Thomas Insel, who directed the National Institute of Mental Health (NIMH), is busy promoting his new book, which carries the odd title of Healing: Our Path from Mental Illness to Mental Health. It is a curious title and a curious endeavor, given that his thirteen years in charge of the nation’s mental health research produced such uniformly dismal results. When the New York Times recently interviewed him about the book, the headline spoke of him as “the Nation’s Psychiatrist.” If he is that, the outlook for those with serious mental illness is a dark one.
Having overseen the expenditure of more than twenty billion dollars during his term of office, Insel confesses that none of that money has produced any clinical advances that help patients, and that is an understatement. And yet he has the chutzpah to promote himself as having the answer to the country’s mental health problems—which turns out to be more of the same singular emphasis on neuroscience and genetics that characterized research at NIMH under his leadership. As the cliché would have it, repeating the same behavior that has proved counterproductive in the past is the very definition of insanity.
NIMH was born in the aftermath of the Second World War, a conflict that showed, once again, that modern industrial warfare is inimical to mental health, with hundreds of thousands of troops succumbing to combat-related mental disorders. For the first three decades of its existence, the new institute pursued an eclectic approach to the problems posed by major mental illness, funding social and behavioral research alongside biological and pharmacological studies. That broad-spectrum approach was abruptly abandoned under Reagan’s presidency. Research that suggested connections between mental illness and social factors was distinctly unwelcome politically, and faced with threats to the organization’s funding, the leaders of NIMH embraced a research agenda that focused narrowly on biological psychiatry.
In many ways, Insel’s time as director of NIMH thus followed what had been its standard approach for more than two decades. But the shift from what one president of the American Psychiatric Association called a bio-psycho-social approach to the problem of mental illness to a bio-bio-bio approach was particularly marked under Insel’s leadership, and has been continued under his successor, Joshua Gordon (whose own research prior to his appointment was on neural activity in mice). Funding genetics and neuroscience has become the Institute’s mantra, regardless of its failure to deliver positive results.
Since the appearance of the third edition of its Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1980, American psychiatry has been fixated on defining mental illness on a purely symptomatic basis. The presence of a certain number of symptoms in a tick-the-boxes fashion is supposed to result, in a purely mechanical fashion, in a diagnosis of schizophrenia, major depression, or bipolar disorder (not to mention a host of other mental disorders). It was an approach that, in the face of a parade of embarrassing studies that showed the profession could not agree on diagnosis, tried to ensure inter-rater agreement while quite deliberately ignoring the issues of whether psychiatrists’ labels corresponded to real diseases in nature.
When the American Psychiatric Association contemplated a fifth revision of this elephantine manual at the turn of the century, its proponents boasted that the new edition would break from this model. With the backing of the neuroscientific research NIMH had been funding under Steven Hyman, the director who preceded Thomas Insel, and with Insel’s renewed commitment to this line of research, the expectation was that DSM-5 would transform psychiatry’s whole approach to diagnosis, using neuroscience to classify mental disorders on the basis of what caused each of the mental disorders it distinguished.
But the science that would permit this simply didn’t (and doesn’t) exist. We remain almost wholly in the dark about the causes of mental illness and the task force charged with constructing the new manual was forced back on the same symptomatic approach the profession had embraced in 1980. None of the hugely expensive neuroscience NIMH had funded had shown what the etiology of mental illness was. It was more than slightly ironic, then, that it was Insel who took the lead in denouncing the new DSM as a monstrosity. In interviews at the time, he voiced his disgust in no uncertain terms.
On April 29, 2013, a week before DSM-5 was officially published, Insel complained publicly that “the final product involves mostly modest alterations of the previous edition.” That was not intended as a compliment. “In the rest of medicine,” he suggested, “this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. . . symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best course of treatment.” DSM-5 set itself up as psychiatry’s Bible, he reflected, but “Biology never read that book,” and “Patients with mental disorders deserve better.”1
It was simply astonishing, he averred, that psychiatrists should practice in this fashion. Most of his psychiatric colleagues “actually believe [that the diseases they diagnose using the DSM] are real. But there’s no reality. These are just constructs. There is no reality to schizophrenia or depression.”2 Henceforth, Insel announced, NIMH would alter its approach to studying mental illness, since “we cannot succeed if we use DSM categories as the ‘gold standard’…That is why NIMH will be re-orienting its research away from DSM categories.”3 In particular, he suggested, “we might have to stop using terms like depression and schizophrenia, because they are getting in our way, confusing things.”4
One sees what motivated such a statement (and it must have been greeted with glee by the Scientologists), but the phrasing was distinctly unfortunate. The labels may need to go (with who knows what consequences for psychiatry’s reputation). Yet the distress and pathology those traditional labels seek to capture will not disappear with them.
Insel’s comments incited a furor, with both medical and scientific journals and the mass media hastening to report his skepticism.5 He had hoped to use the controversy to advance his own pet project, something he called Research Domain Criteria (or RDoC), an attempt to install a research framework based on biology, and more particularly on a nebulous notion that related mental illness to a mysterious something called “brain circuits.” But RDoC was not ready for prime time. No other entity engaged in psychiatric research endorsed his hobby horse, and it has faced fierce criticism since Insel stepped down as NIMH director in 2015.6
In 1886, the American alienist Pliny Earle had lamented that “In the present state of our knowledge, no classification of insanity can be erected on a pathological basis, for the simple reason that, with but slight exceptions, the pathology of the disease is unknown… Hence…we are forced to fall back upon the symptomatology of the disease.”7 Nearly a century and a half later, and despite billions of dollars devoted to neuroscience, nothing, it seems, had substantially changed.
The other major hobby-horse Insel funded during his years as director was the study of genetics. It seemed, on the surface, a promising bet. Dating all the way back to the late nineteenth century, psychiatrists had speculated that mental illness had strong genetic roots. Till the closing years of the twentieth century, such claims rested on evidence from family studies, most notably studies of fraternal and monozygotic twins. These were often plagued by methodological problems and rendered suspect by the ideological commitments of some of the central researchers, but better-conducted studies toward the end of the twentieth century and a greater distance from a prior association with Nazi researches led many biological psychiatrists to expect that imminent scientific advances would uncover strong genetic links to major mental illnesses.
The discovery of the PCR (polymerase chain reaction) technique in 1983, which allowed researchers to make millions to billions of copies of a specific DNA sample, was the first of two major breakthroughs on this front. A year after Insel became NIMH director in 2002, this breakthrough was followed by another major scientific advance, the decoding of the human genome. Taken together, these developments fueled expectations that the genetic underpinnings of disorders like schizophrenia and bipolar disorder would soon be uncovered, and NIMH poured resources into such studies.
Confounding researchers’ expectations, the expected genetic connections have essentially failed to materialize. In the words of two leading psychiatrists, Rudolf Uher and Michael Rutter, “molecular genetic studies of psychiatric disorders have done a lot to find very little. In fact, in the era of genome-wide association studies, psychiatric disorders have distinguished themselves from most types of physical illness by the absence of strong genetic associations.”8 The field as a whole, as the eminent geneticist Kenneth Kendler puts it, has had to absorb some “painful lessons” and acknowledge that “despite our wishing it were so, individual gene variants of large effect appear to have a small to non-existent role in the etiology of major psychiatric disorders.”9
Given the results of nearly twenty years of work, it is now clear that there is no Mendelian gene or set of genes that explain schizophrenia. As that reality became apparent, researchers more and more relied upon an approach called genome-wide association studies (or GWAS). It is an approach that makes no assumption about where genetic associations might lie, but simply scours hundreds of thousands of sites looking for possible linkages and does so for a whole range of psychiatric disorders. The result has been a muddle, one that has disappointed the hopes and expectations of these researchers that a clear picture of the genetics of mental disorder would appear. Studies examining many tens of thousands of patients and controls have failed to show clear genetic links, and even aggregating hundreds of genetic sites, each of which are individually of small effect, explains less than eight percent of the observed variance. Worse still, an individual can harbor many of these genetic variations without ever developing mental illness. Various genes had been hypothesized to be particularly likely to be linked to particular forms of mental disorder. But these so-called candidate genes have been shown to have no closer relationship to the development of schizophrenia than random sets of control genes. That has proved to be as true for bipolar disorder as for major depressive disorder and schizophrenia.
Indeed, these GWAS studies have produced a still more confounding result than these. For rather than revealing one set of vulnerabilities for schizophrenia and others for bipolar disorder or major depressive disorder, most such risks as it identified seemed common to a whole range of mental disorders.10 “The high degree of genetic correlation…among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia,” the international Brainstorm Consortium reported, provides important “evidence that current clinical boundaries do not reflect distinct underlying pathogenic processes. . . This suggests a deeply interconnected nature for psychiatric disorders.”11
In the abstract, negative scientific findings can be seen as just as valuable as positive ones, acting as correctives to one’s original hypotheses and suggesting the need to reappraise research strategies. That is not the message Dr. Insel seems to take from these results. If anything, he suggests, the United States “should double down on brain research.” His successor as director of NIMH, Joshua Gordon, seems to be of the same mind, insisting in the pages of the New York Times that researchers, having identified hundreds of relevant genes, are “starting to understand those genes in the context of the brain,” promising in a decade or two to provide a pathway to better therapies.”12
Psychiatry has been offering promissory notes of this sort for well over a hundred years, and has consistently dishonored them. There are ample grounds for skepticism about these latest assurances from Dr. Gordon and the man who dubs himself “America’s psychiatrist.” The more sensible conclusion to draw from the absence of progress either in understanding the etiology of major mental disorders or in advancing therapeutics is that putting all one’s eggs in the biological basket is a dangerous gamble. If genetics were the royal road to comprehending where mental illness comes from, its effects would have to be exceedingly powerful, and the research of the past twenty years makes that an extremely difficult position to sustain.
Quite unexpectedly, under the weight of the genetic evidence, existing distinctions between disorders are crumbling, and the notion that such artificial constructs identify distinct diseases has become ever-more implausible. The enlightenment genetic researchers have produced threatens to undermine the standing and legitimacy of the “diseases” that psychiatrists had believed in for more than a century—concepts that have woven themselves deeply into the ways the lay public had been taught to view mental illness. To acknowledge that the distinctions between schizophrenia and bipolar disorder may be spurious, and that those constructions might have to be abandoned—but with what to put in their places?—threatens the very foundations of the psychiatric profession’s claims to expertise. If such fundamental building blocks of the psychiatric universe crumble on close inspection, what is left?
Two years after denouncing DSM-5, Insel stepped down from his position as director of NIMH. In the aftermath, he gave an interview to an online MIT magazine. He was asked to summarize his accomplishments while heading the institute, and responded insouciantly, “I spent 13 years at NIMH really pushing on the neuroscience and genetics of mental disorders, and when I look back on that I realize that while I think I succeeded in getting lots of really cool papers published by cool scientists at fairly large cost—I think $20 billion—I don’t think we moved the needle in reducing suicide, reducing hospitalizations, improving recovery for the tens of millions of people who have mental illness.”13
The current situation is even more dire than the one Insel conjures up here. People with serious mental illness live, on average, fifteen to twenty-five years less than the rest of us, and that gap seems to be widening, not narrowing.14 While genetics and neuroscience have flourished within the confines of universities, their therapeutic payoff has been minimal or non-existent. This may change, but it is equally possible that those sponsoring these programs may tire of funding investigations that show few signs of producing practical advances. Meanwhile, advances in psychopharmacology since the introduction of the first antipsychotics and antidepressants in the 1950s have essentially stalled, and the major drug companies have largely abandoned research in this area. 15 In the words of the former head of neuroscience at Eli Lilly and Amgen, “Psychopharmacology is in crisis. The data are in, and it is clear that a massive experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years.”16 Steven Hyman, Insel’s predecessor as the head of NIMH and now director of the Stanley Center for Psychiatric Research at Harvard has made the same point: the discovery of chlorpromazine and related compounds in the 1950s seemed to promise “both therapeutic progress and significant probes of brain function. Looking back, the picture is painfully different. The efficacy of psychotherapeutic drugs plateaued by 1955.”17 And that efficacy is limited indeed, with none of the drugs helping much with the devastating negative symptoms of schizophrenia, and the drugs’ side-effects remaining as troublesome as ever.
In the face of this damning record accrued during the period he oversaw the country’s basic research into the causes and remedies for serious mental illness, Insel is unrepentant. He and his successor continue to fixate on biology and biology alone. In my judgment, that is a profound error, and it threatens to undermine still further the prospects for progress in the mental health arena. The foolish monism that NIMH has embraced has meant that the phenomenological and social dimensions of mental illness have all but disappeared as questions worthy of serious and sustained attention.18 That is an imbalance that has had profoundly negative effects on psychiatry, and more importantly, on the prospects of advancing the clinical care of patients. Given Insel’s role in these developments, I suggest that his is the last voice we should be listening to when we ponder how to deal with the devastation mental illness brings in its train.
- https://www.nimh.nih.gov/about/directors/thomas-insel/blog/2013/transforming-diagnosis.shtml ↩
- Quoted in G. Greenberg, The Book of Woe; P. Bellick and B. Carey, “Psychiatry’s Guide Is Out of Touch with Science,” for the Bible quotation. Steven Hyman had earlier expressed similar incredulity that “grant reviewers, journal referees, editors, and regulatory agencies (all) acted as if DSM criteria…pick out real human diseases.” S. Hyman, “Cognition in Neuroscience,” Trends in Cognitive Sciences 16, 2012: 4. ↩
- https://www.nimh.nih.gov/about/directors/thomas-insel/blog/2013/transforming-diagnosis.shtml ↩
- Quoted in G. Greenberg, The Book of Woe New York: Blue Rider Press, 2013. ↩
- See, for example, “The NIMH Withdraws Support for DSM 5,” Psychology Today, May 4, 2013; Gary Greenberg, “The Rats of NIMH,” New Yorker, May 16, 2013; “Psychiatry in Crisis! Mental Health Director Rejects Psychiatric ‘Bible’ and Replaces with Nothing,” Scientific American May 4, 2013; “NIMH and APA Clash Over Upcoming DSM-5,” Medscape May 7, 2013; “Psychiatry Divided as Mental Health ‘Bible’ Denounced,” New Scientist, May 3, 2013; “Director of Top Research Organization for Mental Health Criticizes DSM for Lack of Validity,” British Medical Journal 346, May 8, 2013; P. Belluck and B. Carey, “Psychiatry’s Guide Is Out of Touch with Science,” New York Times, May 6, 2013. ↩
- Christopher Ross and Russell Margolis, “Research Domain Criteria: Strengths, Weaknesses, and Potential Alternatives for Future Psychiatric Research,” Molecular Neuropsychiatry 5, 2019: 218-235 argue that the whole approach is “fundamentally flawed.” See also D.R. Weinberger et al., “Whither Research Domain Criteria (RDoC)? The Good, the Bad, and the Ugly,” JAMA Psychiatry 72, 2015: 1161-1162. ↩
- Pliny Earle to Clark Bell, April 16, 1886. Pliny Earle Papers, American Antiquarian Society, Worcester, Massachusetts. ↩
- R. Uhler and M. Rutter, “Basing Psychiatric Classification on Scientific Foundations: Problems and Prospects,” International Review of Psychiatry 24, 2012: 594. See also M. Henriksen, J. Nordgaard, and L. Jansson, “Genetics of Schizophrenia,” (Frontiers in Human Neuroscience 11, 2017: 322) who note ruefully that “if common genetic variation implicates an intractable amount of genes of only very small individual effect alleles, we may find ourselves in a situation, where, as Goldstein put it, ‘in pointing at everything, genetics would point at nothing.’” They are referencing here D.B. Goldstein, “Common Genetic Variation and Human Traits,” New England Journal of Medicine 360, 2009: 1696-1698. ↩
- K.S. Kendler, “Psychiatric Genetics and the Nature of Psychiatric Illness,” Molecular Psychiatry 18, 2013: 1065. ↩
- S.M. Purcell et al., “Common Polygenic Variation Contributes to Risk of Schizophrenia and Bipolar Disorder,” Nature 460, 2009: 748-752; S.H. Lee et al., “Genetic Relationship Between Five Psychiatric Disorders Estimated from Genome-Wide SNPs,” Nature Genetics 45, 2013: 984-994; M.J. Gandal et al., “Shared Molecular Neuropathology across Major Psychiatric Disorders Parallels Polygenetic Overlap,” Science 359, 2018: 693-697; Cross-Disorder Group of the Psychiatric Genetics Consortium, ‘Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms Across Eight Psychiatric Disorders,” Cell 179, 2019: 1469-1482; Alastair Cardno and Michael Owen, “Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder,” Schizophrenia Bulletin 40, 2014: 504-515. ↩
- Brainstorm Consortium, “Analysis of Shared Heritability in Common Disorders of the Brain,” Science 360, 2018: 1313. As they note in the accompanying research paper, this situation contrasts markedly with what one finds for neurological disorders like Alzheimer’s and Parkinson’s diseases. The consortium is a cross-national collaboration among researchers at Harvard, Stanford, Oxford and Cambridge, among others. ↩
- Ellen Barry, “The Nation’s Psychiatrist Takes Stock, With Frustration,” New York Times February 22, 2022. ↩
- Antonio Regalado, “Q. and A. with Tom Insel on his Decision to Join Alphabet,” MIT Technology Review September 21, 2015. ↩
- S. Brown, “Excess Mortality of Schizophrenia: A Meta-Analysis,” British Journal of Psychiatry 171, 1997: 502-508; S. Saha, D.Dent and J. McGrath, “A Systematic Review of Mortality in Schizophrenia: Is the Mortality Gap Worsening Over Time?” Archives of General Psychiatry 64, 2007: 1123-1131; T.M. Laursen, “Life Expectancy Among Persons with Schizophrenia or Bipolar Affective Disorder,” Schizophrenia Research 131, 2011: 101-104. ↩
- Sten Stoval, “R&D Cuts Curb Brain-Drug Pipeline,” Wall Street Journal, March 27, 2011. Steven Hyman suggests that this abandonment of the field “reflects a widely shared view that the underlying science remains immature and that therapeutic development in psychiatry is simply too difficult and too risky.” Steven E. Hyman, “Psychiatric Drug Development: Diagnosing a Crisis,” Cerebrum 5, April 2013 PMC3662213. See also David Nutt and Guy Goodwin, “ECPN Summit on the Future of CNS Drug Research in Europe,” European Neuropsychopharmacology 21, 2011: 495-499; Colin Hendrie and Alasdair Pickles, “The Failure of the Antidepressant Drug Discovery Process is Systemic,” Journal of Psychopharmacology 27, 2013: 407-416; and Peter Tyrer and Tim Kendall, “The Spurious Advance of Antipsychotic Drug Therapy,” Lancet 373, 2009: 4-5. ↩
- H. Christian Fibiger, “Psychiatry, the Pharmaceutical Industry, and the Road to Better Therapeutics,” Schizophrenia Bulletin 38, 2012: 649. ↩
- Steven Hyman, “Cognition in Neuropsychiatric Disorders,” Trends in Cognitive Sciences 16, 2012: 4. ↩
- N. Andreasen, “DSM and the Death of Phenomenology in America,” Schizophrenia Bulletin 33, 2007: 111. ↩
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