Editor’s Note: Over the next several months, Mad in America is publishing a serialized version of Les Ruthven’s book, Much of U.S. Healthcare is Broken: How to Fix It. In this blog, he addresses the lack of evidence for antidepressants being better than placebo, as well as a note about ECT. Each Monday, a new section of the book is published, and all chapters are archived here.
Research on the ADM and placebo effects from 2003 to the present are extremely similar to the earlier research findings.
Irving Kirsch and colleagues, again under the Freedom of Information Act,6a were able to obtain all data for all clinical trials submitted to the FDA for the licensing of the four new-generation antidepressants (ADMs). The researchers performed a meta-analysis on the data to obtain drug-placebo HAM-D-Scale scores, the instrument to measure reduction of depressive symptoms. The analysis found no placebo-drug differences for those diagnosed with moderate depression and a relatively small difference in favor of the drug for those in the severely depressed category.
In these six- to eight-week trials, the FDA (as mentioned above) typically requires a 70% subject completion rate for the study to have any scientific value. In these studies, however, 60% of the placebo patients and 63% of the drug patients completed the six- or eight-week trial, which is certainly not at all impressive for a drug effect. Typically, clinical drug trial subjects drop out of these trials prior to completion because of a combination of adverse side effects and/or lack of improvement. One does not have to be a trained scientist to know if a drug does not have a lower drop-out rate than a placebo the drug is likely to be ineffective.
In the above Kirsch trials, 39 studies focused on outpatients, three were conducted on the elderly, and two of the trials were conducted on severely depressed inpatients. The latter is pointed out because psychiatrists continue to say that psychotherapy alone is sufficient to treat mild depression, but drugs are needed for moderate to severe depression, although the research data is contrary to such an assertion.
The Kirsch analysis of the clinical trial data included the negative and unpublished clinical trial data as well as the FDA-approved trials. Historically, about half of the FDA clinically submitted trials went unpublished, which means the drug had no superiority over placebo, a finding which certainly calls into question the efficacy of ADMs in effectively treating depression.
The overall data in the Kirsch studies finds that the new generation drugs fall well below clinical effectiveness as did the first-generation drugs. Efficacy was found to reach clinical significance only in the severest depressed patients, the researchers attributing this finding to a decreased response to placebo in the severely depressed rather than any increase in the clinical response to the medication. Kirsch’s explanation of the latter finding makes clinical sense to me because any treatment or a placebo signals hope for the patient, and very severely (and I would say psychotically) depressed patients are very likely to have less hope of getting better than the less severely depressed.
A word about FDA antidepressant drug clinical trials.
As I have mentioned previously, FDA clinical trials give a brief snapshot on the drug’s efficacy and safety, but how do the trial findings compare with the research on the efficacy of these medications subsequent to their FDA approval? For example, as noted above, the FDA depression clinical trials allow the submitted trials to remove and exclude persons with only mild depression from the trials.
The trials, then, are only applicable to those with moderate and severe depression as defined by ratings of the severity of symptoms. In the real world, however, physicians give all of their patients complaining of “depression” these drugs, those whose “depression” is not diagnosable at all and those with only mild depression as well, which is contrary to the FDA trials.
However, does the post-FDA antidepressant approval research support the FDA data that these drugs are applicable only to moderate and severe depression? J.C. Fournier et al. conducted a study on antidepressant drug effects on severity of depression which questioned one of the major conclusions of the FDA clinical trials. In this meta-analysis of ADM randomized, placebo-controlled trials, it was found that antidepressants did not effectively treat mild or moderate depression, only severe depression! This finding, of course, severely restricts the number of depressed people in the real world who are appropriate for such medications.
Here you may recall Kirsch’s thinking that severely depressed subjects in the trials improved more than the moderately depressed because perhaps the power of the placebo effect was lessened for those severely depressed! In a group of depressed patients, about 23% are defined as having severe depression, which means that of those with diagnosable depression, 77% would not be candidates for antidepressant medication! I would expect of those prescribed ADMs by their physicians for their “depression” less than 10% would be candidates for the drugs according to the FDA clinical trial data!
How much money and professional time are we wasting on the drug treatment of depression? The above also means that 90% of those prescribed the drug would have no more than a placebo benefit and would also be needlessly exposed to the drug’s adverse side effects!
Should electroshock therapy (ECT) be suspended until there is proof of its efficacy and safety?
John Read, Ph.D., and his research group in London, England (see Medscape, July 24, 2020) called for the immediate suspension of electroshock therapy (ECT) because of the absence of evidence to prove its efficacy in treating so called resistant depression, at least until research proves its effectiveness! The researchers noted that the last randomized clinical trial (the placebo control was sham treatment during the ECT procedure) appeared in 1985. The London researchers did not mention the Kirsch re-analysis of the FDA depression-drug clinical trials that found 80% of the drug improvement was the placebo effect!
Another consideration for suspension was the persistence of memory loss in 12% to 55% of the cases! One suspects there was major pushback to the article from ECT proponents, which was quite apparent in the Comment Section of the article. A number of ECT proponents claimed ECT was a viable and safe treatment for seriously depressed patient who failed to respond to other treatments (that is, drug treatment). The following was my comment on the proposed ECT suspension:
The 80 year “unsettled” controversy about the efficacy and safety of ECT is replicated by dozens of other controversial treatments espoused by adherents appealing to clinical opinion and anecdotal “evidence” vs. the detractors like me who appeal to the lack of randomized, placebo controlled studies that would demonstrate treatment effectiveness and safety of many “standard of care” treatments of today. . These dozens of other treatments, similar to the ECT controversy, continue to go on and on as unfortunately ECT will continue well into the future. If you question this look at the history of bloodletting, which was shaped by today’s clinical opinion/patient-provider satisfaction offered as proof of efficacy. The problem is that practitioners—and not those trained to do science or to critically evaluate scientific research—shape everyday healthcare policies and practices, which again are dominated by clinical opinion (“I gave ECT to Mary for her intractable depression and she got better”). As an example, my personal physician read a paper of mine on the lack of any scientific evidence to support Epidural Steroid Injections for back pain and his only retort was that “You can prove anything by research” which I suspect pretty much represents the position of most practicing physicians about the need to subject many of their pet clinical practices to the scientific method. I anticipate that as long as practitioners (and not scientists trained to examine treatment efficacy and safety) shape everyday clinical practice healthcare will continue to have a number of popular but unproven treatments such as ECT! This clinical opinion vs. science is also fundamental to many other of our quality and cost problems in healthcare today.
Proponents tell us that ECT is necessary to treat resistant depression for those depressed patients who do not respond to other “therapies,” by which proponents mean depressed patients who do not respond to one or two courses of antidepressants! What about the TV ads that report that two-thirds of depressed patients on antidepressants are still depressed? It sounds like all depressed patients on antidepressants should be candidates for ECT but I, for one, would not recommend it.
In my review of the health literature, I have noticed that a number of bogus treatments such as ECT go out of favor for a time but tend to rise up from the dead years later. A recent example is the once popular brain surgical “cures” for treating so called intractable mental disorders such as depression and schizophrenia. Lobotomies were fortunately almost completely dead for 40 or so years but they were resurrected recently by a surgical team at Harvard who performed 34 brain surgeries of what was called “state of the art” brain treatments of intractable mental disorders. Why not “state of the art lobotomies” for those depressed patients who do not respond to either drug therapy or ECT? Do you think bloodletting will have a needed revival one day?
Chapter 5 will explain my thinking why many bogus psychiatric and medical therapies appear effective to some providers and patients.
Case study of the utilization and cost of psychiatric drugs prescribed by primary care physicians (PCPs) in a 5000-employee health plan versus the utilization and costs of behavioral treated patients by psychologists and clinical social workers in a similar health plan.
I conducted the above unpublished research study along with National Prescription Administrators (NPA) of St. Louis, Missouri. This was a Preferred Mental Health Management (PMHM) and NPA managed behavioral health plan (Chapter 4) and the study enabled comparison of NPA’s psychiatric drug costs in the plan versus PMHM’s corresponding costs of arranged behavioral care by PMHM’s contracted psychologists and clinical social workers. In the NPA plan, non-psychiatric physicians treated just shy of 10% of the covered members in the plan with psychiatric drugs during the first 12-month period and 13% of covered lives during the next 12 months, resulting in a 25% increase! In the PMHM managed plan, 5% of the covered members received non-drug therapy by behavioral health (BH) professionals or 50% fewer than NPA’s plan in which family physicians treated NH patients with drugs.
The most relevant statistic for the cost of drug treatment versus behavioral treatment is the cost per treated patient. The average cost per drug-treated patient (cost of drugs plus an estimated cost by NPA of office visits to monitor the treatment) was $277.70 versus the average cost for PMHM’s BH treatment, which was $204.56, or 35% less per drug-treated patient! So much for the conventional wisdom that drugs are cheaper than therapy.
Moreover, the average length of behavior therapy was on average less than six sessions versus the average length of psychiatric drug treatment was slightly over two months, which by the way falls far short of the recommended ADM trial of six months. The latter suggests that a number of those who stopped the medication prior to two months may support the thinking than many depressions are self-limiting with or without treatment or lack of response/adverse side effects contributed to shortened treatment.
If the costs of psychiatric drug treatment by physicians not trained to diagnose and treat mental disorders is not in itself an indictment of the practice, the quality of how these drugs were prescribed in this health plan is nothing short of deplorable. Re-reading between the lines of psychiatric drug prescribing practices is a thread such as: “If the patient is not doing well on the one psychiatric drug, increase the dosage; if a dose increase doesn’t work add a second ADM (a tricyclic ADM or another current generation variety).”
In one case a patient was on three ADMs, and in another case four ADMs (just imagine the combined adverse side effects of taking four ADMs). Of all psychiatric drugs available, the PCPs had a strong preference for ADMs, which accounted for 62% of the total psychiatric drug costs in the plan. PCPs prescribed 80% of all psychiatric drugs, again confirming my belief that PCPs have become the largest group of untrained “mental health” professionals in the U.S.
Five hundred sixty-one patients in the plan were prescribed at least one psychiatric drug while 187 of those were prescribed two or more BH drugs. For example, patient #8 in the study received four different ADMs and two antianxiety drugs, patient #14 was prescribed one ADM and one anti-manic drug, patient #33 was prescribed four ADMs, one sedative/hypnotic and one antianxiety drug, patient #88 was prescribed five ADMs and one antianxiety drug, and so on. None of the above prescribing patterns is consistent with drug treatment for a known emotional disorder (most psychiatrists would agree) and multiple medications suggest the physicians were chasing and treating drug side effects of primary medications and not just symptoms of depression!
There is no reason to expect that the psychiatric drug prescribing patterns in this study, one should say deplorable prescribing practices, are at all unique to this one benefit plan, and I am quite confident one would find that these types of inappropriate prescribing patterns exist in all health benefit plans in the U.S. today.
The total costs of the BH drugs in the plan under study was $267,373.20, for a cost of $4.21 per member per month (pmpm), substantially higher than PMHM-arranged BH care costs of $0.85 pmpm or 80% lower than physician treatment of BH problems!
To see the list of all references cited, click here.
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