Edward Shorter: The Rise and Fall of the Age of Psychopharmacology
Robert H. Belmaker’s comment
This book is written by the noted historian of psychiatry and psychopharmacology Edward Shorter who has followed international psychopharmacology from its beginnings and has co-authored the almost official CINP history of psychopharmacology, together with Tom Ban and Edward Healy. So, when he writes about the fall of psychopharmacology, it is time for even psychopharmacology stalwarts to sit up and listen. Sometimes histories of this type are written when it’s already too late to make the necessary salvational changes. However, in the case of psychopharmacology, its accomplishments are so great and its proper place so assured that a history of its rise and more recent fall leaves time for appropriate corrections, self-assessment, repositioning and hopefully continued progress.
The last sentence is not always the feeling that Edward Shorter conveys. Often his opinions are totally condemnatory and carry the tone of a convert who has reverted to apostasy. For instance, Shorter seems to blame entirely the pharmaceutical industry for converting early studies of psychopharmacological breakthroughs into compounds that are merely products for sale and means for companies to maximize profits. There is undoubtedly some truth in this.
I, myself, a president of CINP 2008 to 2010, have been horrified to see the yearly parade to my country Israel of international key opinion leaders (KOLs) pushing the latest antidepressant or latest atypical antipsychotic. The meetings often obtain sponsorship by our psychiatric society without any control of content or presentation of alternative medicines but only of the medicine being “launched.” The data resulting in FDA approval of the compound is presented vs. placebo with these long, impressive p values (eg, p<.0001). Most of the physicians in the audience have limited statistical understanding and assume that the more zeros, the more effective the compound is. Each compound is presented as more effective than the compound presented the year before. Sometimes the same opinion leader comes back each year. No wonder Edward Shorter and the rest of us have become disillusioned. Because if this trend were true, our recent antidepressant compounds would be so much more effective than the original imipramine or even the original SSRI Prozac. And our recent antipsychotics would be so much more effective and so much freer of side effects than our original antipsychotic chlorpromazine. Every clinician knows this is not the case. And so, the credibility of the key opinion leaders and the whole field has been broken and psychopharmacology indeed has entered the age of fall.
But was it only the drug industry to blame? Academic leaders of psychiatry certainly need more of the blame. I do not pretend to be an analytical historian and able to assign blame. I do criticize Edward Shorter, who is an analytical historian, for not giving us a more nuanced picture with a weighing and balancing of the evidence. David Healy has already documented in his books many of the horrible corruption scandals in the pharmaceutical industry that led to litigation. I know from personal experience that an increasing number of academic leaders are experts in designing psychiatric clinical trials that meet FDA guidelines and in analysing the data but see few patients themselves. The patients they see may be unrepresentative patients at tertiary centers or private clinics. How did this happen and how did KOLs become experts in data analysis rather than clinicians? Shorter does not answer this question.
A third source of blame receives short shrift in this book (no pun intended) and Paul Leber, the head of neuropsychopharmacology at the FDA is even often treated with a measure of awe. Again, I am not an analytic historian and I did not read all of the manuscripts involved to weigh the assignation of blame. However, I do remember being very impressed that Paul Leber made frequent antipsychiatry comments. He was sceptical of the efficacy or even the possibility of efficacy of treatments of depression, of psychosis and of mania. To that end he insisted that every psychotropic compound be tested alone vs. placebo.
In contrast, drugs for neurological syndromes such as epilepsy were usually tested in other more clinically relevant designs. For instance, patients with continued epileptic attacks despite moderately effective antiepileptic therapy could enter a drug trial where the new drug or placebo was added to existing therapy. This add-on therapy is far more like real life practice and allowed the development of new anti-epileptic drugs that were truly innovative and useful in some patient groups rather than the me-too compounds that were shown to be active in psychopharmacology vs. placebo but which were not more effective than the original compound. It is a mystery to me why Paul Leber never let up in demanding placebo-controlled studies only for psychiatry. Add-on trials could have been so much cheaper and more attractive to recruit truly suffering patients rather than symptomatic volunteers without current treatment.
Another path not taken would be restricting the study of new compounds to initial studies in treatment resistant groups. Thus, patients who had not responded to imipramine could be studied with a new compound vs. placebo because they were not responsive to the currently available treatment. This would have been far more likely to discover compounds with new mechanisms of action and new clinical value. Paul Leber, to my knowledge, objected to this strategy in psychiatry whereas he allowed it in neurology. The result is that neurology has had an increasing number of compounds, say in epilepsy, with totally different mechanisms of action where in psychiatry we seem stuck on reinventing the wheel every year.
Could covert antipsychiatry have been another one of the causes of the fall of psychopharmacology? Edward Shorter does use in his book the elegant phrase of the “poisoned chalice.” Perhaps worship of the randomized clinical placebo-controlled trial for psychiatry sounded scientific but it may have been a poisoned chalice. Shorter does not evaluate these alternative possible causes of the fall of psychopharmacology.
For the third time in this review, I am going to state the disclaimer that I am not a historical analyst with access and knowledge of historical sources and the ability to weigh and assign blame. However, it sems to me that the international psychopharmacology organisations have contributed to the fall of psychopharmacology by creating a false relationship between basic science and clinical science in psychopharmacology. Sessions in the regular program (I am not talking about the drug company sponsored sessions with dinners in fancy ballrooms) usually began with a basic science speaker in brain physiology, followed by a second speaker explaining the basic chemistry pharmacokinetics and metabolism of the new drug, a third speaker explaining in general terms the DSM, ICD and epidemiological relationships of the diagnosis in question and a fourth speaker presenting the efficacy data of the new compound in the given diagnosis (with those oh so very, very impressive p values!).
The hundreds of listeners were given the strong impression that the basic brain science led to the discovery of the new chemical medicine with its uniquely valuable pharmacokinetics and which is now available and shown in a clinical trial to be so much more effective than what we previously had. This pseudo-Aristotelian four-lecture outline was repeated again and again. Organizers were proud of it because it included both basic science and clinical science. However, there was almost never any relationship between the basic neuroscience presented, the chemistry presented, the pharmacodynamics presented and the clinical trials presented. Nor was there, except rarely, any discussion of a comparative competing drug or an alternative strategy. The design was simply an infomercial but so many organizations bought into it.
Edward Shorter is known to me from his previous books as a careful historian. Therefore, I was surprised in his present book by his frequent use of off-hand quotes such as professor so and so said in 1966 at a party in Los Angles or professor Y said in 1975 in a private meeting with me that. These quotes tended to be off-hand and anyone could, in a moment of criticism or self-revelation, have made a statement that does not reflect his overall viewpoints. In many cases I know for a fact that the viewpoint that Shorter quotes was not the general viewpoint expressed by the person quoted over the course of his career.
Moreover, Shorter seems to accept some facts that he assumes are beyond criticism. For instance, he repeats without discussion that ECT is the most powerful and effective treatment in psychiatry today. The non-psychiatrist reader might be caught off balance thinking “why then isn’t it the one treatment that all psychiatrists always use?” He does not point out at any time that ECT has an extraordinarily high relapse rate, that it is an expensive treatment, that it is considered invasive and is now associated with autobiographical memory loss which is an unacceptable price for many patients. Shorter also reveals his limitations as a non-psychiatrist in his admiration of the pre-DSM-III diagnostic systems. They were in my opinion worse than the DSMs. Perhaps we are not such sinners, but we are struggling with very big problems. Shorter creates a morality play, but maybe this is a Greek tragedy.
I do not think that the reader of this book will be left with the basic understanding that imipramine for endogenous depression, chlorpromazine for psychosis, lithium and mood stabilizers for bipolar disorder, benzodiazepines for anxiety and insomnia, and amphetamines for childhood hyperactivity are solid impressive advances in the history of medicine and part of the basis for satisfying and worthwhile practice of our specialty. The baby should not be thrown out with the bath water. History should not be written by the assembling of off-handed single quotations from individuals obtained at random moments in their career.
Shorter quotes Irving Kirsh, another brave pioneer critic of psychopharmacology, particularly of depression. Shorter quotes Kirsh who believes that most antidepressants are inert or possibly active placebos. As non-biologists, both ignore the activity of antidepressants in animal models of depression such as the Porsolt forced swim test. This is not final proof of human clinical activity, but surely it is more than a coincidence that almost every known human antidepressant is active in this animal behavioral test.
Moreover, at the biochemical level, these substances inhibit reuptake of serotonin, noradrenaline or dopamine. This was admittedly not specific enough to support naïve theories of serotonin deficiency in depression in 2021, but for many years it was heuristic, honest and even exciting. Is it not still an accomplishment to say that we can design in a laboratory computer a new chemical entity that will interact with the serotonin transporter and be almost sure that it will turn out to be an antidepressant in the clinic. The new compound will be a me-too and may not be what we need now in 2022. But if one such compound shows evidence in animal tests that it does not have sexual side effects, I think it does not need large placebo-controlled trials to prove efficacy. It should be fast tracked via small trials compared to imipramine and focussing on sexual side effects. This would save money for companies, focus research to current needs and reduce the cost of innovation. It would of course not give us entirely new antidepressants. In short, Shorter is short on practical and modest ways to improve psychopharmacology research. But practical and modest are the name of the game, because overpromising and grandiose claims are the essence of the problem of our fall.
There is in reality a potential proper relationship between basic science and psychopharmacology. The version presented in Figure 1 which assumes that basic science is the bedrock of discovery and that RCTs are the gold standard built on them, is indeed incorrect. However, we must strive to teach a model as illustrated in Figure 2. In the model of Figure 2, basic science such as the animal models described above, help us to choose compounds for testing in the clinic. Small focussed clinical trials are also critical, and post-marketing data analysis is as important as the larger RCTs. The 2021 Nobel Prize in Economics to Joshua Angrist provides the real direction for the future: natural experiments monitored by big data and computer interconnections to find what medications really do to help patients in the real world in a convincing scientific way at low cost that allows constant innovation.
January 27, 2022