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"The strange professor in my World Religion I Course had a lecture he’d given countless times, always with the same passion as the first day he wrote it. "Primitive man," he said, "had only two paths to follow in the face of an inhospitable nature." After a long pause, he continued, "Pious Petition – praying to the universe for mercy, And…" After another pause, he adopted an impish grin, "Magic! – trying to force the universe into compliance." He went on to talk about how the former became religion and the latter was the precursor to science."
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by Steven E. HymanNeuropsychopharmacology Reviews. 2014 39:220–229.
The term ‘revolution’ in science and medicine is often used hyperbolically, but the period from 1949 to 1957 can fairly be described as revolutionary for psychopharmacology. A remarkable burst of discovery began with John Cade’s recognition of the therapeutic potential of lithium in 1949. Henri Laborit first administered chlorpromazine for preoperative sedation in 1952, but quickly recognized its possible utility for the treatment of psychotic patients. Iproniazid, the first monoamine oxidase inhibitor antidepressant, failed in its intended use as a treatment for tuberculosis in the early 1950s, but in clinical trials, significant elevation of patients’ moods was noted. Imipramine, the prototype monoamine reuptake inhibitor antidepressant, was synthesized as a candidate antipsychotic drug based on modifying the tricyclic molecular structure of chlorpromazine. Imipramine failed to treat psychosis but was recognized to have antidepressant effects. By 1957, both the MAOI iproniazid and the tricyclic drug imipramine were recognized as antidepressants…
Unfortunately for individuals with psychiatric disorders, the astonishing developments of the 1950s have been followed by a similarly improbable half-century of stagnation. This period has been characterized by failure to improve the efficacy of pharmacologic treatments for established clinical indications or to extend effective treatments to additional significant symptom clusters. The most significant success during the past five decades has been in the domain of toxicity. Thus, for example, antidepressants approved since the late 1980s [eg, the selective serotonin reuptake inhibitors] are far safer and more tolerable than the older tricyclic drugs and MAOIs. A second generation of antipsychotic drugs exhibits decreased liability to cause serious motor side effects, including tardive dyskinesia, compared with first-generation drugs — but carries its own serious side effects including significant risk of weight gain and associated metabolic derangements.
It’s hard for me to imagine it now, but I saw that twenty years as an era of biological psychiatry at the time – oblivious to how industry driven it really was. The rash of new drugs came from the pharmaceutical industry. The departments of psychiatry were assisted by grants from the pharmaceutical industry. Many of the journal articles came from the pharmaceutical industry. The DSM categories were targeted by the pharmaceutical industry, both on and off-label. The Clinical Research Organizations were an offshoot of the pharmaceutical industry. Many of the leaders in psychiatry were affiliated with and partially supported by pharmaceutical industry [known as KOLs].
What has not happened for five decades across the range of psychiatric drug classes is any significant improvement in efficacy. No antidepressant drug has proven more effective than imipramine or the first MAOIs. Second-generation antipsychotic drugs are, in general, no more efficacious than the first, and no antipsychotic drug is as efficacious as clozapine, a drug that was discovered in the early 1960s. In the 1980s some anticonvulsants were found to have therapeutic benefits as mood stabilizers, but none has proved so effective as to obviate the need for lithium, despite its side effects and difficulty of use. Many individuals with schizophrenia and related disorders have significant residual psychotic symptoms despite current treatments, and there are no significantly effective treatments for the highly disabling cognitive or deficit symptoms of schizophrenia. Many patients with depression [most notably bipolar depression] and anxiety disorders have substantial residual symptoms despite optimal use of current treatments. Moreover, no effective pharmacologic treatment has been developed for the core social deficits of autism.
Given the significant unmet need, the high prevalence of psychiatric disorders, and their outsized negative effects on disability worldwide, psychiatric drugs would seem to be compelling focus for the biotechnology and pharmaceutical industries. Instead, the past 4 years have seen the industry significantly decreasing its investment in psychiatric disorders while investing in other areas… Payers and regulatory agencies have begun to balk at the marketing of expensive new treatments that fail to advance efficacy. Faced with payer demand for greater efficacy or at least a companion biomarker to identify likely responders, companies have retreated from psychiatry because they can identify no clear path to satisfying such requirements. Upper level management at many pharmaceutical companies recognizes the large markets and unmet need. However, given what they perceive as less mature scientific underpinnings than in competing areas of medicine, they are, for the most part, unwilling to renew their once substantial investments in psychiatry.
It is important to view the stasis of the past five decades with clear eyes, rather than defensively. The disorders of higher brain function that neuropsychopharmacology is concerned with have greater associated challenges than those that face many other fields of medicine. Nonetheless, the difficulties inherent in confronting polygenicity, disease heterogeneity, and limitations of current animal models appear more similar than different across medical disciplines. The pace of technology development seems only to be accelerating, and should thus give us hope. Despite the challenges, there is a substantial opportunity to win back industry and to revitalize psychiatric therapeutics by embracing clear thinking and by putting technologies to work.
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Trying to wrestle nature into compliance with Magic and Science is hard work, but Pious Petition isn’t altogether easy either. Primitive cultures have done all kinds of elaborate things to coax the gods into coming their way – prayer, worship, sacrifice, bargaining, ceremony, even using bait [Cargo Cults].
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While I chose this piece by Dr. Hyman, I could’ve picked any number of Dr. Insel’s NIMH blogs over the last several years, or the conference mentioned above [APF Convenes Unique Pipeline Summit], or Dr. Lieberman’s recent piece [Time to Re-Engage With Pharma?], or many other similar commentaries to illustrate the two dominant themes these days: "we need more and better drugs" and "we need to lure PHARMA back." Even as the pharmaceutical industry exits the scene, Hyman’s appeal remains focused on getting them back – again highlighting how industry-dependent modern psychiatry became.
The lamentations in his opening paragraphs have been true for five decades. Nothing new. They include the quarter century following the introduction of the DSM-III. The exciting and promising new drugs that flowed from the pipeline during that time are now relabeled me-too drugs, variations on the 1950s discoveries. But in their days, they were heralded as breakthroughs rivaling sliced bread. While they may be better tolerated than the originals, even the claim of decreased toxicity is something of a reach. The exuberant medicalization of psychiatry by the 1980’s revolution, the 1990’s decade of the brain, and the dawn of clinical neuroscience that followed span this period Hyman now characterizes as stagnation. Even his title, Re·vitalizing Psychiatric Therapeutics, suggests a previous period of vitality, yet he has just told us that it was, in fact, scientifically stagnant. What was vital about the longed for past was the pharmaceutical industry’s pipeline that produced the string of new drugs whose success rested on hope and hype, rather than enduring improvements in efficacy or safety. But they sure pulled in the revenue that supported all concerned – that kind of vital.
Rather than a continuing monomaniacal focus on reviving this past that relied so heavily on industry and illusion, it seems to me that we would be better placed to harken back to what has been relinquished or laid aside in this era of johnny-one-note psychopharmacology. While cure has always been the ultimate goal of the medical profession, what we do throughout medicine when it’s unattainable is deliver care. And there was a time when psychiatrists prided themselves on having a unique expertise in that area – particularly in those cases where the tangles of biography and life are taking an ongoing toll, cases where medications can never be more than short term adjuncts. And even in cases where medications are effective, there are residual symptoms [see Hyman’s third paragraph above] currently best managed with psychosocial interventions.
Dr. Hyman continues to give us these hortatory anodynes, but I do not see that he produced breakthroughs during his time as an active investigator – he certainly added nothing to the pipeline. After he left the laboratory for administration he cycled through a term as director of NIMH and then another as Provost of Harvard University under Larry Summers.
One could make the opposite case: that close interactions of academic investigators with industry are a net negative. Sure, they bring in money, but they also distract from the primary goal of research, which is the disinterested search for truth. The many experimercials funded by industry can hardly be called disinterested. At the same time, they siphon critical clinical research infrastructure away from genuinely original research. So do the misguided mega-projects that Dr. Hyman kicked off, like STAR*D. President Eisenhower’s warning about the academic-industrial-government complex is still valid after 53 years.
I would add to this that given all of the above, why not challenge some fundamental principles. Rather than repeatedly dismissing those who have successfully utilized other – often non-medical – means, as outliers (“we always knew there were some who recovered”), why don’t we try to understand and listen to what they are saying?