* During the last half of the century, Charles Darwin’s new evolutionary theory exerted a towering influence over the scientific zeitgeist, including psychiatry.6 Darwin (1809–1882) viewed mental phenomena as organically grounded traits that evolved from earlier forms of life. The principle of natural selection, which showed how various psychic qualities had different survival values in diverse environments, guided this process. Those characteristics that most helpfully enabled individuals to adjust to their circumstances were more likely to survive and spread to future generations than those that were less adaptive. Darwin’s theory thus emphasized the intrinsic interplay between natural and environmental forces…
Over the course of the 20th century, biological theories in general became linked to reactionary political thought and were stigmatized and discredited. The association of eugenic thought with the Nazi movement and the resultant Holocaust destroyed the cultural viability of biological thinking about human behavior from the 1930s through the 1960s. As a result, organic explanations largely dropped out of the intellectual landscape during the middle part of the century.12
The rise of the social sciences after their founding in the late 19th century also served to suppress biological explanations of human action. Emile Durkheim’s proclamation that sociology rested “wholly on the basic principle that social facts must be studied as things, that is, as realities external to the individual” was emblematic.13 Beginning in the 1920s, sociologists, anthropologists, and psychologists promoted extreme environmentalist approaches that minimized biological influences on social behavior. Following Durkheim’s example, sociologists strove to develop a field that was independent of biology (and psychology). Likewise, John Watson and B. F. Skinner, the leading figures of behavioral psychology, were absolute environmentalists who denied the relevance of innate factors and internal processes, stressing how people displayed whatever behaviors their environments reinforced. Anthropologists, too, militantly opposed the recognition of inborn human traits. “We are forced to conclude,” Margaret Mead wrote, “that human nature is almost unbelievably malleable, responding accurately and contrastingly to contrasting cultural conditions.”14
During the 1970s a major counterreaction against the sociocultural emphasis emerged as the organic outlook that dominated 19th century thought slowly returned to prominence. E. O. Wilson’s tome, Sociobiology (1975), was a landmark in the return of this view. This influential volume synthesized scholarship on how genes determined most animal behaviors and concluded with a controversial chapter suggesting that human values also might have universal, natural underpinnings. In later works, Wilson expanded on this perspective, attempting to demonstrate how “all tangible phenomena, from the birth of stars to the workings of social institutions, are based on material processes that are ultimately reducible, however long and tortuous the chains, to the laws of physics.”15 In this view, all thought and experience must originate from some organic basis. Similar-minded works from widely read authors including Richard Dawkins, Daniel Dennett, Steven Pinker, and many others, indicated that biologically based views of human behavior had returned to respectability.16 The field of psychology, too, sharply reacted
against behaviorism, turning toward the study of cognitive and brain processes.
Thought about mental illness generally reflected these dominant cultural and scientific trends. Between the 1920s and the 1960s, few researchers or clinicians outside of mental institutions showed any interest in the brain or other biological underpinnings for mental disorders. Twin and adoption studies provided an exception. During the period when analytic and psychosocial models dominated psychiatry, the biological tradition persisted through an undercurrent of inquiries that used twins and adoptees as ways to distinguish internal natural qualities from external learned aspects of behavior.
* Biogenetic explanations have spread from scientific work to dominate popular images of mental illness. Media coverage is far more likely to focus on new findings about the biological roots of mental disorder than findings from other perspectives.33 Since 1980 popular magazines have increasingly used biomedical portrayals and endorsed medications as treatments of choice for mental illnesses.34 Laypeople now use terms such as “chemical imbalance” to explain the reasons for their mental illnesses, “Katrina brain” to describe their responses to natural disasters, and “dopamine hit” to refer to pleasurable experiences.35 In widely publicized testimony regarding the confirmation of Brett Kavanaugh to the Supreme Court in 2018, Christine Blasey Ford asserted that thirty-year-old memories of his sexual assault were “indelible in the hippocampus.”36 Genes have also become consumer commodities: millions of individuals use inexpensive services such as 23andme, Ancestry.com, and MyHeritage that sequence their
genomes and assess their chances of developing various diseases, including mental disorders. The information they receive can become an integral part of the way they understand their selves and their experiences.
* By the end of the 20th century, changes in both the general and scientific cultures had totally transformed the intellectual landscape as biological views had regained preeminence in explaining human behavior. “At present the road to salvation is presumably through biological psychiatry, neuroscience, and genetics,” Gerald Grob observed about psychiatry. Neuroscientific researchers assumed that applying technological leaps in imaging and sequencing to the study of mental disorders would result in unprecedented new understandings. They took for granted that the DSM classifications accurately reflected underlying brain and genetic states and so did not develop any new taxonomy. Yet, the DSM revolution and the symptom-based diagnoses it spawned have turned out to be millstones for the neurobiological study of mental illness.
Understanding the biological underpinnings of mental disorder requires not only knowledge about genes, neurotransmitters, and neurochemicals but also a clear idea of what condition embedded in the brain is being genetically transmitted. In 1942 psychiatrist Felix Brown succinctly summarized this necessity: “The part played by heredity in the development of the psychoneuroses is one of the fundamental unsolved problems in psychiatry, but the chief difficulty is to define the condition the heredity of which one is attempting to trace.”39 Accurate specifications of phenotypes (the presence or absence of some disease) are essential for the discovery of genotypes (the underlying genes that are connected to various disorders). This is especially important because, in contrast to most physical diseases, almost all mental illnesses lack objective markers such as x-rays, blood tests, or heart monitors, which can confirm or deny the presence of some pathology.40 Classifications of disorders thus play an outsized role in studies of mental disorder compared to other medical conditions because they are typically the only tool available for confirming the existence of a pathological state. The DSM was the sole resource that neuroscientists possessed when they defined what condition they studied.
After 1980, interest in the genetic etiology of the DSM’s specific entities flourished. Initially, the manual’s specific and well-bounded categories seemed to provide clear definitions that had the promise of showing “the condition the heredity of which one is attempting to trace.” Genetic researchers in the 1980s and 1990s expected to find the gene or genes that predicted the emergence of the various DSM disorders. For example, the discrete DSM-III categories of anxiety and depression, which earlier manuals had intertwined, implied that the presumed
genetic mechanisms beneath each condition were distinct from the mechanisms that gave rise to the other. Yet, if the symptoms that marked the various DSM diagnoses did not correspond to different genotypes, neurobiological researchers would be led on a fruitless search for underlying causal processes that do not exist in nature. To date, results do not provide much confidence that the DSM categories have discrete underlying biological causes. Indeed, they indicate the opposite: the manual’s distinct diagnoses are extraordinarily heterogeneous internally, highly overlapping with other entities, more continuous than categorical, and share common rather than specific vulnerabilities.
* Other conditions, such as major depressive disorder (MDD) and anorexia, have no replicated genetic associations at all.45 To the extent that mental disorders are inheritable, they arise from complex interactions among many genes with weak cumulative influences. “We do not have and are not likely to ever discover ‘genes for’ psychiatric illness,” Kenneth Kendler concludes.46 Even more bleakly, psychiatrist Randolph Nesse observes: “This is the most
important—and most discouraging—discovery in the history of psychiatry.”
* A second central finding of biogenetic research concerns the internal heterogeneity of the presumably homogeneous DSM conditions. For example, studies consistently indicate that MDD, the core condition of diagnostic psychiatry, is not a single entity. What the DSM criteria call “major depressive disorder” consists of an as yet unknown number of diverse conditions. “There is every reason to believe,” a recent review concludes, “that among the range of individuals currently subsumed under the diagnosis of Major Depression are those with distinct
disease states mediated by very different underlying pathophysiological mechanisms.”48 A second review summarizes: “no variable has been clearly shown to define a more heritable or genetically homogeneous subtype of depression.” This appraisal notes “no clinician or researcher believes that MDD is a single ‘illness.’ ” It concludes: “Despite more than two decades of sustained investment in psychiatric neuroscience, the fundamental pathology underlying
depression remains elusive, and the diagnostic criteria for depression remain descriptive in nature.”
* Perhaps the most important conclusion emerging from biogenetic studies is that, contrary to the DSM assumption of disorder specificity, genes for virtually all psychiatric disorders are nonspecific. Each disorder does not correspond to a distinct gene or group of genes but instead shares a large amount of genetic vulnerability with other conditions.51 Conversely, any given genetic variant that is tied to one diagnosis is also associated with multiple other diagnoses.52 Consider the findings from family studies about the co-occurrence among different relatives of the most common mental illnesses, depression and the various anxiety conditions. One major study concluded that depression “in the proband was associated with anxiety disorders, but only slightly with depression or alcoholism, in the relatives; anxiety in the proband was associated with major depression and alcoholism in relatives, but only slightly with anxiety disorders in the relatives.”53 Indeed, families with a depressed member have elevated rates of bipolar disorders, drug addiction, alcohol abuse, and eating disorders, among others.54
Anxiety, too, which the DSM-III carved into nine distinct conditions, seems more related to common, rather than distinct, processes.
* “[G]eneralized anxiety disorder and major depressive disorder are the same thing genetically,” behavioral geneticist Robert Plomin concludes.58 In addition, as has been proposed since Hippocratic times, results from biogenetic studies suggest that high levels of anxiety can reflect a personality type. Such temperaments, as the French psychiatrist Jean-Etienne Esquirol emphasized in the early 19th century, are not themselves pathological but render people more vulnerable to develop many kinds of psychopathology.
* When people are followed long enough, they move in and out of diagnostic categories: “Today’s patient with
schizophrenia was yesterday’s boy with conduct disorder or girl with social phobia (and tomorrow’s elderly person with severe depression),” psychologists Avshalom Caspi and Terrie Moffitt conclude.
* An inescapable conclusion from familial, genetic, and brain-based studies is that the DSM system artifactually divides a few general underlying vulnerabilities into multiple diagnoses.84 In fact, neurobiological research uncovers overlapping characteristics of various psychiatric disorders and general as opposed to specific vulnerabilities that produce them. Genetic findings show no evidence for the inheritance of specific disorders, over and above the inheritance of more general liabilities to broad tendencies for neuroticism, externalization, or psychoses. Expansive susceptibilities that lie beneath many diverse conditions seem to characterize the genetic basis for mental disorders, a situation that is ill-suited for the current DSM diagnostic system. These results more closely resemble the conceptions of mental disorder in the first two DSM manuals than in those that followed. “We have been trying to map the landscape of mental disorders by drawing lines around clusters of symptoms as if they were islands, but mental disorders are more like ecosystems: areas of arctic tundra, boreal forest, and swamp blend into one another, defying crisp boundaries,” Nesse nicely summarizes.
* Although different products have supplanted them in the marketplace, the initial drugs—chlorpromazine for schizophrenia, lithium for bipolar conditions, and imipramine and the monoamine oxidase inhibitors (MAOIs) for depression—still form the biological template for the most commonly prescribed products such as Abilify, Cymbalta, Zyprexa, Risperdal, and Seroquel. Despite the hyperbole that often surrounds the promotion of new medications,
understandings of how they work have not surpassed those of the breakthrough treatments in the 1950s. “Our current drugs for the treatment of psychosis,” a 2018 appraisal concludes, “are based on the serendipitous discovery of chlorpromazine and the isolation of D2 receptor antagonism as an underlying mechanism.”88 Likewise, sixty years after the discovery of antidepressant medications, neuroscientists still are not clear about how they work.89 “All
currently approved medications for depression,” noted neuroscientist Eric Nestler writes, “are based on chance discoveries that were made more than six decades ago. . . . Despite several decades of research, the changes that the drugs induce in the brain that underlie their therapeutic actions still remain uncertain.”
Growing skepticism has arisen about the effectiveness of current medications; newer classes of drugs do not seem to be more efficacious than their precursors.91 Despite the fact that more than sixty different types of antipsychotic drugs have entered the marketplace since chlorpromazine and Haldol were discovered in the 1950s, none show greater efficacy than the initial antipsychotics.92 Although lithium, which has been widely employed since the 1960s, is now less likely to be prescribed than recent, far more costly medications, it remains an
unsurpassed mood-stabilizing drug for treating bipolar conditions.93 In addition, while current antipsychotic medications have different profiles of side effects than the initial drugs, it is not clear that they have more benign consequences overall than the original phenothiazines or lithium.
The effectiveness of the later generation of the antidepressant serotonin selective reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SSNIs) also does not surpass that of the early antidepressants.
* Many studies also indicate that much of the improvement that occurs with antidepressant treatments is attributable to placebo effects.97 For example, one review that involved over nine thousand patients indicated that 42% of subjects who received an antidepressant improved compared to 30% who received a placebo.98 Psychopharmacologist David Healy concludes that, in a typical group of ten patients who are given antidepressants or placebos, only one responds to the drug while nine either are unaffected or respond to the placebo.99 Even these findings seem to be inflated because of biases where studies with positive results are far more likely to be
submitted and published than those with negative results.100 Analyses that take into account unpublished as well as published research show little difference in outcomes between those who receive an antidepressant or a placebo.
* Suspicions have grown that the DSM categories themselves are responsible for the stagnation in progress in drug development; no new, efficacious therapeutic agents have entered the market for the past thirty years.
* Pharmaceutical companies cannot be enamored with the revival of nonproprietary drugs that are used a handful of times rather than taken in daily doses across lifetimes.