There has been much handwringing within corridors of academic and guild psychiatry about the “dry pipeline” for new psychoactive drugs. So it is surprising that I have of late been the target of much wooing by my local Sunovion rep. I think he leaves messages for me almost weekly and he sends me missives; glossy brochures and reprints from a major psychiatric journal. What is the subject of this attention? The drug lurasidone (Latuda).
This drug was first approved by the FDA in 2010 for the treatment of schizophrenia. At the time, I did not think there was much enthusiasm for this drug. It did not seem to have much to offer above and beyond what the earlier so-called atypical antipsychotic drugs offered and since most of them were now off patent, there seemed to be no good reason to prescribe it. Sunovion boasted about its relative lack of impact on metabolism (weight gain, elevated blood sugar and cholesterol). But we have ziprasidone. They boasted about its possible impact on cognitive function, but the data were weak. This seemed like another “me too” drug, and reviewers – both those critical of and sympathetic to psychiatry – seemed to agree.
So what is the fuss about now? The FDA has just approved lurasidone for the treatment of depression in individuals who have been diagnosed with Bipolar Disorder. This has been the trend in psychiatry – many of the newer antipsychotic drugs have indications for mood disorders. The advantages for drug companies are clear; there are vastly more people who are diagnosed with a mood disorder than with psychosis. The market is much larger.
The push is huge. I have received multiple reprints of the studies that have just come out in the American Journal of Psychiatry. There are advertisements on TV. I have already had people ask me (just as instructed in the commercial), “Is this drug right for me?” In addition, the US government is reconsidering its rules regarding the privileged position the psychoactive drugs have with Medicare D, the program that pays for drugs. When the law went into effect, all psychiatric drugs in any given class had to be offered (albeit with a significant co-pay for some). The government wants to amend the rules. A number of groups are trying to block this. Sunovion is highly active in this fight. I was quoted in a Boston Globe story saying that I did not think we would lose anything if the branded antipsychotic drugs were not included in a formulary.
To be honest, I am agnostic about what approach is best for any individual. I think my role as a physician is to educate the people who consult me, to explain what I know and do not know about the problems they are having, and what I know and do not know about available treatments. If there is a drug that will help, I will offer it. Some of the people who comment here seem a priori against the notion of using a drug to reduce suffering. I do not share that view. Humans have ingested substances – to relieve pain and suffering or just to have a good time – for thousands of years. Some people want to ingest something in order to feel better. Others want to surround themselves with caring people and caring communities. Some turn towards spiritual practices. I see my role as much as an educator or guide as anything else. My gripe with psychiatry is not on methods per se but on its hubris at overstating what it knows, its failure to report on studies honestly, its creation of a narrative that does not fit the data, and its rampant conflict of interests.
So I think I have an obligation to understand lurasidone and how it may help and not help the people who consult with me.
Last week, I wrote about cognitive behavioral therapy. I tried to look at the study as critically as I would review a drug study. To be honest, I am not sure I succeeded. In some subtle ways (using the title “Paradigm Shift”, calling the study “important”), I may have tilted in favor of what I thought was a study showing modest and preliminary support of CBT. So I am mindful of being even-handed here.
In two studies (here and here), both published in the American Journal of Psychiatry, the researchers (and all authors of these studies with two exceptions were Sunovion employees) evaluated the effect of lurasidone on individuals diagnosed with Bipolar Disorder who were depressed. In one study, the drug was compared against placebo. In the other study, lurasidone was added to lithium or valproic acid; the comparator group remained on the mood stabilizer but had placebo added instead. These were both double blind, multi-center studies. This is what allowed for the FDA approval and the presumed patent extension. I am not going to review the studies in detail. In both, the authors reported a significant reduction in symptoms in favor of lurasidone with an effect size of 0.3 to 0.5. This is similar to the effect size reported in the CBT study I reviewed recently. The studies each lasted for 6 weeks although extension studies are underway. They report that the drug appeared to be fairly safe and well tolerated. There was little weight gain or impact on metabolic parameters.
What I want to focus on is the accompanying editorial written by R. H. Belmaker who reports no COI. He ponders what it means that so-called “antipsychotic” drugs appear to be effective for Bipolar Disorder. After all, for over 100 years, psychiatry’s diagnostic classification system is based on the Kraeplinian distinction between Schizophrenia and Bipolar Disorder. He wonders if by the time DSM-6 rolls out, we will need to have a “unitary psychosis” categorization. He then asks if this heralds “a new era in psychiatry and psychopharmacology”? He answers this question modestly. He points out that in the first textbook of psychopharmacology by Klein and Davis, “the usefulness of typical old-fashioned neuroleptics such as chlorpromazine in many forms of depression was emphasized . . . It could be said that we have rediscovered the wheel.”
His comment betrays humility for the field;
Clinicians have become a bit jaded during a long era of ‘me too’ compounds where new antipsychotics and new antidepressants seem to appear daily—hailed by leaders of the field and feted with dinners and weekends for clinicians willing to attend, later to lose their patents and be discarded on the scrap heap of history.
He also raises an important question, “Could there be some more practical mechanism in play here such that perhaps only sedative atypical antipsychotics are useful in depression?”
I appreciated the general modesty of this editorial, but these are the questions I would have asked if I had been asked to editorialize:
- How can we put any stock in a 6 week trial when we now know that over the long term, these drugs may pose some serious risks for individuals? We know that although studied for 6 weeks, these drugs tend to be prescribed for a much longer period of time.
- How can we consider a study that has no active placebo? Dr. Belmaker hints at this issue with his comment about sedation.
- How can we allow ourselves to be influenced solely on the basis of drug company funded studies when we know from past experience that they can be so misleading? By this time, we need to recognize that FDA approval meets the minimum standards of information we require to fully understand drug effects. We also need to know that the initial FDA reviewer did not recommend approval of this drug for Schizophrenia. Why is it that I need to go to the blog of a retired psychiatrist (albeit of a very smart and tenacious one) to find out what other studies were registered (this is critical since the FDA only requires two studies for approval but companies can do as many studies as they want)?
- We know that earlier studies were likely biased by dosing issues. Why not have as an active comparator ultra low dose of a neuroleptic such as perphenazine? It is cheap, it has little impact on weight, it is as effective as other neuroleptics. A major problem with how we prescribed neuroleptics in the 70’s ad 80’s was due to excessive dosing. We began to reckon with this in the late 80’s but the message got lost as the newer drugs were brought on to the market. Why not have as a comparator a sedating non-neuroleptic drug? Even if the drug company was not required to do that, why not specifically point out these limitations rather than just hint at them?
• On a more basic level, doesn’t the lack of specificity of these drug effects support Joanna Moncrieff’s notion of a drug centered vs. disease centered approach to evaluating psychoactive drugs? How much more tortured will DSM 6 be in an effort to explain the disparate effects of these drugs? A unitary psychosis hypothesis will not address this. After all, most people who are depressed, even when the label is bipolar depression, are not psychotic. Dr. Moncrieff points out how the disease-centered approach has, among other things, blinded us to the long-term consequences of drug use. It has blinded us to the risks of drug withdrawal. These are not the challenges of “anti-psychiatrists”, these are questions posed by psychiatrists who want to have a full understanding of the benefits as well as the risks a person takes when she chooses to ingest these drugs. I pointed out that I am agnostic on interventions. But I am also agnostic on the basic “disease” premise. For me, it remains a hypothesis, one that becomes increasingly weaker in its evidence base as we learn more about the brain. This is an area in which I join company with Dr. Insel, the Director of the NIMH. When will we begin to address this serious concern?
Dr. Belmaker, to his credit, addresses the loss of confidence in our profession. But I wish he would have addressed more directly why, over time, these other drugs were discarded.