Saturday, January 01, 2000

Are We “Blaming” Brain Chemistry for Mental Illness?

By: Elliot Valenstein Ph.D and Dennis Charney M.D.

A decade ago, if you told your doctor you were depressed, drinking too much, or having obsessive thoughts, you would have been referred to a psychotherapist to probe your early childhood experiences. Today, your doctor might give you a prescription and one follow up visit. Psychiatrist Dennis Charney and psychologist Elliot Valenstein exchange views on the scientific foundations of biological psychiatry—the understanding of mental illness in terms of the biochemistry of the brain.

In Blaming the Brain: The Truth About Drugs and Mental Health (The Free Press: New York, 1998),2Elliot S. Valenstein, Ph.D., charges that we are “blaming the brain” for mental illnesses and psychological woes of every stripe, but with little actual understanding of those illnesses and of why our drug treatments work (when they do). He asks if psychiatry is in the grip of a plausible new scientific orthodoxy: victorious in the field, impatient with dissent, and blissfully unaware of its own weaknesses.

At issue may be the future of psychiatry. Today, patients who seek help with psychological problems are likely to get a prescription, a follow-up appointment to check its efficacy and side effects, and little else. Many are patients who just a decade ago would have met with a psychiatrist or psychotherapist weekly or twice weekly for a year or more, seeking the source of their problems in early life experiences and emotional conflicts. At the same time, the thrust of research in psychiatry and psychology has shifted from our emotions, beliefs, and behavior to ever more refined exploration of brain chemistry.

Cerebrum invited Prof. Valenstein and a leading researcher on the biochemistry of mental illness, Dennis S. Charney, M.D., to debate the thesis of Blaming the Brain. Prof. Valenstein and Dr. Charney each wrote an initial statement about the book’s thesis, which may be suggested by the following excerpts:

The evidence and arguments supporting claims about the relationship of brain chemistry to psychological problems and personality and behavioral traits are far from compelling and are most likely wrong. (p. 3.)... [T]he evidence claimed to support the various chemical theories of mental illness is not strong, and there is much evidence that contradicts the prevailing view... The truth is that we still do not know what causes any mental disorder or how drugs sometimes help patients get better. (p. 165)

Prof. Valenstein and Dr. Charney exchanged their initial statements and wrote rejoinders. Each then wrote a final comment, responding to the rejoinder and summarizing his views of the entire debate.

VALENSTEIN

STATEMENT

Don’t Blame Brain Chemistry for Mental Illness

When I started to write Blaming the Brain, I did not plan to question biochemical theories of mental illness. By the time I had finished examining the evidence, however, I had become convinced that the theory is probably wrong that mental illness is caused by a biochemical imbalance in the brain. As a result, the book ended up quite different from what I had originally intended.

The accidental discovery of a few drugs that altered mood and thinking provided a catalyst to neuropharmacology and virtually created the field of psychopharmacology.

Only the beginning of my book contains what was to have been the whole book. In it, I describe how the accidental discovery of a few drugs that altered mood and thinking provided a catalyst to neuropharmacology and virtually created the field of psychopharmacology. At the time, Sigmund Freud’s psychoanalytic theory dominated ideas about mental illness and almost nothing was known about brain chemistry. Yet, within less than a decade, there was sufficient evidence to argue that mental illnesses could be explained by biochemical imbalances in the brain. Today, this theory is widely accepted as established.

On that basis, I went on to critique the scientific foundation of the biochemical theories of mental illness, based on a critical examination of the evidence and the arguments on which the theories rest. I concluded by looking at how special interest groups promote biochemical theories and drug treatment and the dangers of accepting these ideas as proven.

I am not in principle opposed to biological explanations of mental illness. My research career has been devoted to studying how biological factors influence behavior. I am convinced, in fact, that there is persuasive evidence that biological factors predispose some people to develop mental illness in response to stressful experiences. The criticisms presented here apply only to the theory that mental illness is caused by a biochemical imbalance in the brain

At the core of the biochemical theories of mental illness is the proposition that biochemical imbalances—excessive or inadequate activity of one or more brain neurotransmitters—cause mental illness and that drug treatment works because it corrects this underlying imbalance. Thus, excessive dopamine activity is believed to cause schizophrenia primarily because “antipsychotic” drugs, such as Thorazine and Haldol, block dopamine receptors and alleviate the disorder. Similarly, depression is claimed to be caused by a deficiency in the activity of certain naturally occurring neurotransmitters, the “biogenic amine neurotransmitters” (serotonin or possibly a combination of serotonin and norepinephrine), since it has been observed that antidepressants increase the activity of these neurotransmitters. There are similar theories for anxiety and other mental disorders. In this brief overview, I discuss only the evidence relevant to depression, but essentially the same criticisms apply to the theories proposed to explain other mental illnesses.

The Flawed Theory

Some of the evidence offered to support theories of biochemical imbalance is based on reports that neurotransmitter imbalances have been found in the brains of patients with mental illnesses. Thus it is claimed, for example, that an abnormally high number of a particular dopamine receptor has been found in the brains of patients suffering from schizophrenia, or that abnormally low levels of serotonin activity are found in depressed patients. That is not, however, what the evidence has actually shown. What has been shown is that, while on average depressed patients may have low levels of serotonin activity, about one half of these patients have normal levels of serotonin, and a few may even have levels that are unusually high. Other studies have found no significant relationship between serotonin activity and depression. If low levels of serotonin activity caused depression, we would not expect to encounter so many depressed patients with normal and even high serotonin activity.

It is also not clear that antidepressants actually increase serotonin activity, except for a relatively brief period. Thus, there may be neither a deficiency in serotonin, nor a correction provided by the treatment. It typically takes several weeks before depressed patients begin to show clinical improvement, even though drugs such as Prozac or Effexor increase serotonin activity within hours. By the time clinical improvement occurs, serotonin activity is probably no longer elevated, because physiological mechanisms compensate for the initial effect of the drug treatment. For example, the number of receptors capable of responding to serotonin will decrease as weeks go by.

An analogy is frequently drawn between insulin treatment of diabetes and the treatment of depression with antidepressants. Insulin corrects an identified deficiency; antidepressants are presumed to do the same. But this analogy is not valid. Before insulin is prescribed for diabetes, laboratory tests, based on glucose metabolism and other indices, first determine if an insulin deficiency exists. On the other hand, depressed patients are commonly told they have a serotonin deficiency (or more generally, a biochemical problem), but no tests are performed to verify this statement— which may not be true for most of them. Moreover, unlike the case with insulin and diabetes, virtually nothing is known about the way a serotonin deficiency could cause depression.

Even if, for the sake of argument, it is assumed that low serotonin activity is found reliably in depressed patients, this would not prove that the low serotonin activity caused the depression. It might just as well be an effect of depression as its cause. Many depressed patients live in an almost constant state of stress. They may be agitated, pacing up and down, or almost immobilized. They may have insomnia or sleep excessively. Some depressed patients lose interest in food, while others indulge in binge eating.

Because many studies in both animals and humans have demonstrated that the state of stress can produce biochemical, physiological, and even anatomical changes in the brain, any unusual feature found in the brains of depressed people should not be assumed to have caused the depression.

The weakness of the claim of a causal relationship between low levels of serotonin (or any other biogenic amine) and depression is further illustrated by the finding that many drugs that change serotonin and norepinephrine activity do not produce the effect that the chemical imbalance theory predicts. Caffeine and amphetamine, for example, elevate serotonin and norepinephrine activity, but they are not effective antidepressants. When the biogenic amine theory of depression was first proposed, it was repeatedly claimed that the drug reserpine, which lowers biogenic amine activity, made normal people depressed. This claim, which was based on anecdotal reports, was accepted uncritically because it supported the theory. Reserpine and other drugs that lower serotonin and norepinephrine activity may make some normal people tired and relatively inactive, but well controlled studies subsequently demonstrated that these people were not clinically depressed. The claim of a causal relationship between serotonin activity and depression is also contradicted by the fact that there are apparently effective antidepressant drugs that do not elevate the activity of serotonin, just as there are antipsychotic drugs that do not block dopamine activity.

Readers may ask if it really matters whether a theory is correct as long as the treatment works. I do believe it matters, because uncritical acceptance of the theory blinds many to the fact that antidepressants help only a fraction of depressed patients. No treatment is 100% effective and completely without any risks, but antidepressants are much less effective than the 7080% rate commonly claimed.

Antidepressants clearly benefit some patients, but their far-from-perfect record is concealed behind an overly promoted theory that has been accepted uncritically.

In a recent investigation sponsored by the Department of Health and Human Services, the results of a number of separate studies of the effectiveness of antidepressants were summarized. Although 50% of people with major depression improved following treatment with antidepressants, 32% improved when given a placebo. Only 18% of the improvement should, therefore, be attributed to the specific action of the drug. Moreover, it was found that Prozac and the other selective serotonin reuptake inhibitors (SSRIs) such as Zoloft and Paxil were no more effective than the older tricyclic antidepressants. Lately, much attention has been given to anecdotal reports describing the wonders of Prozac, but we rarely hear from the many depressed people who were not helped by this drug or by any of the other six or seven antidepressants tried subsequently. Antidepressants clearly benefit some patients, but their far-from-perfect record is concealed behind an overly promoted theory that has been accepted uncritically. 

Science or Pharmaceutical Industry Self-interest?

The common use of individual drugs for treating many different mental disorders raises additional questions about the claim that these drugs work by remedying a specific biochemical problem underlying each disorder. Prozac, for example, is used to treat not only depression, but also obsessive compulsive disorder, panic disorder, various food-related problems (anorexia and bulimia), compulsive gambling, premenstrual dysphoric syndrome (PMS), attention deficit/hyperactivity disorder (ADHD), borderline personality disorder, drug and alcohol addiction, aggressiveness, social phobia, autism, and much more. It has been said, only half jokingly, that the list of psychological disorders that Prozac is claimed to treat is larger than those for which it is not used.

Sometimes the same drug is sold under different names for different indications to perpetuate the illusion that it specifically targets the underlying cause in each instance. The antidepressant Wellbutrin, for example, is also marketed as Zyban, a drug to help stop smoking. There is virtually no scientific justification for the suggestion that the same biochemical imbalance exists in depression and nicotine addiction, or the myriad disorders for which Prozac is prescribed. Marketing forces, not science, best explain this phenomenon.

I am definitely not opposed to using drugs to treat mental illness, but I want to challenge the explanation that the drugs work by remedying a biochemical imbalance that has caused the illness.

Efficacy Versus Explanation  

I do not deny that psychiatric drugs can alleviate some of the symptoms of mental illness and help start many patients on the road to recovery. I am definitely not opposed to using drugs to treat mental illness, but I want to challenge the explanation that the drugs work by remedying a biochemical imbalance that has caused the illness. Treatments can help even if they do not address the primary cause of a disorder. For example, diuretics are used to treat congestive heart failure. They help because they reduce the strain on the heart caused by excess fluid accumulation, although they act on the kidney, not on the heart.

Likewise, psychiatric drugs may help relieve symptoms without remedying the cause of the mental disorder. Antidepressants, which were once called “psychic energizers,” increase interest in the outside world and may, as a result, weaken a tendency to be depressed, whatever the original reason. Antipsychotics, which were once called tranquilizers, tend to calm patients and create a mood of indifference that reduces the impact of distressing thoughts.

The Myth of Specificity

Although many clinical researchers are fully aware of the criticisms that I have raised, they rarely mention them. Instead, they commonly assert that any shortcomings of our present theories and drug treatments will be overcome before long by new developments, some already in the pipeline. For example, because it is now possible to produce drugs that act on only one neurotransmitter receptor, some scientists have predicted that future drugs will be able to remedy the specific cause of each mental illness without producing adverse side effects. They predict that, in the future, psychiatric drugs will act like “smart missiles,” capable of seeking out and eliminating a preselected target without any “collateral damage.”

This prediction, however, is likely to prove illusory, because there is no persuasive evidence that any mental illness is caused by a single biochemical imbalance. Moreover, even if a drug acts only on one specific receptor, all receptors are found both in various parts of the brain and in many organs outside of the brain. The same biochemical receptor plays different functional roles depending on its location and other factors.

Many recent writers seem to assume that there is a single serotonin receptor that is responsible for enhancing only positive attributes of personality, such as self confidence, creativity, optimism, and sociability. Apparently, most of these writers do not appreciate that the name “serotonin” was derived from the first of its functions to be discovered—the capacity to cause blood vessels to contract. Because of this, it should not have come as a complete surprise that the diet drugs fen-phen and Redux, which elevate serotonin activity, could also damage heart valves as well as change appetite. The often repeated phrase that underlying every “twisted thought” is a “twisted molecule” misleads many into believing that a specific molecular abnormality causes each mental disorder.

Some Other Dangers

One of the dangers of relying only on drugs to treat mental disorders is that both patients and physicians fail to consider other relevant factors. When depressed patients are told that they have a biochemical imbalance, they may assume that they cannot contribute anything to solving their problem. They can only hope that their physician knows the right pill to prescribe. Meanwhile, physicians who are under pressure to see as many patients as possible may be forced to neglect other factors while they search, without any theory to guide them, for the pill that may be helpful. More and more in recent years, the training of resident psychiatrists emphasizes drug treatment and neuropharmacology to the exclusion of other factors that may influence the lives of their patients. The patient’s history is all too frequently considered relevant only to the extent necessary to arrive at a diagnosis that will determine the drug to be prescribed. Increasingly, the advice given to psychiatrists is to try drugs first, and if that proves ineffective, change the dose or switch to another drug.

There is no doubt that we have made enormous strides in understanding how drugs interact with brain chemistry, but we have not made nearly equal advances in understanding the causes of mental illness or why drugs help some patients. Yet from the way biochemical explanations of mental illness are being promoted, it appears to many that the theory has been proven and only a few refinements are needed. I believe there are considerable dangers in accepting this view.

CHARNEY

STATEMENT

Biological Psychiatry Is Leading the Way In Explaining and Treating Mental Illness

As I read Blaming the Brain for the second time, I caught myself wondering why Prof. Valenstein was so angry, and at whom. Assuming that he has had an outstanding career and is an excellent scientist, I was perplexed—and eventually angered myself—at his propensity for half truths and one-sided arguments damning research enterprises whose mission is to better understand the causes of mental illness and discover better treatments.

Here, I comment on key passages from Blaming the Brain, grouping them according to several of Prof. Valenstein’s recurring themes.

THEME 1: Little Is Known About the Neurobiology of Mental Illness

Throughout his book, Prof. Valenstein disparages current knowledge of the neurobiology of mental illness:

It may surprise you to learn that there is no convincing evidence that most mental patients have an chemical imbalance. Yet many physicians tell their patients that they are suffering from a chemical imbalance, despite the reality that there are not tests available for assessing the chemical status of a living person’s brain. (p. 4)

Does Prof. Valenstein mean to imply that brain pathology is not relevant to the major neuropsychiatric disorders? Or is he saying that researchers have not yet precisely defined the causes of these illnesses? If the second, he neglects to review most of the current research concerning the neurobiology of schizophrenia, depression, and anxiety disorders. He persists in referring simplistically to the “dopamine hypothesis of schizophrenia” or the “serotonin hypothesis of depression,” without discussing the refinements of those hypotheses over the past decade.1 For schizophrenia, for example, he has largely ignored recent research on events in the developing brain that may contribute to the disease,2 on specific brain abnormalities,3 on increased recognition of the neurobiological basis for the cognitive defects,4 and even on imaging studies that have demonstrated increased release of dopamine in schizophrenia.5

Prof. Valenstein writes:

Considering what we have learned about neuropharmacology, it is indeed amazing how little the biochemical theories of mental disorders have changed over the last half-century. The earliest theories of depression, for example, were based on either serotonin or norepinephrine, or some balance between them. This has not changed. (p. 95)

This comment likewise reflects a superficial understanding of current research into the neurobiology of psychiatric disorders. To take but one example, there have been enormous advances in our understanding of the effects of stress on brain structure and function. Severe psychological stress in non-human primates has been shown to reduce the number of neurons in the part of the brain called the hippocampus. This damage may result from high levels of two brain chemicals (steroid cortisol and excitatory amino acids) produced by the stress.6 Very recent work indicates that stress actually reduces the creation of new cells in the hippocampus of adult monkeys.7 This work is being extended to human patients with post traumatic stress disorder (PTSD). Several investigations using magnetic resonance imaging have now shown that PTSD patients have reduced hippocampal volume. Studies in PTSD patients provide evidence that stress can cause over-responsiveness by adrenalin-producing neurons and other abnormalities.8,9

Evidence from laboratories and from research on patients suggests a role in depression and its treatment of a brain chemical called “corticotropin-releasing hormone” or CRH. In fact, drugs that block CRH’s action have been developed and are now in clinical trials.10 Other brain chemicals like CRH, part of a group called neuropeptides, have now been implicated in depression. Extremely active drug development and clinical trial programs are focusing on the use of a class of drugs that act as antidepresssants by blocking receptors for a neurotransmitter called “substance P.”11 There have also been important recent investigations relevant to the neuropathology of depression. Ongur12 and Rajkowska13 have reported reductions in the density of certain brain cells in post-mortem brain samples. These findings may relate to the molecular and cellular hypotheses of depression put forward by Duman.14

Prof. Valenstein writes:

Judging from the last antipsychotic drugs being marketed, dopamine is still thought to play the major role in schizophrenia. Is this conservatism the result of having been fortunate in getting the theories essentially right at the outset? No, but it reflects two facts: First, a theory that is wrong is considered preferable to admitting our ignorance. Second, the tendency of pharmaceutical companies to develop drugs that are similar to those being successfully marketed seemingly provides support for existing theories without ever really testing them. (p. 96)

There are intense research efforts aimed at identifying brain circuits relevant to the symptoms of schizophrenia.

Here again, Prof. Valenstein treats his subject in a superficial way. There are intense research efforts aimed at identifying brain circuits relevant to the symptoms of schizophrenia, research that goes well beyond dopamine hypotheses of schizophrenia. This work has led to an emphasis on how chemical messengers in the brain, such as glutamate, dopamine, and GABA, interact with serotonin.15, 16 One outcome of this research has been a promising new class of antipsychotic drugs with the highly technical label “metabotropic Type II glutamate receptor agonists.”  Such drugs are poised to enter phase II clinical trials.

Prof. Valenstein writes:

The idea that there may be a distributed circuit that is malfunctioning rather than a single localization is not unreasonable, but it may also be a convenient way to place the best “spin” on the many different brain anomalies reported to have been found in people with the same disorder. It is also not clear to what extent the increasing number of reports that the [brain’s] prefrontal cortex, the striatum, and the thalamus are structurally or functionally abnormal in different mental disorders indicates a common underlying impairment in all these disorders, as often claimed, or whether it is simply reflecting the current interest in these particular structures. (Page 100)

As he does throughout Blaming the Brain, Prof. Valenstein here takes a cynical, superficial view. Research on the neural circuits thought to be involved in obsessive-compulsive disorder, PTSD, depression, and schizophrenia have, in fact, already revealed many distinctive features of those circuits.

THEME 2: Limits of the Biogenic Amine Hypothesis of Depression

Prof. Valenstein writes:

Mendels and Frazer...reviewed a number of studies in which patients were given drugs that blocked the synthesis of either norepinephrine or serotonin, and also dopamine. Their summary of these articles should have delivered a crippling blow to any theory that assumed that either a serotonin or norepinephrine deficiency was the cause of depression, but actually it was ignored. Mendels and Frazer found that marked reductions of norepinephrine, serotonin, or dopamine did not actually produce depression in humans, even though it tended to produce animals that appeared depressed because they barely moved and sometimes remained huddled in a corner. (p. 98)

Once again, Prof. Valenstein has not kept abreast of the research literature.

Since the Mendels and Frazer paper was published in 1974, studies with a chemical that reduces concentrations of dopamine and norepinephrine in the brain (the chemical is called alpha-methyl-paratyrosine or AMPT), and also with a tryptophan-depleting drink that lowers concentrations of serotonin, have shown that reducing levels of dopamine, norepinephrine, and serotonin at least temporarily reverses the effects of antidepressant drugs. In patients whose depression has lifted and who are drug free, AMPT temporarily produced a return of depressive symptoms.17

THEME 3: Psychotropic Drugs Are Being Used Blindly

Prof. Valenstein writes:

Psychiatrists prescribe Prozac and the other selective serotonin reuptake inhibitors [SSRIs] not only for depression, but also for obsessive-compulsive disorders, panic disorders, various food-related problems (including both anorexia and bulimia), premenstrual dysphoric syndrome (PMS), attention-deficit/hyperactivity disorder (ADHD), borderline personality disorder, drug and alcohol addiction, migraine headaches, social phobia, arthritis, autism, and behavioral and emotional problems in children, among many other conditions. It is a paradox that a drug that is praised for the specificity of its pharmacological action should be prescribed as a treatment for such a variety of conditions. (p. 105)

The SSRIs do have a remarkably broad spectrum of action. They have been shown in placebo-controlled clinical trials to be effective for depression, panic disorder, social phobia, and eating disorders. The interpretation of these data by most experts is not that these disorders have a common underlying cause, but that serotonin has a broad effect in modulating functions in the brain. By affecting these modulatory actions of serotonin, the SSRIs affect the functions of diverse neurochemical systems, which may relate in some way to the causes of many disorders.

Prof. Valenstein writes:

Almost all the antidepressant drugs currently being marketed or in various stages of development are based on the assumption that depression is caused by some deficiency in serotonin and norepinephrine activity, due to either low levels of serotonin or some abnormality in receptor sensitivity. (p.108)

As I indicated above, this clearly is not the case. Pharmaceutical companies are actively working on the development of novel antidepressants that affect the neuropeptides CRH and Substance P.

Prof. Valenstein writes:

All of this drug development is essentially a trial-and-error approach, as there is so little known about the functional significance of any receptor subtype...Those who respond to antipsychotic drug treatment are often caught in a “Catch 22” dilemma. If the drug treatment is stopped even after the patient’s condition has been in remission for over a year, over three-quarters of them will relapse. However, if the drug treatment is maintained, the patients run a 25 to 40 percent risk of developing tardive dyskinesia... This raises the possibility that prolonged treatment with antipsychotics may also produce permanent changes in the brain that might increase the possibility of a relapse.(p. 118)

This statement about the risk of tardive dyskinesia (a disorder of facial movement that can result from long-term use of antipsychotic drugs), applies primarily to the older antipsychotic drugs. Newer antipsychotic drugs, such as olanzapine, have a lower risk. To my knowledge, there is absolutely no evidence that prolonged treatment with antipsychotic drugs increases vulnerability to relapse.

THEME 4: Damning the Pharmaceutical Industry

Prof. Valenstein writes:

Many patient advocate groups receive funding from the pharmaceutical industry, which enables the groups to increase newspaper and magazine advertising and the information they distribute by other means. Typically, patient advocacy material has a prodrug bias... (p. 177)

I wonder if Prof. Valenstein has had any involvement with major advocacy groups. I serve on the scientific advisory boards of the Anxiety Disorder Association of America and the National Depression and Manic Depression Association, two of the major advocacy organizations in the United States. Both promote a diversity of treatment options for patients. Both attempt to provide patients with up to date scientific information on rational treatment choices.

Prof. Valenstein writes:

Many consensus conferences are sponsored by pharmaceutical companies, and the reports issued after these conferences are often not distinguishable from the promotional material distributed by these companies. (p.185)...Studies of clinical trials have shown that those supported by pharmaceutical companies are more likely to report results favorable to a company’s products. (p.189)

Prof. Valenstein finds much to criticize, but offers no solutions. He excoriates pharmaceutical companies for introducing bias into clinical trials, propagating false information about the neurobiology of psychiatric disorders through their educational programs, and exhibiting little inclination to survey the use of drugs already approved (p. 190). But the United States pharmaceutical industry leads the world in research. Most medications for treatment of major neuropsychiatric disorders have been discovered and marketed by these companies. Yes, they are in the business of marketing medications to make profits. Yes, there are instances where their advertisements may oversimplify our knowledge of the nature and causes of illness and how drugs act. And, yes, they may, through their representatives, emphasize the positive attributes of their products and the negative attributes of their competitors’ products. In my opinion, however, the good that they do far outweighs these problems.

In particular, the vast majority of clinical trials designed to achieve Food and Drug Administration (FDA) approval of new medicines and other products are conducted in an exemplary manner. The designs and procedures associated with these trials are such that it is hard to see how the companies can routinely bias their study results. Although there are certainly individual clinical trial sites, particularly non-academic, profit-making sites, that have been shown to perform poorly—even, in extreme cases, fraudulently—these are the rare exception.

If the pharmaceutical companies were so successful in biasing clinical trials, why would the outcome of so many large-scale trials of antidepressant medications fail to show the tested drug any better than a placebo—sending the company back to the drawing board?

As a long-time consultant to major drug companies, I am not aware of a single instance in which a company selected a site based on whether or not the site was “favorably disposed” to the company’s product. Sites are usually selected based on their ability to competently perform the trial according to the required criteria. If the pharmaceutical companies were so successful in biasing clinical trials, why would the outcome of so many large-scale trials of antidepressant medications fail to show the tested drug any better than a placebo— sending the company back to the drawing board?

The pharmaceutical companies have had a major role in supporting educational programs, including grand rounds at community hospitals and academic medical centers. Many of these programs are outstanding, with the sponsoring company exerting little or no control over content. Most academic departments of psychiatry, such as mine, do not schedule grands rounds that reflect undue pharmaceutical company influence. The staff of the American Psychiatric Association’s national meeting carefully evaluates pharmaceutical-company-sponsored symposia to ensure that the content of the presentations reflects an objective view of the subject.

On the other hand, I agree with Prof. Valenstein that there are examples of grand rounds and symposia where the sponsoring pharmaceutical company’s product gets too much attention. I am also disturbed when journals publish non-peer-reviewed articles that summarize the presentations of such symposia.

Prof. Valenstein also criticizes the companies for inadequate surveillance of their drugs once they are on the market. When the FDA is concerned about a side effect observed in the approval process, it will frequently require a company to obtain post-marketing data using a specific methodology. What kind of post-marketing surveillance program does Prof. Valenstein recommend that a company be required to conduct?

At present, psychiatry remains behind most other medical specialties, but today there is a far more sophisticated appreciation of the biological basis of mental disorders.

What Comes Next

During the past several decades, our understanding of the causes of disease, the increased availability of tests to diagnose specific diseases, and improved treatments and preventive approaches have transformed medical practice. At present, psychiatry remains behind most other medical specialties, but it is important to acknowledge that today there is a far more sophisticated appreciation of the biological basis of mental disorders. The field has moved well beyond the decades-old hypotheses that are the target of Blaming the Brain.

To be sure, there is much to accomplish. We need to identify disease genes, develop medications aimed at underlying causes of illness, and discover preventive measures. There are many reasons that progress in psychiatry has lagged. The brain is extraordinarily complex and, until recently, there was no way to study its functioning under normal or pathological conditions. Advances in the techniques of molecular genetics and brain imaging promise to overcome many obstacles to progress.

Current diagnostic categories used in psychiatry are limited by our knowledge of the causes of psychiatric disorders. We may be lumping together diseases with different causes. I am confident, though, that the next generation of psychiatric researchers will discover specific genetic abnormalities and pathological processes that will lead to more precise diagnostic classifications and safer, more effective treatments.

VALENSTEIN

REJOINDER

Dr. Charney raises three criticisms of Blaming the Brain. First, he states that the biogenic amine theory of depression and the dopamine theory of schizophrenia that I challenge in my book are “simplistic” and “outdated.” Second, he accuses the book of neglecting or “disparaging” current research on the pathophysiology of mental illness. Lastly, he asserts that the book unfairly criticizes the pharmaceutical industry. I will respond to these three concerns.

Theories Old and New

Dr. Charney states that “the field has moved well beyond the decade-old hypotheses that are the target in Blaming the Brain.” Over the years, it is true, there have been refinements in the biochemical imbalance theories of depression and schizophrenia, most of which are discussed in Blaming the Brain. None of these refinements, however, has changed the underlying assumption that depression is caused by a deficiency in biogenic amine activity. Dr. Charney’s own publications make it clear that the biogenic amine theory of depression is very much alive and well. In an article he published in May 1999 (his reference 17), he first quotes a 1965 paper which states that “some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, particularly norepinephrine...” and then adds that the “landmark observations on which this [the above quotation] is based remain timely and provocative, meriting renewed research interest.” (emphasis added) In another recent article Dr. Charney states: “A wide range of evidence supports the hypothesis that alterations in central serotonergic function are involved in the pathogenesis of depression.”

In Blaming the Brain, I cite a report by Mendel and Frazer that depletion of biogenic amines by reserpine did not induce depression in healthy subjects, even though it induced a relapse in depressed patients who had recovered. This finding casts doubt on any chemical imbalance theory of depression, because it shows that biogenic amine deficiency alone will not produce the disease. Dr. Charney accuses me of “not keeping abreast of the literature” because the reserpine study I cited was published in 1974. Yet the two recent articles written by Dr. Charney and colleagues (cited above) both report similar results:  Patients who had recovered from major depression relapsed following administration of drugs that reduced available norepinephrine or serotonin, but subjects who were never depressed exhibited no sign of depression under the same conditions. It is difficult to understand Dr. Charney’s assertion that the biogenic amine deficiency theory of depression is no longer relevant, when some of his most recent research is grounded in those “outdated” theories.

The biogenic amine theory of depression remains dominant today even though there is still no convincing evidence that most depressed patients have a serotonin or norepinephrine deficiency. The crucial question remains as unanswered today as it did three decades ago: Why doesn’t depletion of biogenic amines produce depression in healthy subjects? Perhaps interventions that have nothing to do with biogenic amines would also cause people with a history of depression to relapse. Does an implicit acceptance of the biogenic amine theory make it seem unnecessary to test this possibility?

To demonstrate the widespread acceptance of the biogenic amine theory of depression, one need look no further than the neighborhood drug store. Ninety-five percent of the antidepressants prescribed today are designed to correct an assumed deficiency of serotonin and/or norepinephrine activity. These antidepressants include the selective serotonin reuptake inhibitors (e.g., Prozac, Zoloft, Paxil), the tricyclic antidepressants (e.g., Tofranil, Elavil, Pamelor), the monoamine oxydase inhibitors (e.g., Marplan, Nardil, Parnate), and the serotonin-norepinephrine and norepinephrine reuptake inhibitors (e.g., Effexor, Remeron, Edromax). Moreover, the great majority of antipsychotic drugs currently used to treat schizophrenia, including the new drugs olanzapine (Zyprexa) and respiridone (Risperdal), are designed to block dopamine receptors.

Neglecting Current Research?

I can turn only briefly to Dr. Charney’s assertion that Blaming the Brain neglected current research on the pathophysiology of mental illness. While not written to review all current psychiatric research, the book does discuss most of the research Dr. Charney mentions. For example, Duman’s theory that some depression might result from a stress-induced loss of the brain’s hippocampal cells is discussed, along with his statement that, at best, this could only account for a small subgroup of depressed people. I also mention Weinberger’s reports that schizophrenia may be associated with underdevelopment of temporal lobe structures and low activity in the dorsal lateral prefrontal brain area and Goldman-Rakic’s theory that schizophrenia may result from a “working memory” deficit caused by dorsal lateral prefrontal area impairment. I discuss the interpretation of several brain imaging studies reporting abnormal activity in different brain areas of obsessive-compulsive and schizophrenic patients and also the reports that glutamates, GABA, acetylcholine, and other non-biogenic amines neurotransmitters might also be involved in specific mental disorders.

While the biogenic amine theory of depression dominates contemporary thinking, a handful of individual researchers do continue to consider other explanations for depression. I share Dr. Charney’s interest and some of his enthusiasm for these new lines of research. However, I am not willing to accept that every preliminary report of a biochemical, anatomical, or physiological correlate of mental disease represents a major breakthrough. These new findings need to be replicated and critiqued. For example, the preliminary report that “Substance P” inhibitors may act as antidepressants was published after Blaming the Brain appeared, but there has been difficulty replicating these results. Besides, because Substance P inhibitors are believed not to affect biogenic amine activity, this report would have only added to my criticisms. While I agree with Dr. Charney that these lines of research should be pursued, it is also important to note that no coherent explanation of any mental disorder has emerged from this new research. The biochemical imbalance theory of depression remains preeminent.

Like Dr. Charney, I am convinced that new research eventually will help us understand why some people are predisposed to develop a mental disorder. My criticisms are directed only at the theory proposed to explain most current treatment—namely, that specific biogenic amine deficiencies and excesses cause depression and schizophrenia.

The Role of the Drug Companies

Lastly, Dr. Charney believes that Blaming the Brain is grossly unfair by “damning the pharmaceutical industry.” I don’t believe that the pharmaceutical industry is an “evil empire,” and I am well aware of its important contributions. The profit motive, however, is not a secondary concern for pharmaceutical companies any more than it is for other companies. The industry’s focus on health care does not preclude unethical behavior. Pharmaceutical companies have paid multimillion dollar fines for price fixing; promoting non-approved uses of drugs; applying pressure to suppress, discredit, delay, or modify reports unfavorable to their products; and for withholding information about adverse effects of drugs.

In the United States alone, pharmaceutical companies spend $12.3 billion dollars promoting drugs and more money lobbying legislators than any other industry.

In the United States alone, pharmaceutical companies spend $12.3 billion dollars promoting drugs and more money lobbying legislators than any other industry. Studies described in Blaming the Brain have shown that much of drug promotion, even the advertising in medical journals, is “exaggerated,” “misleading,” and “inaccurate,” yet it has a significant influence on the drugs physicians prescribe. After a study questioning the accuracy of pharmaceutical advertisements was published in The Annals of Internal Medicine in 1992, drug companies pulled their advertisements and the journal lost approximately $1.5 million dollars in advertising revenue.

I cannot review here all the many ways that pharmaceutical companies promote the sales of psychiatric drugs and the biogenic amine theory of mental disease. As an example, one popular technique is to sponsor “consensus” meetings at which selected participants are invited to issue recommendations on drug use; these recommendations are then widely circulated among physicians. Scientific research has demonstrated that the opinions authors express in peer-reviewed publications are correlated with their financial ties to the pharmaceutical industry. It is difficult today to find “experts” to comment on drugs who have no financial links (through investments, consulting fees, or industry grants) to pharmaceutical companies.

Dr. Charney says that he does not believe drug companies exert significant influence over the outcome of clinical trials, rightly pointing out that many clinical trials are halted if a drug proves to be obviously ineffective or dangerous. Yet this does not change how much companies stake on the outcome of these trials. The cost of developing new drugs is enormous, and the decision to approve a drug may hinge on small differences between it and a placebo or a drug already on the market. Pharmaceutical companies employ “trial monitors,” who design clinical trials, choose and fund the participating investigators, check on how the study is progressing, sometimes suggest changes in midstream, and often assume the major responsibility for analyzing the data and writing articles summarizing the results.

Dr. Charney would dismiss all of this influence by noting that: “as a long-time consultant to major drug companies, I am not aware of a single instance in which a company selected a site [for a clinical trial] based on whether or not the site was favorably disposed to the company’sproduct.” It is gratifying that Dr. Charney has had only good experiences, but I doubt many will be completely reassured.

CHARNEY

REJOINDER

My opening statement highlighted important research on the neurobiology of psychiatric disorders, research largely ignored in Blaming the Brain. This research suggests that our current understanding of the neurobiology of depression, schizophrenia, and anxiety disorders is far more sophisticated than the simplistic hypotheses that Prof. Valenstein persists in critiquing in Blaming the Brain. Since Prof. Valenstein’s opening statement is essentially a summary of some of the major points of his book, which I critiqued, I will focus here on some additional criticisms he makes in that statement. He writes:

“...abnormally low levels of serotonin activity are found in depressed patients.” However, that is not what the evidence has actually shown. What has been shown is that while on average depressed patients may have low levels of serotonin activity, about one half of these patients have normal levels of serotonin and a few may even have levels that are unusually high.  Other studies have found no significant relationship between serotonin activity and depression. If low levels of serotonin activity caused depression, we would not expect to encounter so many depressed patients with normal and even high serotonin activity.

Yes, there is evidence that some depressed patients exhibit abnormalities in serotonin activity in the brain. However, the focus of current research on the role of serotonin in depression is not to identify a simple deficiency in the brain’s serotonin concentrations, but to learn about networks of brain cells in different brain regions that involve serotonin and serotonin receptors.

It is widely believed that major depression, as currently defined by standard diagnostic criteria, may have several different causes in the brain. It is not surprising, therefore, that a group of depressed patients do not all exhibit the same abnormality in serotonin or, for that matter, similar abnormalities in other brain chemistry systems (norepinephrine, corticotropin releasing hormone) also hypothesized to be involved in depression.18, 19

Prof. Valenstein writes:

It is also not clear that antidepressants actually increase serotonin activity, except for a relatively brief period. Thus, there may be neither a deficiency in serotonin, nor a correction provided by the treatment. It typically takes several weeks before depressed patients begin to show clinical improvement, even though drugs such as Prozac or Effexor increase serotonin activity within hours. By the time clinical improvement occurs, serotonin activity is probably no longer elevated, because physiological mechanisms compensate for the initial effect of the drug treatment. For example, the number of receptors capable of responding to serotonin will decrease as weeks go by.

Prof. Valenstein has it wrong. There is clear experimental evidence that chronic administration of many antidepressants, including SSRIs, increases serotonin activity in the brain. The research is quite technical, but one of the mechanisms by which this occurs is through desensitizing the “5HT1A autoreceptor.”20

Prof. Valenstein writes:

Even if, for the sake of argument, it is assumed that low serotonin activity is found reliably in depressed patients, this would not prove that low serotonin activity caused depression. It might just as well be an effect of depression as its cause.

Here, he raises an important point that is currently the subject of considerable research. Whenever a brain abnormality is identified in a psychiatric disorder, the question of cause and effect is critical. In regard to depression, several approaches are being used. Currently, research groups at Yale University and Emory University are comparing neurobiological abnormalities in depressed patients with and without a history of child abuse. Work done by Drevets and his colleagues has reported specific abnormalities in brain structure and function in depressed patients with a family of history of depression.21 These types of investigations may help to disentangle genetic and environmental influences on the neurobiology of depression.

Prof. Valenstein writes:

Moreover, it was found that Prozac and the other selective serotonin reuptake inhibitors (SSRIs) such as Zoloft and Paxil were no more effective than the older tricyclic antidepressants. Lately, much attention has been given to anecdotal reports describing the wonders of Prozac, but we rarely hear from the many depressed people who were not helped by this drug or by any of the other six or seven antidepressants tried subsequently. Antidepressants clearly benefit some patients, but their far-from-perfect record is concealed behind an overly promoted theory that has been accepted uncritically.

The efficacy of antidepressants, even taking into account the placebo response, compares very favorably with drug treatments for other medical conditions, such as cancer, heart disease, and hypertension, especially when considering the percentage of patients who achieve remission of their depression or the prevention of relapse.22

Psychiatric researchers and clinicians are well aware that many depressed patients have inadequate responses to antidepressants. They are not complacent. Large scale efforts are underway to discover new antidepressant drugs with greater efficacy.

Prof. Valenstein writes:

Psychiatric drugs may also help relieve symptoms without remedying the cause of the mental disorder. Antidepressants, which were once called “psychic energizers,” increase interest in the outside world and may, as a result, weaken a tendency to be depressed, whatever the original reason. Antipsychotics, which were one called tranquilizers, tend to calm patients and create a mood of indifference that reduces the impact of distressing thoughts.

These comments are difficult to comprehend and suggest Prof. Valenstein has little knowledge of the clinical effects of psychiatric drugs. Antidepressant drugs have been shown to improve a broad spectrum of symptoms associated with depressive illness. Antipsychotic drugs absolutely do not work merely through their sedative actions or by creating a mood of indifference. They have specific antipsychotic effects.23, 24

Prof. Valenstein writes:

Yet from the way biochemical explanations of mental illness are being promoted, it appears to many that the theory has been proven and only a few refinements are needed. I believe there are considerable dangers in accepting this view.

This comment perhaps best symbolizes the differences between myself and Prof. Valenstein. The field of psychiatry, due in part to tremendous advances in basic neuroscience, is not resting on its laurels or content with simplistic notions about disease causality, but, rather, is poised to better define the neurobiology of psychiatric disorders and to discover better treatments.

VALENSTEIN

CLOSING STATEMENT

Dr. Charney, like many scientists engaged in both research and clinical work, argues both sides of the controversy over the biogenic amine theories of depression and schizophrenia. On the one hand, he characterizes the biogenic amine theories as “simplistic” and “outdated.” On the other hand, he is willing to stretch the scientific evidence to support the basic assumptions of those very theories. In this debate, he asserts that several of these assumptions are true, even while a more objective review of the scientific evidence suggests otherwise.

For example, Dr. Charney insists that there is “clear experimental evidence” that chronic administration of antidepressants “increases serotonin activity in the brain.” He imperiously dismisses as “wrong” my statement that it was not “clear that antidepressants actually increase serotonin activity, except for a relatively brief period.” Dr. Charney cites two studies reporting that chronic administration of antidepressants decreases the sensitivity of serotonin autoreceptors. (The connection being that, since 5HT1A autoreceptors inhibit serotonin release, decreasing the sensitivity of these autoreceptors may potentially increase serotonin release.)

But Dr. Charney’s citation of evidence is selective and incomplete. First of all, the studies he cites were performed on rats, not humans. Second, similar studies performed with other strains of rats have shown completely opposite results.1 Moreover, there is much more involved in making serotonin available in the synapse between brain cells than the sensitivity of these serotonin autoreceptors. One complication is the evidence that chronic administration of antidepressants produces a significant increase in serotonin transporter mRNA.2 Scientists believe that this may cause serotonin activity to decrease—not increase—at the time clinical symptoms are being alleviated.

The crucial point is that there is neither evidence that serotonin autoreceptors are abnormally sensitive in depressed patients nor that serotonin activity is low in most of these patients.

We don’t know how this technical issue will finally be resolved; suffice it to say that a dispassionate review of the scientific literature reveals both conflicting results and no convincing evidence that antidepressants elevate serotonin activity at the time clinical symptoms may be alleviated. Attempting to support the role of serotonin in depression by selective citation of the literature is not in the interest of scientific objectivity. In any case, the crucial point is that there is neither evidence that serotonin autoreceptors are abnormally sensitive in depressed patients nor that serotonin activity is low in most of these patients.

Dr. Charney acknowledges that many depressed people do not have low serotonin levels. He argues that this occurs because depression is a disorder with several different causes. This is a position many psychiatrists are forced into by data that doesn’t fit the prevailing theory. For example, Nancy Andreasen, the editor of the American Journal of Psychiatry, proposed “that there may be two types of depression: one due to norepinephrine deficiency and the other to a serotonin deficiency in the brain.”3

But is this tortured logic helpful? While it is certainly possible that depression has multiple causes, at present, there is little to support this idea. Depressed people with low serotonin are not clinically distinguishable from those with low norepinephrine, or from those with perfectly normal biogenic amine activity. We cannot predict which patients will benefit from serotonin versus norepinephrine enhancing drugs and which will not respond to any drugs. Proposing different subtypes of depression—one based on a serotonin and another on a norepinephrine deficiency—appears to be an effort to cope with the failure of the evidence to support one hypothesis by shifting the burden to another one that is equally inadequate.

Dr. Charney also objects to my comment that drugs might alleviate symptoms without correcting their cause. He argues that it has definitely been shown that antidepressant and antipsychotic drugs alleviate symptoms by correcting the cause of the disorder. I can only ask how it is possible to show that, when we do not yet know the cause of any mental disorder?

The biogenic amine explanations of schizophrenia and depression still prevail, despite the evidence that they are quite possibly wrong. I agree that there is much that is interesting and potentially important in the current investigations of biological factors in mental illness, but an honest appraisal must conclude that no coherent theory of any mental disorder has emerged from the many studies of abnormal brain anatomy and physiology. Is schizophrenia caused by some anatomical or functional abnormality in the temporal lobe or the dorsolateral prefrontal brain areas, for example? Or is the speculation that a thalamic abnormality explains all the diverse symptoms of schizophrenia correct? What should be made of the many different brain imaging studies reporting that depression is associated with reductions in the size of temporal lobes, frontal lobes, brain stem, the vermis of the cerebellum, the caudate nucleus, and more? Is depression caused by high levels of stress causing glucocorticoid to reach toxic levels capable of producing hippocampal damage? Or from hyperactivity of Substance P, the neurotransmitter thought to mediate physical pain?

It is not clear how all of these reports of brain pathology are related or if some of them may be the effects of chronic illness rather than its initial cause. We need to be optimistic and hope that some day we will be able to integrate much of this new research, but at present it is certainly fair to say that no theory has replaced the biogenic amine theories of depression and schizophrenia.

We do not yet have any new theories to replace the biogenic amine theories of depression and schizophrenia, but I believe it would be far better to acknowledge the flaws of the current theories now.

Many years ago, Thomas Kuhn noted that scientific theories (or paradigms) are defended vigorously even in the face of conflicting evidence, and are replaced only when new theories emerge that are better able to explain the evidence. We do not yet have any new theories to replace the biogenic amine theories of depression and schizophrenia, but I believe it would be far better to acknowledge the flaws of the current theories now.

 

CHARNEY

CLOSING STATEMENT

I take issue with key points that Prof. Valenstein makes in his rejoinder to my commentary. He writes:

Dr. Charney’s own publications make it clear that the biogenic amine theory of depression is very much alive and well. In an article published in May 1999, he first quotes a 1965 paper which states “some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, particularly norepinephrine...” and then adds that the “landmark observations on which this (the above quotation) is based remain timely and provocative, meriting renewed research interest.”

This is another example of Prof. Valenstein selectively reviewing research or taking comments out of context for his own purposes. If he was going to quote from my paper, published in the Archives of General Psychiatry in May 1999,25 he should have at least provided readers with the entire statement. “Although this hypothesis has proven limited in explaining newer findings, the landmark observations on which it was based remain timely and provocative, meriting renewed research interest.”

Prof. Valenstein has not reviewed all of my publications—I did not expect him to. However, if he was going to make the blanket statement, “Dr. Charney’s own publications make it clear that the biogenic amine theory is very much alive and well,” he should have been aware of, and perhaps read, the paper “The revised monoamine theory of depression: a modulatory role for monoamines.” This paper reviews research findings that led to my research group receiving the Anna Monika Foundation Award for research in depression in 1995. In it, we discuss the limitations of the biogenic amine hypothesis of depression and suggest new research directions.

Prof. Valenstein writes:

The biogenic amine theory of depression remains dominant today even though there is still no convincing evidence that most depressed patients have a serotonin or norepinephrine deficiency... Why doesn’t depletion of biogenic amines produce depression in healthy subjects?

...reducing norepinephrine and dopamine levels can bring about a return of depressive symptoms in well patients with a history of depression, but not in healthy subjects without a history of depression. Our interpretation is the opposite of Prof. Valenstein’s.

Here he is referring to our May 1999 paper, which indicated that reducing norepinephrine and dopamine levels can bring about a return of depressive symptoms in well patients with a history of depression, but not in healthy subjects without a history of depression. Our interpretation is the opposite of Prof. Valenstein’s. That individuals with a history of depression are experiencing a worsening of mood during a period of biogenic amine depletion suggests that biogenic amines (and other brain systems regulated by biogenic amines) may be dysfunctional in patients vulnerable to depression. That this does not occur in individuals not susceptible to depressive illness suggests that those brain systems regulated by biogenic amines are able to compensate for or adapt to the effects of biogenic amine depletion. This explanation for our findings is not unlike that used in explaining the pathogenesis of other medical disorders in which patients react differently to stimuli than healthy subjects. For example, patients with diabetes, and not healthy subjects, get an elevated blood glucose level in response to glucose challenge, which argues for a role for abnormal regulation of glucose levels in the pathogenesis of diabetes, not against it.

Prof. Valenstein suggests that “To demonstrate the widespread acceptance of biogenic amine theory of depression, one need look no further than the neighborhood drug store.” He says that the medications found there further reinforce his assertion that there is widespread acceptance of a discredited biogenic amine theory of depression. It is true that the currently available antidepressant drugs, which have proven to be highly effective for treatment of depression, work in part by blocking the reuptake of two biogenic amines, serotonin and norepinephrine. However, as I explained in my previous commentary, the focus of current antidepressant drug discovery research goes well beyond the biogenic amine theory. Major pharmaceutical companies are in the process of testing the antidepressant efficiency of what they hope are new classes of antidepressant drugs that affect the function of corticotropin releasing hormone and substance P. It is my hope and expectation that these new agents will prove effective in treating depression and will represent an important new therapeutic option for depressed patients within the next five years. Prof. Valenstein is apparently not so optimistic.

The preliminary report that Substance P inhibitors may act as antidepressants was published after Blaming the Brain appeared, but there has been difficulty replicating these results.

It is unfair to characterize the initial study reporting the effectiveness of a Substance P antagonist as preliminary, given that it was published in one of the world’s premier scientific journals, Science, and was a placebo-controlled investigation of several hundred patients. I agree, however, that the work needs to be replicated. Prof. Valenstein refers to an unpublished study in which the effects of neither a Substance P antagonist nor an established antidepressant drug could be separated from those of a placebo. This is termed a “failed” trial rather than a “negative,” one because a proven effective drug did not work compared to placebo. This is a common occurrence in clinical trials of many medical and psychiatric disorders.

I believe that tremendous advances in basic and clinical neuroscience have brought us to the threshold of making fundamental advances in our knowledge of the pathogenesis of major psychiatric disorders, which will lead in turn to improved therapeutics.

Prof. Valenstein apparently believes he did justice to current research on the pathogenesis of mood and psychotic disorders that goes beyond the role of biogenic amines.

While the book was not written to review all current psychiatric research, it does discuss most of the research Dr. Charney mentions... While the biogenic amine theory of depression dominates contemporary thinking, a handful of individual researchers continue to consider other explanations for depression.

I once again must inform readers that this is simply not the case. In his book, Prof. Valenstein failed to provide an accurate, comprehensive view of basic and clinical neuroscience research pertaining to the pathogenesis of major psychiatric disorders. I refer readers to my recently published textbook for an up-to-date synthesis of this area.28

Prof. Valenstein continues to harrangue the pharmaceutical industry for its unethical behavior. He implies sponsored consensus conferences are mere vehicles for the pharmaceutical companies to inappropriately advertise their product. He criticizes the use of “trial monitors” who

...often assume major responsibility for analyzing the data and writing articles summarizing the results.

As I have noted previously, Prof. Valenstein fails to provide a balanced view of the contribution that the pharmaceutical industry makes to the discovery, evaluation, and marketing of therapeutic drugs for human diseases. Yes, there are examples in which the industry has behaved unethically. Yes, there may be instances in which drug promotion has been exaggerated, misleading, and inaccurate. Yes, there have been “consensus” conferences designed to highlight properties of a specific therapeutic agent. However, this is not the whole story. As I stated before, the pharmaceutical industry spends an enormous amount of money to bring out new drugs that will represent an improvement over what is currently available. I have met hundreds of professionals who work in the industry who are driven not by the profit motive, but by a belief that their drug discovery efforts will lead to products that help people. Dare I say it, but I have met professionals in the marketing sector that are motivated not to inflate the benefitsof their product, but to fairly present it.

Regarding consensus conferences supported by the pharmaceutical industry, there are many examples in which companies have supported scientifically outstanding consensus conferences with little to no input on content. A recent noteworthy example is a consensus conference on the use of placebo in the clinical trials of mood disorders held in Washington, DC, on September 14 and 15, 1999. This conference, which I chaired, was sponsored by the National Depression and Manic Depression Association and financially supported by education grants from several pharmaceutical companies.

Prof. Valenstein asserts that “trial monitors” take major responsibility for data analysis. What is his evidence? In my experience, the data analysis of clinical trials sponsored by pharmaceutical companies for the purpose of obtaining FDA approval is an extremely rigorous enterprise directed by top flight biostatisticians who have no contact with patients or study investigators.

In summary, I hope the series of exchanges between Prof. Valenstein and myself has been useful and informative for readers of Cerebrum. I hope that I have explained why I believe that tremendous advances in basic and clinical neuroscience have brought us to the threshold of making fundamental advances in our knowledge of the pathogenesis of major psychiatric disorders, which will lead in turn to improve therapeutics. We no longer focus on the simplistic biogenic amine hypotheses portrayed in Prof. Valenstein’s book Blaming the Brain.

 

 

References

CHARNEY

  1. Charney DS, Nestler EJ, Bunney BS (eds). Neurobiology of Mental Illness. New York, NY. Oxford University Press. 1999.
  2. Weinberger DR. Schizophrenia: from neuropathology to neurodevelopment. Lancet. 1995:346:552-557.
  3. Rajkowska G, Selemon LD, Goldman-Rakic PS. Neuronal and glial somal size in the prefrontal cortex: a postmorten study of schizophrenia and Huntington’s disease. Archives of General Psychiatry. 1998:55:
  4. Braver TS, Barch DM, Cohen JD. Cognition and Control in Szhizophrenia: A Computational Model of Dopamine and Prefrontal Function. Biological Psychiatry. 1999;46:312-328.
  5. Laruelle M, Abi-Dargham A, Van Dyck CH, et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects. Proceedings of the National Academy of Sciences. 1996:93:92359240.
  6. Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM. Hippocampal damage associated with prolonged and fatal stress in primates. Journal of Neuroscience. 1989: 9:1705-1711
  7. Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proceedings of the National Academy of Sciences. 1998: 95:3168-3171.
  8. Charney DS, Grillon C, Bremner JD. The Neurobiological Basis of Anxiety and Fear: Circuits, Mechanism, and Neurochemical Interactions (Part I). Neuroscientist.1998;4:35-44.
  9. Charney DS, Grillon C, Bremner JD. The Neurobiological Basis of Anxietyand Fear: Circuits, Mechanism, and Neurochemical Interactions (Part II). Neuroscientist. 1998;4:122-132.
  10. Nemeroff CB. Psychopharmacology of Affective Disorders in the 21st Century. Biological Psychiatry. 1998;44:517-525.
  11. Kramer MS, Cutler N, Feighner J, et al. Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors. Science. 1998;281:1640-1645.
  12. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proceedings of the National Academy of Sciences. USA. 1998: 95:13290-13295.
  13. Rajkowska G, Miguel-Hidalgo JJ, Wei J. Morphometric Evidence for Neuronal and Glial Prefrontal Cell Pathology in Major Depression. Biological Psychiatry. 1999;45:1085-1098.
  14. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Archives of General Psychiatry. 1997:54:597-606.
  15. Marek GJ, Aghajanian CK:  The Electrophysiology of Prefrontal Serotonin Systems: Therapeutic Implications for Mood and Psychosis. Biological Psychiatry. 1998;44(11):1118-1127.
  16. Moghaddam B, Adam BW. Reversal of Phencyclidine Effects by Group II Metabotropic Glutamate Receptor Agonist in Rats. Science. 1998;28:1349-1352.
  17. Berman RM, Narasinhan M, Miller HL et al. Transient Depressive Relapse Induced by Catecholamine Depletion: Potential Phenotypic Vulnerability Marker? Archives of General Psychiatry. 1999;56:395-403.
  18. Garlow SJ, Musselman DL, Nemeroff CB. The neurochemistry of mood disorders: clinical studies. In: Charney DS, Nestler EJ, Bunney BS, eds, Neurobiology of Mental Illness. New York, NY: Oxford University Press;1999. pp 348-364.
  19. Drevets WC, Gadde KM, Krishnan KRR. Neuroimaging studies of mood disorders. In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illness. New York, NY: Oxford University Press; 1999. pp 394-418.
  20. Blier P, Pineyzo G, El Mansari M, Bergeron R, De Montigny C. Role of somatodendutic 5-HT autoreceptors in modulating 5-HT neurotransmission. Annals of the New York Academy of Sciences. 1998: 861:204-216.
  21. Ongur D, Drevets WC, Price JL. op cit
  22. Keller MB, Kocsis JH, Thase ME, et al. Maintenance phase efficacy of sertraline for chronic depression: A randomized controlled trial. JAMA. 1998;280:16651672.
  23. Marder SR. Antipsychotic Medications. In: Schatzberg AF, Nemeroff CB, eds. Textbook of Psychopharmacology. Washington DC: American Psychiatric Press. 1998: pp 309-321.
  24. Owens MJ, Risch SC. Atypical Antipsychotics. In: Schatzberg AF,Nemeroff CB, eds. Textbook of Psychopharmacology. Washington, DC: American Psychiatric Press;1998, pp 323-348.
  25. Berman, RM, Narisimhan M. Miller, HL, Anand  A, Cappiello A, Oren DA, Heninger GR, Charney DS. op cit.
  26. Heninger GR, Delgado PL, Charney DS. The revised monoamine theory of depression: A modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry. 1996;29:2-11.
  27. Kramer MS, Cutler N, Feighner J. op cit.
  28. Charney DS, Nestler EJ, Bunney BS eds. op cit.

Dr. Charney has offered to provide additional references to interested readers. Cerebrum will forward inquiries to him.

VALENSTEIN

  1. Burnet  PW, et al. Brain Research. 1994; 638, 311-324.
  2. López JF, et al, Biological Psychiatry. 1994; 35, 287-290.
  3. Andreasen NC. The Broken Brain. The Biological Revolution in Psychiatry. New York, NY. Perennial Library (Harper & Row); 984, p. 234.



About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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