Da “Blaming the Brain – the truth about drugs and mental health” di Elliot S.Valenstein, New York 1997

l’intero capitolo finale conclusivo integrale (pagg 221 – 241) e rispettive note

(testo originale inglese)

Chapter 8

REPRISE,

CONCLUSIONS,

AND REFLECTIONS

I
t is not possible for me to summarize in these concluding remarks all the evidence and arguments that led me to reject the existing chemical theories of mental illness. That was done throughout the book. I can, however, review some of the main arguments by critically examining several statements about psychotherapeutic drugs and mental disorders that are repeated so often they are thought to be axiomatic and incontestable. One such statement is that psychotherapeutic drugs treat mental disorders in the same way that insulin treats diabetes. What is implied by this statement is that psychotherapeutic drugs, like insulin, correct known chemical deficiencies (or excesses, in other instances). This analogy is repeated over and over again not only in promotional material from pharmaceutical companies and in articles published in professional journals, but, judging from reports from patients, every day in the offices of psychiatrists and other physicians. One psychiatrist, who no longer accepts this dogma, recalls what she learned during her psychiatric residency:

As a psychiatric resident, I found these terms helpful when talking with patients and their families. Taking the lead of various mentors, I would explain that mental illness is caused by a chemical imbalance in the brain. Mental illness resembles diabetes, which involves a chemical imbalance in the body, I would explain. The patient’s psychiatric disorder is chronic, I would say, and requires medication every day for the rest of the person’s life. I would then assure the patient that if he took the medication, he would probably live a more normal Iife.1

Most people accept the analogy between psychotherapeutic drugs and insulin uncritically, being persuaded by what seems to be a completely valid and sensible argument. Moreover, the analogy with insulin treatment suggests that it might be necessary to take psychotherapeutic drugs for life, or at least for a long time, just as diabetics and people suffering from other hormonal deficiencies have to take medication for life. Despite its seeming

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reasonableness, I do not believe that the analogy between insulin and psychotherapeutic drugs can be justified.

When insulin is prescribed for a diabetic it is only after a reliable test has measured the extent of the patient’s glucose metabolism problem, from which, in most instances, an insulin deficiency can be inferred. The dose of insulin that is prescribed can be based on a reasonably good estimate of the magnitude of the deficiency. Moreover, we also have a good understanding of how insulin regulates glucose metabolism and how a deficiency of that hormone can produce diabetic symptoms. In sharp contrast, a psychiatrist performs no laboratory test to determine if a mental patient has any chemical deficiency or excess. Instead, the implication that the drug prescribed is correcting an abnormal biochemical condition is, at best, an inference made in part from weak and unreliable group trends reported in the experimental literature, but based mainly on the simple belief that the drug will help. Moreover, while we have a good understanding of how insulin alleviates the symptoms of diabetes, we do not know how psychotherapeutic drugs alleviate the symptoms of mental disorders or why they often fail to do so. Of course, many will insist that there is abundant indirect evidence that indicates that patients with a particular mental disorder do have a specific biochemical abnormality, even if there are no convenient laboratory tests available to confirm it in a given patient. I am convinced that they overstate their case.

There is no shortage of claims, for example, that schizophrenia is caused by a hyperactive dopamine system and that depressed patients have low serotonin levels, but these claims do not stand up to a critical examination. The "dopamine theory of schizophrenia” has been held on to tenaciously in the face of considerable contradictory data because of the hunger for an explanation, however inadequate it might be. When it was found that schizophrenics do not have high levels of dopamine activity, it was then hypothesized that they might have an excess of dopamine receptors, making them hypersensitive to normal dopamine levels. However, it has never been proved that schizophrenics bave high numbers of dopamine receptors, although there are a few claims that high levels of a particular type of dopamine receptor have been found in a localized brain region of some schizophrenics. However, other equally competent investigators have not been able to confirm these claims.

Even in those studies demonstrating that on average schizophrenics have high numbers of a particular dopamine receptor subtype, many schizophrenics do not show this trend, while some normal subjects do, despite not having any history of mental disorder. Moreover, it is now known that receptor numbers can be an effect of either drug treatment or a mental or emotional state common to some schizophrenics, rather than, as is often assumed, the cause of the disorder. What is a cause and what is an effect of a mental disorder has often been confused.

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There are still other difficulties with the “dopamine theory of schizophrenia.” There are, for example, antipsychotic drugs that do not block the dopamine receptors that a few investigators have hypothesized are responsible for schizophrenia. The fact that it usually takes several weeks before any therapeutic effect is seen following the beginning of drug treatment has made it extremely difficult to know what is actually responsible for any improvement seen. A number of investigators are now suggesting that other neurotransmitters and other brain conditions must be involved in the etiology and treatment of schizophrenia. There does not really seem to be much left to the dopamine hypothesis of schizophrenia, as Arvid Carlsson, one of the foremost contributors to our knowledge of dopamine neuropharmacology, has recently commented:

The dopamine hypothesis rests almost entirely on indirect, pharmacological evidence and not even this evidence is unambiguous. Far example, treatment with antidopaminergic agents is often only partially successful in schizophrenia and is frequently attained only at the expense of troublesome side effects. Moreover, the symptomatology of schizophrenia is mimicked not only by dopaminergic agents but also by drugs that act on other neurotransmitter systems.2

Even psychiatrists committed to the idea that schizophrenia is a brain disease have had to admit that recent studies of people with that disorder have failed to provide unequivocal evidence of dopamine hyperactivity in the brains of patients with this disorder.3

The evidence that depression is caused by a biochemical abnormality is even weaker than it is for schizophrenia. Shortly after the discovery of the first few antidepressants, it was hypothesized that patients suffering from depression must be deficient in serotonin or norepinephrine, or both, because the drugs increased the activity of these two neurotransmitter systems. This hypothesis became more firmly entrenched because of the claims that the drug reserpine, which lowers serotonin and norepinephrine levels, can cause depression. However, carefully controlled studies subsequently revealed that reserpine and other drugs that decrease serotonin and norepinephrine rarely produce depression, except, occasionally, in people who are prone to developing depression. Furthermore, there is no convincing evidence that depressed people have a serotonin or norepinephrine deficiency.

These considerations and other evidence and arguments discussed throughout the book have led me to conclude that there is really little solid evidence for either the serotonin/norepinephrine deficiency theory of depression or the dopamine theory of schizophrenia. Yet in all kinds of promotional literature they are touted as though they have been firmly established.

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I have become convinced after examining the evidence and following the twists and turns in the various arguments supporting the different versions of the chemical theories of mental disorders that all of the impressive knowledge of neuropharmacology has not really brought us closer to understanding the origin of mental disorders or even to any real understanding of how drugs may help to alleviate these conditions. People with mental disorders may be encouraged when they are told that the prescribed drugs will do far them just what insulin does for a diabetic, but the analogy is certainly not justified. What is much clearer, however, is that there are a number of groups that benefit from promoting the analogy.

Another statement that needs to be examined more closely is that mental disorders are physical diseases. What is really implied by this statement is that mental disorders are caused by some identified physical (physiological) condition. There may well be biological factors that predispose some individuals toward developing mental disorders, but a predisposition is not a cause. How and whether a predisposition is expressed depends on many nonbiological factors, especially on life experiences and on input from the environment in many different ways. The statement that mental disorders are physical diseases ignores the relevance of psychosocial factors and implies by this omission that such factors are of little importance.

Some of my colleagues have defended the statement that mental disorders are physical diseases by claiming that the statement implies only that all mental states - those that are healthy as well as those that characterize a mental disorder - do not exist in a vacuum, but must emerge from some physical substrate. However, there is more than a little sophistry in this argument. It is surely unnecessary to make such a benign point over and over again, as few people today believe that a mental event can exist without a brain event. The reason pharmaceutical ads for antidepressants and antipsychotics assert that these disorders are physical diseases is that it serves as an easy and natural segue to promoting the chemical theories of mental disorders and drug treatment.

Perhaps the strongest evidence of the importance of biological factors in mental disorders comes from genetic studies. Data obtained by comparing identical and fraternal twins and comparing adopted children with their biological and foster parents suggest that genetic factors may influence personality, temperament, emotionality, and behavior and also predispose some individuals toward developing a mental disorder. However, while genetic factors may predispose people to develop in certain ways, they certainly do not dictate personality, mental traits, or behavior. For example, if one identical twin has schizophrenia or a manic-depressive disorder - the two disorders thought to have the strongest genetic contribution - the probability is less than 50 percent that the second twin will have the same disorder, despite the fact that most identical twins have very sim-

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ilar experiences.4 While there are some physical factors that are not genetic, such as exposure to toxins, infections, and injury that may be a factor in the development of a mental disorder, social and psychological factors undoubtedly play a major role in determining whether and how any predisposition will be expressed. We even know that gross features of the brains of identical twins differ, and a number of studies have shown that life experiences can modify brain anatomy. Some of the differences in brain anatomy between identical twins may well result from different life experiences. The statement that mental disorders are physical diseases implies a lot more than can be justified.

The idea that mental disorders are physical diseases has been widely promoted and accepted for several reasons. It is known that people suffering from mental disorders and especially their families generally prefer a diagnosis of a “physical disease” because it does not convey the stigma and blame commonly associated with “psychological problems.” Also, a “physical disease” often suggests a more optimistic prognosis and a briefer, less expensive course of treatment. However, while patients may be relieved to be told that they have a “physical disease,” they may adopt a passive role in their own recovery, becoming completely dependent on a physical treatment to remedy their condition. It is clear that “physical disease” is often a code word for a chemical excess or deficiency and a justifìcation for drug treatment. It is known that mental patients are often more amenable to drug treatment when they are told that they have a physical disease. Furthermore, as discussed earlier at some length, influential groups such as the pharmaceutical industry, psychiatrists, HMOs, and other medical insurers are likely to be favorably disposed to any theory that emphasizes chemical causes and drug treatment. Most of those who promote the chemical theories of mental disorders genuinely believe that the evidence supporting the theory is convincing, but theories that support one’s interest always seem to make the most sense.

Another statement frequently made, especially during recent years, is that psychotherapeutic drugs are becoming increasingly specific. This is true, but misleading. New techniques have made it possible to develop drugs that will bind to only one neurotransmitter receptor subtype. These new, highly specific drugs are promoted as “smart missiles” capable of seeking out and eliminating the different chemical causes underlying each mental disorder. While this argument may sound eminently reasonable to many, there are good reasons for being highly skeptical about such claims.

In the first place, it is necessary to distinguish between several different meanings of “specificity.” A drug may truly have “pharmacological specificity,” in that it acts primarily on one receptor target (or a very few), but this will not necessarily give it “functional specificity.” Even though a drug may bind primarily to one receptor type, there is no reason to believe

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that the effect of stimulating or blocking the activity of this receptor will be confined to any one mental symptom. On the contrary, there is every reason to believe that all receptors have an influence on many different mental activities and emotional states. Moreover, mental disorders are not simple homogeneous entities. They involve impairment of language, perception, memory, motivation, emotions, and much more. The belief that the complex cognitive and emotional states that underlie any mental disorder are regulated by a single neurotransmitter receptor subtype is probably no more valid than the idea held earlier by phrenologists who believed that complex mental attributes could be localized in one specific part of the brain. Moreover, as with any complex, highly integrated system, changing one component will have effects that inevitably cascade through the entire system. The concept of a specific target refers only to an initial and momentary effect of a drug. Pharmacological specificity refers only to the “first domino” in a series of brain reactions triggered by a drug. Regardless of its pharmacological specificity, it is unrealistic to think that the ultimate effect of any drug will be similarly limited.

I have described the dangerous side effects produced by the diet pills Pondimin and Redux as well as by the so-called fen-phen treatment. These drug treatments were hypothesized to work by increasing brain serotonin. However, unanticipated adverse side effects can occur even when a drug target is relatively specific. Serotonin is not limited to the brain, and it certainly is not involved only in regulating appetite, although some promotional material conveys that impression. Serotonin is located in many parts of the body as well as the brain, and serious heart-valve and lung conditions result from the drugs’ increasing serotonin in those organs.

It is easy to get the impression from the many uncritical books on the wonders of the “psychopharmacology revolution” that increasing serotonin will only enhance personality, making people more self-confident and cheerful, while decreasing any undesirable behavioral traits. Commonly overlooked is the fact that serotonin was originally named for its capacity to constrict blood vessels. There is much that is illusory and misleading about the claims of increased specificity for the newer psychiatric drugs, and it is not yet clear whether these drugs will produce less adverse side effects than their predecessors or just different ones.

Actually the pharmaceutical industry has a very complex and somewhat ambivalent attitude toward the issue of specificity. On the one hand, the companies promote their new ability to design drugs with much more pharmaceutical specificity, making it appear that these drugs will be capable of seeking out and correcting the unique condition that underlies each mental disorder, providing the one key that can fit a predetermined lock. The problem is that there are good reasons for doubting that there is a specific condition that is common to all patients suffering from the same men-

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tal disorder. Considering the heterogeneity of patients diagnosed with the same label, many, if not most, clinical investigators believe that it is likely that different etiologies are involved. Sometimes pharmaceutical companies’ ads will give the impression that their drug has some unique properties that equip it to treat a specific condition even though the drug does not differ significantly from other drugs being marketed. Alprazolan, a benzodiazepine drug, far example, was promoted as a specific treatment for “panic disorder” because it became available around the time that psychiatrists began to use this term as a separate diagnostic category and because of the concern at the time that such benzodiazepine drugs as Valium were being overprescribed for every one of life’s stresses.

Arguing against the claim of drug specificity is the tendency of pharmaceutical companies to encourage the broadening of applications of every drug that they market. Thus, Prozac and the other SSRIs, for example, were initially introduced as antidepressants, but they are now used to treat so many different conditions that it brings into question the whole idea of a specific chemical abnormality underlying each mental disorder. Sometimes a pharmaceutical company will sell the exact same piil under different names for different purposes. Thus the antidepressant Wellbutrin (buproprion hydrochloride) is marketed as Zyban, a pill to help break the smoking habit. There is no convincing evidence, however, that the smoking habit and depression (or most of the other disorders treated by a single drug) have a common etiology.

It is more than a little ironic that despite all the claims being made for drugs with specific pharmacological action, a number of the latest drugs introduced, such as the new antipsychotic olanzapine (Zyprexa), act on many different neurotransmitter systems, and their wide spectrum of pharmacological activity is promoted as a way of increasing effectiveness.

The drugs marketed to treat the same mental disorder tend to have very similar sites of action. Thus, for exampie, most of the latest antidepressant drugs are designed to act primarily on serotonin or on serotonin and norepinephrine, while most antipsychotics act primarily on the dopamine system. This is often promoted as evidence that the chemical abnormalities underlying these disorders have been identified. However, that is not the only possible explanation. A major factor accounting for the similarities in the action of drugs that are marketed as treatments of the same disorder is the high cost of bringing a new drug to market. This cost tends to make pharmaceutical companies “risk aversive” and generally quite conservative in their development of new drugs. It has been estimated that it takes between ten and twelve years to develop, test, and market a new drug, and the cost is between $150 million and $250 million. Therefore, most new drugs are only small modifications of drugs already being marketed successfully. Unless there is a major advance in our knowledge of

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what causes the different mental disorders, or a serendipitous discovery of a different class of drugs that is effective in treating a particular mental disorder, most new drugs will continue to be essentially “copycat” or "me too" drugs, which do not differ significantly from the drugs that preceded them.

All of these considerations and other evidence and arguments presented throughout this book led me to conclude that the theory that mental disorders are caused by specific biochemical imbalances was rnuch weaker than claimed. I began to think more about who was promoting the theory and the many different ways that this is done. It would be disingenuous to pretend that I was unaware when I started this project that certain groups benefited from the chemical theories of mental disorders and reliance on drug treatment, but when I started to dig more deeply into this topic I became aware of the enormity of the influence of these groups and the many different ways that influence is exerted.

For psychiatrists, medical insurance companies, and especially the pharmaceutical industry the benefit derived from promoting drug treatment and chemical theories of mental disorders is primarily economic. Of course, the argument is never framed in that way. Starting around 1930, psychiatrists became increasingly aware of growing competition from nonmedical therapists, mainly psychologists, psychiatric social workers, and counselors of various stripes. Over the years, psychiatrists have been attracted to physical treatments, over and above any therapeutic value these treatments may have had. In the first place, physical treatments give psychiatrists a treatment modality that was not available to the nonmedical competition. Insulin coma, metrazol shock, prefrontal lobotomy, and electroconvulsive treatment have all been useful in this way. Moreover, physical therapies and the theories on which they have been based have helped to make psychiatry more acceptable to the rest of the medical profession, which historically has been skeptical of the scientific basis of the “talking therapies.” Psychotherapeutic drugs, like the other physical therapies before it, have served the interests of the psychiatric profession. Of course, psychiatrists are not all of one mind, but in various ways the profession as a whole tends to promote drugs by exaggerating what is known about the chemical basis of mental disorders and the effectiveness of drugs, and often by discrediting alternative treatment modalities. While traditionally nonmedical therapists such as clinical psychologists have been opposed to physical therapies, lately their attitude toward drugs and the chemical theories of mental disorders has become ambivalent, and many are currently trying to obtain prescription privileges through aggressive lobbying of state legislators. Quite predictably, psychiatrists have moved to protect their turf and have actively lobbied against granting prescription privileges to non-medical therapists.

Medical insurers are obviously concerned with cost, and they particu-

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larly want to discourage treatments that may involve many contact hours and considerable expense. By adjusting payment schedules, medical insurers are playing a major role in shifting treatment toward drugs and away from psychotherapy. The argument advanced for drug treatment and biochemical explanations of mental disorders is always based on claims that the evidence demonstrates the correctness of the chemical theories and the effectiveness and safety of drugs. It is not that a reasonable-sounding argument cannot be presented, but rather that the argument is not based on an objective evaluation of all the evidence. Numerous studies have made it clear that a person’s interest and biases influence the way evidence is selected and evaluated and how persuasive various arguments will seem to him or her. Logical fallacies in an argument are frequently overlooked when one agrees with the conclusions, and when the conclusions do not conform to one’s biases, logical fallacies are often “detected” even when they do not exist.

The influence of the pharmaceutical industry is by far the greatest, not only because of the enormous resources at its disposal, but also because of the diverse ways that influence is exerted. In the United States alone, pharmaceutical companies spend about $ 12.3 billion a year on advertising and other types of promotion, which is about 22.5 percent of the $54.7 billion estimated to be the total sales of U.S. pharmaceuticals.5 The pharmaceutical industry spends huge amounts of money to influence the prescribing habits of physicians. This influence is exerted through massive advertising in professional journals and through direct contact with physicians by the industry’s sales force. Studies have shown that the advertisements placed by pharmaceutical companies in professional journals or distributed directly to physicians are often exaggerated and misleading. While physicians typically resent any suggestion that they cannot recognize the difference between scientific evidence and promotional material, it has been shown repeatedly that their prescription preferences are heavily influenced by promotional material from pharmaceutical companies.

Pharmaceutical companies distribute large amounts of educational material (literature, films, slides) free of charge to medical schools, and they also contribute money to support speaker programs that help in the training of residents and in keeping the attending physicians informed about new trends. Numerous symposia and workshops are sponsored by pharmaceutical companies. Some of the motivation of the pharmaceutical companies that underwrite these expenses is to establish “goodwill.” The "educational" material can be informative and helpful. Rarely is it so heavyhanded as to promote a specific product, but the contents almost always includes a point of view designed to ultimately increase sales of drugs that the company markets. So, for example, the psychiatric material will stress the evidence that suggests that depression has a chemical origin and can be treated successfully with antidepressant drugs. This message wil help a

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company that markets antidepressant drugs even though a specific drug may never be mentioned.

Furthermore, there have been a number of incidents in which pharmaceutical companies have exerted pressure to suppress, delay, discredit, or modify information that they judge will be detrimental to the sales of one of their products. The ads placed by pharmaceutical companies provide a substantial source of support for many medical journals, and while it is certainly not true of all, editors are often reluctant to offend their advertisers. In some cases, the impact of a study critical of a drug’s efficacy or safety is diminished by including a comment written by “experts,” who on several occasions have turned out to be consultants to the company marketing the drug. Surveys have revealed how difficult it is to find an “expert” in a specific medical area who is not tethered by some financial interest to either a pharmaceutical company or one of the smaller "biotech" companies that are developing drugs in that same area. When a study reveals that a particular drug appears to cause some previously unsuspected adverse effects, even before there is time for any additional investigation of the problem, the company involved is likely to issue a statement designed to discredit the study by claiming it is flawed and inconclusive and should not be taken seriously.

Pharmaceutical companies also sponsor most clinical trials of new drugs, and they employ "trial monitors", medical doctors and Ph.D.s in psychopharmacology and other specialties, who design the experiments, choose the clinical investigators involved in collecting the data, fund the collection of the data, check on how the study is coming along, suggest changes in midstream, and often assume the major responsibility for summarizing and publishing the results. As the saying goes: “If you pay the piper, you can call the tune.” The importance of the clinical trials cannot be overestimated, as they provide the data for judging the efficacy and safety of a new drug that the FDA uses in approving a drug for marketing. Once a drug is approved, physicians can exercise their own judgment in prescribing it for other purposes, and pharmaceutical companies may use their sales force and other promotional avenues to encourage physicians to use a drug for purposes other than those for which it was approved.

I have described how pharmaceutical companies are increasing sales of psychotherapeutic drugs by encouraging primary care physicians to use screening devices that will enable them to more readily detect patients who may have a mental disorder. It has been estimated that aver 30 million Americans have had a depressive or anxiety disorder, and primary care physicians are known to prescribe more antidepressant and antianxiety drugs that any other group of physicians, including psychiatrists. There is a huge potential here that has only been partially tapped, and pharmaceutical companies have not only supported the development of brief question-

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naires that patients can complete while waiting in the doctor’s office, but they are actively involved in promoting the use of these materials. Preliminary data indicate that this is exactly what happens when primary care physicians use these screening devices.

Not all of the pharmaceutical industry’s promotional schemes are directed toward physicians. Many are aimed directly at patients, the ultimate consumers of drugs. The amount of money spent promoting prescription drugs directly to patients has been increasing by leaps and bounds over the past several years. There are increasing numbers of patients asking physicians to prescribe a drug they read about in an ad in the popular media, and pharmaceutical companies are aware of studies that indicate that as many as 90 percent of physicians are likely to comply with such requests.6 This trend is likely to accelerate as the FDA, responding to pressure from congressmen, recently (as of 8 August 1997) made it legal for pharmaceutical companies to advertise their prescription drugs aver radio and television, and several pharmaceutical companies almost immediately announced the beginning af large television advertising campaigns far their prescription drugs.

The pharmaceutical industry has for a number of years used patient support groups to get its message to consumers. There are now large numbers of support groups for patients (and their families) who suffer from every conceivable psychiatric disorder. Thus, far example, there are support groups far patients with schizophrenia, depression, obsessivecompulsive disorder, substance abuse problems, attentional deficit disorders, and much more. Most of these support groups receive substantial financial support from the pharmaceutical industry, and this has enabled them to increase their membership, to afford large newspaper ads, and to distribute all kinds of informational brochures, much of which helps to promote the basic premises of the chemical theories of mental disorders. I have described how, not infrequently, the information circulated by patient support groups is exaggerated and misleading, but almost always the message is exactly what the pharmaceutical companies want the public to receive.

Undoubtedly, there will be readers who will consider this account of the activities of the pharmaceutical industry unbalanced and exaggerated. I have already had conversations with friends and colleagues who have expressed this point of view. In responding, I have pointed out that all the statements made in these concluding remarks are well-documented with specific examples in the body of the book. I am convinced that the pharmaceutical industry spends enormous amounts of money to increase its sales and profits by influencing physicians and the public in ways that sometimes bend the truth and that are often not in the best interests of science or the public.

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There is no doubt that the pharmaceutical industry has made important contributions to public health and to research. Drug companies support numerous symposia and other forums that provide opportunities far clinicians and basic scientists to exchange information with their colleagues and to learn about new developments. Many neuroscientists (and I include myself among them) have received help from pharmaceutical companies in various ways. Experimental drugs used in research are often provided without charge, and technical advice and assistance is often given. I have stayed at a “guest house” in London maintained by a pharmaceutical company, and this made ìt possible for me to do research at the Wellcome Foundation’s History of Medicine and Science Museum, which is supported by the Glaxo Wellcome pharmaceutical company. Innumerable basic neuroscientists and clinical investigators have received the funding from the pharmaceutical industry that was necessary to undertake research projects. Faculty responsible for the education of graduate students in the life sciences or for training psychiatric residents or other mental health professionals regularly receive support from the pharmaceutical industry that makes it possible to invite speakers, and the industry provides all kinds of helpful literature and films without charge.

While researchers, educators, and clinicians know that the pharmaceutical industry is in the business of selling drugs, they appreciate any help they receive, and most believe that a healthy, symbiotic relationship exists between them and the industry. They would certainly resent any suggestion that the support they receive (and might continue to receive) influences their judgment on any matter. Nevertheless, in the opinion of many who have investigated this issue, there is a substantial influence, although it is often subtle. Those with the largest grants have the most contact with company personnel and are most exposed to the arguments, evidence, and point of view that support that company’s position on any disputed issue. In my experience, those who have been the recipients of the largest benefits from the industry tend to be most adamant in denying the possibility of any influence. These are often the same people called on for opinions that influence public policy about drugs and the pharmaceutical industry. The influence of the pharmaceutical industry is so pervasive that it often goes unrecognized.

All companies prefer “doing good while doing well,” but they must do well to stay in business. The profit motive is not a secondary concern for pharmaceutical companies any more than it is for any company. A recent ad soliciting investment funds placed by a major pharmaceutical company announced that its “objective remains to increase its earnings per share by 20% in 1997 and 1998.”7 When I am told that pharmaceutical companies behave differently from other companies because they are concerned with

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public health, I am reminded of a number of incidents, such as a major U.S. pharmaceutical company agreeing to pay a $325 million fine when it was charged with fraud for billing the government for lab tests never ordered and in some instances never performed.8

The stakes are enormous and the resources that pharmaceutical companies can invest to advance and protect their interests is commensurate. The annual sales of a single drug can total several billion dollars. With such sums involved, pharmaceutical companies are constantly exploring ways to increase their sales and to protect them when they are threatened by competition or negative reports. Like any other large corporation, pharmaceutical companies give much thought to ways to promote their products and to protect their interests. We should not really be surprised, far example, to learn that the person in charge of marketing drugs for Merck was formerly promoting soft drinks and food for PepsiCo.9 The line between giving the best “spin” to a product and “bending” the truth is often fuzzy. It is unrealistic to believe that companies that market so-called “ethical” (prescription) drugs will be either more or less ethical than any other large company when it comes to marketing.

The influence of the pharmaceutical industry has grown stronger because its enormous resources are being concentrated in fewer hands as a result of the many recent mergers. Among the more notable mergers has been that of the Upjohn Company of Michigan with Pharmacia A.B. of Sweden to form Pharmacia & Upjohn. This company more recently merged with Amersham International, a British health and technology concern, creating Amersham Pharmacia Biotech. Also, Glaxo Holdings has merged with Wellcome ta form Glaxo Wellcome, and Ciba-Geigy, which was an earlier merger between Ciba and Geigy, has joined with Sandoz to form Novartis A.G., now the world’s largest drug campany. In 1995, the Swiss pharmaceutical giant Roche Holding Ltd. (the parent of Hoffman La Roche, Inc.) purchased the Syntex Corporation of California, and in 1997 they purchased Boehringer Mannheim, a German company. Even as I write this, there is talk in the financial community of other huge mergers of drug companies.

Another recent trend, involving a type of merger that will concentrate power even further, is the takeover by pharmaceutical companies of clinics that prescribe drugs. Recently, the British pharmaceutical company Zeneca took over the management of eleven cancer clinics, some located at major American hospitals. The possibility that one company may control both the manufacture and prescribing of a drug has raised justifiable concern. Although a comparable takeover of psychiatric clinics by a pharmaceutical company has not yet occurred, the existence of chains of proprietary psychiatric clinics may increase the possibility of that occurring. The dangers

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are apparent, as Arthur Caplan, a bioethicist at the University of Pennsylvania, has noted:

I think we will see more deals like this in the future and the real question is what sorts of checks and balances ought to be in place. Having your doctor, your clinic, your pharmacy and your testing lab all owned by the same person is not the optimal structure for health care.10

The chemical theories of mental disorders are particularly seductive because they suggest that a relatively simple explanation and solution exist for a problem that has been regarded as complex and often stubbornly resistant to treatment. We are living in an age that has little tolerance for uncertainty and ambiguity. Proposals that might have been rejected at an earlier time as unrealistic are now accepted with great credulity. Those who write popular books are well aware of the public’s voracious appetite for ideas and tools for self-improvement, whether they come in the form of a gadget for achieving “washboard abs” or pills that makes it easy to lose weight or to achieve a better personality. Over the last decade, there has been a spate of popularly written books that have not only exaggerated the capacity of drugs to cure mental disorders, but also frequently claim that there are now new drugs available that can produce “cosmetic” personality changes by adjusting the balance between a few critical neurotransmitters.

A book written by Ronald Kotulak, a Pulitzer Prize-winning science writer and past president of the National Association of Science Writers, is typical of many who claim that personality and behavior can be understood by the perturbations of one or two neurotransmitters.11 Kotulak’s “revolutionary discoveries of how the mind works” rest on the claim that much of personality and many behavioral traits are determined by the balance between serotonin and norepinephrine. Kotulak maintains that when norepmephrine levels are high it produces “impulsive hot-blooded” acts of violence, while low norepinephrine levels produce “premeditated cold blooded acts of violence” and thrill seeking. A high serotonin level, on the other hand, is said to increase shyness, obsessive-compulsive disorders, a lack of self-confidence, and “unduly dampened aggression,” while low serotonin is claimed to create a tendency toward depression, suicide, alcoholism, explosive rage, sexual deviance, and impulsive aggression.

The claim that all these different behavioral propensities can be explained by the levels of two neurotransmitters, while neglecting all other variables, both biological and psychosocial, is totally unjustified. The only evidence for such claims is some “weak” trends based on group averages of a relatively small sample of individuals. There is such a morass of experimental and clinical literature of questionable reliability and validity that it is possible to find studies that can support any theory that someone dreams up and wants to promote. Furthermore, there is a built-in bias in

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the professional literature, because studies that do not confirm trends previously reported only rarely get published, while in the popular media even “weak” trends may be described as though they represent a “revolutionary discovery.” The claims that complex mental and personality traits can be explained by the balance between a couple of neurotransmitters is no more valid than the Hippocratic theory that claimed many of these same traits are determined by the balance between the four basic humors: blood, phlegm, black bile, and choler (yellow bile). Yet, many of these recent claims are widely accepted as true, and the books that promote them are adding to the growing conviction that personality and mental health are completely determined by the levels of a few neurotransmitters that can be adjusted by drugs.

For the reasons just given and for all the additional reasons discussed throughout this book, I now believe that not only has it not been established that chemical imbalances are the major cause of mental disorders, but the theory from which these ideas emanate may well be wrong. The theory has been so widely accepted because a number of groups, each with its own agenda, have promoted this idea, not infrequently by exaggerating and distorting what is known about mental disorders and the effectiveness and safety of the drugs used to treat them.

There are so many diverse interests involved in supporting the various chemical theories of mental disorders that I anticipate the thesis of this book will be criticized on many different grounds. I welcome that and hope that the criticisms are offered in a constructive fashion, as there has hardly been any questioning of the basic assumptions underlying these chemical theories. By questioning basic assumptions, I do not mean a discussion about whether it is this or that receptor subtype that is the cause of schizophrenia or depression. Rather, I hope this book can help to start a dialogue about whether any chemical imbalance has really been shown to be the cause of mental disorders and whether we really know how drugs sometimes help to alleviate these disorders.

Many points might be raised about the evidence and arguments presented throughout this book. It is not possible to anticipate and answer them all, and besides, it could be considered an exercise in “shadowboxing,” much easier than getting into the ring with a real opponent. It may help, however, to respond briefly to a couple of general criticisms that I am certain will be made.

There will probably be some critics who agree that the evidence in the past was not convincing, but will argue that this book has not seriously considered the most recent experimental work and theories, which provide much stronger support for the chemical theories. My response would have to be that a serious effort was made to include a consideration of what was judged to be the more important of the recent theories, and this did not

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change the basic conclusions. I certainly do not want to prejudge any future developments, but I believe that an honest effort was made to consider the most important of the latest revisions of the chemical theories of mental illness, and none of these convinced me to change my basic conclusion.

There are also likely to be critics who will accuse me of being irresponsible in discouraging people suffering from mental disorders from seeking the drugs they badly need to help them. I have stated several times that I am convinced that some people have received significant help from psychotherapeutic drugs, and I certainly would not discourage anyone from trying them. It is possible that a few readers, who are reluctant to take “mind-altering” drugs, may become as a result of reading this book more critical of the claim that the medication prescribed for them acts as insulin does in treating diabetes. I think, however, that such an effect, if there is any at all, will be minimal. When patients trust their physicians it is usually sufficient that they be told that a number of people with conditions like theirs improve on the medication, and it is, therefore, worth trying. A theoretical explanation of how a treatment is supposed to work is rarely necessary and if a patient insists on one, it should not be assumed that he or she will be turned off by the statement that “we really do not know.” A patient may actually gain respect for a physician who is secure enough to admit to not knowing.

A more challenging criticism of the book is whether it really matters whether the chemical theories of mental disorders are right or wrong. It has been argued that what really matters is whether psychotherapeutic drugs work and not whether the theory is correct. This is what is implied by the old saw, “Read all these crackpot theories, if you must. In facts and figures only put your trust.” Theories come and go, but what is important is the effectiveness and safety of a treatment. Many examples can be given that seem to support this argument. Aspirin’s capacity to alleviate pain, fever, and inflammation, for example, was not altered by the fact that for much of the time it has been used, the theories proposed to explain its action were either inadequate or completely wrong. As one critic said sarcastically: “It does not matter how well it works in practice, what’s important is that it doesn’t work in theory.” Certainly, results should not be discredited because there is no adequate theory to explain them. Nevertheless, I am convinced that it is a mistake to trivialize theory, as it can have enormous practical consequences. Practice and theory are not independent of each other, and this is particularly true with respect to drug treatment and the chemical theories of mental disorders, as I will attempt to illustrate in the remaining pages of this chapter.

To accept the chemical theories of mental disorders without reservations is to believe that these disorders are caused by chemical imbalances and that drugs are effective because they correct the underlying chemical origin of

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such disorders. Accepting this strong version of the theory has significant implications for the way patients are treated, for the mental health professions, and for the research that is undertaken. While I did not write this book to give advice to anyone or to any group, I believe that there is a responsibility to discuss some of the practical implications of its conclusions.

I agree that the validity of the chemical theories of mental disorders should not be the basis for accepting or rejecting drug therapy. Having agreed on that point, it is necessary to add that the effectiveness of psychotherapeutic drugs is considerably less than commonly asserted. Drug effectiveness is consistently exaggerated, often by presenting anecdotes of people who seem to have been “miraculously” cured after they started taking a drug. Some of these stories are undoubtedly true, even though they may not be representative, but without experimental controls we never know what is really responsible for any improvement. Medical history is filled with examples of how easy it is to be misled when generalizations are made from a few anecdotal reports. We do know from numerous studies that a significant number of people with mental disorders improve with no drug treatment at all. In a recent well-balanced book on antidepressant drugs, for example, it was noted that:

Seventy percent of all people taking antidepressants report an improvement, meaning that there is at least a 50 percent reduction in their symptoms. This is in comparison with 40 percent of people taking a placebo.12

This means that only 30 percent of the improvement is attributable to the action of the drugs and even some of that was only a partial improvement. Even with many more drugs now available, there are still substantial numbers of patients who are not helped by any of them. Not only do the figures cited usually exaggerate the percentage of people likely to improve on drug treatment, but all the improvement that occurs is credited to the drugs.

It is claimed that patients tolerate the newer drugs better because they produce fewer side effects. Still, every drug has some undesirable side effects, and we will not know what side effects the newer drugs will have until they have been in use for a sufficient period of time. Relapse is also a problem. For some mental conditions, as many as 50 percent of the patients who improve with drug treatment have a recurrence of their condition within a year. It is commonly recommended that patients be maintained on drugs for eight months or more. The possibility of serious and permanent side effects from prolonged treatment cannot be discounted. To frame the issue more realistically, it is not a question of a perfect solution that lacks an adequate explanation, but rather a case of a far-from-perfect solution that is being pushed, too vigorously because of a heavily promoted theory that has been accepted uncritically.

If therapists are persuaded that chemical imbalances are the only factor

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that has to be considered in treating mental disorders, they will neglect other factors that may play an equal or even more important role. Increasingly, the advice given to psychiatrists is to try drug treatment first, and if that proves ineffective after a sufficient trial period, the drug dose should be increased. If improvement is still not evident, the advice is to try a different drug of the same class. A case the author was quite familiar with might help to illustrate the point.

A highly productive and creative research biochemist, who was a colleague and collaborator of the author, began to develop classic manic-depressive symptoms. He had periods of great energy and productivity, requiring less and less sleep, but gradually his behavior became increasingly inappropriate, unrealistic, and eventually quite bizarre. This cycle was repeated a number of times and was regularly followed by a period of dysphoria in which his mood turned ugly At this point he was usually verbally and physically aggressive, and his driving behavior was clearly a danger to himself and to others. Almost overnight, he would “crash” into a deep depression and become almost totally immobilized with suicidal thoughts. Lithium and the other mood-stabilizing drugs were tried at different dose levels, but at best they provided only minimal help, and the manic-depressive cycles recurred repeatedly with little or no abatement in the intensity of the emotional swings. He was hospitalized several times and was treated almost exclusively with mood-stabilizing drugs, but without significant abatement of his condition.

At long last, a psychiatrist began to pay attention to the coincidence of the manic-depressive episodes, long hours working in the laboratory, and the inevitable successes and failures that all research activity involves. There was probably an underlying predisposition, although it had not expressed itself in the six previous years that we were close colleagues. Judging from when these manic episodes started, there clearly seemed to be some environmental events that may have triggered, or least exacerbated, the emotional swings. After discussing the problem with the psychiatrist, my colleague agreed that he would try to rearrange his life to limit his research activities and to shift to doing the more predictable and steady work of supervising biochemical tests in a medical laboratory. A low dose of lithium was also recommended and prescribed, even though this dose had been completely ineffective when tried earlier. Of course, this too is an anecdote, and it does not prove any causal relationships, but over the following five years, with the changes in his life combined with lithium treatment, my colleague’s mood seemed to have finally been stabilized.

The case involved a patient who was probably helped by both drugs and psychotherapy in combination. There are patients who are helped by psychotherapy or counseling without drugs, and other patients who are helped by drugs alone. Kay Jamison, who in her book An Unquiet Mind

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describes how lithium helped stabilize her mood swings, has also commented that she would probably be dead if it were not for psychotherapy.13 The problem that has to be faced is that psychiatrists are increasingly being pressured to rely more and more on drugs and to spend less time trying to look for those psychological factors, interpersonal relationships, and environmental contingencies that often play a major role in the development and exacerbation of mental disorders. Admittedly, it is often not as easy to find a practical and effective way to help a patient to restructure their lives as it was in the above case. It is often necessary to try to help a patient change a much more intractable pattern of living and some very persistent thought patterns. It is unfortunate, however, that many of those promoting the advantages of drugs find it necessary to deprecate the effectiveness of all psychotherapy and counseling.

This is usually done by contrasting drug treatment with a caricature of psychoanalytic therapy in which a number of sessions a week are continued for years, seemingly without any end in sight or any demonstrable benefit. Psychotherapy is described as a way of life, commonly ridiculed by referring to it as “New York” treatment for the “Woody Allen” syndrome. What seems to be purposely overlooked is that most psychotherapy today bears no resemblance to this parody.

If anxiety, phobias, panic disorders, depression, mania, obsessions, compulsions, substance abuse, and other mental disorders are seen only as a reflection of abnormal brain chemistry, then psychic content and life experiences are likely to be regarded as irrelevant. It is highly likely, in my view, that in the past there was too much emphasis on ferreting out the early roots of intrapsychic conflict and the hidden meaning of symptoms, but today most psychotherapy is concerned less with the past and more with exploring ways of establishing healthier mental attitudes and lifestyles for persons with particular predispositions. There is convincing evidence that many of the briefer forms of psychotherapy and counseling may, for some conditions, be as effective as, if not more effective and more lasting than, drug treatment. There is also evidence that psychotherapy or behavior therapy sometimes increases the effectiveness of drug treatment. However, psychiatric residents are being offered less and less training in any form of psychotherapy and are spending an increasing amount of time learning about drugs and neuropharmacology. The number of medical students wanting to become psychiatrists has decreased, and expressions of dissatisfaction with the profession are increasing. As one psychiatric resident expressed it: “I did not select this specialty to dispense drugs like a pharmacist,” but increasingly that is the way psychiatrists have been forced to function, and that is the way their patients perceive them.

In many settings, the treatment of those with mental disorders is increasingly influenced, if not dictated, by health maintenance organiza-

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tions, a number of which are large for-profit corporations. HMOs exert pressure to rely more and more on drugs and to limit the amount of contact with patients. In many settings, there is not sufficient time allotted to learn very much about the lives of patients. We may not have quite reached the point where the treatment is being dictated by the results of “time and motion” studies, but it often seems that we are not far from that point. As one distinguished psychiatrist recently commented:

What’s really transforming the situation is the way mental health care is being structured by huge insurance companies and managed care—who pay physicians only to do pharmacology. They fund 10/15 minutes with a patient once a month for a review of drug treatment. They will not pay adequately for psychotherapy That will be funded only by someone being willing [or able] to pay for it out of his or her pocket. That aspect of a psychiatrist’s professional life will diminish greatly The American medical student is turning away from psychiatry because of poor reimbursement and because they don’t want to do just pharmacotherapy.14

Leon Eisenberg, professor of social medicine at the Harvard Medical School, commented that “managed care and psychotropic drugs are a satanic mix.”15 However, that is only part of the problem. Increasingly, the practice of psychiatry is being controlled by two powerful market forces. On one side, HMOs are exerting pressure to rely mostly on drugs, and on the other side, much of the information about drugs is provided by the pharmaceutical industry.

In a speech delivered in 1986, Morton Reiser, a psychiatrist affiliated with the Yale University School of Medicine, expressed his concern over the little interest many resident psychiatrists seem to have in getting to know their patients:

I talked with some of the residents and found that their approach and mind set in the interviews was astoundingly unpsychological. Once they had done the DSM-III “inventory” and had identified target symptoms for psychopharmacology, the diagnostic workup and meaningful communication stopped. Worse than that, to my mind, so did the residents’ curiosity about the patient as a person—even to the point where often there was no answer to such basic questions as why the patient came for treatment at this time and what seemed to be worrying him or her. Most of these residents could and would have learned more about a stranger who was sitting next to them for an hour on an airplane trip than they had learned in these formal psychiatric interviews.16

In 1983, Lewis Thomas commented on this same problem as it applied to all of medicine:

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The longest and most personal conversations held with hospital patients when they come to the hospital are discussions of finances, and insurance, engaged in by personnel trained in accountancy.17

There is every reason to believe that the problem has become more acute in recent years.

When I started this project I planned to describe the changes that have taken place in the way people think about mental disorders and how best to treat them, and the factors that were responsible for bringing about these changes. Along the way, I became convinced that it was also important to evaluate the evidence and arguments that support the now-prevailing theory that mental disorders are caused by chemical errors that are corrected by drugs. I have concluded that this theory, which is guiding much of clinical practice and our research efforts, is not supported by the evidence and may well be wrong. Yet for reasons that have little to do with science, the theory is being pursued relentlessly on a path filled with many dangers. It is like a ship without any navigational guidance being driven forward by a powerful motor through a sea with many uncharted reefs.


(fine capitolo 8 [ultimo conclusivo di “Blaming the Brain” di Elliot S.Valenstein, New york 1997])

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NOTES FOR CHAPTER 8 PAGES 221-241

8. Reprise, Conclusions, and Reflections

1. Kemker, S. S., and Khadivi, A., Psychiatric education: Learning by assump-

tion, in Ross, C. A., and Pam, A., eds., Pseudoscience in Biological Psychiatry: Blam-

ing the Body (New York: Wiley, 1995), pp. 241-77 (quotation from Susan S.

Kemker, from p. 246).

2. Carlsson, A., Neuroleptics and neurotransmitter interactions in schizophre-

nia, Int. Clin. Psychopharmacol., 1995,10, suppl. 3,21-28 (quotation from p. 21).

3. For example, see Williamson, P. C., Schizophrenia as a brain disease, Archives

Neural., 1993,50,1096-97.

4. Gottesman, 1.1., Schizophrenia Genesis: The Origin of Madness (New York:

W. H. Freeman, 1991), p. 96.

5. Wolfe, S. M., Why do American drug companies spend more than $12 billion

a year pushing drugs? /. of Gen. Internal Medicine, 1996,11,637-39.

6. For a discussion of the increase in pharmaceutical company advertising

directly to consumers, see Zuger, A., "Drug Companies' Sales Pitch: 'Ask Your Doc-

tor;" The New York Times, 5 August 1997, p. B9. See also "Too Clever by Half," The

Economist, 20 September 1997, p. 67.

7. The ad was placed in The New York Times (4 July 1997) by Rh6ne-Poulenc,

the company that introduced Largactil (chlorpromazine) in the 1950s.

8. "Drug Firm to Pay $325 Million" The New York Times, 25 February 1997,

p. A10. The company charged with fraud was SmithKline Beecham. An official of

the company stated that there was no intention to violate any law and that a mis-

understanding resulted from "ambiguities over regulations and guidelines." It

would be hard to find examples when regulatory ambiguities led to a company's

receiving less money than it was entitled to.

9. Don Holdsworth, who formerly worked for PepsiCo, was hired as marketing

manager by Merck in 1995.

10. Quoted by Rosenthal, E., "Maker of Cancer Drugs to Oversee Prescriptions

at 11 Cancer Clinics," The New York Times, 15 April 1997, pp. Al and D4 (quota-

tion from p. D4).

11. Kotulak, R., Inside the Brain: Revolutionary Discoveries of How the Mind

Works (Kansas City, Mo.: Andrews & McMeel, 1996).

12. Appleton, W. S., Prozac and the New Antidepressants: What You Need to

Know About Prozac, Zoloft, Paxil, Luvox, Wellbutrin, Effexor, Serzone, and More

(New York: A Plume Book, 1997). Quotation from pp. 47-48.

13. See Solomon, A., Anatomy of melancholy, The New Yorker, 12 January 1998,

p. 58.

14. Interview with Arthur Meltzer in Healy, D., The Psychopharmacologists:

Interviews by David Healy (London: Chapman & Hall, 1996), p. 506.

15. Leon Eisenberg quoted in The New York Times, 10 August 1997.

16. Reiser, M., Are psychiatric educators "losing the mind"? American J. Psy-

chiatry, 1988,145,158-53 (quotation from p. 151). The speech on which this paper

was based was delivered to a meeting of the American Psychiatric Association in

Washington, D.C., 10-16 May 1986.

17. Thomas, L., The Youngest Science (New York: Viking Press, 1983).

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NO! PAZZIA NOTA : tutti i diritti sono dell'autore E.S.Valenstein e dell'editore FREE Press New York 1997