Since time immemorial, humans have used substances that noticeably alter mood, consciousness, and behavior. Today we call these substances psychoactive or psychotropic drugs1. The main psychoactive compounds in use throughout the world roughly until the last decade of the nineteenth century were alcohol, coffee, tea, tobacco, opium, cannabis, coca, iboga, kola, khat, as well as countless species of mushrooms. People used these and other psychoactive drugs to work, to relieve pain, to induce sleep, to stay awake, to fraternize, to endure sadness and loss, to experience euphoria or joy, to reach or heighten states of transcendence and spiritual contemplation, and to perform religious rituals (Meyers, 1985). These manifold uses indicate that psychoactive drugs touch directly and deeply on what it means to live as a human being. Put another way, psychoactive drugs have helped many human beings to bear, to make meaning of, to celebrate, or to temporarily escape their circumstances. Observing the universality of psychoactive drug use among humans, Andrew Weil (1970) wondered whether it reflected an inborn drive to alter one’s consciousness.
If psychoactive drug use did not provide the user or the user’s group with some perceived benefit in enduring or enjoying life, it seems hardly possible that it would continue, century after century, regardless of migratory patterns or the nature and pace of social and cultural changes. This is an especially compelling consideration, given that the dangers of psychoactive drug use were never lost on their users. As far as we can determine from observations of indigenous peoples around the world, use of psychoactive drugs in premodern societies typically involved communal preparations, elaborate precautions, and rituals that served simultaneously to elevate and restrain drug taking (Naranjo, 1979). In our contemporary society, precautions against much of psychoactive drug use still involve informal rites of passage in families and peer groups, legal drinking ages, as well as formal sanctions, such as laws against impaired driving and public inebriety. Increasingly, however, precautions have involved the transfer of authority and responsibility for psychoactive drug use onto the physician and the addiction specialist. The consequences of this shift have transformed users’ motives to use drugs into diseases or disorders, the use of drugs into a treatment, and the user of drugs into a patient. Of the utmost importance, the physician writes a prescription that allows licit access to various psychoactive drugs. (As more and more “healthy” people want to use certain psychoactive drugs available only by prescription, the rationale for the medical prescription system might be strained beyond credibility, but we are getting ahead of our story.)
Precisely because of psychoactive drugs’ fluid but obvious appeal, rulers, healers, and priests throughout history have never ceased to promote or repress particular drugs, and (by definition) their users (Tracy & Acker, 2004; Porter & Teich, 1997). Psychiatrist Thomas Szasz (1974) has most consistently and clearly made this case. He has argued that using forbidden drugs is the simplest way by which some individuals can affirm their autonomy vis-à-vis authorities. As societies encountered foreign drugs and as social customs and conventions changed, certain psychoactive drugs became socially and legally accepted, rejected, and accepted again, in cycles of varying durations. Almost every psychoactive drug legally banned in America today was, at some point over the last century, freely available for purchase or import or prescribed or dispensed by physicians to their patients. This includes heroin, cocaine, LSD, and methamphetamine. The latter drug is still available by prescription as Gradumet, a brand-name drug indicated for ADHD while considered the “gravest drug threat” by 57 to 80 percent of state and local law enforcement agencies in most of the United States (US Department of Justice, 2010).
The major turning point occurred at the end of the nineteenth century, when the opium derivative morphine, first greeted by physicians as an unequalled painkiller, became demonized. This transformation probably marked the beginning of the linguistic and conceptual separation of “dangerous drugs” from “psychoactive medications.” With time, the first phrase came to designate disapproved substances traded illicitly and about which almost no one cared to distinguish “use” from “abuse.” The second phrase came to designate approved substances that eventually became dispensed under medical supervision and government regulation. Progress in chemistry and pharmacology refined these “medications” as they were brought to market using techniques of mass production, with the goals of treating, preventing, and combating mental disease (Chast, 1995).
No intrinsic material property will ever distinguish a “drug” from a “medication” because the difference rests not on pharmacology but on social, legal, and medical norms and linguistic usage. Those who establish these norms, however, have either tacitly or explicitly supported the opposite view—that “drugs” differ intrinsically from “medications”—shielding the norms from scrutiny. As a result, as both Szasz (1974, 2001) and DeGrandpre (2007) amply document, views and prejudices about drugs have been conflated with chemical properties of drugs. Such a grave confusion could only lead to contradictions and inconsistencies. Amphetamines and methamphetamine, classified legally as controlled Schedule II addictive substances and characterized as “scourges” in the field of drug abuse, are simultaneously prescribed by physicians as essential treatments to children and adults said to suffer from attention deficits. Similarly, some individuals, groups, and states advocate or permit access to “medical marijuana” while supporting or enforcing the ban on marijuana. Regularly, the Drug Enforcement Administration (DEA) hounds physicians for prescribing “excessive” doses of perfectly licit narcotic painkillers (Rosenberg, 2007). As for tobacco, it occupies several roles simultaneously: ordinary agricultural product freely grown with state subsidies; the world’s deadliest drug; illegal drug when used in certain public spaces; addictive psychotropic drug when the FDA wishes to regulate smoking; or approved medication when its ingredient nicotine is prescribed as an aid to quit smoking (Cohen, 1995).
These ambivalences and inconsistencies are reflected in what American authorities have been warning the public about at the start of the second decade of the twenty-first century, though they acknowledge it is not a new problem: prescription drug abuse. The title of a White House call to action uses the appropriate rousing words: Epidemic: Responding to America’s Prescription Abuse Crisis, and the opening words announce the “Nation’s fastest growing drug problem” (Executive Office, 2011, p. 1). Here, the dangerous drugs are not obtained illegally, they are legal remedies found in our home pharmacy cabinets. Their nonmedical or idiosyncratic use constitutes the current public health scourge (Janofsky, 2004). No less than 10 percent of state and local law enforcement agencies now view diverted uses of controlled prescription drugs as their “gravest drug threat” (U.S. Department of Justice, 2010). The National Institute on Drug Abuse (2011) defines prescription drug abuse as “the intentional use of a medication without a prescription; in a way other than as prescribed; or for the experience or feeling it causes” (p. 1).
In addition to wildly inflating the population of potential and actual abusers, prescription drug abuse blends two perspectives that authorities have taken pains to keep separate: the imagery and logic of the war on illegal drugs with the imagery and logic of the medical prescription of approved medicines. Even more than mere drug abuse, prescription drug abuse opens a fruitful terrain for drug experts and drug warriors, in which public health and repressive measures can mix in any manner and quantity and in which patients and prescribers can come under equal scrutiny. Presently, the drugs of concern are opiates, sedatives, and stimulants dispensed under prescription. In principle, however, there is no barrier to extending the concern to antidepressants, antipsychotics, and anticonvulsants, the paradigmatic psychiatric or psychotherapeutic drugs of the past half century.
With the arrival of Prozac, introduced to the US market in late 1987 and prescribed a few years later to over ten million people, the New York Times was announcing in a front-page article the rise of a “legal drug culture” (Rimer, 1993), as if such cultures had not always existed in this country and elsewhere. Testifying to the enduring but unarticulated social ambivalence toward psychoactive substances, the author took pains to distinguish the use of medications from that of drugs. Similar distinctions were being made across the Atlantic shortly after the arrival of Prozac to France. In a magazine article, psychiatrist Marc Bourgeois asked rhetorically whether “the proportion of 11% of users of psychotropics [is] scandalous?” Bourgeois answered reassuringly: “These are not drugs, but of course approved medications” (1994, p. 9).
Undoubtedly, most of the millions of citizens using antidepressants prescribed by their doctors would not have thought that they were “altering their consciousness.” Still, during the early 1990s, media-amplified evaluations by some users and promoters of Prozac and the SSRIs (e.g., “I am free to be me,” “I am better than well”; Kramer, 1993) did sound eerily like the benefits claimed by some users of illicit psychoactive drugs. There was, however, an important difference, as French sociologist Alain Ehrenberg (1995) was one of the first to note: the stated goal of using Prozac was admission to, not escape from, ordinary consciousness; it was “fitting in,” not “dropping out.” The modern user of prescribed psychoactive drugs wished to function better. The search for ecstatic highs morphed into the hope of “cosmetic psychopharmacology.”
We may now more fully consider the notion, repeated several times so far in this book, that prescribed psychiatric drugs should first and foremost be considered as psychoactive drugs. This notion rests on the conclusion that the usual explanations for how psychiatric drugs are supposed to work in the treatment of problems called psychiatric disorders can barely account for the only pertinent effects that can be attributed with any certainty to these drugs: their psychoactive effects (Moncrieff & Cohen, 2009).
Most people have a reasonable understanding of the psychoactive effects of substances that are typically used for recreational purposes, such as alcohol and cannabis. Besides the pleasant or often euphoric effects that lead people to use them, most people understand that these drugs modify how they think or reason, how they speak, how vigilant or forgetful they become, how they experience emotions, and, certainly, how they behave. Most people understand that these drug-induced changes can be quite subtle and relatively easy to hide from observers who do not know them, just as they can be dramatic and obvious. Most people understand that drug-induced changes from recreational drugs can be persistent, if the drug use is persistent. Most people come to recognize and anticipate some effects from these drugs and use them to reach certain ends that might not be considered purely recreational, such as falling asleep more easily, ignoring unpleasant circumstances, completing necessary but annoying tasks, or acting more or less sociably. People also understand that, however pleasurable drug effects might be initially, they might become unpleasant with persistent use or in different circumstances. Similarly, people know from their experience and that of others that with prolonged use, users of recreational drugs often experience difficulty trying to cease using these drugs, even when their effects have become unpleasant.
A similar understanding applied to prescribed psychoactive drugs—popularly called psychiatric medications—is mostly absent, however, because there are virtually no authoritative summary descriptions in psychopharmacology textbooks of how these drugs alter our normal thoughts, emotions, and behavior. This state of affairs results from the single-minded effort in psychiatry over the past half century to portray psychiatric drugs as conventional medical remedies (targeting physiological abnormalities) and those who take psychiatric drugs as conventional medical patients (affected by physiological abnormalities). This has been called the “disease-centered model,” wherein drugs’ therapeutic effects are believed to stem principally from their action on (presumed) disease states or physiological pathways to such states (Moncrieff, 2008). This disease-centered model, as we argue throughout this book, has numerous weaknesses, especially so with respect to understanding and predicting the effects of psychiatric drugs, both in humans and in animal tests (Moncrieff & Cohen, 2005).
We know, however, that drugs used in psychiatry have psychoactive effects because people prescribed these drugs have described such effects, because healthy volunteers given only one or two doses of such drugs have described such effects, and—importantly—because countless experiments with animals from many species unmistakably show that these drugs alter normal animal behavior (make animals more or less active, more or less indifferent, more or less exploratory, more or less avoidant, more or less aggressive, and so on).
The nature of these drug effects appears to depend largely on the particular drug ingested. Each drug seems to trigger a particular sort of altered consciousness, inextricably linked to some altered physiology, and this global effect, though varying somewhat from user to user and often based on how much of the drug is ingested, seem relatively easy to identify when drugs are first investigated in human users and when the investigators are appropriately curious and open-minded about what they expect to observe.
Accumulated observations with psychiatric drugs confirm that certain psychiatric drugs have pleasant, initially desirable, euphoric effects. This is the case notably with stimulants (such as amphetamines and methylphenidate, or Ritalin) and benzodiazepines (such as alprazolam, or Xanax, and clonazepam, or Klonopin). For these reasons, many people interested in experiencing such effects chemically seek out these drugs and may use them “excessively.” These drugs, though prescribed by physicians, are therefore widely available on the black market. Other psychiatric drugs, however, rarely or simply do not produce euphoric sensations. On the contrary, they are reliably observed or reported to produce strongly unpleasant, undesirable, or “dysphoric” sensations. This is the case with antipsychotic or neuroleptic drugs, the tricyclic antidepressants, lithium, and many anticonvulsants. To a lesser but still unmistakable degree, it is also the case with modern antidepressants (usually the SSRIs), as one can tell from the few investigations that note that their subjective effects are judged rather negatively by normal volunteers as well as by diagnosed patients (reviewed by Moncrieff, 2008; Goldsmith & Moncrieff, 2011). Of course, it is crucial to realize that even if these latter groups of drugs do not easily produce euphoric, generally pleasant effects and even if they have almost no value on the black market (i.e., extremely few people seek them out for recreational purposes), this does not mean that they are not psychoactive drugs.
All psychiatric drugs in common use affect how people think, how they feel, and how they behave. Antipsychotic drugs produce states of psychological indifference, clouded cognition, stunted emotions, and sedation. Anticonvulsants, today part of the standard maintenance treatment of bipolar disorders, show a panoply of dysphoric effects, ranging from strong sedation and cognitive slowing to anxiety and agitation (Cavanna et al., 2010). Antidepressant drugs include a large range of substances with effects ranging from mild sedation to severe, mania-like agitation. It remains difficult to characterize them in psychological or subjective terms, as their psychoactive effects have not been seriously investigated up to now. A study by Goldsmith and Moncrieff (2011) examined comments by nearly five hundred users of fluoxetine (Prozac) and venlafaxine (Effexor) posted on a website and categorized the most frequent described effects as sedation (about 26 percent), activation (about 25 percent), and reduced libido (about 20 percent). Benzodiazepines typically produce sedation, relaxation, and indifference. Their deleterious effects on memory are notable. Stimulants typically produce euphoria, wakefulness, increased concentration, and a feeling of endurance—characteristics which combine to give stimulants a privileged place as performance enhancers in several societies.
With only the above cursory observations, one can see that drugs can affect people with and without a psychiatric diagnosis in similar ways, but we can also see how the psychoactive effects of psychiatric drugs can be useful to people undergoing psychological crises or who are misbehaving (and therefore whom others wish to control). This possibility and its implications have been termed the drug-centered model of psychotropic drug action, as an alternative to the disease-centered model (Moncrieff & Cohen, 2005, 2006, 2009).
Cohen and Hughes (2011), for example, suggest that by inducing much-needed sleep, all drugs with sedative effects can trigger positive changes in well-being. All drugs with stimulating or activating effects may help people complete unfinished frustrating tasks or bring about people’s exposure to social situations that provide opportunities for reinforcement and practice of social skills. Emotional blunting, observed with most classes of psychoactive medications but especially with antipsychotics, lithium, and anticonvulsants, may help people distance themselves from sources of stress in their environment. Conversely, it is possible to see how the persistent production of such effects over time, whether of an activating or deactivating sort, may turn into frank disablement. For example, where psychological indifference and cognitive clouding can help an individual and his or her relatives during an acute emotional crisis, it can also impair a person from functioning normally. Where wakefulness and increased activity can help someone focus efficiently on a task, it can lead them to be impetuous or aggressive in unpleasant environments. Where decreased vigilance and increased relaxation can help one during informal social gatherings and before bedtime, it can be deleterious if these effects persist while driving or when having to perform at the office or simply when having to make a decision.
It is extraordinary that such considerations regarding the obviously useful or impairing effects of chemically triggered psychoactive states, depending on one’s psychological problems, situation, or circumstances have not been taken seriously in modern psychopharmacology. Given that psychiatric medications modify thinking, feeling, and behaving, it follows logically that these effects interact with the thoughts, the feelings, and the behaviors that are said to constitute the symptoms or the diagnostic criteria of mental disorders as described in the DSM and other diagnostic manuals. One nonetheless can peruse dozens of manuals of psychopharmacology without encountering any mention, let alone clear acknowledgment, of this possibility. Still, during the introduction of the first modern psychotropics during the 1950s, several clinicians and researchers, regardless of their theoretical orientation, became quite interested in these psychoactive effects and how to distinguish them (e.g., Cole, 1960). In the case of antipsychotics, for nearly two decades, the production of psychic indifference and abnormal involuntary movements became accepted as the very mechanism of action in psychosis (review by Cohen, 1997a, 1997b; Jacobs & Cohen, 1999; Moncrieff, 2008).
The fact is that these psychoactive effects are simply not controlled nor are they accounted for in interpretations or discussions of the results of clinical trials of psychiatric drugs—which are supposed to investigate how these drugs affect symptoms. In other words, we do not know, from the results of countless clinical trials, how sedation, activation, or reduced libido (to use only commonly reported subjective effects of antidepressants) would lead to the conclusion that antidepressants effectively reduce symptoms of depression. Because of the lack of controls for psychoactive effects, no one is really in a position to assert that psychotropic medications have, in reality, any other pertinent action in the treatment of psychological distress over and above their common psychoactive effects.
There have been no discoveries of any sort that indicate how psychotropic medications might, in fact, be modifying any (still unknown) physiological processes hypothesized by psychiatrists and psychopharmacologists to cause psychological distress and misbehavior. Therefore, the failure to investigate rigorously and creatively how psychoactive effects of psychiatrically prescribed drugs—including the effects of tolerance, dependence, and withdrawal—affect psychological and behavioral states called mental disorders seems like a remarkable form of scientific denial.
It is instructive to review with a twenty-year hindsight how the enormous publicity generated around claims that Prozac could “transform” personality or around narratives of persons affected by Prozac led many social commentators to claim that society had entered a “new era” of widespread personal transformation by means of drugs. The expression “cosmetic psychopharmacology,” coined somewhat ironically by American psychiatrist Peter Kramer in his 1993 bestseller Listening to Prozac, quickly took hold during that decade (Farr, 1994; Rothman, 1994).
Cosmetic psychopharmacology promised the design of drugs targeting specific neuronal receptors, a specificity of action expected to produce desired effects with few or no unwanted effects. As a result, it was claimed, people would be able to modify their personalities regularly: they would improve their intelligence, their memory, and their concentration—shape their brain at will (Restak, 1994). Twenty-some years later, the Prozac revolution stands not as a genuine clinical or scientific breakthrough but instead as a stupendous advance in the marketing of drugs (and of psychiatric diagnoses to market even more drugs). The Prozac revolution appears merely as a modern version of the ever-alluring myth of the magic potion.
Optimistic scenarios of the implications of the Prozac revolution seemed to ignore history. Cosmetic psychopharmacology, described by the Prozac faithful as an advance unique to late-twentieth-century psychotropics, had a longer past. Already in the 1880s, as he accustomed himself to using cocaine daily for five years, Sigmund Freud enthused that the drug was transforming his entire personality for the better, made him more “normal,” gave him abundant energy for work, and produced not a single unwanted effect (Byck, 1976). In contrast with the official history of antidepressant drugs as “discovered” in the early 1950s by dedicated biochemists, as early as 1937, the Smith, Kline and French pharmaceutical firm was creating the first antidepressant, by mailing a pamphlet to ninety thousand doctors (the majority of American general practitioners as well as neurologists and psychiatrists), to promote amphetamine, stating that “the main field for Benzedrine Sulfate will be its use in improving mood” (cited in Rasmussen, 2006, p. 311). From that time until well into the 1960s, the amphetamines (Benzedrine, Dexedrine) were actively promoted in medical journals and prescribed by doctors across America and the world for conditions and ailments including depression, fatigue, and being overweight (Breggin & Breggin, 1994; Pickering & Stimson, 1994). Only fifteen years before these drugs became strictly controlled substances considered by medical and legal authorities to have limited medical value and high potential for abuse and dependence, readers of a medical textbook were reminded how, “Gradually, as experience with amphetamines has ripened, they have become firmly established as versatile and helpful remedies, given to millions of people, and under such conditions as to offer remarkably low potential for causing harm or unwanted effects” (Leake, 1958, p. 18). The use of amphetamines as performance enhancers by athletes, pilots, drivers, and soldiers had of course already been well-established and discussed before then (Rosen, 2008).
In truth, during the 1990s on both sides of the Atlantic, commentators raised concerns about the challenges for individuals and society of an anticipated wave of post-Prozac substances. “If one can modify mental perceptions without endangering self or others,” asked Ehrenberg (1995, p. 34), “will our societies be made up of ‘normal’ individuals permanently assisted by psychic products?” For French psychoanalyst Pierre Fédida (1995, p. 95), a seemingly omnipotent psychopharmacology triggered “the anguish of a loss of psychic identity,” in which the individual “would conserve his appearance, while being dispossessed of all that constitutes him genuinely.” For medical historian David Rothman (1994, p. 36), the use of Prozac fed what he termed a typically American illusion, “the possibility of a single act of redemption, of victory without struggle or suffering.”
Despite some of these fears, however, whatever future scenario these authors envisaged rested on rosy renderings of the history of psychopharmacology, especially concerning the discovery of the antipsychotics and the invention of most of today’s psychiatric pharmacopeia. The psychiatric discourse on the progress represented by these accomplishments was accepted lock, stock, and barrel by virtually every commentator on the Prozac phenomenon.
Even as enthusiasm about the SSRIs waned significantly, as it did at the start of the twenty-first century (Scott, 2008), knowledgeable observers could not bring themselves to call the enterprise a scientific failure. Sharon Begley (2010), in a cover story in Newsweek, “The Depressing News about Antidepressants,” summarized the research showing that placebos produce equivalent outcomes, minus the adverse effects. Calling the drugs “basically expensive Tic Tacs” and citing experts acutely aware of the “disconnect between the scientific evidence and public impression,” especially concerning the serotonin-deficit theory of depression “built on a foundation of tissue paper,” Begley nonetheless expressed sympathy for those who would keep patients in the dark. She characterized the truth-propaganda disconnect as a “moral dilemma.” After all, patients who suffer from what Begley termed “a devastating, underdiagnosed, and undertreated disease” and who find their medications helpful “need to believe in their pills.” But it isn’t a “belief in pills” that Begley was promoting, more than a belief in what patients and the public have been told by organized psychiatry and the mental health establishment about pills as specific treatments for depression. Psychiatry, in short, is too big to fail.
It seems to us, on the other hand, that clinical psychopharmacology—the medically sanctioned use of psychoactive drugs for the treatment of medically legitimated distress and misbehavior (termed mental disorders)—has always been a pseudoscientific enterprise. We argue in the rest of this chapter that what has been passed off as the “psychopharmacological revolution” of the 1950s has consisted, at bottom, of the taming of madness via the remote chemical control of madpersons and the strengthening of psychiatry’s medical self-image. The wholesale application of biological language to old psychiatric practices and perennial personal problems constitutes merely the latest pseudomedical façade to the edifice of psychiatry. Besides psychiatric physicians’ singular ability to forcibly medicate and incarcerate, their indispensability as mental health practitioners rests on an exceedingly simple and obvious fact: they alone provide access to licit psychoactive medications. And all this, we and a growing chorus of observers can now affirm with support from abundant evidence, was made possible—indeed, was actively encouraged or manufactured—by psychiatry’s enthusiastic enlistment as a satellite branch of the multinational pharmaceutical industry and the co-optation of the FDA as an agency aiming, not merely to protect the public, but rather to advance the drug industry’s interests and reinforce mainstream cultural notions that nonspecific psychoactive drugs (demons) are, in the hands of medical prescribers, conventional medical remedies (angels) targeting specific mental disorders.
To make this case, we first address the idea that tremendous, rapid advances in the fields of molecular biology and pharmacogenomics may have provided psychopharmacology with a secure scientific basis.
The development of molecular biology seems to represent a radical break contrasting a current era of “rational drug design” from a previous one of chance discoveries. Molecular biology has enabled the amazing feat of designing a molecule introduced into the body from the outside to bind itself on a particular type of cell membrane receptor, thus triggering changes within and around the cell and throughout the pathways comprised of similar cells that communicate with each other. Paradoxically, this feat merely confirms that in the domain of brain-behavior interactions, we are taking our first baby steps. As philosopher of science Isabelle Stengers observed, “Between the richness of the psychic effects of a drug and the hypothesis that it disturbs the effects of a type of neurotransmitter, there exists a gulf that no contemporary theory can cross” (1995, pp. 134–135).
The future of all medications is often said to depend on biotechnologies. These techniques consist of mapping and then mastering the genetic code and functioning of a bacterium, a cell, or a whole living organism in order to make it produce various substances at will. A well-known example is the synthesis of human insulin from bacteria. However, not even a miracle of genetic engineering could contribute to the design of psychiatric drugs that do not merely sedate, stimulate, render indifferent, or provide nonspecific subjective relief for emotional distress or mental disorder. This is because there are no demonstrated biological anomalies for any drug to target to “cure” the mental disorders in question.
Such biological targets, a sine qua non for rational drug design, would be identified from a detailed knowledge of the cellular and molecular biology of a disease. Nothing of the sort exists in the case of psychiatric “diseases” and drugs. Not only does the field lack basic biological understanding of any presumed disease process, psychiatric researchers that we cited earlier in the book—who have committed their careers to developing this biological understanding—state flatly that nothing biological has been reliably associated with any DSM diagnosis that aids to make the diagnosis or to predict how someone will respond to drug treatment. There are no biomarkers for psychiatric disorders—no biological signs that can be used reliably to measure the presence, change, improvement, or worsening of the condition that one might deem “pathological.” To be sure, every month, investigators propose new biological measures in the literature as candidate biomarkers, but none survives for long. Most telling, none is used in any clinical trial testing a drug for the treatment of any psychiatric condition.
We repeat: no distinct biological determinism has been demonstrated in any mental disorder. For decades this was occasionally acknowledged, but discreetly, deep in textbooks and professional articles, rarely by experts in popular discourse. According to a survey of a probability sample of the US population, conducted by the American Psychiatric Association (2005), 75 percent of people believe that mental disorders result from “chemical imbalances.” But, already, chemical imbalances are passé, at least according to the director of the NIMH.
Given the belief that mental disorders are brain disorders, a good way to assess the concrete scientific fruits of the decade of the brain for psychiatry and for understanding mental disorders is to compare what Thomas Insel as the director of the National Institute of Mental Health, and Story Landis as the director of the National Institute of Neurological Disorders and Stroke state about progress in their respective fields. Neurological disorders, by definition, are diseases of the brain. Mental disorders are claimed to be diseases of the brain. Both Insel and Landis were invited by the Dana Foundation to summarize, in one thousand words, what the massive investments into research in their respective fields had produced.
Insel (2010) wrote: “If scientists introduced mental disorders as brain disorders in the Decade of the Brain, researchers in the past 10 years have demonstrated the importance of specific brain circuits” [emphasis added]. The caveat: “Unlike neurological disorders, which often involve areas of tissue damage or cell loss, mental disorders have begun to appear more like circuit disorders.” As evidence for his statement, Insel writes that “specific brain pathways are involved in major mental disorders.” Also, “deep brain stimulation has shown promise as a treatment for depression and obsessive-compulsive disorder.” Due to laser technology, “for the first time, researchers can conduct specific tests of theories about brain circuits and behavior.” About schizophrenia, Insel states that “The disorder might result from excessive loss of synapses in a critical cortical pathway.” He reasserts: “recent research suggests that mental disorders are really developmental brain disorders, caused by disruptions in the circuitry map of the developing brain.” Finally, he concludes: “The answer for psychiatry will likely be the same as the answer for the rest of medicine: Basic discoveries regarding genes and proteins will point the way to molecular and cellular mechanisms, which in turn will yield new targets for treatment and prevention.”
In her assessment of progress in neurological research, Story Landis (2010) states that “in the past decade, the list of gene defects that contribute to neurological disorders grew at an extraordinary pace, leading to almost an embarrassment of riches.” She gives a specific example: “Classification for ataxias by genetic profile has replaced the clinical classification based on time of onset, rate of progression, and subtleties of the clinical exam.” At least six additional Parkinson’s-related genes “appear to underly the disease in as much as 35 percent of patients with Parkinson’s disease.” For some diseases, Landis writes, “An inexpensive genetic test can now bring [patients’ odysseys in search of a diagnosis] to a rapid and conclusive end.” Then, Landis counters with the sobering assessment that “to date this translation has proved to be much more difficult than we had imagined. For example, in 1987, researchers discovered that mutations in the dystrophin gene cause Duchenne muscular dystrophy [a fatal disease in affected boys usually before the age of twenty]. Despite two decades of research and the availability of both mouse and dog models, the only treatment currently in use is corticosteroids.”
We note Insel’s assertion that the long-held view of mental disorders as conditions characterized by “loss of cells” should now give way to one of conditions characterized by “disruptions in the circuitry map.” In essence, Insel states that the dominant neurobiological hypothesis of mental disorder has been abandoned. Will the 75 percent of Americans who believe in “chemical imbalances” be informed that circuitry has dethroned chemistry? Does it matter to anyone? Yet it indicates an important scientific event: the failure of research to support the biochemical paradigm. Touting a new conduction paradigm, however, Insel gives no example of any “circuit disorder,” nor of any mechanisms underlying any such disorder. The transformation brought about by the decade of the brain, we have grounds to conclude from Insel’s exhibit, is mainly metaphorical.
Landis names actual discoveries of genetic markers that definitively replace clinical diagnosis of various neurological disorders—something psychiatry can still only dream of concerning its “brain-based” disorders. Yet, progress notwithstanding, Landis sounds an important cautionary note: in one specific disorder, the identification of no less than a causative gene resulted in no improvement in palliative, let alone curative, treatments. The gap between neurology and psychiatry, even between hoped-for psychiatry and actual neurology, appears quite large.
In the general area of drug development, however, molecular biology has enormously helped researchers to screen for molecules that would resemble one or more aspects of currently (commercially) successful drugs, so that these can be copied. This was the case with the various SSRIs and the second-generation or atypical antipsychotics, designed to copy the initial leader in their class. The sophistication and efficiency of the screening tools have increased exponentially, so that the stock of potentially testable molecules (designed by computer) is nearly infinite. As one or another neurotransmitter pathway becomes more intently discussed (in the literature by key opinion leaders hired as consultants by drug companies) as a potential target for drug action in one or another mental disorder, scientists can use supercomputers to model molecules that could bind themselves to the desired target. Also, as gene-to-behavior and environment-to-gene pathways and interactions are increasingly understood, the effects of drugs on the expression of genes are also beginning to be better understood.3 In principle, this knowledge might help to reduce the risk of harm from drugs based on individuals’ genetic profiles. But, to repeat, no radical innovation based on genetic knowledge is leading the way to find any curative compounds in psychiatry, because there is simply no idea about what specific part of the body, if any, needs fixing when people suffer or misbehave.
None of the products derived from current biotechnologies are psychiatric medications, and the number of FDA approvals for psychiatric drugs over the past decade has significantly declined (Cutler et al., 2010), as has, in general, the number of new molecular entities (drugs never used before in clinical practice) approved by the FDA, from thirty-one in 2004 to seventeen in 2008 (Dorsey et al., 2010). That number had risen back to thirty in 2011, but included only a single drug approved for a mental disorder (FDA, 2012). The tendency in psychiatry has mostly consisted in recycling existing drugs for expanded uses. To illustrate, a drug evaluated by the FDA for approval for the treatment of sleepiness in narcolepsy in the mid-2000s was merely an old stimulant on the European market for more than forty years (Provigil, or modafinil). The second-to-last antipsychotic approved by the FDA in late 2007 was paliperidone (Invega), the major active metabolite (a byproduct formed during metabolism) of risperidone—itself on the market since 1994 and whose patent of exclusive marketing to its manufacturer, Janssen, was expiring.
In the spirit of providing the illumination that often comes from visiting old exhibits of the future, here is how a Newsweek article by Sharon Begley published in 1994 announced imminent drug breakthroughs. The author described the use of five “new mind drugs”—though none were new at the time. In the article, beta blockers, largely used around the world to lower blood pressure, were renamed “anxiolytics”; Ritalin, on the United States market since the late 1950s, was promoted to increase concentration in adults (part of the intriguing shift to “adult ADD” starting in the mid-1990s); dexfenfluramine, another stimulant long available in Europe as a diet pill, was renamed a “mood stabilizer”; phenytoin (Dilantin), one of the oldest antiepileptic drugs on the market, was dubbed a “stress reducer”; and phenelzine, prescribed sporadically since the 1950s as an antidepressant, was presented as an innovative treatment for “hypersensitive patients.” What happened to these drugs? Of the five, dexfenfluramine was later withdrawn from the market for toxic cardiac effects, and phenytoin and phenelzine are barely used.
To Begley’s list one might add the antipsychotic clozapine, prescribed modestly in Europe since the end of the 1960s, but launched in North America in 1990 as a “revolutionary new treatment for schizophrenia,” with a publicity campaign that included a Time magazine cover (July 6, 1992) and a story displaying a photograph of a young man diagnosed with schizophrenia dancing wildly and happily at a party. In reports to the FDA between 1998 and 2005, however, health professionals named clozapine as a suspected cause in nearly 3,300 deaths—more than any other prescribed psychoactive drug (Moore, Cohen, & Furberg, 2007).
Several observers of the rise of Prozac in the 1990s predicted that the psychopharmacologist would soon hold the keys to understanding the brain and to shape it at will. Another analogy seems more fitting during the second decade of the twenty-first century: facing the somewhere around 100 trillion glia, neurons, receptors, and synapses in the brain, the psychopharmacologist resembles the astronomer facing the cosmos.
Most medications have a long, complex, and unpredictable lifecycle. Although modern psychoactive medications are implicitly and explicitly portrayed as pure substances whose indications for prescription are intrinsic to their chemical structure, no such medication appears to have ever existed. Psychoactive drugs, let us note, are prescribed in the absence of demonstrated physical pathology. Thus, how and why drugs end up being prescribed for one clinical indication in psychiatry rather than another is the result at least as much from trial and error and marketing as from clinical necessity (Cohen et al., 2001; Horwitz, 2010).
To transform a molecule into a medication approved by the FDA for marketing and prescription takes several years. Of thousands of molecules screened in the laboratory, only a handful start the journey to approval. The most widely cited estimate of the average cost of the process to approval for a single drug—what is commonly referred to as research and development (R & D)—was $802 million in 2000, updated to $1.32 billion in 2006 (cited in Light and Warburton, 2011, p. 3), and again to $1.8 billion in a 2010 NIMH report (“From Discovery to Cure,” 2010). However, Donald Light and Rebecca Warburton have demonstrated that the $802 million estimate constitutes a hodge-podge of unverifiable early development costs, costs of “profits foregone” by choosing to invest in R & D (about half of the $802 million estimate), largely inflated costs of clinical trials, exaggerated time for R & D, and other questionable strategies, such as using mean rather than median costs. Despite this, the R&D estimates are immediately 100 percent deducted from taxable profits for the companies involved, a convenient federal incentive for them to exaggerate the actual costs.
Light and Warburton’s analysis deserves close reading. They suggest that “based on independent sources and reasonable arguments, one can conclude that R&D costs companies a median of $43.4 million per new drug, just as company supported analysts can conclude they are over 18 times larger, or $802 million” (2011, p. 14). They conclude that, “Readers should appreciate the constructed nature of R&D cost estimates and always ask very closely about where the data for an estimate come from, how they were assembled and whether they can be verified” (p. 14). Our view is that this caution also applies to claims of drug effectiveness and safety as we will describe below.
For a new molecule (one that has not already been approved by the FDA for any indication), the approval process includes overlapping phases involving many players. Each phase is well-outlined in the literature, but only the latter phases—large, randomized controlled clinical trials (RCTs) in humans—have been examined by scholars in any depth. Under the legally enforced principle that drugs are proprietary products and that competitors in the drug industry may unfairly benefit from a company’s disclosures of its commercial practices, most of the activities during the early phases of drug development remain shielded from serious scrutiny. The components of the various phases, and regulatory agencies’ expectations about them are well-known in theory, but how the phases are orchestrated in practice is not. Over the last decade, however, more glimpses have been obtained as confidential documents have been unsealed or leaked during lawsuits against drug companies.
Animal Tests and Phase I Human Tests. The first step in drug development consists of preclinical testing. Computers simulating the precise chemical structure of the chosen molecule allow investigators to make predictions about its affinity for certain receptors in the body and its resemblance to other molecules with known effects. Then, testing on several animal species (rodents, cats and dogs, occasionally primates) is undertaken to rule out the drug’s potential to cause obvious physical damage, including genetic or chromosomal mutations, birth defects or malformations, and cancer.
Preclinical studies may be conducted in the manufacturer’s own facilities or contracted out to private research labs and university departments. Typically, the initial work is conceived in a university laboratory receiving government funding. Breakthrough pioneering work is inherently unpredictable, and few drug companies are willing to invest in such uncertainties, especially, as in the case of mental disorders, if there is no understanding of how the “disease” works and thus no established path to breakthrough drugs. Thus, once a potentially useful substance is discovered or identified in a university lab, the drug firm, betting on the potential clinical value of the particular substance, enters into a commercial agreement with a researcher and/or the university to pursue its development. After having amassed the required data indicating that the drug is not likely to cause gross physical damage to animals and outlining general neurochemical and behavioral effects of the molecule as determined through in vitro and in vivo tests on animals, the sponsor might then apply to the FDA to begin testing it on humans.
If the FDA agrees and the sponsor decides to undertake human testing, phase I of clinical trials may begin. The aim now is to determine the major parameters of the drug’s effects in humans. Starting with tiny doses, the drug might be administered to approximately twenty to a hundred younger, healthy men. Close medical monitoring is necessary, since the first administration in humans—despite the extensive animal studies that preceded it—may lead to completely unforeseen effects. An example was revealed in March 2006 when six volunteers receiving the first-ever injections to humans of TGN1412, tested as a potential remedy for autoimmune diseases, became desperately ill and suffered multiple organ failures. Five of the six recovered only after a full month in intensive care. Doses up to 500 times as high as those received by this first group of volunteers had been given to animals, with no sign of toxicity whatsoever (Wood & Darbyshire, 2006).
Testing for “abuse liability” might take place during phase I. At the urging of the FDA, the sponsor might be asked to determine whether the substance is pleasurable to take, whether experienced users (“abusers”) of illicit substances report some equivalence of effect with the new substance, or whether ordinary participants in clinical trials diverted it to friends. This reflects one of the rare instances of interest in specifically psychoactive effects by any responsible authorities. A clear indication that a new drug intended for prescription creates euphoria in a few users or is diverted by a few clinical trial participants to their relatives or friends would certainly delay if not doom its prospects of obtaining FDA approval as a prescription medication. Yet, that a drug creates dose-dependent dysphoria (unpleasant emotions or behavior such as depression, agitation, restlessness, or anxiety) in more than a few users would evoke absolutely no concern among regulators unless the effects are clearly and repeatedly described as dramatic or observed frequently in the trials’ reports submitted to the FDA. The implied reasoning is that these unpleasant effects are most likely manifestations of the subjects’ pre-existing psychiatric disorders and need not be considered from the start as attributable to the drugs.4
Banishing the Psychoactive. Based on the results of animal trials, it is likely that a distinctive profile of the psychoactive drug has begun to emerge: the drug has either energized, or sedated, or paralyzed, or rendered animals indifferent, or inhibited some learning and memory tasks, or increased or decreased various species-like or un-species-like behaviors in contrived settings. At present, it is impossible to imagine a drug with no noticeable behavioral effects in animals being viewed as a potentially useful psychiatric medication and thus proceeding to human testing. Despite these definite observations that drugs intended for psychiatric use have clear behavioral effects in animals, no systematic search of equivalent psychoactive effects in humans takes place during the drugs’ clinical trials. Neither drug firms nor the FDA have developed (or publicized) methodical procedures to test, in human volunteers, emotional, cognitive, and behavioral effects—which psychoactive drugs produce and are expected to produce, by definition. The case of Strattera (atomoxetine), a claimed “nonstimulant” approved by the FDA for the treatment of ADHD in 2002, is illustrative. Records and data released by the FDA show that atomoxetine was administered to nearly three hundred healthy volunteers during phase I studies. Yet in several hundred pages of FDA evaluation summaries, neither the drug firm nor the FDA reviewers who pored over these data made a single comment on anticipated psychoactive effects besides those related to the potential abuse of the drug. This bears restating: No exploration of Strattera’s effects on mood, attention, memory, or any other emotional or intellectual quality in healthy humans was reported in the FDA review of the sponsor’s application for marketing (Cohen, 2011).
In any case, based on a combination of animal and phase I observations, on the resemblance of the tested substance to others on the market, and on whether its use can be justified by marketable theoretical considerations such as dopamine, serotonin, or other still-undiscarded hypotheses related to the anticipated indication, a testable clinical indication in humans has been proposed, worded by means of the DSM psychiatric disorder. This is obligatory because federal regulations define a drug as something intended for the prevention or treatment of “disease.” A drug cannot be approved by the FDA because it has potent or potentially useful stimulant or sedative effects—it must be judged efficacious for a recognized disease or disorder: for example, Attention Deficit-Hyperactivity Disorder, General Anxiety Disorder, or Schizophrenic Disorder. (There are exceptions to this rule, as for example when the FDA approved risperidone for the treatment of “irritability” associated with autistic disorder in 2006.)
In this connection, it is noteworthy that the FDA has explicitly recognized that psychiatric diagnoses have no validated physiopathology. A consumer queried the FDA on whether it agreed with a statement by Health Canada, the Canadian government’s drug regulatory agency, that “For mental/psychiatric disorders in general . . . there are no confirmatory gross, microscopic or chemical abnormalities that have been validated for objective physical diagnosis.” In its reply to the consumer, the FDA’s Center of Drug Evaluation and Research agreed that “psychiatric disorders are diagnosed based on a patient’s presentation of symptoms that the larger psychiatric community has come to accept as real and responsive to treatment. We have nothing more to add to Health Canada’s response” (cited in Pringle, 2009, p. 1). This statement by the FDA explains why any discussion by the sponsor of the expected or presumed biological mechanisms by which the tested psychiatric drug might reduce symptoms of the mental disorder of interest in the clinical trial is itself reduced to an absolute minimum in the sponsor’s application for drug approval. For example, Cohen (2011) observed that in approximately 695 pages making up the FDA-released evaluation of Strattera, the presumed biochemical rationale of Strattera as a treatment for the proposed indication, ADHD, was discussed in two sentences, with no references.
Phase II Trials. Phase II consists of relatively small trials, lasting about two to eight weeks, usually including anywhere from fifty to three hundred people diagnosed with the DSM condition for which the sponsor hopes to market the future medication. Thus phase II trials attempt to establish that the drug will, indeed, improve the officially designated symptoms of an officially designated psychiatric condition. To determine for which disorder the drug will be tested is, as we have mentioned earlier, probably based on a combination of factors, none of which appears in the literature as decisive. It is possible to suggest that the decision is not an inherently complicated clinical matter (although it may be a risky marketing matter). For example, looking at a number of previous drug approvals, it may be that drugs having revealed a distinctive behavioral profile of sedative effects (and a molecular activity profile somewhat consistent with that of other sedative drugs on the market) will likely be tested for the treatment of DSM disorders characterized by symptoms of anxiety or agitation, for which sedating drugs are often found useful. Similarly, drugs having revealed a distinctive profile of deactivating effects will likely be tested for DSM disorders characterized by delusions, loss of control, and severe agitation.
Phase II studies vary greatly in methodological rigor and are usually “open,” meaning that if the studies involve control groups of participants receiving a comparison drug or placebo, investigators know who these participants are. To measure outcomes, rating scales that usually list the appropriate DSM symptoms of the particular disorder—as well as other symptoms of general psychological distress (especially anxiety, agitation, and depression)—are used. From the sponsor’s perspective, phase II trials must succeed to justify the next phase of testing, phase III, because this is where the most examined trials will take place. It appears that less than one-tenth of substances that enter phase I trials make it to approval. Over half of the failures apparently result from an inability to demonstrate efficacy during phase II trials: that is, superior response of patients on the drug compared to placebo, even in open trials (Hurko & Ryan, 2005).
Controlled Trials out of Control. Phase III trials are often called “pivotal” trials because they employ what experts in medicine widely consider the gold standard design: the randomized, controlled clinical trial (RCT). In RCTs for most psychiatric drugs, eligible participants (about five hundred to three thousand people in total, recruited from multiple sites in different cities and, increasingly, different countries) are randomly assigned to receive either the drug or an alternate treatment, usually an inert placebo. Because random assignment is the strongest way to ensure similar groups and thereby minimize important threats to the methodological (logical or internal) validity of a study, RCTs are believed to produce the highest-grade evidence to determine how much observed change in participants is due to the treatment rather than to any confounding variables.
The validity of the RCT rests on several assumptions, one of which is that participants in the trial are all the same on the key reason why they have been enrolled in the trial (i.e., they all have the same “mental disorder” to be treated). The point of the RCT is to determine the specific influence of a treatment on the outcome of the trial; therefore one needs to rule out the influence of other factors (within and outside the participants) that could cloud this determination. Thus, FDA clinical trials of psychoactive drugs always specify that the participants meet the specific diagnostic criteria necessary for mental disorder X, as determined by a structured DSM psychiatric diagnostic interview and confirmed by experienced clinical psychiatrists. Yet that participants meet the DSM criteria for the disorder in question does not in any way guarantee the sameness of their problem. The issue is not merely one of the “heterogeneous presentation” of a disorder, just as one person with lung cancer might differ from another person with lung cancer. At issue here is the nature of the problem. The sadness or despondency experienced by one person’s unemployment and by another’s realization of a spouse’s infidelity might both meet the DSM’s diagnostic criteria for “Major Depressive Disorder” or its synonyms, but they are worlds away in cause, meaning, and experience (Jacobs & Cohen, 2010). The sameness that characterizes lesions or infections in physical disorders cannot exist in the case of psychological problems that are only diagnosed based on an individual’s subjective view of their own circumstances and predicament, a view that develops and differs according to circumstances (including the very circumstances of a clinical trial). If this is the case, the whole point of conducting a psychiatric drug RCT and randomizing participants in separate groups in order to ensure that only treatment (drug or no drug) differs between groups so that only treatment can be implicated in the outcomes is exposed as nonsensical. This foundational issue is not, to our knowledge, ever discussed in the psychiatric clinical trial literature, so strong is the tacit acceptance of DSM disorders as conventional medical diseases, impersonal and invariant medical disorders, the same in every person.
A well-known refinement of the RCT involves double-blind placebo-control, wherein neither researchers nor participants are supposed to know who is receiving an active drug and who an identical-looking but inert placebo. This precaution is meant to counter the potentially enormous impact of researcher and participant expectations on the outcome. But the actual effect of the precaution is rarely if ever tested or reported in modern psychotropic drug trials, possibly to avoid knowing that patients and clinicians can guess correctly (apparently, more than 80 percent of the time in older trials of benzodiazepines or antidepressants) which treatment they are receiving (Even et al., 2000). Blindness in psychotropic drug trials is therefore a completely relative notion, which means that the scientific value of the RCT in the enterprise must also remain a relative notion. This bears repeating: although the whole preapproval drug-testing process culminates with phase III randomized controlled trials with their obligatory double-blind feature, the breach of blindness in these trials may be routine and widespread, tainting impartiality of the raters (assuming such impartiality can exist in the sponsor-controlled clinical trial environment) and rendering the whole exercise no different than phase II open trials. For example, Benson and Hartz (2000) compared RCTs and merely “observational” studies of nineteen different treatments (excluding psychotropic drugs) but found estimates of treatment effects from the lesser-grade studies to be neither larger nor qualitatively different than those from RCTs. In sum, the RCT, erected as a massive stone guardian of the medical validity of testing psychoactive drugs for mental disorders by the FDA and the drug industry, has feet of clay.
Besides their larger size and supposedly more rigorous design, phase III trials are essentially similar to phase II trials in length (about two to eight weeks) and outcome measures (a predefined average percentage improvement on rating scale scores in the drug-treated group that should exceed any improvement seen in the non-drug-treated group and not be attributable to chance, as determined by statistical tests).
Finally, phase IV trials (also known as post-marketing surveillance trials) might be undertaken after the drug has received market approval from the FDA. Regularly, the FDA requires the sponsor to promise to conduct such trials as a condition for approval. Phase IV trials serve as an explicit recognition that the premarketing clinical trial process is inherently limited as the types and numbers of patients studied, the durations of treatment, and the overall conditions of use differ greatly from the real-world patients, durations, and conditions of use expected once the drug hits the market. Only after several years or decades of such use might one expect a more realistic safety profile to be established. The three major drug studies discussed in chapter 6 (CATIE, STAR*D, and STEP-BD) may all be considered phase IV trials. As of 2006, 71 percent of phase IV trials that sponsors had promised the FDA to conduct as a condition of the approval of their drug had not yet started (Avorn, 2007).
We mentioned earlier that choosing the tested indication for a drug (e.g., the “disease” that it will be officially approved for) may be a more risky marketing than clinical issue. This is because, years before the possibility of market approval, the drug maker must anticipate future therapeutic needs in the field—or, if necessary, create such needs—so that the medication appears to clinicians and the public to arrive just in time to allay a serious problem and that a respectable return on investments (or better, blockbuster status for the drug, usually defined as $1 billion or more in yearly sales) is obtained. After having received a brand name, the psychotropic medication will now be the subject of a promotional blitz targeted to all persons, groups, and institutions who might have some interest in its use. A key part of this campaign involves formulating a simple way to understand how the drug works and why it is so essential (Nesi, 2008). From these strategies are born or reborn invented phrases such as “chemical imbalance,” “mood stabilizer,” and “treatable medical condition.” The money spent on this marketing will greatly exceed the sums invested in all the phases of preclinical and clinical testing that led to the drug’s approval by the FDA and any subsequent studies once on the market (Gagnon & Lexchin, 2008).
The drug will be placed in a therapeutic class corresponding to the disorder for which the FDA approved it for prescription (such as antipsychotic, antidepressant, anxiolytic). This classification may at first matter to doctors, pharmacists, patients, and journalists, as it will be the first and perhaps the only formally advertised indication for that drug. Quickly, however, this classification will mean little in practice, as nearly all psychotropic drug classes end up prescribed for all groups of disorders (Bezchlibnyk-Butler & Jeffries, 2005). Rapidly, by means of the tools and techniques of pharmaceutical promotion, the drug’s uses will expand in the form of off-label prescribing (use of the drug for different problems than its official label specifies), which constitutes the principal means for psychotropic drugs to reach blockbuster status. A couple of years after Neurontin (gabapentin) was approved by the FDA as an adjunctive treatment for epileptic seizures, 90 percent of its prescriptions were for conditions such as ADHD, bipolar disorder, migraine, and depression (Fullerton, Busch, & Frank, 2010). In its heyday, Prozac, initially approved in 1987 for depression, then bulimia and obsessive-compulsive disorder, became prescribed for more than a dozen other conditions, in and out of psychiatry. As Eli Lilly’s patent on selling Prozac neared expiration, the company resubmitted Prozac to the FDA for approval as a treatment for Late Luteal Phase Dysphoric Disorder (later renamed Premenstrual Dysphoric Disorder in the DSM-IV). Prozac re-emerged in 2000 as Sarafem. Lilly then changed the coating on the Prozac pill so that it would only dissolve fully in the intestine, keeping it longer in the body, and changed its name to Prozac Weekly, which the FDA approved in 2001.
Once on the market, the observation of undesirable or absence of desirable effects not previously detected (or detected during the drug’s journey to FDA approval but suppressed from publication) can transform the medication into a public health hazard and limit its use—if patients are lucky. A drug might be available only by prescription for years and then become available for purchase over-the-counter. Immediately, its price, its indications, its usual dosage, and how the public perceives its risks and benefits will dramatically change (Mahecha, 2006).
Different years have been proposed as marking the start of the twentieth century’s so-called psychopharmacological revolution. According to Frankenburg (1994), it’s 1931, year of the first studies of rauwolfia serpentina, a plant whose extract, reserpine, had a meteoric rise and fall as a treatment for mental illness in the 1950s. According to Strassman (1995), modern biological psychiatry started in 1943, when Albert Hoffman discovered the hallucinogenic lysergic acid diethylamide (LSD). The year 1949 has also been proposed, when psychiatrist John Cade first published his account of administering lithium salts to the inmates of his mental hospital in Australia. Most everyone else, however, has chosen 1952 as the start of the revolution, when the first observations were made public in France that a drug called chlorpromazine could subdue agitated inmates in insane asylums.
Chlorpromazine was the first to be baptized “neuroleptic” (“that seizes the nerve”). Without putting the subject to sleep, the drug induced a state that its pioneer observers termed “psychic indifference” and which sometimes progressed to a stupor. The unique emotion dampening and behavior subduing effects of neuroleptics (still unequaled by any other drug class) radically changed the internal organization of the asylums and the relations between inmates and their keepers (Cohen, 1997b; Freyhan, 1955).
Over a ten-year period, neuroleptics began to replace impaludations, (a method of treating psychosis by injecting blood infected with malaria), sleep cures, barbiturate comas, insulin comas, electrically-induced seizures, and lobotomies, treatments that had been vogue since the end of the 1910s but had done little to change a popular perception of madness as incurable or of psychiatry as only vaguely related to medicine. In the 1950s, by enabling psychiatrists to prescribe pills to suppress psychosis, chlorpromazine allowed psychiatry to officially accede to the rank of a medical discipline. According to the late French psychiatrist Edouard Zarifian, “There is no medicine without prescriptions. To be medical, psychiatry needed drugs” (1995, p. 74).
Within a year of chlorpromazine’s introduction, however, psychiatrists began describing how its tranquilizing action seemed inseparable from newly-appearing neurological impairments, notably parkinsonism and various types of abnormal involuntary movements termed dyskinesia, akinesia, and akathisia. Intriguingly, as a group these movements closely resembled the sequelae of encephalitis lethargica, an epidemic that swept through the world between 1915 and 1926. Pierre Deniker, the French psychiatrist credited with Jean Delay for the first psychiatric uses of chlorpromazine without other drugs, stated he and his colleagues had long realized that, although the neuroleptics were new drugs, their adverse effects were not: “All the side effects of neuroleptics had already been described between 1920 and 1935 as a sequelae of encephalitis” (Deniker, 1989, p. 255). Such realizations, however, did not raise concerns for the simple reason that psychiatrists were not surprised that their treatments could cause damage, even extremely serious damage. Indeed, since the very beginnings of hospital psychiatry, an “effective” treatment was one that could disable the person receiving it. Psychiatrists were completely familiar with the amnesia provoked by electroshocks, the occasional deaths or anoxia produced by prolonged hypoglycemia from insulin coma, and the emotional blunting and loss of volition following lobotomy, a procedure some of them openly described as “partial euthanasia” (see Constans, 1992).
Consider the reminiscences of Heinz Lehmann, who introduced chlorpromazine to North America in 1953, on the sorts of interventions that he used in his Montreal hospital in the 1940s:
“Our two major therapies were insulin-induced hypoglycemic coma and electric shock therapies . . . Paraldehyde and the barbiturates were about our only means to quell agitation and violence in addition to seclusion and restraint . . . 70% to 80% of [patients] relapsed” (1993, p. 294).
Lehmann therefore experimented with procedures “that would be impossible to repeat today” (p. 295). In an earlier paper, he mentions, among others, “brain biopsies” done on “randomly selected psychotic patients”; “carbon dioxide treatment”; the use of “very large doses of caffeine. . . of course with no results”; nitrous oxide “to the point where there was complete loss of consciousness”; injections of sulphur in oil and typhoid antitoxin, both of which only produced high fevers; injections of “turpentine into the abdominal muscles which produced—and was supposed to produce—a huge sterile abscess and marked leucocytosis” (1989, p. 263). Lehmann’s candid accounts, which are here obviously truncated and deserve to be read in full, illustrate how, in devising treatments for their forgotten and socially devalued wards, asylum doctors had little incentives, desires, or training to choose treatments causing least harm.
Most retellings of the revolution brought about by neuroleptics completely ignore that it was only in comparison to these other extremely damaging yet consecrated treatments that neuroleptics were first appraised, and this, inside the twisted world of the asylum (Breggin, 1983; Cohen, 1997b). The ease of administering pills and the indisputable gains in bringing order to the asylum carried the day over any strictly medical considerations. Within ten years after the first psychiatric use of chlorpromazine, about thirty similar drugs had been brought to market. The damaging effects of neuroleptics came to preoccupy psychiatry only thirty years later, when an epidemic of tardive dyskinesia (and its legal consequences in the United States in particular) had to be faced and when the modest therapeutic gains from neuroleptics were discussed unambiguously in professional journals and meetings (Cohen & McCubbin, 1990). Until that occurred, neuroleptics were universally lauded as the decisive psychiatric advance of the century.
In 1994 a team of four American research psychiatrists analyzed 368 studies spanning the century (published between 1896 and 1992) that reported on clinical outcomes for individuals diagnosed with schizophrenia (or dementia praecox, as it was known or recorded until the 1920s–1940s) and who had received whatever treatment was in vogue during their time (Hegarty et al., 1994). These authors found that overall, 46 percent of patients were rated as improved with antipsychotics, 42 percent with convulsive treatments (electric, insulin, or cardiazol shocks), and 28 percent with lobotomy. The small difference between drugs and shock, considering the reputation held by neuroleptics as uncontrovertible advances over all existing treatments against psychosis, is quite revealing. Moreover, Hegarty and colleagues also found that 29 percent of patients were rated as improved with “nonspecific” interventions, which they defined as “placebo trials, psychotherapy, hydrotherapy, fever therapy, and nonneurological surgery” (p. 1411). This 29 percent might be considered a baseline improvement rate in psychotic disorders, regardless of—or despite—any intervention. If so, one would be justified to subtract it from each of the other totals, to get a better sense of their net value, just as in a two-group clinical trial one may deduct placebo response rates from drug response rates to approximate the net response from drugs.
Also, when Hegarty and colleagues examined the twenty studies published just before the end of their review (1986–1992), they calculated an improvement rate (36.4 percent) that they termed “statistically indistinguishable from that found in the first half of the century [35.4%]” (p. 1412). Hegarty and colleagues’ investigation provided a unique long-term view showing—just as the twenty-first century CATIE study—that a full generation of antipsychotic drug treatment of schizophrenia did not appear to be any more effective than interventions in vogue during the pre-drug era.
Starting in the early 1990s, forty years after chlorpromazine, a new generation of antipsychotic drugs, called “atypicals” by their promoters, made its appearance. The occasion allowed many psychiatrists to finally rail openly against classical neuroleptics, now portrayed as ineffective and exceedingly toxic, and to express the hope that the newer drugs would solve the problem of psychosis. The atypicals—so called because their makers claimed (1) that their biochemical actions were much broader than those of the older drugs, (2) that they effectively suppressed psychotic symptoms yet did not cause the typical neurological impairments of the older drugs, and (3) that they actually helped reverse the apathy observed in treated patients—were greeted enthusiastically as a new dawn in the treatment of schizophrenia.
One by one, except for clozapine, the five atypical antipsychotics introduced between 1994 and 1999 became blockbusters, their off-label use flourishing due to extremely aggressive marketing. In most cases, this occurred despite early signs that the drugs increased risks of inducing weight gain and metabolic complications such as diabetes. A few dissonant analyses and observations (e.g., Geddes et al., 2000; Cohen, 2002) also showed that the perceived therapeutic progress rested on strained tests or ignoring evidence and common sense, but these were drowned out. One advertisement for Risperdal (risperidone) in the American Journal of Psychiatry went as far as to claim that the drug was as harmless as a placebo pill (appeared in April 1994, p. A11).
The atypicals experienced an unprecedented surge in use, spreading to children and older persons and to any diagnosis in which the existing drugs seemed less than satisfactory. We have mentioned that Zyprexa (olanzapine), first approved in 1995 for the treatment of acute schizophrenic episodes, had grossed $45 billion dollars by 2011, becoming one of the world’s most profitable medications. However, the publication of the CATIE study in late 2005 and of several other large and non-industry-funded studies around the same time confirmed that these new antipsychotics were neither more effective nor better tolerated than the drugs they had so quickly replaced.
Most observers agreed that, among children and adolescents (targets for off-label prescriptions in the United States during the two decades straddling the centuries), aggressive or hostile behavior probably accounted for most antipsychotic prescribing (Patel et al., 2005). Yet one controlled study of a classic antipsychotic (haloperidol), an atypical antipsychotic (risperidone), and an inert placebo among three groups of youths with intellectual disabilities who showed “challenging aggressive behavior” found that “aggression declined dramatically in all three groups by four weeks, with placebo showing the greatest reduction (79%) (vs. 57% for combined drugs)” (Tyrer et al., 2007). Here again, demonstrations of clinical gains under real-world conditions lagged far behind the claims that drug manufacturers and their proxies made even before their drugs had passed the FDA approval hurdle.
It is still too soon to know the full story of the atypical antipsychotic debacle and to understand how the owners of the drug treatment of schizophrenia,—tens of thousands of highly educated medical practitioners—swallowed drug industry propaganda that the exceedingly complex problem of schizophrenia could be solved by the industry’s latest drugs. Jeffrey Lieberman (2006), the lead CATIE investigator and a previously unabashed proponent of the atypicals, summed up the affair:
The claims of superiority for the [atypicals] were greatly exaggerated. This may have been encouraged by an overly expectant community of clinicians and patients eager to believe in the power of new medications. At the same time, the aggressive marketing of these drugs may have contributed to this enhanced perception of their effectiveness in the absence of empirical information. (p. 1070)
It is tempting to let this quote speak for itself. Still, Lieberman not only described presumably rational psychiatrists “eager to believe in the power of new medications” and embracing “greatly exaggerated” claims “in the absence of empirical information,” but doing so fifty years after the arrival of the first antipsychotic, during the flowering of clinical psychopharmacology as the foundational, “evidence-based” activity of psychiatry.
In 1962, researchers showed that antipsychotics bound to neuronal receptors that normally attracted the neurotransmitter dopamine. The drugs were blocking dopamine’s flow through its habitual neuronal pathways. Thus was born the “dopamine hypothesis,” according to which an excess of dopamine activity causes schizophrenic psychosis. This hypothesis (modified and refined) remained dominant, though it has never enjoyed any directly supporting evidence. In other words, no dopamine abnormality in the brains of never-medicated people diagnosed with schizophrenia has ever been confirmed reliably (Tandon, Keshavan, & Nasrallah, 2008).
As we’ve discussed, the search for new drugs (for physical disorders) uses animal models to test possibly curative compounds on animals with the disease or to analyze biological causes. The ease with which animals can be studied and sacrificed is the obvious perceived advantage here. “Depressed mice” or “psychotic monkeys,” however, can hardly serve as adequate models for depressed or psychotic states in humans (even putting aside the definitional and diagnostic problems covered throughout this book). In psychiatric drug studies, therefore, “animal models” typically consist of observing drug effects on various instinctive or conditioned animal behaviors that only have a tenuous connection to the problems purportedly treated in people. Many animal tests merely screen for drugs that will produce similar effects to those produced by commercially successful drugs on the market, which is how “me-too” drugs appear.
One reason for the focus on neurobiology in the absence of definitive findings may be the extent to which descriptions of biomedical facts over the last two decades have become tied to technological advances that dazzle observers with their appealing images of brain function. Finding that the brains of different people seem to function differently has provided endless fascination for those who see in these differences confirmation that biology “explains” everything disordered in humans. That taxi drivers or musicians show different brain activity on certain spatial or musical tasks than other people seems merely interesting. That depressed people occasionally show different brain functioning than other people, however, “proves” that they’re diseased. This logic is erroneous, because subtle physiological difference might arise from experience or learning; it might be a consequence, not a cause, of the person’s problem diagnosed as a psychiatric disorder. And such a difference does not mean “disease” unless the meaning of disease is—as we have been suggesting—distorted beyond recognition.
Other advances in molecular biology, especially the ability to label drug molecules with radioactive tracers, allowed scientists to deepen their knowledge on the micromechanisms of neurotransmission and to chart a drug’s distribution in the brain. Whereas five to ten substances were identified as neurotransmitters in the 1960s, more than one hundred are identified today, and their multiple functions are only beginning to be revealed. For example, in the 1970s, psychiatrists used to write generally about “dopamine receptor blocking.” Dopamine cells are now known to possess five different families of receptors, each of which seems to have quite different functions. For serotonin, at least five subfamilies of receptors have been cloned for only a single of the fourteen families of receptors for that neurotransmitter already identified. But receptor pharmacology, the Holy Grail of psychiatric drug development in the 1990s, is passing on. The post-genomic focus is on proteins and genes whose expressions appear to affect physiological processes that, in some theoretical or in some animal model, might be related to the core physiopathology that—the whole field has committed itself to assume—underlies the DSM disorder for which the drug is tested. Moreover, the latest insights within conventional psychopharmacology suggest that current thinking about the importance of neuronal transmission be reevaluated to consider “the other brain,” that is made up by glia, the once-thought-inconsequential neural glue that holds the brain together (Fields, 2009).
The notion of chemical imbalance evaporates when reproducible evidence must be provided about the exact nature of pathophysiology in the serotonin or dopaminergic system. The enormously complex play, interplay, and counterplay of the cascades of alterations triggered by drugs binding to receptors and subreceptors has no connection to the claims made for years in advertisements, oft-repeated by journalists, that certain “drugs restore the balance of the serotonin system,” as if this balance was actually known or charted (Leo & Lacasse, 2008). Furthermore, as each newly identified neurotransmitter has been immediately considered as a possible player in depression, anxiety, or psychosis, the number of biochemical hypotheses of these problems increased radically during the 1980s, though few lasted for more than a few years. It is difficult to overemphasize how much value these hypotheses, and the new brain imaging technology, had for marketing drugs. Psychiatrist and historian David Healy (2008) put it this way: “When in the 1990s neuroscience threw up colorful images of the brain, marketers found these invaluable for purportedly showing the cleaner effects of SSRIs compared to older antidepressants. There was little neuroscientific value to the images—but they provided wonderful marketing copy” (p. 226). In Healy’s view, the monoamine hypothesis of depression—positing a lowering of neurotransmitters that drug treatment corrected—was abandoned by the science of psychopharmacology as early as 1970, but “the serotonin hypothesis was resurrected within the marketing departments of SSRI companies, because it was marketing copy par excellence” (p. 226).
In practical terms the discovery of neuroleptics gave birth to modern biological psychiatry and provided a springboard to develop the neurosciences generally. Yet do we understand psychosis? The inescapable answer is no. Neuroscientifically, after decades of intensive research, it remains completely mysterious why about 1 percent of young people develop “schizophrenia.” Scientists merely repeat, mantra-style, that schizophrenia results from an interplay of genetic, biochemical, and environmental factors. A recent review purports to identify no less than seventy-seven distinct “facts” about schizophrenia, yet its authors cannot mention a single universal biological abnormality, let alone specify a single necessary or sufficient cause (Tandon et al., 2008). The authors nonetheless conclude their article by emphasizing the importance of calling schizophrenia a disease.
At the level of the day-to-day management of very disturbed persons, the discovery of neuroleptics marked a change: the management began to operate from inside patients’ bodies even if their keepers and clinicians were physically distant. Centuries ago, controlling the madman meant restraining his body at close proximity, for inside the madman resided a wild beast thought to require restraints and beatings. Later, with electroshock and insulin coma, the “treatments” were directed more specifically toward the brain, but their administration still required close contact between the inmate and the clinician/keeper, a contact that even elicited psychodynamic interpretations of why inmates were terrorized to receive shocks (Dunham & Weinberg, 1960, pp. 181–182). Giving a pill to swallow makes control more efficient because it involves still less contact: hundreds of patients could be treated daily in a single institution. Finally, with the development of long-acting injectable neuroleptics by the late 1960s, a single intramuscular injection every four to six weeks sufficed to maintain the patient under the medication’s effect. Between injections, no need to see the patient, to talk with him, to know what he did—he was, after all, deinstitutionalized and others were taking care of his “social integration into the community.” Taking in these linear developments, one of us speculated fifteen years ago that the administration of antipsychotic drugs would take a logical next step: subcutaneous implants allowing continuous, unmonitored drug administration for months or years (Cohen, 1996). It should come as no surprise that this option has been studied seriously (Irani et al., 2004; Metzger et al., 2007).
Tranquilizers and sedatives such as the barbiturates and chloral hydrate were widely used prior to the neuroleptics (Lopez-Munoz et al., 2005). Starting in the mid-1950s, two other classes of psychoactive drugs were named: the antidepressants—originally, some anti-tuberculosis medications but mostly modifications of neuroleptics—and the “minor tranquilizers” or “anxiolytics,” originally identified because of their muscle-relaxing properties.
The first modern anxiolytic was meprobamate, introduced in 1955 into clinical practice under the brand names Miltown and Equanil. Within five years, it was the most widely used prescription drug in the United States and many other countries. Then came chlordiazepoxide (Librium) in 1960, and diazepam (Valium) in 1963 (Ban, 2006). These two drugs and their cousins, known as benzodiazepines, became hugely popular in primary care medicine, and their prescription increased 100 percent in most Western countries between 1965 to 1970, compared to about 20 percent for other classes of psychotropics (Lader, 1978). The drug industry’s promotional efforts, extending a variety of techniques of mass marketing to doctors, has been proposed to explain much of this success (Smith, 1981). Valium appeared in more medical advertisements than any other drug and—cause and effect relation according to some (Krupka & Vener, 1985)—climbed to the rank of number one prescribed drug in the world by 1970.
Observing this phenomenon, sociologists began to produce accounts of the social control function of a growing “medical-industrial complex.” They proposed hypotheses that have remained fruitful: tranquilizers medicalize the daily hassles of modern life (especially for women), pacify those people with legitimate grounds for making social and political claims, and distract professionals from discerning any social determinants of psychological distress (Koumjian, 1981). Crowning the 1970s as the “era of benzodiazepines,” British psychiatrist Malcolm Lader (1978) designated these drugs as “opium of the masses.”
As with other tranquilizers in previous decades, however, a consensus emerged within the medical profession in the 1980s that benzodiazepines carried a risk of dependence with prolonged use (including a withdrawal syndrome when stopped abruptly). These concerns about unwanted effects of benzodiazepines stabilized, then decreased their use in most Western countries, as health authorities enacted various measures (such as triplicate prescriptions, with copies sent to state justice agencies to monitor “unorthodox” scripts) to dissuade doctors from prescribing them. Recently, a spike in prescriptions of Valium was observed in Great Britain, but a comment from Professor Steve Field, chairman of Britain’s Royal College of General Practitioners, nicely illustrated the change in attitudes since Valium was number one: “In my own practice we have reduced dramatically the amount of prescribing we do of these kinds of drugs, because they are horrifically addictive, and people can get hooked on them within just a few days” (cited in Donnelly, 2010, para. 8). Similarly, in Louisville, Kentucky, Seven Counties Clinic decided to stop writing all prescriptions for its three thousand patients on Xanax (alprazolam), and some of these patients have been switched to clonazepam (Klonopin), described as “a longer acting benzodiazepine that does not kick in as quickly and is thought to pose less risk of addiction.” One doctor stated that on clonazepam, “They don’t get the high that’s associated with Xanax, nor the withdrawal associated with it” (Goodnough, 2011).5 The benzodiazepines too followed the path of stigmatization, or the Seige cycle.
The rise of a medical and social debate about tranquilizers and sleeping pills did not mean that doctors abandoned these drugs. Probably because of their quick onset of relaxing effects, benzodiazepines have remained a staple for people in acute distress (especially over losses of spouses, relatives, jobs, and status) who want rapid tranquilization or sleep but not stupor. The drugs provide more than respectable revenues to their manufacturers and are also actively traded on the black market. Importantly, about one quarter of older persons who were introduced to benzodiazepines a generation ago still use them regularly, and fully 40 percent of these users view themselves as “dependent” (Voyer et al., 2010). They generally have no difficulty obtaining benzodiazepines from doctors, who are in effect maintaining these users’ dependence. Alprazolam (Xanax), considered one of the most addictive benzodiazepines, vigorously traded in the illicit drug trade, and the subject of extremely little advertising to doctors today, was the sole psychoactive drug appearing among the top fifteen most frequently dispensed (i.e., sold or delivered by pharmacies) prescription drugs in the United States in 2008 (41.5 million prescriptions, up from 33.5 million in 2004; IMS National Prescription Audit, 2010).6
Starting in the late 1980s, the backlash against benzodiazepines prompted industry-influenced “key opinion leaders” to encourage general practitioners to alter their prescription of a psychotropic drug (usually to a woman in distress), away from benzodiazepines and toward the new SSRI antidepressants exemplified by Prozac. Precisely as occurred previously and would occur again, the new disorder of concern—depression—was presented as widespread and damaging, and the new class of drugs promoted as effective and harmless—and without the bothersome effects (dependence) that were stigmatizing the existing drugs. Perhaps something else a bit more encompassing did happen, as Pieters and Snelders (2009) aptly summarized: “The age of anxiety and blaming society gave way to the age of depression and blaming your own brain” (p. 71). But the new fashion probably would not have occurred without at least two other overlapping events: the arrival in 1980 of the third edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, and an ever-deepening involvement of the pharmaceutical industry in every facet of psychiatric thinking, research, and practice.
By the 1970s psychiatrists were prescribing about fifty different psychoactive drugs to their patients but could not claim that they had any validated diagnoses. As has been discussed previously in this book, there is still no clinical, radiological, electrical, or other physical test or exam that can reveal, during life or after death, reliable markers in the body of a purported condition called a mental disorder—except of course for drug intoxications and organic psychoses still inexplicably called “mental disorders” in the DSM. Thus, how was psychiatry to ensure that diagnoses did not remain merely subjective judgments about distressing thoughts or behaviors, robbing the profession of its medical aspirations?
As we have seen in chapter 4, the DSM-III listed criteria for each diagnosis, defined each mental disorder as distinct from others, and added eighty new diagnoses to the previous edition of the DSM. The new manual was adopted fairly quickly by other professions sharing the treatment turf. This was a truly significant event because psychology, social work, and counseling had evolved precisely by adopting nonmedical perspectives on deviance and distress. Their embrace of the DSM-III began to perfect a theoretical, financial, and bureaucratic integration of the mental health industry, with psychiatry at the top (Kutchins & Kirk, 1988).
More relevant for our discussion of psychoactive drug use, by modifying its diagnostic manual, psychiatry and its institutions of leadership, research, and treatment strengthened their already close association with the pharmaceutical industry into a full-fledged partnership. The whole question of classification and diagnosis did not concern clinicians when conversation (psychotherapy) was the prototypical treatment. With the arrival of new drugs and the regulatory requirement that drugs must be effective to treat a “disease,” clinicians were directed to classify presenting problems as specific diagnoses, so that their prescribing would resemble prescribing in other branches of medicine (Eisenberg, 1995; Klerman, 1978).
Drug treatment fit beautifully with the DSM-III, which presented on the surface a descriptive, symptom-based approach to diagnosis. Mental illnesses became mental “disorders,” defined as “not culturally sanctioned” distressing or impairing “symptoms” that resulted from undefined physical, behavioral, or psychological dysfunctions (though the dysfunctions could not be ascertained independently of the symptoms). These symptoms constituted the criteria to make a diagnosis. In turn, the criteria were—in a perfect lateral move—used to compose the items in rating scales that would help to evaluate patients’ states in clinical drug trials. Each mental disorder named in the DSM-III was automatically assumed to be a clinical entity, the pathophysiology of which was unknown but assumed to be elucidated with future research.
The technological advances we briefly described earlier, which allowed researchers to trace drug molecules until they reached cell membrane receptors, stimulated the development of speculative animal models and of molecules synthesized to bind more tightly to receptors. As psychiatrist Edouard Zarifian remarked, pharmacologists and neurobiologists “formulate hypotheses on the causes of a disorder and, once they have invented a molecule, explain to the doctor the effects that they are expected to observe” (1994, p. 88).
Thus, during most of the century no one seemed to complain of “panic attacks” and doctors could not name this problem when they saw it, nor did they easily assimilate it within the realm of anxiety. But two drugs (imipramine, an old tricyclic antidepressant and alprazolam [Xanax], a new benzodiazepine anxiolytic) began to be promoted as specific treatments for DSM-III’s new panic disorder in the early 1980s. According to Kramer (1993), psychiatrists had to re-create anxiety in theoretical terms. Several authors have described the symbiosis between drug makers and the diagnosis: the Upjohn drug company apparently funded the entire effort, culminating the creation of the diagnosis of Panic Disorder in DSM-III with the sole intention of obtaining approval to market Xanax as specific treatment for . . . panic disorder (Elliott, 2003; Lane, 2007). Almost instantly, panic disorder acquired an incontestable “reality.” This made psychologist David Jacobs (1995) observe how remarkable it was that problems without distinct boundaries, created with the pragmatic aim of drug treatment, came to be promoted as if medicine possessed discriminating data on their pathophysiology.
In the background, psychiatric epidemiology was reporting an increase in the prevalence of mental disorder, notably depression. In 1984, using DSM-III criteria, the vast Epidemiological Catchment Area Survey of the National Institute of Mental Health estimated the prevalence of depression during a person’s life to be 6 percent, the highest rate ever reported (Robins & Regier, 1991). Ten years later, another national survey using DSM-III-R criteria reported the rate as 17 percent, and for all mental disorders, 48 percent (Kessler et al., 1994).
At the level of populations, psychological distress waxes and wanes and is affected by political and economic instability (Cross-National Collaborative Group, 1992). Nonetheless, this new increase seemed inflationary, reflecting medicalization and the promotion of antidepressant drugs. According to business journalist James Krohe (1994), who wrote in the midst of the Prozac craze, “Depression is the latest product—and the most promising—of the wellness industry” (p. 24). In the workplace, concern about depression began to replace concerns about alcohol and substance abuse, creating new possibilities for counselors and administrators. Krohe described a web of phone hotlines, support groups, conferences and seminars for health administrators, free anonymous screening programs, infomercials, and public interest TV shows launched “to catch the two out of three depressed Americans who are not seeking treatment—almost 7.5 millions people who, in their misery, persist in confusing treatable depression with life” (p. 24). The National Depression Screening Day was inaugurated in 1991 on a college campus, subsidized by the maker of Prozac. By 1995, “In each of the 50 states and the District of Columbia, people can be tested for free to see if they are depressed or are at risk of so becoming” (Screening the Public, 1995, p. A42).
Its territory greatly enlarged, mental disorder became banal. Abnormality became, well, normal. Validly distinguishing whether someone truly had a mental disorder became somewhat irrelevant, given that half the population of the United States was designated as diagnosable with a chronic, recurrent, unpredictable mental disorder. Indeed, how could one even distinguish disorder from nondisorder if the former was characterized by impossible-to-detect variations of neurotransmitter circuits? Pieters and Snelders (2009) have also alluded to what they call this “democratization of mental disorders.” They recall that a drug company once advertised depression as “the most democratic of all disorders. It can affect everyone at any moment, for shorter or longer duration, without a recognizable course” (p. 71).
Two decades earlier, self-styled antipsychiatrists were claiming that everyone was sane, or everyone was insane. Their goal had been to abolish boundaries between sanity and madness, pushing society toward their ideal of equality. In some fashion, that goal was realized with the arrival of the SSRI antidepressants of the late 1980s and the widespread popular acceptance that despair, deviance, and distress were actually symptoms of medically treatable mental disorders. The drugs and the DSM seemed to have energized a new societal project of moral leveling, in which everyone is equal because everyone is diagnosable and treatable. Society and government could not be changed, but neurochemistry certainly could (Greenberg, 2010).
By focusing on the many symptoms of disorders finely chopped by the DSM and by invoking variations in neurotransmitter functioning that were becoming more easily imaged and presumably targeted by drugs, psychiatry could cease pursuing an elusive goal required for unquestioned membership in the realm of scientific medicine: to validate traditional diagnostic entities according to cellular models of disease. The new psychiatric diagnoses and their symptoms multiplied the possibilities to observe, in any behavior the least bit disturbing to a person or their network, a symptom calling for drug treatment. Mere descriptions of the habitual neuronal effects of drugs were recast as demonstrations that symptoms hid specific neurochemical imbalances. The way was open to validate a diagnosis by medicating a complaint.
American journalist James Wright (1994) illustrated the sway of this logic when he indicated that American policymakers who wished to provide equal insurance coverage for mental health as for physical health claimed that “the simple fact that pharmacology gives results is proof that mental illness are bona fide illnesses.” Wright asked approvingly: “But if a successful chemical treatment constitutes the distinctive sign of an illness, why are not all conditions treated by means of cosmetic psychopharmacology considered as illnesses? And why shouldn’t they be?” (p. 25). Scientific demonstration of the existence of disease had been turned on its head, replaced with circular definitions. What is an illness? Whatever a medication treats “successfully.”
The necessity of a medication was indicated by its positive results. In turn, these were demonstrated by the medication’s widespread use, especially by an increasing chorus of users’ appreciative testimonies. Consumers wanted and were incited by marketing to ask for antidepressants, drugs only available from physicians. As a result, scientific constraints on psychiatrists were loosened. They were again freed from justifying why one scientific/clinical model is worthier than another. Comforted by their patients’ narratives of relief, improvement, or recovery, psychiatrists could view the whole point of their enterprise as prescribing drugs in response to patients’ complaints. Predictably, such use of drugs bred dependence on drugs, and an avalanche of well-publicized clinical trials demonstrating contrived improvements for other complaints isolated remaining skeptics. Other interventions besides prescription grew more unfamiliar, and trying them would trigger uncomfortable discussions about the point of looking at distress as medical pathology.
If consumerism does indeed drive prescription, if patients receive just what they ask for, how then can we distinguish psychopharmacology from quackery? For philosopher of science Isabelle Stengers (1995), modern medicine is defined by the awareness of a single fact, itself stemming from the scientific repudiation of Anton Mesmer’s “magnetic treatment” at the end of the eighteenth century. The fact is this: “Cure proves nothing” (p. 121, italics in original). Then, as now, reports by people that they felt better or cured as a result of exposure to some intervention (then, magnets, trees, or objects “magnetized” by Mesmer; today, psychoactive drugs consecrated by clinical trials and FDA approval) cannot constitute proof that the people suffered from genuine diseases or that magnets or drugs are genuine treatments. Stengers adds a corollary to her fact: “The aim pursued by medicine (cure) does not suffice to distinguish between rational practice and quackery” (p. 121). In other words, the physician’s intention to cure the patient also cannot distinguish medical practice from that of the charlatan who merely seeks profit or aggrandizement. Yet, in psychiatry, as exemplified by the success of Peter Kramer’s Listening to Prozac, it was precisely the personal testimony of symptom relief, the narrative of transformed personality—in sum, the tale of the “cure”—that was put forth as the irrefutable proof of the validity of psychopharmacology.
The long history of drugs and medications amply demonstrates the richness of their effects on users as well as on the experts and authorities charged with regulating drugs. No discovery in neurobiology is necessary to grasp that psychoactive drugs have powerful effects that people might find desirable or undesirable or both. With a high enough dose, a psychoactive drug will affect virtually all people who take it. Yet its effects can vary slightly or greatly between individuals and are often unpredictable in any one person or even in the same person at different times. Depending on a person’s state of distress, for example, a drug effect might be experienced positively, and the person might decide that the drug is beneficial to him or her. Is there any reason to think that this person is reacting in a way that indicates underlying pathophysiology? We believe not.
We have argued so far that a great deal of the measurable success of a prescribed psychotropic medication appears to rest on a placebo effect—admittedly an inadequate concept insofar as it refers to something that can include suggestion from oneself, suggestion from other people and institutions, spontaneous remission of one’s troubles, as well as active self-improvement through deliberate and unknown methods triggered by the mere fact of having ingested what one believes to constitute a genuine treatment. But, in a complementary though not similar line of thought, we have also argued that another ingredient seems necessary for the success of a psychoactive drug, and that is, of course, a psychoactive effect. We have argued that psychoactive effects of prescribed drugs are ubiquitous, but that clinical trials and conventional psychiatric investigations have rarely if ever focused on the nature of such psychoactive effects, and especially how psychoactive effects as reported by users are related to the occasional evaluations of therapeutic benefits reported by users or inferred by clinicians. Thus we conclude that very much remains to be discovered about the nature of the varied psychoactive effects produced by the panoply of psychiatric medications on the market today. We venture what we consider to be reasonable observations, but their limitations will be immediately apparent.
In the case of nonconsenting or disturbing individuals (for example, children, psychotics, and the demented elderly in nursing homes), the aim of drugging is simply the control of outward behavior that bothers or offends other people or hampers the smooth functioning of institutions. In these cases, the finality of the prescription is to please these other people, and the favored psychoactive and behavioral effects for the conditions displayed by such individuals therefore usually consist of some form of compliance, reduced spontaneity, on-task-performance (stimulants), sedation or drowsiness, or indifference (neuroleptics). How the drug users themselves might appreciate the drug is of secondary concern, if at all.
The aim of drugging obviously differs in the case of consenting, consumerist adults, but here the situation gets increasingly murky and difficult to understand. The SSRIs, exemplars of the modern consumerist medications, may have succeeded partly because in the social, cultural, and economic context since their FDA approval, their most marketed psychoactive effects seemed to consist of a mild arousal believed to enhance the competitive capacities of citizens in the West, “exhausted by work, scared by unemployment, anxious about the future, [and] spellbound by the media” (Ramonet, 1995, p. 13). But with hindsight, the picture must be much more complex, as the SSRIs appear to produce sedation as much as they produce activation and arousal, and the latter are not seen by users as improving but rather as impairing function. And what to make of another important psychophysiological effect of SSRIs, the suppression of libido or sexual desire (the prevalence of which might suggest classifying the SSRIs primarily as sex-drive reducers)? It is tempting to speculate how such an effect might have dovetailed with many adults’ anxiety-laden experiences of sexuality in the age of AIDS and on-demand online pornography.
But neither placebo nor psychoactive effects can fully account for how Valium, Prozac, and Zyprexa became blockbuster drugs that dramatically altered or reinforced professional practices, popular perceptions, and pharmaceutical profits. Another ingredient has been necessary, especially in the age of science. We have referred to it repeatedly throughout this book, and we turn presently to examine it in more detail, paying special attention to its intertwining with research in psychiatry. This ingredient is the marketing of drugs by the pharmaceutical industry. The topic has been covered admirably in scholarly, insider, and journalistic accounts over the past decade (e.g., Critser, 2005; Elliott, 2010; Healy, 2012; Moynihan & Cassels, 2005; Petersen, 2008), and we have little original analysis to add to these, except to reinforce the notion that it is today no longer possible to discern where psychiatry and psychiatric science begin and where drug industry marketing ends.
Since the passage in 1951 of the Humphrey-Durham amendment to the Pure Food, Drug, and Cosmetic Act of 1938, getting certain psychoactive drugs inside people’s bodies has required a physician’s prescription (Abood, 2011). Accounts of pharmaceutical marketing agree on one thing: the pharmaceutical industry has magnificently honed its ability to make physicians “decide” to prescribe its products. Given the time, effort, and money spent by the industry to promote drugs, this should surprise no one.
As noted earlier, Canadian accountant Marc-André Gagnon and emergency physician Joel Lexchin (2008) analyzed several databases and proprietary expenditure reports to generate a startling estimate of the US pharmaceutical industry’s total spending to push pills in 2004: $57.5 billion. This gargantuan amount is in addition to the $31.5 billion that the industry said it spent that year on clinical trials and tests for its products. With total sales of pharmaceuticals in the US that year totaling $235.4 billion, promotional spending therefore made up 24.4 percent of sales (nearly double the spending on research and development). In 2011, sales of antipsychotics, antidepressants, stimulants, and anticonvulsants in the United States were reported to total $43.0 billion (IMS Health, 2011). Using 24.4 percent of sales for promotional spending as our yardstick gives the sum of nearly $10.5 billion spent by the industry to promote only these four classes of drugs in America. Using Gagnon and Lexchin’s breakdown of the categories and proportions of marketing expenses for all pharmaceutical products, table 7-1 gives one idea how the $10.5 billion might have been spent to promote antipsychotics, antidepressants, stimulants, and anticonvulsants.
Table 7-1
Estimate of Promotional Spending on Four Classes of Prescribed Psychotropic Drugs, USA, 2011
| Type of promotion | Spending (in $ billions) | % of total spending |
| Detailing by sales representatives | 3.73 | 35.5 |
| Drug samples | 2.9 | 27.7 |
| Unmonitored promotion | 2.6 | 25.0 |
| Direct-to-consumer advertising | .73 | 7.0 |
| Continuing medical education | .37 | 3.5 |
| Journal advertising | .11 | ∼1.0 |
| E-promotion, mailings | .05 | ∼0.5 |
The billions of dollars spent each year obviously show how industry marketing can operate on a gigantic scale. The marketing of no other treatment or intervention comes close to drugs in terms of the support that these products enjoy and in terms of the creative energies continually invested to make everyone view them as indispensable. The success of the enterprise hereby appears not as natural or self-evidently justifiable. Rather, it appears to require these billions of dollars to ensure that, first, prescribers cooperate, and second, the public asks for or is willing to accept drugs, to keep the American psychiatric drug enterprise moving along smoothly each year. But the figures suggest that at least (and probably much more than) three-quarters of all promotional spending targets physicians or health care professionals. One might conclude that it has been relatively easy to turn the public into a willing participant, a willing believer.
The monies spent on drug marketing operate in myriad ways. One way is via free or subsidized continuing education courses offered to physicians by key opinion leaders. Communication companies earned over $1 billion in 2004 to deliver industry-sponsored continuing medical education. Industry-sponsored courses find subtle but effective ways to highlight sponsors’ drugs and are associated with increased prescriptions of those drugs (Elliott, 2004; Wazana, 2000). The US Senate expressed concern over drug firms’ influence on continuing medical education and its impact on off-label drug prescriptions. The Committee on Finance (2007) of the US Senate describes how pharmaceutical firms have “too much influence” over the content of “supposedly independent educational programs.” At least one quarter of all accredited CME providers fail to ensure independence of content. The courses are described as forms of “veiled advertising.”
Pharmaceutical companies’ money is used for lobbying at all levels of government and making donations to political parties and to senators’ and congressmen’s re-election campaigns. The money influences legislators and government agencies to approve drugs and create favorable conditions for the industry (such as deducting opportunity costs to develop drugs that fail to gain approval). In addition, the drug industry agreed with the provisions of the Prescription Drug User Fee Act, which requires drug manufacturers to pay substantial user fees to the FDA’s Center for Drug Evaluation and Research to finance the process of government approval of the manufacturers’ drugs, in return for speedier approval times. In 2011, users fees were expected to add up to $707 million, fully 65 percent of the budget of the FDA department responsible for evaluating the efficacy and safety of prescription drugs and about 25 percent of the total FDA budget (Dutton, 2011). It is easy to understand how such fees, presented as natural payments for services rendered, make the FDA a stakeholder in the commercial success of the pharmaceutical industry.
Looking at lists of the recipients of funds from some drug companies’ charitable foundations (which some states have been requiring be disclosed and federal legislation has mandated as of 2011), one gets a sense of the intimate penetration of drug company money into the widest-ranging activities and to countless groups, organizations, and individuals (Cohen, 2008). These funds paid for scholarships; fellowships and research awards for medical students, young researchers, and established senior researchers; consulting and teaching opportunities for clinicians; endowed chairs for professors in academia; large research project and other centers within academia and university-affiliated hospitals; mental disorder screening initiatives and events in universities, workplaces, and communities; continuing education courses for health care professionals on “diseases” in the public eye for which particular drugs are now being advertised; professional and consumer magazines and newsletters; diagnostic task force committee members; grand rounds in hospital departments; breakfasts and lunches in medical schools, clinics, and hospitals; encyclopedias, books, prescription guides, and subscriptions to journals; funds (and sometimes lent personnel) for operation, research, and promotion of small, medium, and large nonprofit interest and advocacy groups that can be counted on to propagate a pro-drug message to their constituencies. In this connection, for example, the National Alliance for Mental Illness, widely considered the nation’s leading family and patient advocacy organization and therefore obligatorily represented in any mainstream policy forum, received no less than 81 percent of its 2009 funding from drug firms, becoming, for all practical purposes, more of an advocate for drug companies rather than for families of patients (NAMI’s Pharma Funders, 2010).
Table 1 shows that visits to doctors by drug reps constitutes the key marketing vehicle in the drug industry. The amount devoted to drug reps is consistent with estimates of their number in the United States, with about 85,000–100,000, or one rep for every six to ten doctors (Oldani, 2004; Greene, 2004; Fugh-Berman & Ahari, 2007). A Time Magazine guest column entitled “Attack of the Pharma Babes” emphasized the personal attractiveness and seductiveness of many drug reps (Haig, 2007). In a first-rate account of the tactics drug reps use with physicians and of the psychology of gift-giving in these relationships, physician and ethicist Carl Elliott (2006) writes:
When an encounter between a doctor and a rep goes well, it is a delicate ritual of pretense and self-deception. Drug reps pretend that they are giving doctors impartial information. Doctors pretend that they take it seriously. Drug reps must try their best to influence doctors, while doctors must tell themselves that they are not being influenced. Drug reps must act as if they are not salespeople, while doctors must act as if they are not customers. And if, by accident, the real purpose of the exchange is revealed, the result is like an elaborate theatrical dance in which the masks and costumes suddenly drop off and the actors come face to face with one another as they really are. Nobody wants to see that happen.
Drug marketing via individual detailing influences physicians to prescribe drugs essentially by offering them gifts, such as free drug samples. The importance of drug samples, again indicated by the amount of money that drug companies spent on them, lies in the simple fact that the sample introduces a drug into a doctor’s office for the first time. This will influences both patients’ and doctors’ brand choices, and later generate sales. The return on this investment can be substantial, with studies suggesting that up to $10 in sales can result for every $1 spent on samples (Chew et al. 2000; Adair & Holmgren, 2005; Backer et al. 2000). Contrary to common sense, small and relatively inexpensive gifts (such as pens, pads, and meals) may be a powerful form of influence: in some studies, the more small gifts a doctor received, the more the doctor believed that they had no influence on his prescribing (Reist & VandeCreek, 2004; Dana & Loewenstein, 2003; Oldani, 2004). These studies suggest that the small gift, precisely because it is inexpensive and therefore easy to accept, has enormous strategic significance. It simultaneously confirms (for the rep) and masks (for the doctor) the realization that the doctor can be bought.
Direct-to-consumer advertising (DTCA)—which took off in the United States in 1997 when the FDA dropped its requirement that any advertisement for a prescription drug must contain the complete list of adverse reactions—would be likely to increase psychiatric drug use via three main mechanisms: it encourages people to visit doctors for ailments portrayed; it encourages patients to request drugs advertised; and it influences doctors’ behavior through patient requests. There is evidence that physicians “are frequently unaware of and denied the degree to which their thinking was biased by patient requests [for antidepressants]” (Tentler et al., 2008), alongside evidence from controlled trials that patient requests for an antidepressant—either brand-specific or in general—“have a profound effect on physician prescribing in major depression and adjustment disorder” (Kravitz et al., 2005, p. 1995). The argument has been made that the most heavily advertised drugs are the newest drugs, by definition, those about which least is known, and also by definition the costliest drugs, thus increasing spending by stimulating their sales (Donohue & Bernd, 2004; Gellad & Lyles, 2007).
The accuracy of DTC ads has regularly been questioned by the FDA, whose mandate includes reviewing ads for accuracy of content. Only people who believe that ads are an easily accessible form of information and education might be surprised that they are frequently misleading. From 1995 to 2004, the FDA sent 1,359 warning letters to drug companies for what it deemed false or misleading advertising. Throughout the early 2000s, four FDA staffers reviewed thousands of ads (Zalesky, 2006). Between 2001 and 2005, the FDA found ads for a hundred and fifty different drugs false or misleading. Misleading messages mostly targeted doctors; 35 percent of the ads misrepresented the degree of risk from the drug, 22 percent promoted unproven uses, and 38 percent made unsupported claims. For example, according to the FDA, a 2007 ad for Geodon (atypical antipsychotic) aimed at doctors neglected to mention the risks of neuroleptic malignant syndrome (a potentially fatal explosive neurological and metabolic attack), tardive dyskinesia (permanent abnormal movement disorders), hyperglycemia, and diabetes. The ad also exaggerated claims of efficacy of Geodon over older, unbranded generic antipsychotics (think back to the CATIE study). To what extent the FDA succeeds in enforcing its requests for drug companies’ conformity to the law remains completely unclear, as, despite some massive financial penalties imposed on various manufacturers for not divulging safety data, for misbranding drugs, and for illegal marketing, the same companies are observed to be in violation year after year.7
Pharmaceutical companies or their subcontractors enlist academics to form expert panels to construct guidelines and algorithms that assert or argue that newer, more expensive drugs (SSRIs and atypical antipsychotics) are more effective and must become first-line treatments in the absence of definitive data or the presence of contradictory data (Healy, 2006a). In some states, such algorithms are promoted by means of covert, illicit cash payments to state officials responsible to make the drugs eligible for government funding (Moynihan, 2004). In other cases, generous payments—licit and later disclosed—are made to members of state advisory panels that help select the billions worth of drugs that Medicaid programs will reimburse for the poor and disabled (CBS News, 2007). In his later analyses, Healy (2012) has made the more encompassing and worrying argument that industry-paid academic panels as well as independent government-funded councils always appear to agree to recommend the industry’s latest drugs for whatever ailment is being considered, for the simple reason that the “evidence” (the studies and clinical trials) these different sources review is, in large measure, industry-generated.
On the one hand, the drug industry’s marketing efforts and its massive infusions of money to support psychiatric activities, and on the other hand psychiatry’s enthusiastic acceptance of the partnership, have completely subsumed psychiatry as a satellite branch of the multinational pharmaceutical industry. Undoubtedly, several branches of medicine are “on the take” (Kassirer, 2005), with many of their practitioners, researchers, and professional associations awash in (mostly undisclosed) conflicts of interests that destroy the credibility of their pronouncements and the trustworthiness of their conduct (Committee on Finance, 2011). Yet, as we have indicated throughout this chapter, psychiatry may be unique in the extent to which intellectual and practical innovations and fashions in that field center around the industry’s introduction of new drugs, the “discovery” and marketing of new uses for recently introduced drugs, and the expansion of DSM disorder categories both to accommodate and to stimulate the popularity of new drugs. Some partial data from Minnesota appear to illustrate the special impact on psychiatry of the industry’s funds. In that state between 1997 and 2005, not only did psychiatrists as a group receive more money from drug companies than any other types of physicians (Harris, 2007; Ross et al., 2007), but within the group of psychiatrists, those who received more than $5,000 wrote on average four times more prescriptions of atypical antipsychotics off-label to children than those receiving less than that amount (Harris, Carey, and Roberts, 2007).
The virtually complete blurring of marketing and science has paralyzed science—or what has passed as science. Conflicts of interest permeate the FDA and its advisory committees, scientific journals, and the scientific literature. Telling an infomercial from a scientific article requires analysis of primary (usually proprietary) sources (Jureidini, McHenry, & Mansfield, 2008), most of which are only revealed accidentally, during legal proceedings, for example (Steinman, Bero, Chren, & Landfeld, 2006). Commenting only on ghostwriting—the practice of paying academics to lend their names to publications without having seen or collected the data reported (Lacasse & Leo, 2010)—the PLoS Medicine editors (2009) lamented that marketing campaigns now
center on “evidence” provided by seemingly respectable academic review articles, original research articles, and even reports of clinical trials. What, a cynical reader might ask, can I truly trust as being unbiased? The answer is that, sadly, for some or even many journal articles, we just don’t know. (p. 1)
More recently, however, Healy (2012) has provided some extremely sobering estimates, with supporting sources, to answer the PLoS Medicine editors’ question: “We also now know that close to 30 percent of the clinical trials that have been undertaken remain unreported, and that of the 50 percent that are reported almost all will be ghostwritten and roughly 25 percent of the published trials altered to the extent that a negative result for a drug will have been transformed into evidence the drug works well and is safe. In 100 percent of cases, the data from trials remain inaccessible to scrutiny” (pp. 252–253).
When the editor of the New England Journal of Medicine sought a research psychiatrist with no ties to the drug industry to evaluate an SSRI trial, she could find none (Angell, 2000). When the American Journal of Psychiatry published a pediatric trial of citalopram (Celexa) that reported positive results, neither the authors nor the editors disclosed (or knew) that a previous unpublished pediatric trial funded by the same sponsor had observed opposite results (Meier, 2004). When an article in JAMA warned pregnant women not to stop taking antidepressants because of the risk of re-experiencing depression, most of the thirteen authors did not disclose their financial ties to makers of antidepressants (DeAngelis, 2006). Medical journals appear to struggle to manage disclosure but not necessarily with great success, as virtually no negative consequences are imposed, or even threatened, on violators (Lacasse & Leo, 2010). Occasionally, the editors of prominent journals shoot themselves in the foot in full view of their readership and constituencies, asserting that they fully control the problem while simultaneously failing to screen obvious violations and then awkwardly managing the consequences (Leo, 2009).
It has now become well established that the funding source of a drug’s clinical trial is associated with the trial’s formal conclusion that the drug should be used. Als-Nielsen and colleagues (2003) showed that in RCTs in eight medical disciplines, regardless of the magnitude of the drug’s effect relative to placebo or the presence of adverse effects, trials funded by for-profit organizations were 5.3 times more likely to recommend the drug than trials funded by not-for-profit organizations. In the case of antipsychotics, researcher Stephan Heres and colleagues (2006) examined the outcomes of thirty head-to-head comparisons of different atypical antipsychotics and looked for relationships with sponsorship. In twenty-seven comparisons (90 percent), the outcome favored the sponsor’s drug. This pattern “resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared” (p. 185). In other words, when Eli Lilly funded a study comparing its Zyprexa with Janssen’s Risperdal, Zyprexa came out ahead. When Janssen funded the exact same comparison, Risperdal came out ahead.
In light of their own observation of “biased interpretation of trial results,” Als-Nielsen et al. warned readers to “carefully evaluate whether conclusions in randomized trials are supported by data” (2003, p. 921). Indeed, when Australian child psychiatrist Jon Jureidini and colleagues (2004) published their groundbreaking review of pediatric SSRI trials that concluded that benefits had been exaggerated while risks downplayed, they had (not yet) found a smoking gun (Leo, 2006). They had simply underlined misleading conclusions in the original publications, such as their authors’ pronouncing a 10 percent drug-placebo difference as “clinically significant” and downplaying strikingly high rates of serious adverse effects in drug-treated children relative to placebo. But what if the study’s data are not published, or a report of the study is published with different data than were actually collected? Psychiatric researcher Erik Turner and colleagues (2008) retrieved seventy-four FDA-registered antidepressant trials of several antidepressants and compared their data to what had appeared in refereed journal publications. They found that thirty-six of thirty-seven trials with positive results had been published, compared to three of twenty-two with negative results. For eleven other trials with negative or questionable results in the FDA database, their journal publications spun the results positively. Overall, 94 percent of published trials showed drugs as superior to placebo, whereas only 51 percent of the full dataset of seventy-four trials showed such positive results. The problem here is simply that the published trial reports are much more easily available and distributed with the approval and review of peer reviewers and prestigious scientific journals and therefore are customarily taken as the record of the trial, the scientific literature. (Most readers might not know that an FDA record exists and is usually available to them from the FDA website, though it might need to be searched for within a voluminous FDA review of a particular drug.)
The authors of the two major reviews of psychiatric trials we have discussed, Turner and colleagues (2008) and Heres and colleagues (2006), make some seemingly obligatory hedging statements in their articles, wanting to appear to be completely fair by considering all possibilities, or perhaps having acquiesced to an editor or reviewer’s request. Turner et al. (2008) state that selective publication of data and trials misleads all those who rely on the scientific literature, but they state that they cannot establish for certain just why negative trials of antidepressants are not published. Similarly, Heres et al. (2006) identify a dozen possible sources of bias in the head-to-head comparisons of antipsychotics but cannot state which might end up favoring the sponsors’ drugs and “limit the validity” of such comparisons. It is, of course, entirely appropriate and even desirable for scientists to be cautious in drawing conclusions. Perhaps they are personally unsure about which conclusions should be reached. They may entertain doubts about the purposes of the drug industry and the extent to which the industry might plot to alter outcomes of studies to favor its products. But in this case, researchers’ and editors’ and conscientious practitioners’ willingness to hedge, to consider every possible interpretation, to step back from what is the most probable reality, leaves only one player in this drama that has no doubt, no hesitancy, no incentive to pursue the truth, and no ambivalence about its goals and the behavior of other players—and that is the drug industry.
In our view, what has occurred and what is occurring is the systematic manipulation of the scientific process to reach predetermined conclusions, which means, the paralysis of science as an unbiased enterprise to advance knowledge or even as a pragmatic enterprise to improve the quality of human life. The current trend is toward increased disclosure and transparency in scientific publications and increased verification (for example, via the constitution of clinical trial registries in which the aims and protocols of drug trials are announced in advance) of the drug industry’s claims. New rules, however, require broader enforcement, while existing rules have yet to be enforced consistently. In any case, increased scrutiny often leads violators to search new outlets to practice their reproachable but enormously profitable behavior. This being the case, increased transparency is bound to trigger, at least temporarily, even more creative marketing efforts designed to mislead and seduce professionals and the public with the appearance of science.
Does the psychiatric drug treatment of emotional distress and misbehavior constitute a genuine improvement over the practices of the past, or is it merely the recycling of age-old tendencies to palliate distress and control disturbing behavior by psychoactive sedation or stimulation? Are clinical psychopharmacologists members of a scientifically driven discipline or merely the willing executors of mad science, the vast, well-orchestrated advertising campaigns by the pharmaceutical industry to increase market shares of the drug du jour? Our questions purposefully impose a dichotomous template on complex and multilayered issues because the former positions have been too uncritically promoted and accepted as self-evidently true. Still, if simple answers were to be given, we think the evidence overwhelmingly supports the latter positions in both of these questions.
As psychoactive drugs continue to be promoted as harmless and essential products for modern citizens, but as the boundaries between licit and illicit drug use continue to blur, more profound changes may be in the works. For example, the Internet has helped to democratize to some extent the conversation between doctors, patients, and regulators. Online, laypersons now frequently disseminate their views and reviews of psychoactive drugs, unfiltered by professionals, and freely offer each other advice on using this or that drug in this or that way, obtaining it this or that way, or ceasing to take it this or that way. Some consumer-constructed websites (e.g., askapatient.com) offer thousands of individual patient reviews for hundreds of drugs, including real-time graphs and charts of efficacy and adverse effect evaluations from large groups of users (e.g., patientslikeme.com). No comparable data has ever existed before, anywhere.
A first comparison of discourse about two prescribed psychotropic medications (an antidepressant and an antipsychotic) appearing on consumer-constructed and professionally controlled websites on the Internet found that both types of sources “generally reported similar effects” of the two medications “but differed in their descriptions and in frequency of reporting. Professional medication descriptions offer the advantage of a concise yet comprehensive listing of drug effects, while consumer reviews offer the advantage of greater context and situational examples of how effects may manifest in various combinations and to varying degrees” (Hughes and Cohen, 2011). No one can tell where the trend regarding consumer contributions is headed, but these and many other findings we have discussed throughout this book make one thing clear: knowledge about psychiatric drugs is increasingly being constructed completely outside the usual expert disciplines and will involve possibly as-yet-unknowable players.
Public cynicism concerning the integrity of psychiatric knowledge continues to grow, in parallel with the democratization of information and the appeal of self-care and self-directed performance enhancement that have always characterized much of the use of psychotropic drugs throughout history and culture. As a result, psychiatric-professional assertions of unique or specialized knowledge in psychopharmacology will become increasingly contested, just as they have been in this and the previous chapter.
But there is more. Periodic revelations concerning the profession’s unjustified, scientifically unsophisticated, and crassly bought enthusiasm over this or that psychoactive drug class, and the sweeping under the carpet of the victims of the enthusiasm may also threaten drug prescription authority—the key legal prerogative presently resting on the assumption of medical and psychiatric expertise and accountability. We find it intriguing that two of the best-known psychiatric critics, the late US psychiatrist Thomas Szasz, and UK psychiatrist David Healy, whose views on the nature of mental illness and the legitimate sphere of state-sponsored psychiatry differ dramatically, have nonetheless both proposed the abolition of medical prescription privileges (and not merely their redistribution to clinical psychologists, for example). Do people really need psychiatrists (or anyone else claiming special knowledge) to give them permission to take the psychoactive drugs they want?
1.Although we use these two words interchangeably in this chapter, the careful speaker might wish to distinguish them. We borrow here from Thomas Szasz (2007), who notes that according to Thomas Ban (2001), the first person to use the word psychotropic was Ralph Waldo Gerard (1900–1974), an American physiologist, in the late 1950s. Under the new moniker, Gerard included only the six then-modern psychiatric drugs: “neuroleptics, i.e., chlorpromazine and reserpine . . . antidepressants, i.e., iprionazid . . . and imipramine . . . an anxiolytic, i.e. meprobamate . . . and a mood stabilizer, i.e., lithium carbonate” (Ban, 2001, p. 712). Szasz points out: “All of these drugs were introduced in a 6-year period, 1949–1957. Note that chlorpromazine heads the list and that not one of these drugs is a substance a healthy person uses, or would want to use, as a recreational drug” (p. 173–174). Szasz’s point is that psychotropic is a modern semantic confusion designed to bracket modern psychiatric drugs from other psychoactive substances, that is, to avoid putting all psychoactive drugs—drugs that have a direct effect on mental activity and behavior—on an equal footing for accurate comparison purposes. Google’s N-gram database shows that the use of both terms between 1960 to 2000 in American English runs parallel, with psychoactive experiencing a relative decline between 1980 and 1990. Our own impression is that authors who use both terms use them interchangeably. However, we think authors usually favor psychotropic, especially when discussing prescribed psychoactive drugs.
2.This section is drawn from a number of books and articles written by and with British psychiatrist Joanna Moncrieff (Moncrieff, 2008; Moncrieff & Cohen, 2005, 2006, 2009; Moncrieff, Mason, and Cohen, 2009; Moncrieff, Porter, & Cohen, 2012).
3.Although this is far beyond the scope of this chapter and this book, we note that biochemists and molecular biologists increasingly discuss drugs as acting not merely on cells’ membrane receptors to change processes inside and around the cell but also—in some as yet not well-understood manner—changing the expression of genes. Gene expression is the process by which a gene’s encoded information is used to create proteins that shape or dictate the structures and functions of cells. In principle, by modifying gene expression, the potential effects of drugs on the human body and human functions, short- and long-term, grow exponentially.
4.In the world of illicit psychoactive drug use, drug users have no difficulty attributing unpleasant or pleasant experiences mainly to the drug, with acknowledgments that the setting and the user’s preparation may shape the experience. Popular and scholarly writings about marijuana, LSD, or ecstasy illustrate this point. However, in the controlled world of testing of psychoactive drugs to conform to the psychiatric and regulatory vision of these drugs as conventional medical remedies, researchers and regulators have the greatest difficulty to treat them as capable of producing complex and unpredictable experiences from individual to individual. Here, the presumed sameness of the subjects’ mental disorders, the moralistic opposition to intoxication, and the channeling of the subjects through evaluation procedures copied directly from the world of physiological medicine—all combine to dictate the expectation that pleasant or euphoric psychoactive effects originate in drugs and will probably create drug addicts, while unpleasant psychoactive effects probably originate in psychiatrically disturbed subjects and can be tolerated or further treated.
5.In the experience of one of us (DC), however, clonazepam withdrawal is always extremely difficult. Working with over a dozen individuals who had been taking clonazepam for periods ranging from six years to nineteen years, and who had previously tried different methods, sometimes including inpatient hospital-based detoxification, it was found all of them experienced excruciating withdrawal symptoms and none were able to reach their goal of being completely clonazepam-free.
6.Recent repeated associations of chronic benzodiazepine use with the onsent of dementia in careful cohort studies (see, most recently, de Gage and colleagues, 2012) will hasten the demise of these drugs and will lead to increases in the promotion of other tranquilizers and sedatives to physicians and patients. Although benzodiazepines have long been observed to cause memory problems, such problems are reported with virtually all psychotropic drugs on the market today.
7.Since 1991, pharmaceutical manufacturers in the United States have paid the staggering sum of $30 billion to settle allegations of wrongdoing, notably illegal marketing of drugs and deliberate overcharging of government health programs like Medicare and Medicaid (Almashat & Wolfe, 2012). The pace of such criminal and civil suits from the federal government and states has increased: of the 239 settlements and court judgments occurring during that period, 74 (totaling $10.2 billion) occurred between November 2010 through July 2012. As the authors point out, these financial penalties “still continue to pale in comparison to company profits and a parent company is only rarely excluded from participation in Medicare and Medicaid for the illegal activities . . .” (p. 5). While overcharging of public health programs has been the most common alleged violation, illegal (off-label) marketing has resulted in the largest settlements. The three largest settlements involved accusations of the illegal marketing of the antidepressants Paxil and Wellbutrin by Glaxo Smith Kline, the antipsychotic Risperdal by Johnson & Johnson, and the anticonvulsant Depakote by Abbott Laboratories.
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