thus, upon withdrawal of the drug, are they more likely to relapse than if they hadn’t been exposed to an antidepressant in the first place?

This is the question investigated by Paul Andrews and his collaborators at Virginia Commonwealth University in a report that was published online this week in Frontiers in Evolutionary Psychiatry. In the study, Andrews compared relapse rate for patients who remitted while on placebo during the initial phase of a study and then remained off-drug during a follow-up period (placebo-placebo group) with the relapse rates for patients who remitted while on an antidepressant during the initial phase of a study and who were then withdrawn from the drug during the follow-up period (drug-placebo group.) He hypothesized that the drug-exposed patients, because of oppositional tolerance, would have a higher rate of relapse, and he found that to be true. In a meta-analysis of 46 studies, he determined that the relapse rate for the placebo-placebo group was 24.7%, compared to 44.6% for the drug-placebo patients.

Next, Andrews teased apart the relapse rates by antidepressant type. His hypothesis was that the relapse rate upon drug withdrawal would increase according to the drug’s potency. For instance, SSRIs increase serotonin levels much more than tricyclics do (and thus are more potent in that regard), and Andrews reasoned that the strength of the brain’s “oppositional tolerance” response to an SSRI would be greater than it was to a tricyclic. Then, when the antidepressant is withdrawn, the “oppositional forces” that have arisen in response to the drug operate unopposed, and thus the greater the oppositional forces, the greater the risk of relapse.

Andrews uses this metaphor to explain this process:  “As one pulls a spring from its equilibrium position, the spring exerts an oppositional force that attempts to bring the spring back to equilibrium; the more one displaces the spring from its equilibrium position, the greater the oppositional force that the spring produces. Similarly, antidepressants with greater perturbational effects should trigger stronger oppositional forces that attempt to bring [neurotransmitter] levels back to equilibrium. The buildup of oppositional tolerance under antidepressant treatment could then cause the system to overshoot its equilibrium upon discontinuation, and the degree of overshoot should be proportional to the perturbational effect of the antidepressant.”

In his meta-analysis, Andrews found that the risk of relapse does indeed vary according to the potency of the antidepressant. The greater the potency, the greater the risk of relapse. This finding, he concludes, is consistent with the idea that the drugs induce an “oppositional tolerance,” and that this change puts patients at increased risk of relapse upon drug discontinuation.

Length of Initial Exposure to Antidepressant May Affect Relapse Rates

The next question raised by this “oppositional tolerance” model is this: Does it, in any way, become more pronounced over time, such that the risk of relapse upon drug withdrawal increases? The findings from a French study of more than 35,000 patients, which were published in Pharmacopsychiatry, suggest that it may. The French investigators studied patients treated with an antidepressant for an “index” episode of depression who then subsequently stopped taking the medication for at least two months. The researchers then looked at whether those patients—after that two-month period had lapsed—subsequently started taking an antidepressant again, as this was seen as a marker for relapse.

The French scientists found that those who initially took an antidepressant for less than one month before withdrawing were less likely to relapse than those who took an antidepressant for two to five months. Those who were exposed to an antidepressant for longer than six months had more than twice the risk of relapse compared to those exposed for less than one month (as measured by a subsequent return to the use of antidepressants.)

The French investigators didn’t consider whether this higher risk of relapse could be due to a biological change triggered by the antidepressants. Indeed, it could be that those who took an antidepressant longer the first time around were more severely ill. But another possible explanation is that  “oppositional tolerance” changes induced by an antidepressant become more pronounced over time, which would then increase the risk of relapse upon drug withdrawal.

Clinical Ramifications

As is now well-documented, in the clinical trials of SSRIs, the drugs did not provide a significant clinical benefit compared to placebo for patients with mild-to-moderate depression. Given this absence of benefit, the review by El-Mallakh and the findings by Andrews and the French scientists provide a compelling rationale for not prescribing an antidepressant to first-episode patients with this severity of depression.

According to El-Mallakh’s review of the literature, if patients respond well to the antidepressant and then stay on the drug indefinitely, they are at high risk of eventually suffering a recurrence of symptoms (even while on the drug.) Once that happens, the patient is at significant risk of becoming chronically depressed. Yet, if patients respond well to an antidepressant and then withdraw from the medication, Andrews’ study shows they are at a higher risk of relapse than if they had gotten better on placebo. In addition, the French study suggests that this risk of relapse may increase with time on the drug before withdrawal. But if a patient does indeed relapse and then goes back on an antidepressant, that person may now be on a path that  leads to chronic illness.

In other words,  initial exposure to an antidepressant—because of this drug-induced “oppositional tolerance”—can often lead to a poor long-term outcome. In contrast, people who remit on placebo have not undergone “oppositional tolerance” brain changes, and thus may have a much better long-term prognosis.

Minnesota’s Glum Report on Depression Outcomes

The STAR*D trial, which was funded by the NIMH, provides evidence of how, in our modern SSRI era, depression runs a very chronic course. Once Ed Pigott and others carefully parsed the STAR*D data, it became known that only 108 of the 4041 patients who entered the trial remitted, and then stayed well and in the trial during the yearlong follow-up. All of the other patients either failed to remit, relapsed, or dropped out.

Now comes a report from MN Community Measures, a non-profit organization in Minnesota, which gathers data health outcomes in that state. In 2010, they reported that only 5.8% of the 23,887 patients treated for depression were in remission at the end of six months, and that only 4.5% were in remission at the end of twelve months. In other words, 95% of the patients in Minnesota with major depression now appear to be chronically ill.

What Next?

The historical context for these dispiriting results is this: In the 1960s, at the start of the antidepressant era, experts in this disorder regularly wrote that depression was an episodic disorder, which could be expected to clear up with time. As Dean Schuyler, head of the depression section at the NIMH explained in a 1974 book, most depressive episodes “will run their course and terminate with virtually complete recovery without specific intervention.” In 1969, George Winokur, a psychiatrist at Washington University, made the same point: “Assurance can be given to a patient and to his family that subsequent episodes of illness after a first mania or even a first depression will not tend toward a more chronic course.”

But now here we are 40 years later, with perhaps ten percent of American adults taking an antidepressant, and researchers are writing about “oppositional tolerance,” and drug-induced “tardive dysphoria.” That is surely a health outcomes story that needs to investigated, and if we want to put this into an even sharper moral context, we need only consider this: Many teenagers are now being prescribed an antidepressant, and when they take the drug, their brains will develop “oppositional tolerance” to it. What percentage of these youth will end up with drug-induced tardive dysphoria, and thus suffer a lifetime of chronic depression?

Thursday, June 30, 2011

The post Now Antidepressant-Induced Chronic Depression Has a Name: Tardive Dysphoria appeared first on Mad In America.

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1. The Brain Remains a Black Box

During the past 25 years, the National Institute of Mental Health (NIMH) and academic psychiatrists have regularly informed the public that mental disorders are “brain diseases,” just like diabetes and other physical illnesses. But if that were so, the industry’s development of new psychiatric drugs would be flourishing, as companies would be finding novel ways to ameliorate the disease process. Unfortunately, as the drug companies well know, the biological causes of major mental disorders remain unknown.  While researchers may report that PET scans show differences in blood flow with different patient groups, or announce that they have identified small differences in brain function for some patients in various diagnostic categories, they haven’t been able to elucidate a disease pathway for any mental disorder. As a result, drug firms lack molecular targets for new drug development.

In a recent report published in European Neuropsychopharmacology, British neuroscientists David Nutt and Guy Goodwin explained it this way: “Predictive and prognostic biomarkers for psychiatric disorders are largely non-existent.” As such, they wrote, there are “deficiencies in the science that underpins drug discovery.”

Undoubtedly, we will continue to hear from the NIMH and from academic psychiatry that researchers are making great progress in untangling the biology of mental disorders. We have been hearing this same story for decades now, and we will be told that such discoveries will one day bring new and better drug therapies. But the drug companies, with their retreat from this field, are revealing a different reality: the biology of mental disorders remains a mystery, and this is not a mystery they expect to be solved any time soon.

2. The NIMH-Funded Studies of Prozac-Era Drugs Told of a Failed Form of Care

When the SSRI antidepressants and atypical antipsychotics came to market, the public was told that these new drugs were much better than the old ones. The pharmaceutical industry, it seemed, had developed new “wonder” drugs. But then the NIMH funded a number of longer-term studies of psychiatric drugs, and time and again those studies failed to shows that these medications regularly helped a majority of people get well and stay well, or that the new drugs were any better than the old ones.

    To wit:

•    In the CATIE study of antipsychotics for schizophrenia, 74% of the 1,432 patients stopped taking the assigned medication within 18 months, mostly because of “intolerable side effects” or the drug’s “inefficacy.” The atypical antipsychotics did not produce better results than the standard antipsychotic.

•    In the STAR*D study of antidepressants, fewer than half of the 4,041 depressed patients ever remitted, even for a brief period, and at the end of 12 months, there were only 108 patients–3% of the original cohort –who had remitted, stayed in the trial, and not relapsed.

•    In the STEP-BD study of 4,360 patients, antidepressants were not found to be beneficial for bipolar patients. Furthermore, in the one-year naturalistic follow-up study involving 1,742 patients, only 409 patients (23%) remained well and in the trial throughout the 12 months. The remaining patients either dropped out (32%), or suffered one or more new mood episodes (45%).

•    In the MTA study of children with ADHD, by the end of three years,  ”medication use was a significant marker not of beneficial outcome, but of deterioration.” At the end of six years, continued medication use was “associated with worse hyperactivity-impulsivity and oppositional defiant disorders symptoms,” and with greater “overall functional impairment.” As one of the principal investigators confessed, “there were no beneficial effects (with medication), none.”

•    In the TEOSS study of antipsychotics for teenagers with early onset schizophrenia spectrum disorder, only 12% of the initial cohort responded to an antipsychotic and then successfully stayed on the medication for a year.

These results did not tell of a paradigm of care that “worked” for most people. In a 2009 paper, NIMH director Thomas Insel summed up the results for the antipsychotics and antidepressants in this way: “For too many people, antipsychotics and antidepressants are not effective, and even when they are helpful, they reduce symptoms without eliciting recovery.”

For pharmaceutical companies, these poor results—and the fact that the second-generation drugs weren’t more effective than the first-generation agents—provide a second reason for exiting this field of research. Drug companies want to invest their research dollars in a venture that is likely to produce a true advance in treatment (and thus will be quite profitable.) They like to build on past progress in a disease area, as this gives the companies confidence that their investment in R&D will pay off.  But in psychiatry, drug companies have spent billions of dollars researching mental disorders during the past 40 years, yet that research has failed to produce any real therapeutic progress. The second-generation drugs are no more effective than the first-generation agents. And thus drug companies are left with this sobering fact: in the absence of any new insight into the biology of mental disorders, why should the future be any different? If they spend billions more on research and development, how likely is it that this  investment will pay-off?

3.  Having Spent Their Goodwill on Prozac-Era Drugs, Drug Companies Can’t Expect to Use Their Marketing Prowess to Tell the Public a Story of a New Generation of “Wonder” Drugs.

Pharmaceutical companies did hit the financial jackpot with their second-generation psychiatric drugs. But that success was built from marketing, rather than true therapeutic progress, and the drug companies know that this marketing door—in terms of their ability to convince the public that new wonder psych drugs have arrived— is partially closed to them now.

Up until the Prozac era, the American public generally viewed the pharmaceutical industry in a favorable light. The industry did have a good track record of bringing helpful drugs to market for infectious diseases, for treating cancers, and for any number of other physical ailments, and that medical progress generated public goodwill.  The industry capitalized on that goodwill—and our society’s faith in medical progress and academic medicine—to create a booming market for the SSRIs, the atypical antipsychotics, and other psychiatric drugs. But now that goodwill has been spent.

The public is coming to understand that the market for the Prozac-era drugs was built on dishonest science and through a story-telling partnership—between industry and psychiatrists at academic medical centers—that can’t be trusted. The industry-funded trials of many of the Prozac-era drugs were biased by design; the published results were spun to make the drugs look better; negative studies went unpublished; and harmful side-effects were downplayed or hidden. Investigations by Senator Charles Grassley and others revealed that the drug companies paid academic psychiatrists handsome sums of money to promote the drugs; i.e., that they were acting as shills for the drugs. Finally, both the federal government and states have sued a number of drug companies for their illegal off-label marketing of psychiatric drugs, with many companies having paid large fines to settle the complaints.

As a result, the public is now quite wary of the pharmaceutical industry, at least when it comes to its promotion of psychiatric drugs. The industry can’t ramp up the same marketing machinery it used to sell its Prozac-era drugs in order to sell a new generation of “wonder” drugs. This time around, the drug companies will have to develop drugs that truly are superior to the existing ones, and they don’t have any scientific vision for doing that.

The Pipeline Has Dried Up . . . Which Provides an Opportunity for Society to Rethink Psychiatric Care

In a recent editorial titled “Vanishing clinical psychopharmacology,” the British Journal of Clinical Pharmacology detailed the dire state of affairs in this field. In 2010, the journal noted, the FDA only approved two drugs with a broadly defined “psychiatric or neurological indication,” and the two were actually older drugs that had been on the market for other uses. No novel drugs have come to market in a long time, and the journal concluded that there wasn’t anything “promising in the pipeline” either. At the 2011 meeting of the American Society for Clinical Psychopharmacology, only 13 of the abstracts were on psychopharmacology, and there were no abstracts that told of novel drugs.

While this is disheartening—it would be a very good thing if the drug industry could develop new agents that were more effective and caused many fewer side effects—there is a silver lining to be found in this story of “vanishing clinical psychopharmacology.” As the existing Prozac-era drugs continue to go off patent, with more and more generics in use, the manufacturers of the brand-name drugs will likely reduce their advertising budgets for these products. If so, it is possible that the drug tsunami that has swept over our society will begin to ebb, and this will provide our society an opportunity to rethink its psychiatric care.

With our current medical model, drug treatments focus on reducing the symptoms of a “disease.” In the future, perhaps our society will embrace a “wellness” model, and thus focus on treatments—whether drug therapies or psychosocial care—that promote physical, emotional, and social well-being. Peer groups are already advocating for this change in focus. Furthermore, the scientific literature provides evidence of non-drug therapies that are effective in this manner, and thus if our society does decide to rethink psychiatric care, there is an “evidence base” that it can rely upon for guidance.

The post Drug Companies ‘Just Say No’ to Psych Drugs appeared first on Mad In America.

Adults

1) CATIE. In this study of antipsychotics for schizophrenia, 74% of the 1,432 patients stopped taking the assigned medication within 18 months, mostly because of “intolerable side effects” or the drug’s “inefficacy.” The atypical antipsychotics did not produce better results than the standard antipsychotic.

2) STAR*D. In this study of antidepressants, depressed patients who failed to respond to an initial medication were switched to another, with this process then repeated several times. In the initial stage of the trial, fifty-one percent of the 3,671 patients “remitted” at some point, which meant their depressive symptoms cleared. Then, during a one-yer followup study, 737 patients (20% of the original cohort) reported at some point that they were still doing well. But drop-out rates were high, and by the end of the 12-month followup, there were only 108 patients — 3% of the original cohort — still in the trial who had remitted and not relapsed.

3) STEP-BD. This large, 22-site study enrolled 4,360 bipolar patients from 1999 to 2005, and researchers conducted multiple randomized trials and naturalistic investigations to assess their outcomes. In regards to drug therapy, there were two primary findings. First, antidepressants were not found to be beneficial for bipolar patients. Second, in a one-year naturalistic follow-up study involving 1,742 patients, 409 (23%) remained well and in the trial throughout the 12 months. The remaining patients either dropped out (32%), or suffered one or more new mood episodes (45%).

Children and adolescents

4) MTA Trial. In this ADHD study, stimulants were basically compared to behavioral therapy, and at the end of 14 months, those treated with stimulants were doing better. Their core ADHD symptoms had abated to a greater degree, and there was a hint that their readings skills were better too.

The study then entered a second phase, in which the researchers periodically assessed how the children in the study were doing and whether they were taking a stimulant, and at the end of three years, “medication use was a significant marker not of beneficial outcome, but of deterioration. That is, participants using medication in the 24-to-36 month period actually showed increased symptomatology during that interval relative to those not taking medication.” In addition, those on stimulants had higher “delinquency scores, and they were also now shorter and weighed less than their non-medicated counterparts.

At the end of six years, the results were the same. Continued medication use was “associated with worse hyperactivity-impulsivity and oppositional defiant disorders symptoms,” and with greater “overall functional impairment.”

5) TEOSS Trial. In this study of antipsychotics as a treatment for early onset spectrum disorder, 54 out of 116 youth (ages 8 to 19) responded to the drug treatment in the initial eight weeks. The 54 responders were then entered into a 44-week “maintenance” study, and at the end of that period, only 14 youth were still on the study medication, with the remaining 40 dropping out, or going off the medication because of “inefficacy” or “intolerable” side effects. Thus, 12% of the initial cohort responded to an antipsychotic and were still taking the medication at the end of one year.

To sum up, the NIMH studies documented the following long-term findings:

• 26% of schizophrenia patients in CATIE were able to stay on their assigned antipsychotic for 18 months.

• 3% of the depressed patients in STAR*D remitted and then stayed well and in the trial throughout the 12 month followup.

• 23% of the bipolar patients in STEP-BD stayed well and remained in the study during a one-year follow-up.

• Medication usage in the MTA ADHD study was a marker for deterioration at the end of three years, and associated with worse outcomes at the end of six years.

• 12 percent of the early onset schizophrenia spectrum patients in TEOSS responded to an antipsychotic and were still taking the medication at the end of one year.

Now that these outcomes are in, our society can better address this question:  Do these results tell of a successful paradigm of care?

Friday, May 28, 2010

The post Summing Up the NIMH Trials: Evidence of an Effective Paradigm of Care? appeared first on Mad In America.

He has posted 25 times. Many readers have written to me to tell of how much they enjoy his blog, and are moved by it. And now here is the news: On March 15, his employer, Littleton Adventist Hospital, fired him.

Mark’s employer told him his termination was “without cause,” meaning that there was no “reason,” in terms of his performance, for his being fired. At that meeting, Mark said, his employer denied that it had anything to do with his blog. Instead, this was what Mark was told: “It is clear that your interests and the hospital’s have diverged, and it is best that we part ways.”

As I reported in Anatomy of an Epidemic, there is a long list of physicians and researchers who have had their careers threatened, or suffered a career setback, for having publicly questioned the merits of psychiatric medications.  Forty years ago, Loren Mosher was ousted from his position as head of schizophrenia studies at the NIMH after running a study, the Soteria Project, that showed better outcomes for the patients treated in the Soteria home with minimal use of psychiatric medications than those treated conventionally with antipsychotics. After Peter Breggin spoke about how antipsychotics can cause tardive dyskinesia on the Oprah Winfrey show, NAMI filed a complaint with the Maryland State Commission on Medical Discipline, asking that the commission take away his medical license. In 2000, Irish psychiatrist David Healy spoke about how SSRIs could stir suicide, and when he did, the University of Toronto’s Centre for Addition and Mental Health, where Healy had accepted an offer to head up its mood and anxiety program, rescinded the job offer. Nadine Lambert, a psychologist at the University of California at Berkeley, reported in 1998 that children treated with stimulants for ADHD had elevated rates of cocaine abuse and cigarette smoking as adults; soon the National Institute on Drug Abuse stopped funding her work. When Joseph Glenmullen, a clinical instructor in psychiatry at Harvard Medical School published Prozac Backlash, Eli Lilly mounted a campaign to discredit him. After Gretchen LeFever, a psychologist at East Virginia Medical School, published research showing that an overly high number of children in Virginia schools were being diagnosed with ADHD, an anonymous “whistleblower” charged her with scientific misconduct. Psychiatrist Grace Jackson, who has written two books critical of psychiatric drugs, Rethinking Psychiatric Drugs and Drug-Induced Dementia, can tell of how her views on the medications led to a derailing of her career as a practicing psychiatrist. On and on the list goes, and now we have Mark Foster’s story to consider.

In the spring of 2008, Littleton Adventist Hospital offered Mark a job to start a clinic, Chatfield Family Medicine, from scratch. The hospital expected that his primary care clinical would funnel patients to the hospital, and thus serve its financial interests in that way. Mark’s employment contract contained this clause: the hospital “shall not interfere with the usual patient-physician relationship . . . (or the) Physician’s independent exercise of judgment in the practice of medicione.”

In January of 2009, Chatfield Family Medicine opened, and within 15 months, Mark had built up a clinic with enough patients that he was operating “nearly at capacity.” Then, in April of 2010, the twin management corporations for the hospital and the clinic, Centura Health and Physician Enterprises, introduced an electronic medical records system that, Mark said, was “cumbersome and inefficient” and caused the clinic’s “productivity and growth to come to a halt.” This caused the clinic to experience some ongoing “financial stress.”

In July of 2010, Mark read Anatomy of an Epidemic. “It created a revolution in my head,” he wrote. “It crystallized all that I had so long perceived as wrong with the mainstream, standard-of-care provision of mental health services, which means, basically, prescribing meds.”  

Once Mark began posting on madinamerica.com, I regularly heard from readers who praised his writing, and the thoughtfulness of his posts. I know that several policy makers at the federal level read his blog, and in January of this year, he began getting invitations to speak at public forums, including one for Colorado policy makers organized by Amy Smith (a well-known consumer activist in that state.) He then spoke to his employer about cutting back his hours at the clinic this coming summer, as he wanted to expand on his blog to write a book. The hospital, Mark said, told him it would support him in this endeavor.

However, after Mark announced this plan, corporate administrators began to raise questions about his madinamerica blog at their meetings. Then, on February 18, Mark received a phone call from the chief medical officer of Physician Enteprises, who spoke to him about it and stated that he had received a “complaint” about his new prescribing practices.

“We are concerned about your methods falling outside of the standard of care and that they may adversely affect patient safety,” Mark was told. “We need to make sure that our physicians are representing the hospital well.”

“First of all,” Mark replied, “I am not promoting any new or unproven therapies, procedures, or drugs. I am not forcing med withdrawal on anybody. I am merely engaging with patients who wish to reduce their dependence on potentially harmful psych meds. If I am able to prescribe the medications, then I should be able to take them away, right? But your question begs a follow-up question: you question the safety of my methods, but what are the known risks of continuing patients on long-term psychiatric drugs, especially patients on multiple medications? What research could we bring to bear on the question of the safety and efficacy of long-term psych med treatment?’ ”

Mark’s response, of course, goes to the crux of the issue regarding “standards of care.” The standard of care in the United States supports continual use of psychiatric medications and even polypharmacy, even though there is no good evidence that those practices improves long-term outcomes for those with psychiatric diagnoses (in the aggregate), and plenty of evidence that they may cause a great deal of long-term harm.  I reviewed that long-term evidence base in Anatomy of an Epidemic, and it was in response to that evidence that Mark began to alter his use of the drugs. He was moving away from “standards of care” even as he moved toward—in my opinion—using the drugs in an evidence-based way.

On March 15, three corporate administrators came to Mark’s clinic for what Mark had understood was going to be a meeting to renegotiate his contract so that he could work part-time for three months. Instead, once they arrive, they informed him that he was being “terminated without cause.” The parent company thought its interests and Mark’s had now “diverged” and Mark was told that this would be his last day. Mark said they then had this exchange.

“Does this have anything to do with my blog?” Mark asked.

“What blog? What are you talking about?” they responded.

“The one I spent twenty minutes telling you about six weeks ago,” Mark said. “The one the Chief Medical Officer called to speak to me about.  The one I am trying to turn into a book, which is the reason this meeting was arranged in the first place.”

“I haven’t read your blog,” one of the administrators told him.

Mark intends to continue writing for madinamerica.com, and to continue with his plans to write a book, which will tell, among many things, of Amy Smith’s remarkable story of recovery, which involved withdrawing from psychiatric drugs she had been on for a long time. He is currently evaluating his options for starting his own clinic or joining another practice in his immediate area in Colorado. He and Amy also hope to open a facility where people who want to try to withdraw from their psychiatric medications, or at least decrease the number of meds they take, can get professional support for doing so.

Such is Mark’s story as of this date, March 24, 2011.  I, of course, feel some personal responsibility for this bad turn in his life and career. After he wrote me in the summer of 2010 about his reaction to Anatomy of an Epidemic, I invited him to blog for madinamerica.com.  His blog attracted a number of readers, and, I fear, he has now paid a high personal price for writing it.

Mar 25, 2011

The post After 25 Posts on this Website, Dr. Mark Foster is Terminated by his Employer appeared first on Mad In America.

However, the medical community and the public have long thought—or at least hoped— that psychiatric drug studies funded by the National Institute of Mental Health are not similarly tainted. Here, at least, the published reports would tell of studies that were not biased by design, with the results honestly reported.  At least that is the expectation. And this is why the NIMH’s STAR*D study is such a disappointment, and why it is so important that the full details of that scandal be made known.

As Maryland psychologist Ed Pigott explained last week, in his blog on this site, he is now asking that two journals, the Journal of Clinical Psychopharmacology and Psychological Medicine, retract two STAR*D articles they published.

By doing so, Pigott is continuing to put a spotlight on this scandal, which I believe needs to be thoroughly investigated by the NIH, or other governmental investigative body. We need to know all of the scientific sins that were committed, and we need an accounting of the investigators’ financial conflicts of interest. STAR*D was hailed as the largest trial of antidepressants ever conducted, at a cost of $35 million to the American taxpayers, and we deserve to know why the results weren’t honestly reported.

His request to the two journals that they retract the two articles raises a larger question: Should the medical literature be cleansed of all STAR*D reports?

As the British Medical Journal has noted, The Committee on Publication Ethics recommends retraction of an article if the journal has “clear evidence that the findings are unreliable.” This is necessary to “correct the literature and ensure its integrity.” So let’s apply that standard to the STAR*D literature.

The STAR*D investigators have now published more than 100 papers, and the bottom-line message, one touted to the medical community, is that if antidepressants are tried and tried again, most people will see their symptoms “vanish.” In this trial, 67% of the 4,041 patients were said to have seen their depression remit in this robust way. More than half of those who got well in this trial were then said to stay well during the year-long followup (or about 40% if you do the relevant math for the various groups of remitted groups.) Those are the published results. But as best as I can calculate, in truth, fewer than 40% the protocol-eligible patients ever remitted, even for a brief period, and it is now clear that only 3% of the 4,041 patients remitted and then stayed well and in the trial throughout the maintenance period.

When I give talks, I often hear psychiatrists and others respond by quoting the fake STAR*D results. That study is touted as evidence that antidepressants—if you just keep trying them—work for most people. They help people get well and stay well. In short, the falsely-reported results are driving prescribing practices and instilling a medical delusion about the effectiveness of these drugs.

So hear’s my question: Shouldn’t the NIMH, in an effort to clean up this scandal, ask for the retraction of all 100-plus STAR*D articles? If the purpose of retracting articles it to “correct the literature and ensure its integrity,” isn’t that is what is now needed?

Thursday, May 5, 2011

The post Should the Medical Literature Be Cleansed of All STAR*D Articles? appeared first on Mad In America.

Book:Robert Whitaker for “Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America.” This eye-opening investigation of the pharmaceutical industry and its relationship with the medical system lays out troubling evidence that the very medications prescribed for mental illness may, in increasing measure, be part of the  problem. Whitaker marshals evidence to suggest medications “increase the risk that a person will become disabled” permanently by disorders such as depression, bipolar illness and schizophrenia. This book provides an in-depth exploration of medical studies and science and intersperses compelling anecdotal examples. In the end, Whitaker punches holes in the conventional wisdom of treatment of mental illness with drugs.

Tuesday, April 26, 2011

The post Anatomy of an Epidemic wins investigative journalism award appeared first on Mad In America.

Here is why this makes me happy: The research fund will enable the Foundation to support studies and pilot projects of a type that aren’t being funded today (studies, for instance, that involve using psychiatric medications in a selective, limited way.) This, I believe, is the very endeavor that could lead to a new paradigm of care that truly promotes long-term recovery and wellness.

While I helped the Foundation get started, once it was up and running I resigned from the board (for reasons I will explain later in this blog.) Since then, I have been waiting for the right time to write about the Foundation, and yesterday’s news provides the perfect opportunity to do that.

The Roots of the Foundation

The Foundation came to be in a rather roundabout way. After Anatomy of an Epidemic was published in April of 2010, I began to hear from a number of mental health professionals who wanted to discuss its implications. Several psychiatrists in the Boston area contacted me, and they formed a group that began meeting on a semi-regular basis. I heard from Jack Rockefeller, who was then director of Windhorse, a provider of care in Western Massachusetts, and we discussed forming an “institute” that would fund research and “evidence-based” pilot projects that might involve using medications in a more selective way. Most important, leaders of several provider organizations and peer groups in Oregon began taking steps to publicize the issues raised in Anatomy of an Epidemic. The book looks at how psychiatric medications shape long-term outcomes, and the Oregon discussion soon focused on this question: Did our drug-based model of care need to be rethought?

I am not sure why this discussion took root in Oregon, but I think one factor was the influence of the “peer voice” in that state. MindFreedom, which is led by David Oaks, is headquartered in Eugene, and while MindFreedom may be seen by many providers in Oregon as a “radical” group, “radicalism” can be a potent force for changing the dialogue about a subject and opening minds to new possibilities. In Portland, Will Hall, who nearly a decade ago co-founded the Freedom Center in Northampton, MA, has set up a Hearing Voices group, and thus he is now bringing his considerable organizational talents to that community. Finally, there is a well-established peer organization in Portland, Empowerment Initiatives, that has been very ably led by Amy Zulich, Kristi Jamison and others, and this group also appears to be a potent voice for change.

Three providers of mental health services in Oregon took the lead in pushing forward this discussion. They were Bruce Abel, director of LaneCare, a state-funded organization that manages public mental health services in Lane County; Gina Nikkel, executive director of a state association of community mental health programs; and Bob Nikkel, who served as Oregon’s commissioner of mental health for a number of years. They — and the various peer groups — brought me to Oregon to speak on several occasions, and then, last fall, Bruce, Gina, and Bob began talking about organizing a “medication optimization” symposium. Their thinking was that psychiatrists and others would be invited to lead workshops that would focus on investigating the evidence base for psychiatric medications, both short-term and long-term, and that these workshop groups would then try to set forth “best-use” protocols. I knew others around the country who had expressed an interest in a symposium of this type, and soon, with Gina Nikkel taking the lead in organizing the symposium, the interested parties were all chatting via email about the proposed meeting (and sharing, I must add, their often wildly divergent opinions about the merits of psychiatric medications.)

Enter Virgil Stucker. Virgil has been a leader in running and developing “therapeutic communities” for more than thirty years, first at Gould Farm in western Massachusetts, and more recently at CooperRiis in North Carolina, which was founded eight years ago with the financial support and leadership of Don and Lisbeth Cooper. After reading Anatomy of an Epidemic, Virgil called to say that he was committed to “acting” on the issues raised in the book. He immediately became involved in the planning of the proposed symposium in Oregon, and as he threw himself into this effort, he got Don Cooper involved as well.

Now the challenge became how to fund the proposed symposium. Another reader of Anatomy of an Epidemic, Louisa Putnam, is a trustee for The Putnam Foundation, and that philanthropic organization stepped forward to provide the necessary grant. We then set up a non-profit to receive that funding, and we asked Virgil Stucker, who had experience running non-profits, to serve as chairman of the newly named Foundation For Excellence in Mental Health Care.

The Oregon Symposium

Because of financial constraints, the symposium had to limit the number of people who could attend. Fifty-four people from 13 states participated in the two-day event (February 11 and 12), including 22 psychiatrists. The other participants included administrators and directors of mental health programs (private and public), and leaders from peer groups.

The symposium featured four “workshops.” One was devoted to developing “medication optimization” guidelines for antipsychotics as a treatment for psychotic disorders; a second to developing such guidelines for antidepressants; the third for developing medication-tapering protocols; and the fourth for how such medication-optimization protocols could be introduced and covered by public and private insurance programs.

The psychiatrists who led the two medication-related workshops have yet to finish their research and write their conclusions. When they do so, their papers will be posted by the Foundation on its website (which has yet to be developed.) However, at the end of the conference, both workshop groups presented a “consensus statement” that reflected their investigations of the outcomes literature, and both statements, if incorporated into protocols, would provide a departure from current standards of care. This is particularly so in the case of the schizophrenia group.

That workshop was led by two Massachusetts psychiatrists, Chris Gordon and Mark Green. They and the others in the workshop concluded that there is a subset of first-episode psychotic patients who can recover without being put on antipsychotics, and thus, in certain instances, delayed administration of the drugs could prove useful (to that subset of patients.) In addition, the group concluded that there is a subset of schizophrenia patients (and patients with other psychotic diagnoses) that can do well off medications long-term. The group did not come up with any recommendations on how to incorporate such findings into drug protocols, but the consensus statement nevertheless established a rationale for funding pilot projects that would try to do just that.

The depression workshop was led by Jonathan Betlinski from Oregon Health Sciences University and other Oregon psychiatrists. After its review of the outcomes literature, the group concluded that the prescribing of antidepressants as a first response to “mild depression” was not recommended (but rather alternative treatments should be tried first), and that there was a lack of evidence showing that antidepressants provided a long-term benefit (beyond 12 months). That consensus statement, while not at all radical, nevertheless would provide support for a protocol that sought to taper people from antidepressants after an initial period of use.

The Future of the This Initiative

The Foundation held its first official board meeting at the close of that symposium, and at that first meeting, I resigned from the board. I did so for two reasons. The first was that my serving on the board presented an obvious journalistic conflict, and thus I knew that by resigning I could more easily continue to write about this topic. The second was that I knew my presence on the board could hamper the Foundation’s future success. My two books on this topic, Mad in America and Anatomy of an Epidemic, are often seen as “controversial” books, and thus I knew that my presence on the board would open the Foundation to criticism by those who may be quite content with the current medical model of care (and profit from it.)

Virgil and the rest of the board are still in the process of fleshing out the Foundation’s mission. Theirs is a discussion that I am certain will continue to evolve and deepen as new members are brought onto the board (and onto a scientific advisory council.) But — and I am speaking now as an outsider — I hope that the Foundation works toward three goals:

a) As I wrote in Anatomy of an Epidemic, I think that this corner of medicine suffers from a lack of honest storytelling. The public has been led to believe that psychiatric medications fix chemical imbalances in the brain and thus are like “insulin for diabetes,” even though research has repeatedly failed to show that this is so. In addition, the results from long-term outcome studies, which time and again have told of better outcomes for the unmedicated cohort, have been kept hidden from the public. Our society needs an honest broker of information about the nature of psychiatric disorders and the drugs used to treat those disorders, and my hope is that the Foundation can fill that role.

b) I hope that the Foundation will continue to sponsor symposiums, where psychiatrists and others will review the relevant literature, which includes studies that focus on long-term outcomes, and develop recommendations for “best use” of the drugs. In addition, the symposiums will need to explore psychosocial therapies that have been shown to help people recover and stay well.

c) I hope that the Foundation will fund research and pilot projects that will help turn such “best-use” recommendations into practice.

And Now for The News . . .

Don and Lisbeth Cooper founded CooperRiis Healing Community eight years ago (Riis is Lisbeth’s family name.) It offers its residents “holistic” treatment — diet, exercise, group therapy, music, and farm chores are all part of the “therapeutic” environment. The farm community is located in the foothills of the Blue Ridge Mountains south of Asheville, and there is a second campus near the University of North Carolina at Asheville. Don Cooper is a board member of the Foundation for Excellence in Mental Health Care, and yesterday, he and Lisbeth pledged $2 million to the Foundation.

“Lisbeth and I feel deeply about the mission of the Foundation to find excellence in mental health care and to facilitate change in the United States where needed,” he said. “We hope that this initiating gift will provide for strong staff leadership, important new research, and encourage other donors to join with us in funding this initiative.”

The Foundation is now planning a second symposium, which will be held in the fall and focus on the use of medications in pediatric populations. I asked Virgil for his thoughts about this gift, and I thought it would be best to simply print his answers in full.

Q. What will the donation be used for?

This wonderful resource will allow us to promote better mental health outcomes by engaging the research community to help us answer questions such as: What are the best approaches to helping people to recover from their mental health challenges while also helping them to decrease their long-term reliance on psychotropic medications?

As an educational foundation, we will use this donation to help us develop and share the emerging research-based knowledge. As ‘best approaches’ are identified, we will also use this resource to leverage the formation of new programs. Some of us with the Foundation are already involved in efforts to replicate recovery programs like the CooperRiis Healing Community. We are also deeply curious about the Open Dialogue approach from Finland. In general, we are focused on supporting the reality and dream of recovery, while appreciating broad approaches that embrace the complexity of humanity rather than reduce our despair to a chemical imbalance that is supposed to be resolved by a medication.

The Foundation is not ‘anti-medication’ but we are indeed aware that our overuse of medication in this country has not been successful in producing better, long-term mental health outcomes. As we form the ‘New Mainstream’ we seek to discover the optimal balance between medication use and the use of non-medication approaches, the combination of which will foster long-term, improved recovery outcomes.

In addition to supporting the development of a ‘New Mainstream’ this generous donation from Don and Lisbeth Cooper will help us to build a staff infrastructure for the Foundation. To date, all efforts of the Foundation have been through volunteers.

Q. What is the significance of this pledge to the Foundation?

The Foundation is new, having had its first full Board meeting on the 12th of February this year. Its first symposium “Medication Optimization in the Service of Recovery” was funded largely by the Putnam Foundation, which has also agreed to fund a fall symposium that will focus on optimizing (reducing) the use of psychotropic medications by children.

Now, with the magnanimous support of Don and Lisbeth Cooper we can capture the myriad opportunities that are arising and fully launch our efforts. There is much demoralization and despair in the mental health field today; this support from the Coopers will help us begin to restore optimism. You might say that the Coopers have provided a foundation for the Foundation.

Q. Can you speak more about the composition of your board, and your plans to create a scientific advisory council?

The Board of the Foundation consists of program providers, philanthropists, public policy leaders, a former state mental health commissioner, an international consumer advocate, and an attorney. Some nationally and internationally known psychiatrists and psychologists have also agreed to stand for election at the next Board meeting. In addition to the Board, we are beginning to assemble a Scientific Advisory Board that will help to guide the research projects that we will fund.

Q. What are the Foundation’s fundraising plans?

This donation from the Coopers has lifted us into a place of credibility and capacity. We have many opportunities that stand before us and a sense of optimism that the Foundation can seize them and help to swing the pendulum of mental health care toward improved long-term mental health outcomes and away from reductionism (the magic pill), chronicity/disability (warehousing), and imprisonment (too often the substitute mental health system).

The tasks before us are awesome and will require many millions of dollars to accomplish. We are actively looking for other philanthropic partners, like Don and Lisbeth Cooper, who are willing to donate significant resource to help us make a difference.

Mar 30, 2011

The post Rethinking Mental Health Care: The Story of the Oregon Symposium and the Foundation that Sponsored It appeared first on Mad In America.

“The medications currently used cannot modify an injurious process occurring in the brain, which is the underlying basis of symptoms,” Andreasen wrote in her 2003 paper.

However, even as she was publishing those findings, other research–in animals and schizophrenia patients–indicated that the drugs might exacerbate this brain shrinkage (or be the primary cause of it.) Then, in a 2008 interview with the New York Times, Andreasen confessed that the “more drugs you have been given, the more brain tissue you lose.”

This was something of a bombshell, particularly since it came from Andreasen, who was editor-in-chief of the American Journal of Psychiatry from 1993 to 2005. Now, in the February issue of the Archives of General Psychiatry, she has published those findings, and thus the bombshell has officially landed in the scientific literature.

In this study, Andreasen took periodic MRI scans of 211 schizophrenia patients treated from seven years to 14 years. She found that long-term use of the old standard antipsychotics, the new atypical antipsycotics, and clozapine are all “associated with smaller brain tissue volumes.”

Moreover, she found that this shrinkage was dose related. The more drug a person is given, the greater the “association with “smaller grey matter volumes,” she reported. Similarly, the “progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment.” Finally, Andreasen reported that this shrinkage “occurs independent of illness severity and substance abuse.” Those two factors–illness severity and substance abuse–had “minimal or no effects” on brain volumes.

In this February report, Andreasen does not tie the drug-related brain shrinkage to an increase in negative symptoms, functional impairment, and cognitive decline. But in earlier articles, she did just that. And it is that larger context that makes this February report such a bombshell: When pieced together, this is a story of drug treatment that, over the long-term, causes long-term harm.

The other reason this is such a bombshell is that antipsychotics are widely prescribed now to children, often to control their “behavior,” and to adults with bipolar diagnoses. They are being used to treat “non-psychotic” conditions. The risk-benefit analysis for those patients will be dramatically changed by the findings of this study.

One hopes that the study will be widely publicized in the media, and it will stir a vigorous discussion. Here are a few of the questions that I believe need to be asked:

    •    Does long-term use of antipsychotics for people diagnosed with psychotic disorders need to be rethought?

    •    Is there reason to prescribe these drugs to people with non-psychotic disorders?

    •    Should the prescribing of these drugs to children and youth, whose brains are still developing, be halted (or, in essence, banned?)

    •    Many adults diagnosed with psychiatric disorders are mandated by court orders to take antipsychotics. Should society have the right to require such treatment, given that the drugs shrink brain volumes and this shrinkage is associated with cognitive decline?

For some time, here has been reason to believe that antipsychotics shrink the brain, and I wrote about this in Anatomy of an Epidemic. But this worry has largely been kept out of the public domain. Perhaps now it will become a public concern, and in particular, one hopes that our society now takes a hard look at whether prescribing such drugs to children is a good thing to do.

Monday, February 14, 2011

The post Andreasen Drops a Bombshell: Antipsychotics Shrink the Brain appeared first on Mad In America.

But two notes, both very revealing from that radio show.

At some point in the discussion, the host Meghna Chakrabarti begins to read a statement made by one of the lead investigators of the NIMH’s long-term study of treatment for ADHD, known as the Multisite Multimodal Treatment study. Here is the full  statement from William Pelham, which the host began to read:

“We had thought that children medicated longer would have better outcomes. That didn’t happen to be the case. There were no beneficial effects, none. In the short term, [medications] will help the child behave better, in the long run it won’t. And that information should be made very clear to parents.”

Now readers need to know the backdrop to this trial to understand the importance of this finding. The prescribing of stimulants to children began in the 1970s, and then really took off in the 1980s. Numerous studies found that over the short-term, medications diminished “motoric overactivity, impulsivity and inattentiveness” in classroom settings. Thus they were seen as effective for treating ADHD. But by the early 1990s, there was no evidence that the drugs were benefitting the children long-term. As the 1994 edition of the American Psychiatric Association’s Textbook of Psychiatry admitted, “Stimulants do not produce lasting improvements in aggressivity, conduct disorder, criminality, education achievement, job functioning, marital relationships, or long-term adjustment.”

The NIMH launched its MTA trial, which it touted as the “first major clinical trial” the institute had ever conducted of a “childhood mental disorder,” in order to more properly assess whether there was a long-term benefit. And what it found was that by the end of three years, “medication use was a significant marker not of beneficial outcome, but of deterioration.”   By the end of six years, the findings remained the same. Medication use was associated with worse hyperactivity-impulsivity and oppositional defiant disorder symptoms,” and, if you look closely at the data, with greater “overall functional impairment.” Hence, Pelham’s conclusion that they found that medications provided no long-term benefit, none.

So, as the host begins to bring this up, Dr. Nierenberg breaks in and says, “that’s not true.” He says there are many studies that show the drug-treated patients do better, and that untreated ADHD children grow up into adults who have a lot of car accidents, get in trouble with the law, etc. And thus WBUR listeners were led to believe that research showed that studies had, in fact, found that medications helped prevent that adulthood disaster that awaited ADHD children. The long-trerm studies showed that the drugs provided no benefit; Dr. Nierenberg told a story of how they were necessary and helpful long-term.

The conversation then bounced to some other topic, and when it came my turn to speak again, I should have returned to that ADHD story. I failed to do so–the conversation was already on some other point. But my point here is that in this radio interview, you can clearly see the misleading of the public about the scientific literature,  and the hiding of the poor results from long-term studies, which is one of my themes in Anatomy of an Epidemic.

Now to the second point.

If you go to the WBUR website where the radio interview is archived, you’ll see an intro that describes me as a “local journalist and author.” Fair enough. But then it says “my claims are refuted by reputable members of the psychiatric community here in Boston.” Notice that adjective, “reputable.” And notice too how Dr. Nierenberg becomes part of a larger cohort of probessionals? (Note: I sent an email to WBUR about that this morning, and it might end up changed by the time you check it out.)

During the interview, I  avoided mentioning anything about Dr. Nierenberg’s deep ties to pharma, even as he complained about my “gratuitous” reporting in Anatomy of an Epidemic about that relationship. I refrained because I think the important thing in such forums is to focus on the scientific literature. But Vince Boehm did a little work and sent out a notice this morning that specifically listed Dr. Nierenberg’s ties to pharma. Here is what he found:

Andrew A. Nierenberg, MD receives or received Grants/research support: from Bristol-Myers Squibb Company; Cederroth AB; Cyberonics, Inc; Eli Lilly and Company; Forest Laboratories, Inc; GlaxoSmithKline; Janssen Pharmaceutica; Lichtwer Pharma; NARSAD; NIMH; Pfizer Inc; Shire; The Stanley Foundation; Wyeth-Ayerst Laboratories.  Retained consultant: Abbott Laboratories; AstraZeneca; Basilea Pharmaceutica, Ltd; BrainCells Inc; Bristol-Myers Squibb Company; Eli Lilly and Company; EPI-Q, Inc; Genaissance Pharmaceuticals, Inc; GlaxoSmithKline; Innapharma Inc; Janssen Pharmaceutica; Jazz Pharmaceuticals; Merck & Co, Inc; Novartis; Pfizer Inc; PGxHealth; Schering-Plough; Sepracor Inc; Shire; Somerset Pharmaceuticals, Inc; Takeda Pharmaceuticals North America, Inc; Targacept, Inc. Honoraria: Bristol-Myers Squibb Company; Cyberonics, Inc; Eli Lilly and Company; Forest Laboratories, Inc; GlaxoSmithKline; MGH Psychiatry Academy; Physicians Postgraduate Press, Inc; Shire; Wyeth-Ayerst Laboratories Stock shareholder: Appliance Computing II, Inc (Mindsite); BrainCells Inc 

I was frustrated by that interview, and later unhappy with myself for allowing the conversation to proceed onto new topics without correcting what had been said (such as explaining the context of the ADHD studies.) But if you want to understand why our society believes what it does, the interview does provide its revealing moments.

The comments from listeners to the show and readers of the article are many, but my favorite is the one that compares me to a “Holocaust denier.” I have had my share of barbs come my way, but this one may top the list.

Jan 21, 2011

The post Speaking at MGH Grand Rounds, and More appeared first on Mad In America.

To do their study, Moore and his collaborators extracted all serious events reports from the FDA’s database from 2004 through September 2009, and then identified 484 drugs that had triggered at least 200 case reports of serious adverse events (of any type) during that 69-month period. They then investigated to see if any of these 484 drugs had a “disproportionate” association with violence. They identified 31 such drugs, out of the 484, that met this criteria.

The 31 “suspect” drugs accounted for 1527 of the 1937 case reports of violence toward others in the FDA database for that 69-month period. The drugs in that list of 31 included varenicline (an aid to smoking cessation), 11 antidepressants, 6 hypnotic/sedatives, and 3 drugs for attention deficit hyperactivity disorder. Antidepressants were responsible for 572 case reports of violence toward others; the three ADHD drugs for 108; and the hypnotic/sedatives for 97.

Of the 1937 total case reports of violence toward others, there were 387 cases of homicide, 404 physical assaults, 27 cases of physical abuse, 896 reports of homicidal ideation, and 223 cases of “violence related symptoms.”

The adverse events reported to the FDA are known to represent but a tiny fraction of all such adverse events. This study simply identified 31 drugs responsible for most of the FDA case reports of violence toward others, with antidepressants near the top of that list.

In light of this finding, the many past shootings at school campuses and other public venues should perhaps be investigated anew by government officials, with an eye toward ascertaining whether psychotropic use may have, in the manner of an adverse event, triggered that violence.

Moore and his collaborators concluded: “These data provide new evidence that acts of violence towards others are a genuine and serious adverse drug event that is associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and serotonin reuptake inhibitors were the most strongly and consistently implicated drugs.”

Jan 5, 2011

The post Psychiatric Drugs and Violence: A Review of FDA Data Finds A Link appeared first on Mad In America.

1) Antidepressants are depressogenic over the long term

In a 2008 study by Dutch investigators, “Continuation and Maintenance Use of Antidepressants in Recurrent Depression,” 172 adults who had recovered from a bout of “recurrent depression,” were then followed for two years. The relapse rates for patients during that followup period, according to antidepressant use, was as follows:

    Continual antidepressant use: 60.4%.

    Intermittent antidepressant use: 63.4%.

    No antidepressant use: 26%.

As in the many longer-term studies I cited in Anatomy of an Epidemic, those who stayed on antidepressants in this study were much more likely to become depressed again.

2) Antipsychotics increase a person’s biological vulnerability to psychosis

During the 1970s, researchers learned that antipsychotics blocked a particular subtype of dopamine receptor, known as the D2 receptor. In response to that blockade, the brain increases the density of its D2 receptors. This, reasoned two Canadian physicians, Guy Chouinard and Barry Jones, makes a person “supersensitive” to dopamine, and thus more biologically vulnerable to psychosis.

Chouinard and Jones reasoned that this was why so many schizophrenia patients relapsed when they tried to go off an antipsychotic, and also why schizophrenia patients who stayed on the medications long-term nevertheless worsened. Many patients develop “tardive psychosis” over the long-term, and when this happens, Chouinard and Jones reported, the “illness appears worse” than ever before.

When Chouinard and Jones raised this hypothesis in the late 1970s and early 1980s, it caused a brief fury, and then was largely forgotten. This hypothesis, which in fact was supported by clinical findings, suggested that antipsychotics worsened psychotic symptoms over the long term, and that understanding clearly imperiled the story that psychiatric had told to the public, which was that people diagnosed with schizophrenia needed to be on antipsychotics all their lives.

However, in 2005, Philip Seeman at the University of Toronto revived it with a report that in animal models of psychosis, all of the various psychotic triggers—such as amphetamines, angel dust, genetic mutations, or brain lesions—caused an increase in D2 receptors that have a “HIGH affinity” for dopamine, and that so did antipsychotics, including the newer atypicals like Zyprexa. In other words, antipsychotics caused the very biological abnormality identified as the “common pathway” in animal models of psychosis.

Then, in 2007—and this is the study I recently came across—Seeman and his colleagues reported that this dopamine supersensitivity was why “ongoing antipsychotic treatment leads to treatment failure over time.”

Here’s how they determined this. When rats are given amphetamines, which up dopamine levels in the brain, they show increased locomotion. An antipsychotic—at first—blocks  this amphetamine-induced locomotion in rats, and that is because the drug blocks dopamine receptors (and thus counter the effects of an amphetamine.) But over time, the antipsychotic induced a notable increase in D2 receptors in the rat brain, and more than a doubling of D2 receptors with a high affinity for dopamine, Seeman reported. The rats had become “supersensitive” to dopamine, and after this happened,  when they were given amphetamines, the antipsychotic no longer blocked the amphetamine-induced locomotion.

This, Seeman reported, explained why “antipsychotics so often fail” over time . . . our results suggest that an antipsychotic-induced increase in dopamine sensitivity might predispose certain individuals to psychotic relapse.”

In other words, their study animal confirmed the  “dopamine supersensitivity” hypothesis advanced by Chouinard and Jones 30 years. Antipsychotics increase a person’s biological vulnerability to psychosis over time, and this leads many to become chronically ill.

3) Acknowledgement that chemical imbalances do not underlie mental disorders

As I wrote in Anatomy of an Epidemic, the chemical imbalance theory of mental disorders arose in the 1960s and 1970s, but researchers subsequently failed to find that people diagnosed with depression actually had low levels of serotonin, or that people diagnosed with schizophrenia had overactive dopamine systems. Still, the psychiatric profession, pharmaceutical companies, and NAMI continued to promote the chemical imbalance story, such that a study published in 2010 found that 87% of Americans thought that schizophrenia was due to a “chemical imbalance,” and 80% thought that depression was due to one as well.

In an article published in November in the American Journal of Psychiatry, Eric Nestler and Vaishnav reviewed the chemical imbalance theory of depression. They wrote:

“After more than a decade of PET studies (positioned aptly to quantitatively measure receptor and transporter numbers and occupancy), monamine depletion studies (which transiently and experimentally reduce brain monamine levels), and genetic association analyses examining polymorphisms in monoaminergic genes, there is little evidence to implicate true deficits in serotonergic, noradrenergic, or dopaminergic neurotransmission in the pathophysiology of depression.”

In a similar vein, Nestler and Stephen Hyman, who is a former director of the National Institute of Mental Health, in their 2009 text Molecular Neuropharmacology, reviewed the chemical imbalance theory of schizophrenia. They wrote:

“It must be emphasized that neurotransmitter related-hypotheses that attempt to explain the etiology of schizophrenia are based solely on pharmacological evidence, and thus are likely to be incomplete or misleading. Although pharmacologic manipulations of neurotransmitter systems may exacerbate or ameliorate psychotic symptoms, aberrations in these systems do not necessarily underlie psychotic disorders.”

Once again, we see in these quotes admissions by leaders in the field that there is no actual evidence that people diagnosed with mental disorders actually suffer from chemical imbalances. And yet the vast majority of Americans believe that they do.

4) The Epidemic in Children Grows

The widespread prescribing of psychiatric medications to American children and youth began in the early 1990s. In Anatomy of An Epidemic, I reported on how the use of stimulants and antidepressants has “created” many juvenile bipolar patients. Now comes more evidence of this epidemic.

In a poster presentation at the 2010 annual meeting of the American Academy of Child and Adolescent Psychiary, Joseph Blader reported that psychiatric hospitalizations for children five to 13 years old nearly doubled from 1996 to 2007. Psychiatric hospitalizations for adolescents, 14 to 19 years old, rose 42% during this period.

The prescribing of psychiatric medications to children and adolescents jumps, and sure enough, the number of psychiatric hospitalizations for American youth soars.

Dec 5, 2010

The post Updates on the Epidemic appeared first on Mad In America.

SSRIs and Fetal Brain Development

Researchers from the University of Washington studied the effects of an antidepressant, citalopram (Celexa,) on the development of the fetal mouse brain. During embryonic development, many brain regions experiences waves of spontaneous depolarizations called “spontaneous synchronous activity” (SSA). This activity plays an important role in the formation of neuronal circuits. The researchers found that fetal exposure to citalopram altered this SSA activity in the hindbrain, which is where serotonergic raphe neurons originate.

The University of Washington scientists concluded that “this aberrant and persistent pattern of SSA in the citalopram-treated embryonic hindbrain suggests a potentially adverse effect of acute SSRI exposure on fetal hindbrain development, and specifically on the serotonin neuron circuitry itself.”

SSRIs and Breast Feeding

In this study, by researchers at St. Mary’s College of Maryland, male rat pups were exposed to fluoxetine through dam’s milk (i.e. lactation), for 13 days, starting when they were eight days old. The baby rats were then allowed to “mature undisturbed until adulthood.”

As adults, the researchers reported, the rats were much clumsier than normal. “These results,” the researchers concluded, “indicate that postnatal exposure to fluoxetine may have long-term emotional and motor side effects.”

Antipsychotics and Long-Term Behavioral Dysfunction

In two related studies, investigators at the University of Maryland and the University of Lethbridge in Canada focused on the long-term effects of early exposure to olanzapine (Zyprexa.)

In the first study, rats were exposed to olanzapine for three weeks, starting when they were 28 days old. As adults, these rats had “significant deficits of working memory.” They were also “more reactive to handling and had an enhanced response to social novelty.” The Maryland and Lethbridge researchers concluded that “these data suggest that adolescent exposure to olanzapine induces a pattern of long-term behavioral deficits consistent with alterations in dopaminergic function.”

In the second study, the researchers looked at the long-term change in dopamine function in the olanzapine-exposed rats. Four to six months after that early-childhood exposure, the binding activities of dopamine receptors in their “adult” brains were significantly different than normal.

Hundreds of thousands of children in the United States are being medicated today with Zyprexa and other atypical antipsychotics; this study raises the worry that, even if this exposure is for a short period, it might produce permanent deficits.

“Early-life antipsychotic drug exposure can potentially cause long-lasting, functionally significant changes in neural circuitry,” the researchers wrote. “Animal experiments increasingly indicate that exposure to drugs that modulate monaminergic neurotransmission at stages corresponding to human fetal life or early childhood produces long-term behavioral dysfunction.”

Our National Experiment

The widespread medicating of children in the United States is often described by scientists as a grand “experiment,” since the long-term effects of the drugs on normal brain development have not been well studied. Unfortunately, these animal studies suggest that this experiment is not going to turn out well.

December 4, 2010

The post Do Psychiatric Drugs Impair Normal Brain Development? appeared first on Mad In America.

According to the documents posted by POGO, in early October 1993, STI laid out a ghostwriting plan to help SmithKline Beecham market its new antidepressant, Paxil. This would begin, STI proposed, with a meeting of SmithKline’s “Psychiatrist Advisory Board” on November 5-7 in Palm Beach, Florida. STI had recruited ten well-known psychiatrists for the board, which was to be chaired by Nemeroff, and STI promised to recruit ten more. All of the psychiatrists on the advisory board were to be flown first class to Florida, and paid between $2,500 and $5,000 for the weekend event.

At the opening session, STI promised, Nemeroff would discuss how to “generate information for use in promotion/education” of Paxil.

Over the next ten years, SmithKline Beecham (now GlaxoSmithKline) paid STI to ghostwrite editorials, journal articles and at least one medical textbook (the 1999 text “authored” by Nemeroff and Schatzberg.) The draft of that textbook was written by two STI writers, Sally Laden and Diane Coniglio, with SmithKline Beecham signing off on the final text. Together, Schatzberg and Nemeroff have received $23.3 million in NIH funding since FY 2006.

In a November 29 letter sent to Francis Collins, director of the National Institutes of Health, POGO also detailed the following instances of ghostwriting by STI for GlaxoSmithKline.

• In 2001, STI’s Sally Laden helped write a scientific article on “study 329,” which was published in the Journal of the Academy of Child & Adolescent Psychiatry. In that paper, lead author Martin Keller of Brown University Medical School and 21 other prominent child psychiatrists reported that the study provided “evidence of the efficacy and safety of the SSRI, paroxetine, in the treatment of adolescent major depression.” They drew this conclusion even though internal GlaxoSmithKline documents confessed that “the study did not really show [Paxil] was effective in treating adolescent depression, which is not something we want to publicize.” The ghostwriters had turned a failed study into a positive one, and the academic psychiatrists signed off on that scientific fraud. Dr. Keller has received $7 million in NIH funding since FY 2006.

• In 2002, STI’s Sally Laden and another STI employee ghostwrote a study for Kimberly Yonkers, from Yale School of Medicine. When STI sent the draft to Yonkers for her review, it reminded her to remove evidence of STI’s involvement in writing the paper before submitting it to a journal, Psychopharmacology Bulletin. Dr. Yonkers has received $6.4 million in NIH funding since FY 2006.

• In 2003, STI’s Sally Laden ghostwrote an editorial, which was published in Biological Psychiatry, for Dwight Evans, chairman of the psychiatry department at the University of Pennsylvania School of Medicine, and for Dennis Charney, who at that time was an NIH employee and today is dean of research at the Mt. Sinai School of Medicine at New York University. Evans and Charney have received $30.6 million in NIH funding since FY 2006.

The POGO documents reveal aspects of the extensive ghostwriting enterprise that supported the marketing of Paxil. The full tale of ghostwriting involved in the promotion of Paxil undoubtedly has many more chapters, which perhaps will be revealed in the future. But the point that POGO made in its letter to Francis Collins is this:  Prominent academic psychiatrists signed their names to those ghostwritten papers, and yet today they continue to receive generous NIH grants.

One “would think NIH policies would prevent such practices,” wrote POGO authors Danielle Brian and Paul Thacker. “You must set policies that require NIH-funded academic centers to ban ghostwriting to strengthen scientific integrity.”

That seems like a reasonable solution to me. If academic scientists sign their names to ghostwritten articles, with that ghostwriting paid for by a pharmaceutical firm, then they shouldn’t be allowed to subsequently obtain NIH research funds. That rule, I believe, would shut down the commercial ghostwriting enterprise quickly, much to the long-term benefit of American science.

Wednesday, December 1, 2010

The post The GlaxoSmithKline Ghostwriting Documents, Part Two appeared first on Mad In America.

But, in fact, this ghostwriting revelation simply hints at a much larger, very pervasive problem, which is that financial lbias profoundly affects the authorship of psychiatric textbooks at every turn. And it is quite easy to document that this is so.

In its article, the New York Times reported that SmithKline Beecham (now part of GlaxoSmithKline) had provided Nemeroff, who today is chairman of psychiatry at the University of Miami medical school, and Schatzberg, who was chairman of psychiatry at Stanford University from 1991 to 2009, with an “unrestricted educational grant” to author “Recognition and Treatment of Psychiatric Disorders: A Psychopharmacology Handbook for Primary Care.” But SmithKline Beecham also paid a writing company, Scientific Therapeutics  Information, to develop an outline for the book and—apparently—to actually write the text. Once the ghostwritten book was published, SmithKline Beecham purchased 10,000 copies for distribution to American family physicians.

This is indeed egregious. But the larger problem is this: Commercial interests influence the writing of most psychiatric texts.

First, psychiatric textbooks are regularly authored by leading psychiatrists at academic medical centers, many of whom are paid by pharmaceutical companies for their work as “advisors, consultants, and speakers.” Thus, while writing a particular textbook they may not be receiving any money from a pharmaceutical company, they still have an ongoing financial relationship with the makers of psychiatric medications. As such, they have a financial reason for writing about psychiatric medications in a way that promotes their use.

Second, psychiatry as a field naturally has reason to promote the safety and efficacy of psychiatric medications. After all, this is the field’s main product today. Psychiatrists have turned into psychopharmacologists, and you can’t expect the leaders in the field to author texts that might question the fundamental merits of that product.

In my book Anatomy of an Epidemic, I investigated this storytelling process. In the first sections of the book, I reported on a number of studies funded by the National Institute of Mental Health, the World Health Organization, and other governmental agencies that told of unmedicated psychiatric patients doing better over the long-term than those who stayed on the drugs. In the latter part of the book, I investigated whether these studies were ever written about in psychiatric texts. Here’s what I found: None of the studies was discussed at any length, and in the few instances when one of the studies was mentioned in a textbook, the authors spun the results to protect the image of the drugs.

For instance, Martin Harrow, a researcher from the University of Illinois College of Medicine, reported in 2007 on the 15-year outcomes of a group of schizophrenia patients he had been following since the early 1980s. Forty percent of the patients off antipsychotic medications were in recovery at the end of 15 years, versus five percent of those on medication. He also reported on the 15-year outcomes of patients with milder psychotic disorders, and once again it was those off antipsychotics that were doing much better.

Now, this is the best longitudinal study of modern schizophrenia outcomes that we have today. This was an important NIMH-funded study. So how did the authors of the 2009 edition of the American Psychiatric Association’s Textbook of Psychiatry deal with it? They mentioned the study in passing, but they didn’t detail the actual results. They didn’t report that the recovery rate for unmedicated patients was eight times higher than for the medicated patients; instead the authors simply wrote that Harrow’s study reveals that there are some schizophrenia patients who are “able to function without the benefit of continuous antipsychotic treatment.”

This was spinning at its best. The authors came up with a sentence that told of the “benefit of continuous antipsychotic treatment.”

Now, let’s put this larger storytelling process together. As is well known now, the published scientific literature on the clinical testing of psychiatric medications during the past 20 years does not accurately portray the efficacy and safety of those drugs. Trials were biased by design, results were spun, articles were ghostwritten, and negative results went unpublished. As such, the source literature is corrupted, and that tainted literature then serves as the source material for authors who write psychiatric texts. Then those authors—when confronted with an upsetting study like Harrow’s—add their own layer of spin.

The New York Times article tells of a ghostwritten book, and observers—like former FDA commissioner David Kessler—express their shock. But it’s really not so out-of-step with larger storytelling forces that have been at work in psychiatry for some time.

Tuesday, November 30, 2010

The post A Ghostwritten Psychiatric Textbook Hints at a Much Larger Problem appeared first on Mad In America.

Volunteers for Psychotherapy, which is led by pschologist Richard Shulman, offers therapy to clients who “pay” by doing volunteer work at a non-profit charity of their choice. The clients do two hours of volunteer work for every hour of therapy, and of course that volunteer work provides its own powerful therapeutic benefit. People get to serve others, and this is almost always a rewarding experience.

To support Volunteers in Psychotherapy, you can vote here.

Friday, November 26, 2010

The post Volunteers for Psychotherapy Is A Finalist for International Award appeared first on Mad In America.

As this storytelling has occurred, the psychiatric establishment has run anti-stigma campaigns, arguing that if the public understood that mental disorders were brain diseases, then societal “stigma” toward the “mentally ill” would lessen.

A study published in the November issue of the American Journal of Psychiatry, which was led by Bernice Pescosolido at Indiana University, provides an interesting look at how this storytelling effort has worked out.

As I wrote in Anatomy of an Epidemic (and as others have written, too), the chemical imbalance hypothesis of mental disorders, which arose in the 1960s, basically fell apart in the 1970s and early 1980s. Researchers studying whether people with schizophrenia had overactive “dopamine” systems failed to find that this was so. Similarly, researchers failed to find that people with depression had low levels of serotonin in the brain. These chemical-imbalance investigations continued to sputter along throughout the 1980s and the 1990s, but the bottom-line never changed. As Kenneth Kendler, coeditor in chief of Psychological Medicine, explained in 2005: “We have hunted for big simple neurochemical explanations for psychiatric disorders and have not found them.”

However, that scientific finding — that the chemical-imbalance hypothesis of mental disorders failed to pan out — was never told to the public. Instead, Prozac came to market in 1988 and the public heard all about “chemical imbalances,” and as the study in the November issue of the American Journal of Psychiatry reveals, this PR campaign by the psychiatric establishment was quite successful. In 2006, 87% of the adults surveyed believed that schizophrenia was due to a chemical imbalance, up from 78% in 1996. Eighty percent of those surveyed said that depression was due to a chemical imbalance, up from 67% in 1996.

This is data that tells of an extremely successful propaganda effort. The overwhelming majority of Americans have been led to adopt a false belief.

But — and this shouldn’t be a surprise — the dissemination of this false belief has not led to a lessening of societal stigma toward people with psychiatric diagnoses. If anything, it has increased it. In their survey, Pescosolido and the other researchers asked a number of questions to flesh out attitudes toward the mentally ill, and in 2006, there was “no significant decrease in any indicator of stigma” compared to 1996. Moreover, “significantly more respondents in the 2006 survey than in the 1996 survey reported an unwillingness to have someone with schizophrenia as a neighbor.”

Equally revealing was this: In both the 1996 and 2006 surveys, those who believed in a “neurobiological conception of mental illness” — i.e., the chemical imbalance story — were more likely to have a negative attitude toward those with mental disorders than those who did not.

While this finding confounded the researchers’ expectations, it is easy to see why the chemical-imbalance story leads to negative attitudes about people struggling with mental illness. It tells the public that people with a psychiatric diagnosis have “broken brains,” and that their moods and behaviors are governed by faulty brain chemistry. This is an understanding that separates the “mentally ill” from the rest of society. The “mentally ill” are different from “us.”

Now imagine what societal attitudes might be if the public were told that the biological causes of major psychiatric disorders remain “unknown” (which would be a scientifically accurate message.) That conception of mental illness suggests that it may be possible for anyone — faced with certain environmental stresses or setbacks in life — to suffer a severe bout of psychiatric distress. Readers of Shakespeare might sum it up this way: To be human is to have the capacity to go “mad.” That is an understanding of “mental illness” that evokes a sense of our common humanity, and a sense of a shared vulnerability to mental suffering.

The lesson to be drawn from this study seems to be this: If the psychiatric establishment wants to reduce stigma towards the mentally ill, all they need to do is run a pr campaign that — and how else to put this — tells the truth.

Thursday, November 4, 2010

The post The Successful Creation of a Societal Delusion . . . and the Increase in Stigma It Has Spawned appeared first on Mad In America.

Today, an email correspondent sent me a study, which was led by Scott Woods at Yale University School of Medicine and published in the April 2010 issue of the Journal of Clinical Psychiatry, that assesses TD rates in the 1980s among patients at the Connecticut Mental health Center with rates among patients there in the early 2000s. Their findings lend credibility to my friend’s eyewitness accounts.

In their TD study in the 1980s, the Yale researchers followed 362 patients who, at the start of the study, did not show signs of TD. Over the course of the next 3.1 years, this group developed persistent TD at the rate of 5.6% per year.  In their study conducted in the early 200s, the researchers followed 352 patients for 2.2 years. Fifty-two patients developed persistent tardive dyskinesia during that time, a rate of 6.6% per year. The severity of the cases was the same in both periods.

The researchers also looked at the overall prevalence of TD in patient cohorts  from the 1980s and from the early 2000s, and found that it was the same: 33% in the 1980s and 32% in the early 2000s. They concluded: “Overall TD prevalence, incidence and incident case severity in the current cohort differed little from estimates obtained from a similar cohort studied at our site with similar methods before the introduction of atypical antipsychotics.”

Finally, the Yale investigators looked at whether patients in the 2000s study developed TD at different rates according to whether they took conventional neuroleptics, atypicals, or a combination of both. The patients on conventional neuroleptics developed TD at an annual rate of 5.6%; the patients on atypicals developed TD at an annual rate of 5.9%; and those on a combination of old and new antipsychotics at an annual rate of 9.6%.

After making some statistical adjustments for prior years of exposure to drugs, the researchers concluded that “subjects treated with atypical antipsychotics alone developed TD at approximately two-thirds the rate as subjects treated with conventionals alone.” Patients treated with a combination of both developed TD at nearly double the rate for conventional neuroleptics alone.

Their findings are at odds with a number of previous studies that had found a reduced risk of TD with atypicals. But as the Yale investigators observed, the previous studies did not have TD as their primary focus, whereas theirs did, and in their study, those examining the patients had been schooled in recognizing TD.

“Despite the feeling among some clinicians that TD is much less of a problem now in the atypical era, such a conclusion may unfortunately be premature,” Woods and his collaborators wrote. “In the 1960s and 1970s, there was some well-intentioned resistance and skepticism about conventional antipsychotics being associated with risk of TD, and now, during the atypical era, we are perhaps not immune to some of the same forces. Until we are certain that we have developed antipsychotics that carry minimal risk, we should continue to inform patients prescribed antipsychotics about TD and continue monitoring for it.”

TD, of course, is evidence that the drugs have damaged the basal ganglia, and often permanently so, as the movement disorder may not go away upon drug withdrawal. TD is also associated with a global decline, as other areas of the brain that rely on dopaminergic neurons–the limbic system and the frontal lobes–may also become permanently compromised as well.

Tuesday, November 2, 2010

The post Tardive Dyskinesia in the Atypicals Era: Is The Risk Any Less Today Than Before? appeared first on Mad In America.

In the study, the researchers administered citalopram to the rats for two weeks (there was a control group as well), and then the drug-treated rats were either abruptly withdrawn from the drug or continued on it for another three days. The rats were then sacrificed and their brain tissue analyzed. The investigators likened this dosing regimen to a “long-term treatment paradigm.”

In the drug-maintained rats, serotonin content at the end of 17 days was “reduced by 60% on average in nine areas of the brain,” compared to controls. This depletion appears to be part of a compensatory response to the drug. Since an SSRI blocks the normal reuptake of serotonin from the synaptic cleft, the neurotransmitter stays in this extracellular space longer than normal, and in response, the brain’s synthesis of serotonin dramatically decreases. As a result, serotonin levels in brain tissues end up markedly depleted.

At the same time, the withdrawal of citalopram triggered volatile fluctuations in the rats’ serotonergic systems. Brain synthesis of the neurotransmitter rose, slightly beyond normal levels, but with the drug no longer blocking the reuptake of serotonin from the synaptic cleft, “extracellular” levels of serotonin likely dropped during this withdrawal period. There also was a dramatic jump in “serotonin turnover” during  withdrawal, which meant that enzymes were rapidly converting serotonin released into the synaptic cleft into a metabolite, which was then carted off as waste. This would have depleted serotonin from the synaptic cleft as well.

During this withdrawal period, when the serotonergic system was undergoing these dramatic fluctuations,  the rats exhibited “increased behavioral reactivity” to a startling sound. The researchers noted that when people withdraw from SSRIs, they may experience a “discontinuation syndrome” marked by “aggression, irritability, agitation, anxiety, and low mood.”

While notable, these results are not particularly surprising. The finding that serotonin in the brain becomes markedly depleted in response to “long-term” treatment with an SSRI is consistent with earlier studies. And the problems associated with SSRI-withdrawal are fairly well known. However, this study is yet more evidence that SSRIs do not “normalize” brain chemistry, which explains why they may be so problematic long-term and why, at the same time, withdrawing from them can be so difficult.

“The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment,” the investigators concluded. “These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes” when the drug is abruptly withdrawn.

November 1, 2010

The post New Rat Study: SSRIs Markedly Deplete Brain Serotonin appeared first on Mad In America.

Here is a sampling of what he found in the research literature:

• After six months of antidepressant treatment, the drugs “generally fail to protect” against a return of depressive symptoms. (In other words, maintenance treatment is ineffective, compared to placebo.)

• Two-thirds of patients maintained on antidepressants suffer from “residual symptoms,” with “anxiety, insomnia, fatigue, cognitive impairment, and irritability the most commonly reported.”

• As patients are switched from one antidepressant to another or to a polypharmacy regimen, their illness may be propelled “into a refractory phase, characterized by low remission, high relapse and high intolerance.”

• Antidepressants increase the risk of a “switch” into mania, and thus into bipolar illness. Antidepressants also increase the risk that bipolar patients will become rapid cyclers, and that bipolar patients will develop a syndrome dubbed “Chronic Irritable Dysphoria.”

As I wrote in a previous post, our society desperately needs to have an informed discussion on this issue: Do psychiatric medications worsen the long-term course of psychiatric disorders (in the aggregate)? Fava has focused his attention on the “affective disorders,” and in this article on antidepressants, he concludes:

“When we prolong treatment over 6-9 months, we may recruit processes that oppose the initial acute affects of antidepressant drugs (lack of clinical effects.) We may also propel the illness to a malignant and treatment-unresponsive course that may take the form of resistance or episode acceleration. When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are not necessarily reversible.”

Fava has been banging this drum for 16 years now. One wishes that the NIMH and American psychiatry would, at long last, address this concern head-on, and inform the public about it too. But I am not holding my breath.

Oct 25, 2010

The post Do Antidepressants Worsen the Long-term Course of Depression? Giovanni Fava Pushes the Debate Forward. appeared first on Mad In America.

To understand the importance of his comments, let me first set the scientific context.

In Anatomy of an Epidemic, I ask this question: How do psychiatric medications affect the long-term course of psychiatric disorders? What does the outcomes literature show?

 Now, as you investigate that literature, following it over a span of 50 years, you find repeated instances where researchers, in response to their findings, worry that the medications are worsening the long-term course of psychiatric disorders. In addition, they have put forth biological explanations for why this may be so.

For instance, in the late 1970s and early 1980s, two physicians at McGill University, Guy Chouinard and Barry Jones, argued that antipsychotics induce changes in the brain that cause it to become “supersensitive” to dopamine, and that this supersensitivity may then lead to psychotic “symptoms of greater severity.”

 Similar concerns were raised about the benzodiazepines in the 1980s. Next, in the 1990s, an Italian psychiatrist, Giovanni Fava,  worried that antidepressants “worsen the progression of the disease in the long term, by increasing the biochemical vulnerability to depression . . . Use of antidepressant drugs may propel the illness to a more malignant and treatment unresponsive course.” He then raised this broader question:

 ”Within the field of psychopharmacology, practitioners have been cautious, if not fearful, of opening a debate on whether the treatment is more damaging [than helpful] . . . I wonder if time has come for debating and initiating research into the likelihood that psychotropic drugs actually worsen, at least in some cases, the progression of the illness which they are supposed to treat.”

In response to Fava’s articles, Harvard Medical School psychiatrist Ross Baldessarini, who has been one of the most prominent researchers in the field for more than 30 years, wrote this: “His question and the several related matters . . . are not pleasant to contemplate and may seem paradoxical, but they now require open-minded and serious clinical and research consideration.”

And now let’s return to the comment written by Dr. Ragins, in response to my first blog. After noting that he “too felt discouraged by the events at the Alternatives conference,” Dr. Ragins briefly describes his experience there. He then moves onto the main theme of my book, which is that psychiatric medications do indeed worsen the long-term course of mental disorders. He writes:

 ”My main disappointment, however, goes beyond Alternatives, and is that I don’t think we’ll ever have an honest, comprehensive scientific evaluation of your most startling assertion — That medications induce a feedback response from the brain that worsens mental illnesses. I’d really like to know more about that, but I’ve lost all faith in our research system to inform me — for the reasons you detail in your book.

 ”For me the last straw with drug companies was when I found out that they knew about diabetes and Zyprexa all along and intentionally hid it from doctors leading us to put people at risk without knowing it. That felt like a terrible betrayal to me. (though, of course, not in the same league as what the people who got diabetes or even died went through.) I don’t know of any other field where the producers of something are so untrustworthy that the retailers regularly ban them from their offices). Although I’m sure that I’ve helped many people with medications, the drug companies are extraordinarily dangerous partners. I can’t believe anything they say and no one else has enough money and independence to do a full scientific study instead of a journalistic study.”

So let us now all think about this. In the 1970s and 1980s, prominent researchers worried that antipsychotics might be causing changes in the brain that led to psychotic “symptoms of greater severity.” Researchers then began worrying about similar problems with other classes of psychiatric medications (such as the benzodiazepines), and in the mid 1990s, Giovanna Fava urged psychiatry to investigate whether antidepressants and other psychiatric medications worsen the long-term course of mental disorders. A leading American psychiatrist agreed that Fava’s concern was legitimate and needed to be investigated. Yet, what happened? This concern was never communicated to the public or ever investigated. Instead, the public was told again and again about how these medications fix chemical imbalances in the brain, and need to be taken forever, with tens of millions of Americans having followed this advice (and millions of children prescribed the pills as well.)

And here is the source of Dr. Ragin’s despair: He doesn’t believe that a research enterprise even exists in the United States that can honestly investigate this question of whether psychiatric medications “induce a feedback response from the brain that worsens mental illnesses.” The reason, he writes, is that research in this country is financed by pharmaceutical firms that can’t be trusted to conduct honest science.

What, then, are we — as a society — to do about this?

Sunday, October 10, 2010

The post SAMHSA, Alternatives, and A Psychiatrist’s Despair over the State of American Science appeared first on Mad In America.

The Background to the “Controversy”

In Anatomy of an Epidemic, I basically followed a tried-and-true journalistic path. I followed the evidence. I looked at how the chemical imbalance theory of mental disorders arose, how it was investigated, and how it never panned out. As Kenneth Kendler, coeditor in chief of Psychological Medicine wrote in 2005, “We have hunted for big simple neurochemical explanations for psychiatric disorders and have not found them.” Then I investigated how psychiatric medications affect the long-term course of four major mental disorders (schizophrenia, anxiety, depression, and bipolar illness), and that involves doing an exhaustive survey of studies conducted (or funded) by the National Institute of Mental Health, the World Health Organization, and foreign governments for the past 50 years.

Now, when you do that, you discover a story of science quite at odds with our societal belief that psychiatric medications fix chemical imbalances in the brain and that they have dramatically improved long-term outcomes. And when you write up this history of science, as I did in Anatomy of an Epidemic, you do become unpopular in certain circles.

In July, the National Empowerment Center, which is a peer-run advocacy organization, invited me to be a keynote speaker at the Alternatives Conference. The National Empowerment Center is funded by the Substance Abuse and Mental Health Services Administration (SAMHSA), and SAMHSA, I was told, had signed off on having me speak. However, once the National Empowerment Center announced that I would be speaking at the conference, SAMHSA quickly rescinded the invitation. In response, MindFreedom, which is an activist group, organized a protest via the Internet, asking people to contact both SAMSHA and the White House, and within 36 hours, I had been publicly re-invited to speak.

What people following this “controversy” didn’t know was that my re-invitation came with considerable strings attached. I had originally been scheduled to give a workshop in addition to a keynote, but the workshop was still cancelled. (I had planned to speak about a Finnish program for treating psychotic patients that was producing excellent results, and the prescribing of exercise as a treatment for depression, which is now being done in Britain.)  The other condition was this: The National Empowerment Center was required to recruit a psychiatrist, from a list of names provided by SAMHSA, to “rebut” my keynote. And I would not be given an opportunity to respond to that rebuttal.

Now, if SAMSHA had wanted to organize a debate following my talk, that would have been terrific. But this was a setup that SAMHSA seemed to have torn from the pages of a 25-year old Soviet Union handbook: invite dissident speaker and then denounce him!  Normally, I wouldn’t have accepted such an arrangement, but I had been quite moved and humbled by the protest that had led to my “reinvitation,” and so I figured, what the heck. It wasn’t every day that you got to sit in a ballroom with more than 1,000 people and hear your work denounced.

As the conference approached, a new controversy reared its head. Will Hall, who many years ago was given a diagnosis of “schizoaffective disorder/schizophrenia,” and who today works as a therapist (having been off psychiatric medications for 17 years), had planned to give a workshop that included a discussion of a  “harm-reduction” approach to withdrawing from psychiatric medications. Several years ago, Hall had written a book on the subject, which had been published by two advocacy groups, The Freedom Center and the Icarus Project, and given that there are few books written by professionals on the circuit, his had proven to be quite popular. But a few days before the conference began, Hall was told that the printed description of his workshop had been changed to remove any mention about “coming off drugs.” Hall announced that he couldn’t accept such censorship, a new protest erupted, and then he was told that the offending words could in fact be mentioned in an updated description that would be added to the conference brochure.

And all this occurred before an alternatives conference.

Friday, October 1

On Friday morning,I was given about 45 minutes to speak, and after I gave a brief overview of Anatomy of an Epidemic, I spoke at greater length about this question: Is it true that people diagnosed with schizophrenia (or other psychotic disorders) need to be on antipsychotic medication all their lives? There is a fairly long line of studies dating back to the 1960s that bear on this question, and the conclusion to be drawn is this: If psychiatry wants to maximize long-term outcomes, it needs to use antipsychotic medications in a selective, limited manner. Time and time again, the studies showed that there is a large subgroup of patients that would fare better if they were never put on the drugs in the first place, or if they were maintained on the drugs for only a short while.

The beauty of this particular story of science is that it concludes with a description of how western Lapland, in northern Finland, started using antipsychotic medications in this manner in 1992, and today their psychotic patients enjoy the best long-term outcomes in the western world.  Five years after the first psychotic episode, eighty percent of their patients are either back in school or working. About one-third of the patients have been exposed to antipsychotics during this period, and about twenty percent end up taking the medication regularly. And what I like most about this success story is that it cannot be viewed, in any way, as an “anti-medication” story. It’s a “best-practices” story.

Most of the audience understood this to be a “good news” tale, with science telling us of a therapeutic path that led to high recovery rates. And imagine if the program, at this national conference, had been structured to have psychiatrists (or other providers) discuss the talk I had just given. We could have spoken about whether a similar therapeutic approach could ever be tried here, and with representatives from SAMHSA there, perhaps this possibility could even have leapt onto a national agenda. This could have been a moment for transformative change in the treatment of first-episode psychosis in this country, a change designed to put young people back onto a path of real recovery, rather than down a path that led all too often to chronicity and disability. But unfortunately, in that Hyatt Regency ballroom, a much different process was underway. Several SAMSHA officials were nervously huddled with the psychiatrist, Mark Ragins, who had been selected to rebut my talk, apparently with a sense of urgency that he effectively counter what I had said. No good news allowed!

When Dr. Ragins took the stage at lunchtime, he was remarkably candid.  He was here because SAMSHA wouldn’t let me speak unless a psychiatrist had a chance to rebut what I had said. This, of course, was startling news to most in the audience, as few had ever been to a conference where a second keynote speaker was brought in to discredit the first.

There was, however, no real discussion of the talk I had given, or the issues brought up in Anatomy of an Epidemic.  Instead, Dr. Ragins used this metaphor to criticize Anatomy: In the book, he said, I had provided readers with a “compelling picture” of a “close-up of a car accident,” but “we have to widen our view to decide if freeways should be torn down.” Dr.  Ragins then discussed other factors besides medication that might be causing the astonishing rise in the number of disabled mentally ill in our society, such as the fact that once people are on SSI or SSDI, there is a financial disincentive to return to work (which I agree is a factor.) Finally, in apparent reference to the many studies I cited in the book that had found that medicated patients have worse long-term than the off-medication group, he said:

    “Medical interventions are always correlated with worse (long-term) problems . . . It is likely that all interventions ‘done to’ someone to give them help or take care of them will have short-term benefits that wane over time and may well become long-term negatives.”

I still am not quite sure how that was supposed to be a “rebuttal” to Anatomy of an Epidemic. But that is how it was being pitched, and then when Dr. Ragins detailed some of his thoughts on what promoted long-term recovery—“Love other people, family, partners, kids” was one of the things he advised—I could only think: Am I supposed to be against this? Indeed, I had the feeling that if Dr. Ragins and I had been on a panel together, we would have found much common ground, and that he might have thought  that there was considerable merit to the Western Finland approach. But the chance to have that productive discussion had been lost.

A Postscript

During the conference, D. J. Jaffe, who has close ties to the National Alliance on Mental Illness, having served on its national board of directors, wrote a blog about the conference for The Huffington Post, describing it as a waste of taxpayer money. My presence there, he argued, was evidence of why this was so. The keynote speaker, he said, had written that  “antipsychotic drugs do not fix any known brain abnormality nor do they put brain chemistry back into balance,” and readers were left to understand that, given that everybody knew that mental disorders were caused by chemical imbalances,  I was a bit of a loony-tune.

So what was the purpose of this blog? NAMI is a powerful political group, heavily funded by pharmaceutical companies, and in my opinion, Jaffe was delivering a warning. He was telling the National Empowerment Center and other consumer groups that they might lose their funding if they did not, in the future, march in lockstep with psychiatry’s official story, which is that mental disorders are known brain illnesses, and that the drugs are like “insulin for diabetes.”  No more invitation to speakers who would say otherwise.

At such moments, I have to confess that I begin to lose all hope. It seems quite impossible that our society will ever be able to have a thoughtful, honest discussion about what is truly known about mental disorders, and about the merits of psychiatric medications. The forces lined up against such a discussion are simply too great.

Wednesday, October 6, 2010

The post SAMHSA, Alternatives, and the Story of an Opportunity Lost appeared first on Mad In America.

The CNN story tells of how psychiatrists are getting better about diagnosing bipolar disorder in children, and how, once it is properly diagnosed, medications can be such a big help. But if you read the article closely, you’ll see that both of the children in this story were treated iitially with an antidepressant, which led to a manic episode in one child and to a further deterioration in behavior in the second child, and it was then they were diagnosed with bipolar disorder.

Before psychiatry began prescribing stimulants and antidepressants to children, juvenile bipolar illness was unknown. Researchers regularly concluded that bipolar disorder (or manic depressive illness, as it was called in the past,) simply didn’t occur in prepubertal children.  But then psychiatry began prescribing those drugs to children and youth, and the juvenile bipolar boom followed. Indeed, when researchers have surveyed juvenile bipolar patients, they have found that the overwhelming majority had been treated with a stimulant or an antidepressant prior to their being diagnosed with bipolar disorder.

In other words, the CNN story should perhaps have been titled: “Creating the Bipolar Child: The Risks of Prescribing Antidepressants to Youth.”

In the New York Times article, Weill Cornell Medical College psychiatrist Richard Friedman tells of how illicit drugs like cocaine and methamphetamine activate the brain’s reward system by releasing dopamine. However, he notes, the brain then tries to compensate for the drug’s presence, and it does by becoming less sensitive to dopamine release. The brain may end up with a “less responsive reward circuit,” which never fully repairs itself even after the drug use stops, he writes. The result is that the person may then be condemned to “endure a dulled life.”

All of that may be true. But here is what is missing from this article. Ritalin and the other stimulants used to treat ADHD in children also activate the “dopamine system.” Ritalin, in fact, does it in much the same manner that cocaine does, and with equal potency. The difference is that Ritalin is not cleared from the body as quickly as cocaine, and thus a dose of Ritalin has longer-acting effects than cocaine. In response, the stimulant-using brain undergoes changes that make it less sensitive to dopamine release—it is trying to compensate for the drug’s presence. And so now the obvious question. If this process, in those who use cocaine or other illicit drugs, may lead to a “less responsive reward circuit,” which never fully repairs itself even after the drug use stops, isn’t there a similar risk with putting children on Ritalin or other stimulants? Is this treatment that may then lead children to “endure a dulled life” as adults?

It seems like a question that psychiatry—based on this article by Richard Friedman in the New York Times—should ask.

Tuesday, August 31, 2010

The post And Now For the Rest of the Story appeared first on Mad In America.

The STAR*D trial, which was funded by the NIMH at a cost of $35 million and took six years to conduct, was touted as as the “largest antidepressant effectiveness trial ever conducted.” As it was designed to study treatment strategies for helping people recover and then stay well, with a one-year followup, it would produce results, the investigators announced at the start of the trial, that would have “substantial public health and scientific significance.” As the public well knows now, pharmaceutical funding of antidepressant trials produced scientific literature that was biased and profoundly misleading, a tale of persistent scientific misconduct that has now been reviewed by many authors. But STAR*D was a publicly-funded trial, and of course we would hope and expect that the results would be honestly reported.

So, with the new paper authored by Edmund Pigott, Allan Leventhal, Gregory Alter, and John Boren as a guide, let’s go through the scientific sins. The results consisted primarily of two data sets, the percentage of patients whose depression remitted, and then the percentage of remitted patients who stayed well during the one-year followup, and thus we can review whether the NIMH and the STAR*D investigators accurately reported those results, and also disclosed the relevant data.

A. The percentage of patients whose depression fully remitted

What was reported

The STAR*D trial was designed to test whether a multistep, flexible use of medications could produce remission in a high percentage of depressed outpatients. Those who didn’t get better with three months of initial treatment with an SSRI (citalopram) then entered a second stage of treatment, in which they were either put on a different antidepressant or given a second drug to augment an antidepressant. Those who failed to remit in step two could go on to a step three, and so on;  in total, there were four treatment steps.

In a November 1, 2006 press release the NIMH announced the positive news. “Over the course of all four levels, about 70% of those who did not withdraw from the study became symptom free.”

In an article published at the same time in the American Journal of Psychiatry, the researchers — in the abstract of the article — told a similar story. “The overall cumulative remission rates was 67%,” they wrote. In the text of the article, they did note that this was a “theoretical” remission rate, as “it assumes that those who exited the study would have had the same remission rates as those who stayed in the protocol.”

Still, the 67% figure was the bottom-line message being communicated to physicians and the public, and in a paper published in 2007, titled “The STAR*D Project Results: A Comprehensive Review of Findings,” the researchers emphasized this bottom line: “With all steps included, almost 70% of participants who remained in the study experienced remission. Patients and clinicians are encouraged not to give up.”

The actual results

Now the investigators did publish charts with data on the number of patients who stayed in the trial and actually remitted, and after I plowed through those charts, I calculated that 1854 of the 3671 patients (50.5%) who entered in the trial remitted at some point during these four steps of treatment. (I wrote about this in an earlier blog.) However, as Pigott and his collaborators make clear in their paper, even this percentage, from a scientific standpoint, is an inflated number.

When the investigators designed the study, they stated that the Hamilton Rating Scale for Depression (HRSD) would be the primary tool used to measure depressive symptoms, and that all patients, in order to be eligible for analysis, would have to have an entry HRSD score ≥ 14. Yet, their reported results strayed from those study parameters in two ways, both of which inflated remission rates.

First, during the trial, the researchers also used the Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) to periodically assess depressive symptoms. Higher remission rates were found with this assessment tool than with the HRSD scale, and the researchers then highlighted this higher remission rate in their published articles. Using the more lenient QIDS-SR scale, Pigott and his collaborators found, added more than 200 patients to the remitted group. (In essence, highlighting the QIDS-SR remission rates is a form of post-trial cherry-picking of data.)

Second, the investigators enrolled 607 patients into the study who had a baseline HRSD score ≤14 (and thus were only mildly depressed), and, in several published reports, they included these patients when announcing a “67% cumulative remission rate,” even though — based on study criteria — they were “ineligible” to be included in the analysis. Naturally, these mildly depressed patients were more likely to remit than those with higher baseline HRSD scores, and so including them in the published studies inflated the remission numbers.

In their paper, Pigott and his collaborators determined that there were 3,110 patients who began the study with an HRSD score of ≥ 14, and found that 1,192 of this group remitted during the study, based on a HRSD score of ≤ 7. Thus, if the study protocol had been followed and the results honestly reported, the researchers would have announced that 38% of the patients remitted during the four steps of treatment, and that the remaining 62% either dropped out or failed to remit.

B. The percentage of remitted patients who stayed well throughout a year of “continuing care.”

What was reported

When the STAR*D investigators designed the study, they sought to maximize the stay-well rate during a one-year period of “continuing care.” During this stage of the study, physicians could change the patients’ medications, alter dosages, and add new medications. Patients were paid $25 each time they had their symptoms assessed, as it was thought this would help keep patients in the study.

In their reports, the STAR*D investigators announced that 33.5% to 50% of the remitted patients relapsed during this period of continuing care, with the lower percentage for those who remitted in stage one of treatment and the higher percentage for those who remitted in stage four of treatment. Thus, it seemed that a majority of the remitted patients had stayed well, which was fairly encouraging. And if you did a rough back-of-the envelope calculation — multiplying the percentage of patients who remitted times the percentage stay-well rates during the followup — it appeared that the 12-month stay-well rate for all of the patients who had entered the trial was around 40%.

The actual results

When I was researching and writing Anatomy of an Epidemic, I did my best to figure out the precise number of patients who remitted and stayed well throughout the trial. In particular, I puzzled over “figure 3″ on page 1913 of a 2006 article on long-term outcomes, as it appeared the numbers might be there, but the data was presented in such a confusing manner I gave up. Ultimately, all I could determine was that of the 3,671 patients in the trial (including the 607 who had baseline HRSD score ≤ 14,) 737 had remitted and then reported, at some point during the 12-month followup, they were still well. The remaining 80% of the patients had either never remitted, relapsed during the followup, or dropped out at some point.

This was not such an encouraging number, but, it turned out, my calculations were once again too kind. In a 2009 paper, Allan Leventhal and David Antonuccio were able to make sense of that mysterious graphic on page 1319, and they reported that only 108 patients — out of the initial cohort of 3,671 — had a “sustained remission.” In other words, only 3% of the patients who entered the trial remitted, and then stayed well and in the trial during the year-long followup.

But, as Pigott and his collaborators explain, even this number may be a bit high. They noted that many of the 108 stay-well patients may have come from the group of 607 patients who had a baseline HRSD score ≤14, and shouldn’t have been included in the analysis in the first place. Moreover, since relapse was defined as a HRSD score ≥ 14, it was possible that some of the 108 patients actually had a higher HRSD score during the followup period (say a score of 13) than they did at baseline (say a score of 12), and yet would still have been reported as having remitted and stayed well throughout the 12-month period.

Why This Is A Scandal

This is my fourth post on the STAR*D results, and thus it may seem I am a bit obsessed about the study. And in a sense, I am. This was a publicly funded study, and the bottom-line message conveyed to the doctors and to the public was that it had shown that antidepressants enabled 67% of depressed outpatients to recover. That’s what The New Yorker reported in an article published on March 1 of this year, adding that this “effectiveness rate” was “far better than the rate achieved by a placebo.” Now let’s sum up the scientific sins used to create that false impression:

• The STAR*D investigators reported a “cumulative” remission rate of 67% in the abstract of an article, when in fact this was simply a “theoretical” rate.

• They reported remission rates based on the QIDS-SR scale, even though the pre-specified primary outcome scale was the HRSD, and this switch inflated the remission numbers.

• They included remission numbers for patients who weren’t depressed enough at baseline to meet study criteria, and thus weren’t eligible for analysis.

• They reported that 33.3% to 50% of remitted patients relapsed during the 12-year followup, which suggested — when combined with the inflated 67% remitted rate — that perhaps 40% of all patients who entered the trial had recovered and stayed well, when in fact only 3% of the entering patients had a “sustained remission” (and stayed in the trial.)

As Medscape Medical News noted, the real results “point to a lack of long-term efficacy for antidepressants.” But the fake results pointed to medications that were “far more effective” than placebo.

A STAR*D Investigator Responds

In her article, Medscape Medical News writer Deborah Brauser asked STAR*D investigator Maurizio Fava, who is a prominent psychiatrist from Massachusets General Hospital, whether the published analysis by Pigott and his collaborators was correct. “I think their analysis is reasonable and not incompatible with what we had reported,” he said.

His answer is revealing for two reasons. First, he is acknowledging that the low remission and stay-well rates reported by the Pigott group are accurate. Those are indeed the real results. Second, he is acknowledging that the STAR*D investigators knew this all along, and that, in fact, this information was in their published reports. And in a sense, that is true. If you dug through all of the published articles, and spent weeks and months reading the text carefully and intently studying all the data charts, then maybe, at long last, you could — like Pigott’s group — ferret out the real results.

But that is not the way that honest science is supposed to work.

Friday, August 27, 2010

The post The STAR*D Scandal: A New Paper Sums It All Up appeared first on Mad In America.

(See minute 29:30 of video.) The idea being presented by Lieberman was that schizophrenia is a neurodegenerative disease, characterized by brain tissue loss.

In the discussion, Lieberman also implied that antipsychotic medications, in some way, protect against this neurodegenerative process. The drugs “stabilize the illness,” he said. But when people “stop taking the medicines, they get sick again, and when this happens, they have repeated insults to the brain . . . and this leads to a progression, and the progression, like somebody who has multiple little strokes, can lead to some decline in which people are not able to recover to the same level. And if you actually take brain scans over time, you can see the subtle, perceptible loss of brain grey matter.”

To the public, this is a new paradigm for understanding why antipsychotics are an essential treatment for schizophrenia. Schizophrenia is a neurodegenerative illness, characterized by brain tissue loss, and antipsychotics are “neuroprotective” agents that thwart that pathological process in some way.

Given that this idea is taking hold, it seems worthwhile to check the literature to see if it is well grounded in science.

MRI Scans

Making sense of MRI studies of schizophrenia patients can be a difficult task, partly because the results can be so inconsistent, and partly because the results are confounded by exposure to antipsychotics. However, earlier this year, Joanna Moncrieff and Jonathan Leo brought new clarity to this topic by analyzing the studies based on the patients’ exposure to antipsychotics.

Here is a summary of their findings, which they published in Psychological Medicine.

Studies of chronic patients never exposed to antipsychotics

They identified three studies of schizophrenia patients who were ill for extended periods of time and were never exposed to antipsychotic medications. In comparison to the “controls” in the studies, these never-exposed patients showed “no major differences in global cerebral, grey-matter, ventricular, or CSF (cerebrospinal fluid) volumes.”

Studies of first-episode patients with limited exposure to antipsychotics

A number of studies have found brain abnormalities in first-episode schizophrenia patients, and these findings have been seen as proof that the abnormalities must be due to the disease and not the treatment. But as Moncrieff and Leo noted in their paper, many of the patients in the first-episode studies had been on antipsychotics for months, and there is evidence that antipsychotics may induce changes in brain structures in a short period of time. As such, the results from first-admission studies — as a group — are confounded by drug exposure.

To counter this problem, Moncrieff and Leo analyzed the results from studies of schizophrenia patients who were either drug naïve or had limited exposure to antipsychotics (on average less than four weeks.) They found 18 such studies (in addition to the three studies discussed above.)

In 13 of them, researchers did not find any differences between the patients and controls in whole-brain volumes, total grey matter, and CSF volumes. Of the five studies that did show differences in brain volumes, one included a subset of patients that had taken antipsychotics for up to 24 weeks, which could have confounded the results. A second study reported differences in an initial sample of 18 patients, but then, in a larger sample of 51 patients, no global differences were found. The remaining three studies found a difference in the size of the “third ventricle only;” a “trend level reduction in whole-brain volume;” and “smaller cerebellar volumes.”

Longitudinal studies of patients treated with antipsychotics

In 14 of 26 MRI studies of schizophrenia patients treated with antipsychotics for periods ranging from eight months to 10 years, the patients “showed a greater reduction in whole-brain, cortical or grey-matter volumes, or a greater increase in CSF or ventricular volumes, compared with controls.”

Several of the 14 studies quantified the brain-volume loss. In adult patients, “grey matter, whole-brain or cerebral volume showed a decline of 1.2% to 2.9% per year.”

Summing Up The MRI Studies

With the MRI literature parsed in this way, it’s easy to see that the studies do not provide convincing evidence that schizophrenia patients, if they were not treated with antipsychotics, would regularly suffer “a loss of brain gray matter.” A reduction in whole brain volumes is not regularly seen in first-episode patients with limited exposure to neuroleptics, and it was not seen in the three longitudinal studies of never-exposed patients. The fact that it shows up in the majority of studies of drug-treated patients simply leads to this possibility: It could be due to a disease process, or it could be due to the medication, or it could be due to a combination of the two.

The Effect of Antipsychotics on Brain Volumes

To best assess the long-term effects of antipsychotics on brain volumes and to distinguish drug effects from disease processes, you would need to run a long-term study that compared brain volumes in four groups: healthy people on the medications, healthy people off the drugs, schizophrenia patients on the drugs, and schizophrenia patients off the drugs. But you can’t put healthy people on antipsychotics and it is considered unethical to withhold antipsychotics from schizophrenia patients for long periods, and so you can’t run studies of that type. However, animal research and MRI studies of medicated schizophrenia patients do provide evidence that antipsychotics may cause “brain gray matter loss.”

In animal studies, typical antipsychotics have been found to cause neuronal loss and gliosis in the striatum, hypothalamus, brain stem, limbic system and cortex. In a study of non-human primates (macaque monkeys), a daily dose of haloperidol or olanzapine for 18 months led to an 8% to 11% reduction “in mean fresh brain weight compared to controls.”

Next, as Moncrieff and Leo reported, a majority of studies of schizophrenia patients on the drugs for longer periods found that they had reduced brain volumes, while in the three longer studies of never-exposed patients, there was no such finding. Furthermore, researchers have found that gray matter loss varies according to whether a typical or atypical antipsychotic is prescribed, and if the drugs did not affect brain volumes, there shouldn’t be this variability. Lieberman and others recently conducted a study of this type, mapping the cortical changes seen in 36 first-episode schizophrenia patients treated with either haloperidol or olanzapine for one year. 

Here are their results, which they published in 2009:

• In the haloperidol patients, “a dynamically spreading wave of significant gray matter loss was detected . . . progressive gray matter reduction began in lateral parietal-temporal cortices by three months, spreading into the dorsolateral, medial frontal and prefrontal cortices by six months, and involving most of the frontal cortex by one year after the first psychotic episode.” The “total loss is severe by 12 months.”

• In the olanzapine patients, “regions of significant progressive gray matter loss were found at all time points, but these were less intense and widespread. These changes also evolved in a distinct antatomical trajectory” compared to the haloperidol-treated patients.

So how should these results be interpreted? Given the effects of haloperidol and olanzapine in macaque monkeys, you might conclude that both drugs cause brain gray matter loss in schizophrenia patients, with olanzapine perhaps less toxic than haloperidol. However, since there was no control group in this study and thus no mapping of gray matter loss in unmedicated schizophrenia patients, the researchers concluded that it was also possible that olanzapine was “neuroprotective,” i.e. that it slowed down the loss seen in the haloperidol patients (which presumably was due mostly to the disease.) But, they wrote, without a control group “it is difficult to be sure that the effect is either due to toxic effects of one drug versus protective effects of another (among other interpretations), and it cannot be determined what the normal trajectory of such change is in schizophrenia.”

The Bottom Line

While the public may be hearing that schizophrenia is a neurodegenerative disease characterized by a loss of brain gray matter, with atypical antipsychotics neuroprotective against that process, even a quick review of the scientific literature reveals that it is unclear whether the gray matter loss is due to the disease, or to the drug, or to a combination of both.

Here’s what Moncrieff and Leo wrote in their conclusion : “Overall, there seems to be enough evidence to suggest that antipsychotic drug treatment may play a role in reducing brain volume and increasing CSF or ventricular spaces . . . although it remains possible that the underlying disease process also causes brain volume changes, we suggest that antipsychotic drug treatment may be responsible for some of the changes that are usually attributed to schizophrenia.”

Thursday, August 12, 2010

The post Charlie Rose and the Mentally Ill Brain appeared first on Mad In America.

1) Psychotropics can cause eye problems.

S. Richa. “Ocular adverse effects of common psychotropic agents.” CNS Drugs 24 (2010): 501-26.

All psychotropic drugs may induce numerous and diverse unwanted ocular effects. These unwanted effects include blurred vision, galucoma, retinopathy, eye-movement disorders, and decreased ability to perceive colors and to discriminate contrast.

2) It’s easy for college students to fake ADHD

MJ Sollman, “Detection of feigned ADHD in college students.” Psychol Assess 22 (2010): 325-35.

In this study by University of Kentucky researchers, college students, after briefly reviewing information about ADHD on the Internet, were able to successfully “fake” ADHD symptoms and thus obtain a prescription for a stimulant. “The study confirms that self-report ADHD checklists . . . are probably of no value in differentiating individuals with ADHD from those faking the disorder,” the researchers concluded.

3) Britain reports 1.5 million “involuntary addicts” to benzodiazepines

The Independent newspaper reported that there were1.5 million people in Britain addicted to benzodiazepines, and noted that “prolong use causes symptoms which could result in patients being unable to work.” People trying to withdraw from the addictive drugs can “get very ill,” the paper said.

(This is the sort of story that is virtually never reported in U.S. newspapers.)

4) Male neonates of mothers diagnosed with schizophrenia (and treated with antipsychotics) have abnormal brain volumes.

J. Gilmore. “Prenatal and neonatal brain structure and white matter maturation in children at high risk for schizophrenia.” American Journal of Psychiatry, published in advance online, June 1,2010.

In this NIMH-funded study, researchers reported that male neonates born to mothers diagnosed and treated for schizophrenia were found to have “several larger than normal brain volumes.” The researchers concluded that this was evidence that “prenatal and early neonatal brain development is abnormal in males at genetic risk for schizophrenia. “

 In other words, researchers saw this abnormality as evidence of a “schizophrenic” process already underway in the male neonates. But the mothers diagnosed with schizophrenia in this study were taking antipsychotics, which are known to cause changes in brain volumes. Thus, it may be that the abnormalities seen in the brains of the male neonates were due to the drugs, rather than to any underlying genetic risk for schizophrenia.

The female neonates born to mothers diagnosed with schizophrenia did not have “larger than normal brain volumes,” which of course leads to further doubt about any conclusions that can be drawn from this study.

Monday, July 5, 2010

The post News Roundup From June appeared first on Mad In America.

But today, in this blog, I get to brag a bit about Brandon Banks.

Brandon Banks grew up poor in Elizabethtown, without a father at home. After graduating from high school in 2000, he moved to Louisville, where he attended college part-time and worked nights at United Parcel Service. There, he became depressed, and shortly after he began taking an antidepressant, he suffered a manic episode. “This was a serious shove into seriousness,” he says.

Diagnosed now as bipolar, he came to understand that he would be struggling with this illness the rest of his life. During the next four years, he was hospitalized several times, and unfortunately, none of the endless combination of drugs he took — Depakote, Neurontin, Rispderdal, Zyprexa, Seroquel, Haldol, Thorazine, lithium, and a number of antidepressants — brought him lasting relief. Instead, he became a rapid cycler who suffered from mixed states, and he also developed a number of new psychiatric symptoms — worsening anxiety, panic attacks, obsessive compulsive behaviors, voices, and hallucinations. At one point, his ability to concentrate declined so severely that Kentucky took away his driver’s license.

“What my life became was staying at home all day, getting up in the morning and laying my pills out on the counter, taking them, and then going back to sleep because I couldn’t stay awake if I tried. Then I would get up, play some video games, and hang out with my family,” he recalls.

The story of his recovery from that dark moment is a long and complicated one. But suffice to say, it involved rejecting the idea that he had a “broken brain.” Perhaps he was just “screwed up,” he thought. Gradually, he regained a sense of hope about his future, about being able to make something of himself, and in the fall of 2008, he began pursuing his interest in journalism. He quickly became managing editor of the Elizabethtown Community College student newspaper, and under his leadership during the 2008-2009 school year, the newspaper won 24 awards from the Kentucky Intercollegiate Press Association. Banks personally garnered ten such honors for the articles he’d written, including first place in a deadline-writing competition.

During that year, Banks did continue to struggle with “bipolar” symptoms. But he had discovered that he had an incredible talent for journalism, which boosted his self-confidence. He could now realistically think of fashioning a career as a journalist, and this past fall he wrote an in-depth article, which was quite well reported, on how easy it was to “cheat” when taking an Internet class. In the spring, his article won a regional award from the Society for Professional Journalists, and then Banks emailed me with his big news: In the national competition, the Society for Professional Journalists awarded his article first place for in-depth reporting by a student at a two-year college.

I know there is an obvious lesson to be drawn from his story, but I have to confess that I am writing this note for a different reason. When Brandon Banks told me of his award, I felt such joy that I simply had to tell as many people as possible.

Friday, July 2, 2010

The post ”Broken Brains” and “Beautiful Minds” appeared first on Mad In America.

The case, United States ex-rel Law Project for Psychiatric Rights v. Matsutani, was unsealed earlier this year, and legal papers were recently filed that have brought this novel question — which obviously has profound implications for the prescribing of psychiatric medications to poor children and adolescents – into sharp focus.

The Law Project for Psychiatric Rights (PsychRights), which is headed by Alaskan attorney James Gottstein, filed its whistleblower complaint in April 2009. Known as a qui tam lawsuit, PsychRights sued on behalf of the federal government under the False Claims Act, which allows private individuals to pursue legal complaints against individuals or companies that are allegedly defrauding the government. In December, the federal government declined to join PsychRights in the case.

PsychRights named Alaskan state officials, hospitals, mental health agencies, psychiatrists, and pharmacies as defendants. In its complaint, PsychRights argues that the federal government has agreed to provide Medicaid reimbursement only for those outpatient drugs that are prescribed for an FDA-approved use or for a use supported by a medical compendium (such as the DRUGDEX Information System.) PsychRights maintains that the defendants defrauded the federal government when they billed Medicaid (or the federal Children’s Health Insurance Program) for outpatient drugs that didn’t meet this standard.

As part of its complaint, PsychRights identified 16 commonly prescribed psychiatric medications that have no “medically accepted indication” for youth under 18 years old, and it also identified the limited number of “medically accepted indications” that exist for 32 other psychiatric drugs. PsychRights compiled this list of “approved” uses by methodically going through the drug compendiums, and it serves as the evidential heart of the complaint, for it reveals that psychiatric medications are regularly prescribed to poor children for non-approved uses. PsychRights is asking the federal court to stop this practice (which it argues is harmful), and to pay hefty financial penalties for the fraudulent claims made to date.

In early April, the defendants petitioned the court to dismiss the complaint, arguing that it was “fatally flawed” for a number of reasons, including several technical ones. For example, the defendants maintain that PsychRights has not “disclosed” private information that is required of “whistleblowers” in qui tam suits. But the defendants also argued –and this goes to the core legal issue of interest to healthcare providers — that PsychRights has misinterpreted the applicable Medicaid law. Medicaid is a joint state-federal program, with each state establishing a Medicaid plan that must be approved by the federal government, and the defendants argue that a state may in fact choose to provide Medicaid reimbursement for outpatient drugs that are not FDA approved or “medically indicated” by drug compendia. The defendants argue that Alaska implicitly made that choice in regard to off-label use of psychiatric medications in children, and thus no fraud was committed.

The U.S. District Court in Alaska will likely take months to rule on the defendants’ motions to dismiss the complaints. If the court rules on the central issue, it will help define whether Medicaid law supports off-label, non-compendia-approved use of psychiatric medications in children, or deems this commonplace practice to be medically unjustified.

Wednesday, June 2, 2010

The post Medicating Children: A “Whistleblower’s Lawsuit” Raises a Novel Legal Question appeared first on Mad In America.

Now the 12-month results from the NIMH-funded “Treatment of Early-Onset Schizophrenia Spectrum” study are about to be published, and, unfortunately, in this age group (eight to nineteen years old), the results are even more disappointing. Only 14 of the 116 youth (12%) responded to the study medication and were able to successfully stay on it for one year. In other words, the 74% failure rate in adults climbed to 88% in youth. The results will be published in the June issue of the Journal of the American Academy of Child & Adolescent Psychiatry (and have already been published by the journal online.)

The TEOSS study was not placebo-controlled. The 116 youth entrolled into the trial were randomized either to a standard antipsychotic (molindone) or to an atypical antipsychotic (olanzapine or risperidone.) The investigators hypothesized that “treatment with olanzapine and risperidone would be associated with greater treatment response and greater tolerability than treatment with molindone,” but that did not turn out to be the case. At the end of eight weeks, the response rate was 50% for those treated with molindone, 46% for risperidone, and 34% for olanzapine. Adverse events were “frequent” in all three groups.

Only those youth who “responded” during the initial eight weeks — 54 of the 116 — were entered into the 44-week maintenance study. Forty of the 54 youth dropped out during this period because of “adverse effects” or “inadequate response.” Thus, only 14 of the 116 youth who entered the study responded to the study medication and stayed on it for as long as one year.

These study results are disturbing for three reasons.

First, as is well known, the prescribing of antipsychotics to youth took off in the mid 1990s based on a belief, among psychiatrists, that the atypicals were safer and more efficacious than the old drugs. CATIE showed that not to be true in adults, and now we see the same thing in youth. So this trial tells of prescribing patterns that arose from a delusion, and that generally is not a recipe for good medicine.

Second, we see in the 12-month results evidence of a failed therapy. The bottom-line might be summed up this way: The drug treatment could be said to have worked for 12% of the patients, and to not have worked for the remaining 88%.

Third, we now have to ask this question about the youth in the latter category: Was the drug treatment therapeutically “neutral” for the 88% who tried one of the three antipsychotics and then couldn’t stay on that drug for a year, or was the treatment ultimately “harmful,” given that antipsychotics can cause so many troubling side effects? In other words, would these patients — 102 of the original cohort of 116 in the trial — have been better off at the end of one year if they had been treated from the beginning with a non-drug therapy, instead of an antipsychotic?

The TEOSS trial can’t answer that question. But it’s clearly one that needs to be asked.

Tuesday, May 25, 2010

The post Yet Another Disappointment: First Catie, and Now the 12-Month Results from TEOSS appeared first on Mad In America.

But this left an obvious question, one that I hadn’t been able to find an answer to in the published STAR*D reports. How many of the 3,671 people who entered the trial remitted and then stayed well and in the trial throughout the entire 12-month follow-up? That number would provide a documented long-term recovery rate for patients in the trial.

A few days ago, Allan Leventhal sent me a 2009 article he coauthored with David Antonuccio, and in it, they successfully identified this number (finding it in a confusing graphic I hadn’t been able to decipher.) In their computations, they relied on STAR*D reports that told of 4,041 initial participants (3,671 was the number of “enrolled” patients counted in the analysis of drug-remission rates), and then they came to this bottom-line conclusion about the documented long-term recovery rate:

“Although the study’s reports make no mention of this outcome, their data show that after a year of continuation treatment following remission, of the 4,041 patients who entered the program only 108 (3%) had a sustained remission — all the other patients either dropped out or relapsed. Yet STAR*D’s authors and the NIMH have publicized the study as showing a 67% success rate for antidepressants.”

Such is the gap, rather considerable in size, between what the New Yorker reported as the recovery rate, and the actual numbers.

Wednesday, May 19, 2010

The post Update on the Star*D Report appeared first on Mad In America.

But today, according to a recent report by Eli Lilly investigators who are conducting a study of 17,000 schizophrenia outpatients in 37 countries, that disparity in outcomes has largely disappeared. And therein, I believe, lies a clue to solving the original mystery.

WHO’s Hypothesis

After the first study, the WHO researchers naturally speculated about the causes of the disparity in outcomes, and one of their hypotheses was this: Perhaps the patients in the developing countries were more medication compliant. This hypothesis made sense — antipsychotics presumably improved long-term outcomes — and so the WHO researchers, in the second study, assessed medication usage. However, they found that in the three developing countries-India, Colombia, and Nigeria-only 16% of the patients were regularly maintained on antipsychotics, compared to 61% of the patients in the developed countries. Outcomes were better in countries where patients weren’t regularly maintained on the drugs.

Once the WHO researchers had this data in hand, they turned their attention to cultural differences as the likely source of the disparity in outcomes. Perhaps patients in the poor countries are not as isolated and are better able to find work. Any thought that a variance in medical treatment might be the cause of the disparity in outcomes was mostly forgotten. But, if we return to their initial hypothesis today, it seems fair to raise this long-neglected question: Is it possible that a paradigm of care that involves selected, limited use of antipsychotics would produce better long-term outcomes?

The Outcomes Literature for Antipsychotics

Thorazine was introduced into asylum medicine in 1954, and so there is a 50-year history of outcomes studies that can be tracked to determine how the drugs affect the long-term course of schizophrenia. Here are just three of the many surprises to be found in that history:

    •    When Boston University’s Courtenay Harding studied the long-term outcomes of 168 chronic schizophrenics discharged from Vermont State Hospital in the 1950s and early 1960s, she found that 34% were recovered 20 years later. This meant they were “asymptomatic and living independently, had close relationships, were employed or otherwise productive citizens, were able to care for themselves, and led full lives in particular.” All of the people in this recovered group shared one thing in common: They all had “long since stopped taking medications,” Harding told the APA Monitor. It was a ”myth,” she concluded, that people with schizophrenia “must be on medication all their lives.”

    •    During the mid 1990s, MRI studies found that antipsychotics can cause basal ganglion structures and the thalamus to swell, and the frontal lobes to shrink. Then, in 1998, Raquel Gur at the University of Pennsylvania reported that the swelling of the basal ganglia and thalamus was “associated with greater severity of both negative and positive symptoms.” In other words, this research showed that the drugs cause morphological changes in the brain that are associated with a worsening of the very symptoms the drugs are supposed to treat.

    •    In 2007, Martin Harrow reported on the 15-year outcomes of a group of 64 schizophrenia patients he had been following since the 1980s. Forty percent of those off meds were in recovery (and more than 60% were working), whereas only five percent of those taking antipsychotics were in recovery (and few were working.) Only 28% of those off meds still suffered psychotic symptoms at the end of 15 years, versus 64% of those still on meds. “I conclude that patients with schizophrenia not on antipsychotic medication for a long period of time have significantly better global functioning than those on antipsychotics,” Harrow said at the 2008 annual meeting of the American Psychiatric Association.

At the very least, these three studies provide support for the idea that selective, limited use of the medications would produce better long-term outcomes than a “continual use for all patients” paradigm of care.

Two Experiments

Now if we wanted to test whether the different medication usage in the WHO studies was a key reason for the disparity in outcomes, we would like to see two experiments run. We would want a developed country to use antipsychotics in a selective, limited manner, and see how their patients fared over the long term. Then we would want a developing nation to use antipsychotics in a more comprehensive manner, and see how their patients fared. Fortunately, we now have evidence of both types.

Since 1992, the medical community in the western Lapland region of northern Finland has been using antipsychotics in a selective, cautious manner. At the end of five years, only about one-third of their first-episode psychotic patients have been exposed to antipsychotics, and only about 20% are regularly maintained on the drugs. This is a “continual use” rate similar to the rate for schizophrenia patients from developing countries in the second WHO study, and here are the long-term outcomes for western Lapland’s first-episode psychotic patients: Eighty-six percent are working or back in school at the end of five years, and only fourteen percent are on long-term disability. These outcomes are far better than the norm in Western Europe and the rest of the developed world.

Eli Lilly’s ongoing study of 17,000 schizophrenia outpatients in 37 countries (in all global regions except North America) provides evidence of the second type. Ninety percent of the patients enrolled into the study had been on antipsychotics for some time (with a median duration of illness of seven years,) and thus, as the Lilly investigators assessed their “baseline characteristics,” they were looking at cross-cultural outcomes for patients who had been treated with a paradigm of care that emphasized regular use of the drugs. The medical treatment was much the same for all of the patients enrolled into the study, and Eli Lilly investigators concluded that patients in “developing” and “developed” countries showed a “substantial similarity” in their outcomes, which could be described as fairly poor. Only 19% of the patients entering the Eli Lilly study were employed, and 69% were living in “dependent housing.” The patients were symptomatic much of the time, and many were burdened by drug side effects. “Coupled with the symptom scores, these data demonstrate that patients in this study population are experiencing a significant burden of illness,” the Eli Lilly researchers wrote.

In short, in this Eli Lilly study, the disparity in outcomes between patients in developing and developed countries had disappeared. The patients in the developing countries were no longer enjoying the “exceptionally good social outcome” they had in the earlier WHO studies.

Summing Up the Evidence

I know that this post, given that it contradicts the conventional wisdom that schizophrenia patients need to be on antipsychotics all their lives, will seem “outlandish” to some readers. But I think there is a consistent evidence trail here, and that it does lead to the conclusion that a difference in medication usage in the WHO studies was a primary reason that patients in the developing countries fared better. And if so, that has profound implications for a “best use” model of care today.

Tuesday, May 18, 2010

The post A Schizophrenia Mystery Solved? appeared first on Mad In America.

Saturday, April 24, 2010

The post Time Magazine and Anatomy of an Epidemic appeared first on Mad In America.