Monday, January 01, 2001

Genome Map + Brain Map = Brave New World

Brave New Brain: Conquering Mental Illness in the Era of the Genome

By: Nancy C. AndreasenM.D., Ph.D.

Roughly half of our genes are devoted to determining characteristics of our brains. Among those characteristics, the range of variation is staggering. For example, there are more than 700 known genetic causes of mental retardation. Our genes can predispose us to Alzheimer’s disease or protect us from it. And, although arguments over intelligence still rage, genes seem to account for 40 percent, give or take, of our IQ. What vistas will open, therefore, as we discover what “brain genes” relate to which mental illnesses, talents, or temperaments? What, in short, will happen when we are able to line up our gene map with our brain map?

To take on that question is to peer into the future of humanity. It is fortunate, then, that the seer is a pioneer in explaining brain science and its ramifications. Nancy Andreasen’s 1984 book, The Broken Brain: The Biological Revolution in Psychiatry (Harper & Row), helped introduce the educated public to the idea that psychiatry deals with brain disorders. In 1999, 15 years after its publication, Andreasen’s neuroscience colleagues voted The Broken Brain among the “Great Brain Books” in Cerebrum’s spring 1999 survey.

Now, in the final chapter of her new book, Brave New Brain: Conquering Mental Illness in the Era of the Genome,Andreasen looks ahead at a world that may have mastered the human genome and mapped the brain. Is it a brave new world in the wondrous Apollonian sense of Shakespeare’s Ariel or in the bleakly Faustian sense of Aldous Huxley’s science fiction anti-utopia?


From Brave New Brain: Conquering Mental Illness in the Era of the Genome by Nancy C. Andreasen.

To be published by Oxford University Press, April 2001. Used by permission of Oxford University Press.





...We live in an era when two large knowledge bases will meet and mingle: the map of the human genome and the map of the human brain. The products of this union will be many. The synthesis of these two knowledge bases will give us the power to understand the mechanisms that cause major mental illnesses and to use this knowledge to relieve the pain of the millions of people who at present suffer from them. The time when we can realistically declare a war on mental illnesses, with some hope of eventually achieving a victory, has finally come...

We are now living in an era...when we can be guided by rational principles that derive from our knowledge of molecular and cellular biology and our understanding of how changes in one point of a complex dynamic biological system, the human brain and mind, can affect other sites in an elegant cascade that occurs each day in each individual human life. [The table above] illustrates the nature of this cascade.

...Recent decades have not only added many weapons to our arsenal for attack on mental illnesses, but they have also given us a map of the terrain on many different levels in the cascade from genes through mind and brain. We no longer need to aim blindly and hope we might hit the enemy. At the most fine-grained level, we have created a crude map of the human genome that will be steadily refined over the next few decades, until we reach a point when we have figured out exactly how many genes there are, what they do, and the mechanisms by which they are turned on and off. This fine-grained map of the genetic activity of our brains is complemented by large-scale maps of neurotransmitter systems, anatomical circuits, and functional circuits.

We now have maps of “normal brain terrain” that show us where to look when we want to understand how the mind/brain is able to learn, remember, or feel emotions. Ingenious techniques have also shown us how various brain regions are connected to one another, giving us increasingly refined wiring diagrams of neuronal connections and providing us with maps of anatomical circuits. We also have maps of chemical circuits, which have shown us the distribution of the multiple neurochemical systems of the brain and how they interact with one another to send specific messages or to fine-tune the level of activity within regions by exciting or inhibiting nearby nerve cells.

During the next several decades, we can expect to identify the abnormalities in brain geography and topography that define the various types of mental illnesses. Once this is accomplished, we will know where the enemy is. The techniques of molecular biology will give us the targets at which to aim. 

Now that we have relatively detailed maps of the chemical, anatomical, and functional circuitry of the normal brain, we have a basis for seeking out the sites of abnormality in the vast array of human mental illnesses. Using the in vivo tools of modern neuroscience, we can create comparison maps of brain terrain for diseases such as schizophrenia, bipolar disorder, major depression, Alzheimer’s disease, panic disorder, autism, or attention deficit hyperactivity disorder (ADHD)... During the next several decades, we can expect to identify the abnormalities in brain geography and topography that define the various types of mental illnesses. Once this is accomplished, we will know where the enemy is. The techniques of molecular biology will give us the targets at which to aim.


There will be interesting and unexpected surprises as this story unfolds. For most mental illnesses, we are still in the process of identifying the place or places in this cascade of events that a given illness is “caused.” For most, we already know that, although genes will be a key factor, a “single cause” is not likely to be found. Therefore, as we define our targets for attack, we will work using two different insights, which may seem paradoxically contradictory. First, our strategy for attack should be designed to search multiple points on this cascade. That is, finding the gene, or even repairing it completely, might not be enough to prevent a particular disease from occurring. We already know that possessing a gene explains, at most, less than 50% of the casualty of most illnesses, including mental illnesses. Second, even before we find the cause or causes, we may be able to produce dramatic improvements by aiming treatment or prevention at one crucial site in the cascade. Since the brain is an interactive dynamic system, making an adjustment in one site can have reverberating effects in other places and produce a significant change.

The case of schizophrenia illustrates how some of the recent advances in neuroscience, based on the tools of neuroimaging, neurobiology, and molecular biology, have changed how we think. Our progress during the 50 years leading up to 2000 appears to be substantial, since “mental hospitals” were virtually emptied. The major achievement between 1953 and 2000 was the development of drugs, initially discovered by serendipity, that reduced psychotic symptoms and made patients more manageable. We later learned that these drugs were effective because they blocked dopamine receptors, which were located primarily in basal ganglia structures such as the caudate and putamen. Although emptying mental hospitals by reducing these symptoms was a significant achievement, the “clinical target” was nonetheless still insufficient. The earliest antipsychotics affected only psychotic symptoms and had little or no impact on negative symptoms or the more basic cognitive problems that define the essence of schizophrenia. At the anatomical level, the target was selected by accident rather than by rational knowledge of enemy location. By striking the basal ganglia, the older antipsychotics probably reduce symptoms through secondary effects on other interconnected brain regions. The newer “atypical neuroleptics” that became available in the 1990s and early 2000 have a better symptomatic target because they also attack negative symptoms and cognition (by mechanisms we are still learning to understand). But more dramatic and more rational approaches to designing treatments are now underway.

Using the tools of in vivo neuroimaging such as magnetic resonance and positron emission tomography, we have found new and sometimes unexpected “enemy sites.” These neuroimaging studies suggest that we should explore alternative targets, both for the development of new treatments and in the search for causes. One of these new targets, for example, is the thalamus, shown to be smaller in schizophrenia by the anatomical tools of MR, to have abnormal cellular structure using the tools of postmortem tissue analysis, and to have abnormal functional connectivity using fMR and PET. The next stage of the story, likely to unfold over the next decade, will be to map the chemical systems and connections of the thalamus in more detail, to explore the neurodevelopmental processes that shape its connections at the genetic and cellular levels, to determine the neural functions performed by the thalamus, and to map the activities of gene expression and the proteins that genes produce. Somewhere in this small haystack we may find the quixotic needle that can be used to slay one of the biggest giants of mental illness.


Scientists once hoped that finding the genes for mental illnesses would be a simple process. A single gene, or perhaps two, would be identified, and the “cause” of a specific mental illness would then be discovered. We now know that the story is much more complicated and challenging.

Scientists interested in the genetics of mental illness now murmur the mantra of “multiple genes of small effect.”

First, most major mental illnesses are almost certainly caused by more than one gene. Scientists interested in the genetics of mental illness now murmur the mantra of “multiple genes of small effect.” Sorting through the human genome to find the multiple genes for a specific illness will take time, but the detail on the map of the human genome is steadily accumulating, under the leadership of Francis Collins. Cleverly efficient computer technologies and statistical methods are now available to sift through this mass of information. Within a few years, we will probably be able to identify the genetic mutations that differentiate people who have developed manic-depressive illness (for example) from those who have not. These comparisons will help us determine both “bad alleles” that predispose to the development of illness, as well as “good alleles” that protect against it. We are already well on our way with Alzheimer’s disease, which will probably serve as a model for the attack strategy for other diseases such as schizophrenia, mood disorders, or anxiety disorders.

Second, we now recognize that “finding the genes” is not enough. We must become increasingly nimble in moving up and down the dynamic and bi-directional cascade between genes and the activity of the mind/brain, as well as wise enough to recognize when it is time to pause on one level in order to survey the terrain in more detail. Discussions about “finding the genes” will ultimately switch to the topic of “functional genomics,” the branch of genetics that focuses on figuring out what proteins the genes produce, what their functions are, and the medical mischief that occurs when the functions are abnormal.

We usually begin by figuring out “where the genes are.” This information will not be simple. It will be something like: 50% of the people with manic-depressive illness have a mutation on Chromosome A, which has 4 alleles, one of which is “bad.” Among those 50%, 10% have mutations on Chromosome B, G, and X, while 30% have mutations on Chromosomes C, L, and Y, and the remainder have mutations on M and W. The remaining 50% of people with manic-depressive illness fall into smaller groups. Perhaps 5% will have a single major gene with a large effect that is incompletely penetrant, coupled with only one other gene. Others will be small groups of 5% or 10% (or even less) that have other polygenic patterns, containing some genes that overlap with those in group one. The story for schizophrenia, other mood disorders, and the various anxiety disorders (as well as the array of childhood disorders and other disorders not discussed in this book) will probably be quite similar.

This prediction of polygenic “causes” may seem pessimistic, but it is probably also fairly realistic. We will not win the war if we underestimate the power of the enemy. Nevertheless, the scientists leading the war are intelligent and determined, and therefore likely to win many battles and ultimately achieve victory. The important question is not, “Will it happen?” It is, “How long will it take?”

As discussed earlier in this book, an important clue about the causes of mental illness lies in the fact that they are caused by other factors besides genes. That is, identical twins who share the same genes only have the same mental illness at most 50% of the time, indicating that the “ill twin” experienced some non-genetic influence that permitted his “bad alleles” to exert their toxic effect. Here, we may be looking at the first step in the cascade: the relationship between the presence of a gene and its expression. Much of the effort during the next few years will focus on the factors that cause disease genes to turn on, which will lead in turn to identifying preventive strategies that may turn them back off again.

Other efforts will move further up and down the cascade, attempting to determine how the expressed genes actually exert their effect. This process is the domain of functional genomics. It will explore how “bad alleles” produce an excess of “bad molecules” and lead to “bad functions.” The molecules themselves may be fine, but there may be too many of them. Alternatively, the bad molecules produced could be truly “bad,” in the sense that they have an improper chemical structure that has a toxic effect...


Some day we all may be carrying the ultimate identity card: a small disc or chip that contains our genetic fingerprint... Right now, both the costly equipment and the technological tools that can scan a tissue sample from a single individual and summarize the information in a “snip profile” are not widely available. At the moment, the profiles are still crude, and our knowledge of what they mean is relatively vague. As the Human Genome Project matures, however, these blurry images will sharpen their focus and achieve amazing predictive power. The technology used to scan tissue samples will also become more widely available, and genetic fingerprints may then become widely used in both medical research and medical care.

A genetic fingerprint will tell us, for each gene, the specific allele that a person carries. For example, we already know that there are three different alleles for apolipoprotein E and that the 4 allele increases the risk for Alzheimer’s disease, while the 2 allele appears to protect against it. We know that there is a similar pattern of protective and destructive effects for the BRCA1 and BRCA2 alleles that influence the development of breast cancer. As our armamentarium of information about the genes for specific diseases increases, and as we identify the patterns of alleles that predispose to specific diseases, our genetic fingerprints will tell us which diseases we are at risk to develop. Inevitably, we are all predisposed to develop something. None of us will be free of disease alleles.


Importantly, we know that carrying a “bad” allele does not necessarily cause a specific disease to occur. It may only indicate that we are “at risk.” A “positive snip” indicating a bad allele can serve as a “wake-up-call” to warn us that we have the potential to develop a disease...and should perhaps initiate changes in our lifestyle that will reduce our risk. For example, if our genetic fingerprint tells us that we carry an allele that makes us prone to develop adult-onset diabetes, we can potentially forestall its effects or perhaps even prevent them by losing weight and consuming a better diet. If we know that we carry an allele that predisposes us to developing Alzheimer’s disease, we can do more than review our will with our attorney. We can attempt to maintain healthy spines and synapses on our neurons by exercising brain cells and circuits through challenging mental activities–learning a new skill, doing arithmetic calculations in our heads, training ourselves to memorize names and faces...and of course reading books rather than watching TV or surfing the net. We can also maintain good health by exercising regularly to insure that our brain receives a good blood supply and eating a balanced diet to make sure that neurons are well nourished.

Using the information available through genetic fingerprints may eventually become as routine in medical care as electrocardiograms, x-rays, or blood tests. They may be used not only to determine the predisposition to or presence of an illness, but also to make more intelligent decisions about how to treat it.

For example, one of the big puzzles that psychiatrists confront is why some patients respond to one drug and not another...

Consulting a patient’s genetic fingerprint can help answer this question. We already know that patients differ from one another in their rate of drug metabolism. Some people break drugs down quickly and are known as “rapid metabolizers,” while others do it more slowly and are prone to build up larger amounts of drug in the bloodstream on lower doses. One of the important liver enzymes that breaks down drugs is known as cytochrome P-450. The chain for this enzyme has already been characterized and its mutations identified. We know that the reason people vary in their rate of metabolism depends on their genetic endowment: whether they carry the wild type allele or the mutated allele. If they have two wild type alleles, they metabolize rapidly, while if they have one wild type and one mutation they metabolize more slowly. If they have two mutations, then they metabolize poorly. This genetic polymorphism can already be measured, but the laboratory procedures are too cumbersome and costly for routine use. When and if the genetic fingerprinting of point mutations is routinely done for everyone, however, we will have molecular explanations as to why a person may not be responding to a given drug. In fact, a psychiatrist can know in advance that a person is a slow or rapid metabolizer and prescribe a dose of medication based on scientific knowledge rather than trial and error, no longer delaying recovery because the dose was too high or too low...


...The precise manner in which identification and early intervention are implemented will vary depending on the particular illness. As we define the multiple genes that lead to the various illnesses that we now call bipolar mood disorder, panic disorder, major depression, schizophrenia, or Alzheimer’s disease, we will achieve increasingly precise information about the extent to which each individual carries alleles that predispose to or protect against particular mental illnesses. Psychiatrists and other clinical and basic neuroscientists may work together to identify and promote basic public health programs for those who carry disease alleles...

Another strategy for arresting an illness before it becomes fully manifest is to use prophylactic medications that prevent its occurrence. However, no true prophylactic drug is as yet available for any mental illness, although this strategy is currently widely discussed. A few relatively controversial experimental studies have used standard neuroleptic medications for schizophrenia in predisposed young people and reported hopeful results. This effort is hampered, however, by two serious concerns. First, at present we do not have optimal tools for identifying high risk individuals, since the predisposing alleles and the related non-genetic factors have not yet been mapped in detail. Second, the pharmacologic treatments used to intervene are also relatively crude, since they were designed primarily to work on symptoms rather than to do pinpoint bombing of abnormal processes that occur earlier in the gene to mind/brain cascade. Therefore, they may not work effectively in actually preventing the onset of the illness.

As improved treatments with minimal risk and a more focused emphasis on basic disease mechanisms are developed, however, such early interventions may become routine, particularly when and if they can be coupled with precise identification of vulnerable individuals. Use of this strategy may be close for one mental illness. If a drug can be found that prevents beta amyloid protein build-up, and if it does not have serious side-effects on other aspects of brain function or other organs within the body, then it might be used both to treat the symptoms of Alzheimer’s disease and to prevent amyloid build-up in predisposed individuals.

Ultimately, we would like to prevent mental illnesses by identifying the mechanisms that cause them. This approach is, in effect, “total prevention,” equivalent to developing a vaccine for polio or preventing malaria through the use of quinine. As these examples illustrate, so far this strategy has worked best for infectious diseases. Many feel that other biomedical illnesses, including those that affect the mind and brain, are too complex and multifactorial in their causes and are therefore likely to be forever refractory to total preventive measures.

Prevention may be possible for mental illnesses, however. Some, for example, such as Huntington’s disease, Alzheimer’s disease, and schizophrenia are disorders in which the brain is apparently normal prior to onset of illness. In all three cases, these illnesses may have dormant seeds in place that only sprout when the appropriate climatic conditions occur in a particular season of life. Because it is a fully penetrant single gene disease, Huntington’s disease may be the “easiest” to prevent, although even it still has eluded our grasp. However, people with Huntington’s disease are essentially well and normal for many years, and therefore blocking the effect of the Huntington’s gene should permit us to figure out a way to prevent its expression. The key is to figure out what the gene actually does (i.e., its gene product and the effect of that product on brain development and degeneration). Schizophrenia and Alzheimer’s disease are “less genetic,” and very likely polygenic as well. This may not matter, however, if these diseases have a single common mechanism produced by multiple genes—whatever produces the plaques and tangles of Alzheimer’s disease, or whatever produces the faulty wiring of schizophrenia. In these illnesses as well, the goal is to find the mechanism and to arrest it—perhaps by vaccinating with beta amyloid protein, as has already been done for Alzheimer’s disease.




As biomedical tools grow more powerful, both scientists and private individuals will confront new and difficult choices. Great knowledge bestows great responsibility. Although we cannot anticipate all the risks and perils of our growing ability to modify human life as we seek to conquer human disease, we are obligated to ponder the ramifications of our new powers and to insure that [in the words of Albert Einstein] they will be “a blessing and not a curse to mankind.” We do not want to create Huxley’s brave new world, in which we “predestine and condition,” or in which “we decant our babies as socialized human beings, as Alphas and Epsilons...” Instead, heeding Einstein’s cautionary warning, we must do all we can to insure that “concern for man himself and his fate will be the chief interest of our endeavors.”


Only a few years ago, our primary worry about the misuse of genetic information was based on the recognition that some mental illnesses run in families. Because Uncle Will had schizophrenia or Mom suffered from manic-depressive illness, other family members worried that they might either develop these illnesses themselves or pass them on to their children. In many parts of the world, ill relatives are still treated like skeletons in the family closet, because of fears of a “hereditary taint.” Children from these families may be seen as unworthy candidates for marriage and childbearing.

The technology of modern genetics far surpasses these old style observations of transmitted hereditary taints in its potential for both use and abuse. As a multiplicity of disease genes and alleles are mapped, and as “snip and chip” technology becomes faster and more efficient, we can imagine many ways in which too much knowledge may be dangerous. Genetic fingerprints could eventually be created relatively easily. Who will decide when and if such fingerprints should be created? Who will have access to them? 

The potential perils of genetic fingerprinting make our concerns about misuse of credit card information, banking records, or social security numbers look like child’s play. Such records simply indicate what we have done. A genetic fingerprint indicates what we are.

The potential perils of genetic fingerprinting make our concerns about misuse of credit card information, banking records, or social security numbers look like child’s play. Such records simply indicate what we have done. A genetic fingerprint indicates what we are.

Many frightening scenarios can be imagined. Employers, medical school or law school admission committees, or the military could require that we be genetically fingerprinted as a condition for hiring, admission, or acceptance. Despite strenuous efforts to maintain confidentiality and accuracy, some records are virtually certain to be lost, swapped, or leaked. The health insurance industry could band together and require that all applicants be genetically fingerprinted prior to being insured, with the possibility that coverage might be denied if a person tests positive for some specified diseases, which might include mental illnesses. (Parity in the coverage of treatments for mental illness is still far from a reality in the United States and most of the rest of the world.)...

Fortunately, we are wise enough to anticipate these many risks. By the time meaningful and accurate genetic fingerprints become a reality, reasonable regulations will almost certainly be developed that will protect individual privacy and prevent the misuse of such information. The guiding principles are likely to be that the information will be kept strictly private, accessible only to physicians and to patients who wish to have the information. Obtaining unauthorized access to genetic information is likely to become a serious criminal offense.

Not that life will be easy, even with such safeguards in place. The possibility of having so much knowledge about our vulnerabilities to disease places a great burden on all of us. Even the simplest of cases is difficult. For example, right now any person from a family with Huntington’s disease can determine whether her or she carries the abnormal gene. This information is very useful, since those who test negative know in advance that they are free from worry, and they can marry and have children without a concern about passing the trait onto their offspring. Those who test positive, however, know they face a grim future and may find the remainder of their healthy lives clouded by their ominous sense of foreboding.

Many intelligent people may decide they do not want to know their future, just as they may not want to know the sex of a future child when they have the opportunity. Nancy Wexler, one of the scientists involved in the discovery of the Huntington’s gene and a potential carrier, chose not to know for many years. Since most genes are not fully penetrant like the Huntington’s gene, and since most illnesses are polygenic and multifactorial, having information about the presence of a disease allele could be more harmful than helpful for some people. Worrywarts may walk under a sky filled with thunderclouds for the remainder of their life, not recognizing that there are many pockets of sunshine as well...

How much can we, and should we, tinker with our genes and our other worn out and damaged body parts?... If DNA is the “blueprint of life,” who has the right to play God by altering it? 


...How much can we, and should we, tinker with our genes and our other worn out and damaged body parts? As with genetic fingerprinting, we have many concerns. If DNA is the “blueprint of life,” who has the right to play God by altering it? What guidelines can make such alterations permissible? Apart from actual gene transplants, what about the use of genetic knowledge to alter the gene pool in more subtle ways? How can we avoid the Huxleyan dystopia in which our knowledge of how to produce “better strains” of human beings could slowly slide down a slippery slope into a society composed of Alphas (who have the knowledge and wealth to use the new technology) and Epsilons (who lack these assets)? Although we have become comfortable with adults donating their organs or sperm for transplants or artificial insemination, how do we feel about the use of fetal tissue to replace diseased or missing cells in debilitating disorders such as Parkinson’s disease?

We have many questions and fewer answers in this youthful era of the genome. In recognition of the problematic issues, an impartial Panel of Wise Men and Women, officially known as ELSI (Ethical, Legal, and Social Implications branch) was created under the auspices of the Human Genome Project, under the leadership of Nancy Wexler. They have made it clear that they will be guided by “concern for man himself and his fate” as they struggle to establish fair and reasonable guidelines that will govern the use of genetic engineering and the other ethical dilemmas that the new knowledge will create. The functions of this original committee (now disbanded) have now been dispersed through the various multiple components of the project, so that ongoing careful surveillance of all aspects will occur...


Aldous Huxley’s prescient vision of a “brave new world” not only included genetic engineering, testing, and determinism, but it also portrayed a world in which mind-altering drugs were used for both control and self-indulgence. Is Huxley’s description of a mind-altering drug, “soma,” a prophetic forewarning of modern somatic therapies and their potential for misuse or abuse? Peter Kramer’s widely read book, Listening to Prozac, also raised the possibility that in some cases our present ability to create more and better medications to treat the mind may be simply a form of cosmetic surgery, not a medical necessity. 

We do not expect people to have surgery without anesthesia, to be left to die after they experience a cardiac arrest, or to limp around on an unset broken leg. It would be strange indeed to apply a different standard to mental illnesses.

In most instances, the psychoactive drugs available in our armamentarium are valued assets. We need more medications and better ones, not fewer. To think otherwise is to revert to the old tradition of stigmatizing mental illnesses and seeing them as moral failures caused by weakness of will or bad parenting. We should be grateful (and most of us are) that we do have medication that can “change minds.” It is a blessing that we can lift depression that might otherwise drive a person to suicide, reduce disabling panic attacks that interfere with daily function, or quiet the anguished thoughts and perceptions of schizophrenia or mania. We all believe that doctors have a moral obligation to reduce or relieve suffering. We do not expect people to have surgery without anesthesia, to be left to die after they experience a cardiac arrest, or to limp around on an unset broken leg. It would be strange indeed to apply a different standard to mental illnesses such as dementia, schizophrenia, mood disorders, or anxiety disorders.

Yet a nagging concern may remain in many people’s minds. In some cases, are psychoactive medications used when they are not necessary and when a problem can be handled more appropriately in some other way? Some psychiatric disorders such as depression or attention-deficit/hyperactivity disorder (ADHD) are diagnosed more frequently now than in the past, and psychoactive medications are often used to treat them. Are the medications being overused? Is this a form of “cosmetic surgery for the mind?”

This concern tends to arise for those disorders that have a continuum of severity. When such disorders are severe, there is usually no question that they represent an illness and little question about the need for medication. When the problem is milder, however, the situation is more complicated. When is an energetic and rambunctious child just too active and inquisitive? When is a period of sadness so severe that it becomes an illness best treated with medication? And when should treatment move from good behavioral management or psychotherapy to medication?...


...Surveying the current psychiatric landscape with a jaundiced eye, one might observe that three forces converged on psychiatry at the same time like a wave of barbarian invaders. They ransacked its humanistic aspects and left a desolate landscape behind. A more sanguine view is that some of these changes have been good, that much humanism remains, and that we must work to preserve it.

A book that I wrote in 1983, The Broken Brain: The Biological Revolution in Psychiatry... predicted a major paradigm shift: America in the 1980s, the balance between these points of view has begun to shift. The emphasis is swinging, and swinging quite strongly, toward a biological model.

As The Broken Brain argued, the shift to a biological model occurred for many good reasons: the growth of a strong scientific base in neurobiology, the development of new and effective pharmacologic treatments, the value of reducing stigma by understanding mental illnesses within a medical framework as diseases of the brain, and the growing body of evidence that demonstrated brain changes and abnormalities in a variety of mental illnesses. As predicted, the biological model now prevails in most of psychiatry, and this shift has produced many benefits. The stigma against mental illness has decreased and we have made enormous strides in understanding the neural basis of diseases of the mind. However, I now share with many the concern that psychiatry may have moved too far, and that it must make corrective adjustments to prevent losing its identity as the most humanistic of the medical specialities. After all, modern neuroscience also teaches us that the brain is plastic and that it can also be changed by psychotherapy...and should be.

An emphasis on empirical observation, coupled with the development of objective criteria for making diagnoses, also occurred at the same time. DSM III was published in 1980, and it had a major impact on psychiatric education and clinical practice over the ensuing decade. Again, introducing standardized approaches to diagnosis and assessment had many advantages... Essentially, psychiatry embraced a fundamental tenet of modern medicine: the importance of an evidence-based approach to diagnosis and treatment. This has been a significant achievement that has placed psychiatry on a sound clinical foundation. But again, it is time for reassessment and readjustment, particularly in the area of psychiatric education. In addition to learning and using diagnostic criteria, young psychiatrists must be taught to think first about the whole person and to appreciate that each one is interesting and unique...not simply a composite of symptoms that are used to make a DSM diagnosis and provide treatment according to using a standard algorithm, making the erroneous assumption that “one size fits all.”

The third force, the economic revolution in the provision of health care in the United States, also began in the 1980s and has had its greatest impact in the 1990s. Its impact on psychiatry has been especially bad, since the economic revolution follows principles that are unabashedly non-humanistic. Spending time talking to patients...or listening to an expensive luxury, to be avoided whenever possible. Talking, and especially listening, are central to good psychiatric evaluation, and they form the basis for most psychotherapy.

The economic revolution has dramatically changed the philosophical framework that guides medicine. Essentially, medical care in general is now perceived and discussed primarily in economic terms, often to the dismay of both physicians and patients. The provision of medical care is now referred to as “health care industry.” Doctors are “providers,” and patients are “consumers” or “clients.” Large managed care organizations and health maintenance organizations (HMOs) formed during the 1980s, and they are now a powerful and even dominant force in American medicine. 

The principle that the health and welfare of each patient should come first has been replaced by the dictum that saving money and increasing the profits on the health company’s bottom line should come first.

This third force has changed the social contract between patient and doctor, which historically has been guided by the humanitarian principles of the Hippocratic oath, to an economic contract that is guided by the principles of free market competition. The principle that the health and welfare of each patient should come first has been replaced by the dictum that saving money and increasing the profits on the health company’s bottom line should come first. Only too frequently, key decisions about patient care have been taken out of the doctors’ hands and placed in the hands of “health care managers,” who have minimal medical training and no direct experience in confronting human suffering. Yet, health care managers may decide how long a doctor can see a patient, what medications she can prescribe, whether she can provide psychotherapy in addition to medications, how frequently the patient can be seen, and even the amount of information that can be included in a medical record. Many psychiatrists are being told that obtaining a comprehensive patient history, which includes personal information about family and social relationships and personal interests—those things that make the patient a unique individual—is a waste of time. Instead, the psychiatric history may consist only of a symptom checklist that is entered into a computer and serves as a basis for making a DSM diagnosis. Most managed care organizations and HMOs do not wish psychiatrists to do psychotherapy. They are considered to be “costly providers,” whose time would be better spent just writing prescriptions.

In my experience, the majority of psychiatrists are discouraged and demoralized by these changes...

There is no “easy fix” for the overemphasis on economics mandated by changes in our healthcare delivery system. The changes in education and training created through an over-emphasis on DSM are the responsibility of psychiatry. They should and will be addressed by its governing boards and organizations, such as the American Psychiatric Association and the American Board of Psychiatry and Neurology. The economic revolution, and to a lesser extent excessive DSMism, have had a far greater impact on dehumanizing psychiatry than the biological revolution or the growth of biomedical technology.

To create a polarity between science and humanism is a false dichotomy. The purpose of science is to advance knowledge, and knowledge can be used in turn to promote the health and welfare of human beings.

Psychiatry is, and should remain, the most humanistic of the medical specialties. To create a polarity between science and humanism is a false dichotomy. The purpose of science is to advance knowledge, and knowledge can be used in turn to promote the health and welfare of human beings. The growth of biomedical technology in the era of the genome will give us unparalleled opportunities to reduce suffering by providing better diagnoses, better counseling, and better medications. If we live up to the opportunities that are our potential, the result will be a substantial improvement in the human condition by reducing the burden of mental illnesses throughout the world....


During recent decades one major social problem, the stigmatization of mental illness, has been successfully addressed. Although patients and families have taken the lead in creating this social change, psychiatrists have stood beside them and fought hard as well.

Thirty years ago almost all mental illnesses were skeletons in the closet. A person diagnosed with depression would skulk guiltily into the pharmacy to pick up his prescription for one of the new antidepressant medications, barely willing to look the pharmacist in the eye. As recently as 1972, George McGovern’s running mate candidate for the vice presidency, Tom Eagleton of Missouri, had to withdraw when the public and press learned that he had been treated for depression. Yet if we disqualified earlier candidates because of the mental illness, we would never have had Teddy Roosevelt or Abraham Lincoln as presidents. Both also suffered from mood disorders...

...[M]any prominent public figures have “opened the closet” and discussed their experiences with mental illnesses or those of their families. Examples include Ronald Reagan, Mike Wallace, Dick Cavett, William Styron, and Rod Steiger. Tipper Gore has described how psychotherapy helped her cope with the trauma of their son’s serious injury...Hollywood and the film industry, which gave a negative tint to public perception with films such as Snakepit or One Flew over the Cuckoo’s Nest, have introduced a positive spin with powerful and sympathetic films such as Rainman and Shine. Thirty years ago these subjects would have been dismissed with a “Who cares about autism?” or “No one wants to learn about schizophrenia.” Now films about the mentally ill win academy awards.

The battle to improve public understanding and to reduce stigmatization of mental illnesses has made great progress. With the help of the “biological revolution,” we have advanced beyond the misconception that mental illness results from a defect in a person’s character and can be cured simply by “shaping up.” We now recognize mental illnesses as biomedical diseases similar to heart disease or cancer. By and large, we have gotten past the vicious cycle of inappropriate blaming and failure to diagnose and treat with appropriate medications, which prevailed 30 years ago. Should we do more? In particular, should psychiatrists do more?

At its best, psychiatry is a humanistic specialty. Because they care about people, psychiatrists often want to reach out and help as much as they can. Sometimes this has led psychiatrists to want to assume the role of helping more than individual patients. They would like to help society as a whole.

To aspire to this may, however, be aspiring to too much. Psychiatrists can help, but they must also recognize the limits of their power. The role of psychiatry in society certainly includes public education and the battle against misunderstanding. Psychiatrists also chip away modest fragments of collective social suffering by helping the individual people whom they see. However, psychiatry must recognize that its role is to treat diseases, not the social discontent of “unhappy people” or pervasive psychosocial malaise. We simply lack the knowledge to cure society as well as individuals...

The answer to our many current social problems must come from the individual people, who must reappraise their sense of “self” and reach an appropriate perspective on what constitutes a sound moral compass and meaning in life. The need to search for a personal moral compass to guide our individual lives in the twenty-first century is a need that transcends medical intervention, but which has a very real impact on how we choose to employ medical science and what we expect from it. In the era of the genome, fraught as it is with a variety of crucial moral questions, we must all make an agonizing reappraisal of who we are, what life is, what life means, what we must do to help the other human beings who share our world with us, and what we can do to make it a brave new world.  

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
Charles Zorumski, M.D., Washington University School of Medicine

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