11. PSYCHIATRIC ILLNESSES AND PSYCHOPHARMACOLOGY

LEWIS L. JUDD, MD

Lewis Judd is a psychiatrist whose research has focused on psychopharmacology: the effects of drugs on the brain. At the time of this conference he was the director of the National Institute for Mental Health (NIMH), the primary federal agency concerned with the study of mental illnesses and providing leadership for the treatment of the mentally ill.

He presents an overview here of recent developments in his field: the growing understanding of mental illnesses as biomedical disorders, the importance of noninvasive imaging techniques and pharmacology to this understanding, and the impact of a systematic classification of mental illnesses for diagnostic purposes and treatment.

LEWIS JUDD: What I would like to do today is to give you a feeling for how our concept of mental illness has developed, in this country and in the West more generally, a concept which has been undergoing considerable change during the last twenty-five years. I also want to give you a sense of our current ideas about this field. I shall be very interested to learn from your side what commonalities might be shared with Tibetan medicine, which is so richly interwoven with Tibetan Buddhism.

The reason that we in the West have been undergoing a considerable shift in our understanding of mental illness is because of some of the very things that you have been exposed to during the last day and a half. The growth in brain sciences has had an important impact on our understanding of mental illness. There has been an increasing trend within the field of mental illness to begin defining distinct entities of mental illness and their specific characteristics. In addition, as an outgrowth from some of the brain sciences, there has been a virtual explosion of information coming from the very important branch of pharmacology known as “psychopharmacology,” which is the study of the effects of medications on brain and mental functions. Another important recent influence is the growing understanding of the role of genetics as a causal factor in mental disorders.

Currently we see mental disorders very much the way we view medical illnesses. That is, mental illnesses are essentially biomedical disorders that stem primarily from abnormal functions of the brain. We are now convinced that mental illness in its seemingly infinite variety is made up of a series of highly discrete disorders that have their own characteristics, their own symptoms and signs, such that they can be recognized and diagnosed as independent entities with specific treatments. Further, we now are convinced that a number of the most significant and severe mental disorders are controlled, at least in part, by genetic inheritance. I will touch on each of these topics briefly and present some evidence as to how we have come to this current concept of mental disorders.

The neurosciences are obviously a relatively new branch of science, coming into full fruition in the last thirty years. To give you an idea of how fast this area of science is growing, the Society for Neuroscience started in this country in the early 1970s with 200 scientists. There are now over 15,000, and we have another 15,000 in training, supported by funds from the National Institute for Mental Health and other institutes in the federal government. Neuroscientific research is a major enterprise in this country, and it is growing in other Western countries. In fact, it is about to receive a major boost in the United States because within the last two months the Congress, both the House of Representatives and the Senate, passed a Joint Resolution to declare 1990 as beginning the “Decade of the Brain.” This is to launch a major national science effort to demystify through research what is certainly our most mysterious and complex organ system, our brain. This national endeavor will be the equivalent, we hope, of going to the moon, but in this context, we shall be examining inner space.

Growth of knowledge in the field of neuroscience has been phenomenal. Our staff at the institute did a survey within the last six months in which we found that 90 percent of what we now know about the brain has been published within the last ten years. So we are on an accelerating curve of discovery with respect to mind/brain problems. As new findings have emerged, they have had a powerful impact on our understanding of mental illnesses, and on our understanding of mental disorders. Right now we are seeing that brain dysfunctions usually lie at the core of mental disorders. Much as someone with cardiac failure has a diseased cardiovascular system, or someone with insulin-dependent diabetes has a diseased pancreas, people with mental disorders have dysfunctional brain structures.

Thus, we are conceptualizing mental illness in ways very similar to those described by Dr. Damasio when he pointed out to you yesterday how highly specific insults to the brain create very discrete deficits in the way people perceive, memorize, and think. Except that the brain lesions of the mentally ill are often not so discrete or delimited. They are more diffuse in nature, often spread throughout a wide variety of structures, and still very elusive. Yet we believe that we are beginning to find definite evidence of relevant disorders present in the brain.

NONINVASIVE IMAGING: A WINDOW ON THE BRAIN

One of the technical developments that has helped us enormously has been the new capacity within the last decade to get detailed pictures of the internal structures of the brain in living patients, without doing them the least harm. This gives us windows on the functioning brain and constitutes a major step forward. We had been held back in our understanding of mental disorders for centuries, because we could not readily get detailed information on brain function and structure that was sufficiently sophisticated and detailed to address the kinds of functional abnormalities we encounter with mental disorders.

Dr. Judd illustrated his point with a series of magnetic resonance image (MRI) scans. The first was from a study of identical twins then being conducted at the National Institute of Mental Health. The study compared the brains of pairs of identical twins, in which only one member of the pair was schizophrenic. He noted that, in terms of genetic inheritance, identical twins share about 85 percent of the same chromosomal material. The scan showed that in the twin afflicted with schizophrenia there was some loss of neuronal mass which had been filled in with cerebrospinal fluid from the ventricles.

LEWIS JUDD: Another MRI scan relates to a very severe disorder of children called autism. As a clinical syndrome, autism has been recognized since the 1940s. Originally it was attributed to cold, unemotional parenting. We have now discovered, using imaging techniques which have recently become available, that in autistic children there may be a lag in development of the cerebellum. This suggests that we are dealing not with a problem of poor parenting but with a severe developmental delay or arrest in this particular brain structure.

Autistic children have very late development of language, and sometimes they never develop language capabilities. They are often severely retarded intellectually. They do not relate well to the human social environment. The diagnosis of autism designates a child who is independent and aloof, not interacting with his human environment, not even with his parents and people the child knows well. An autistic child tends to be fascinated with things, with mechanical devices.

DALAI LAMA: Is it possible to recover from this structural defect, to create normal functions?

LEWIS JUDD: In autistic children it is not. There may be some later structural development of the cerebellum, but that is accompanied by minimal changes in the child’s outlook and behavior. With medication, we can control certain behaviors of the child, such as self-destructiveness, but there is very little that can be done to rehabilitate the child in a comprehensive way.

I shall give you another example of how imaging techniques help us look at mental illnesses for which we previously had no evidence for abnormal brain structure or function. Using composite pictures of the brain obtained during dynamic changes in its function, we can show changes in blood flow from one part of the brain to another, indirect evidence of changes in biochemical or metabolic action. Nerve cells in the brain take in primarily the simple sugar glucose, oxygen, and, in lesser amounts, amino acids. In this particular study done at the NIMH, we are measuring the actual shift in blood flow from one part of the brain to another in a group of normal individuals compared with a group of schizophrenic patients.

Schizophrenia is a profound disorder of the brain that results in severe problems of thinking and cognition. Schizophrenic patients suffer from incoherent thinking. Individuals may have delusions, which are stable, false beliefs that they hold despite evidence to the contrary. They may also have hallucinations: they may hear voices, see things, or smell things that are not present. They often have a very difficult time adapting and living in the world. Frequently, they cannot take care of themselves. They may experience a profound absence of feelings and emotions, or their feelings and emotions may be quite inappropriate. Things they say may not be accompanied by appropriate expressions of feeling. They might, for example, describe something very horrible and sad, yet laugh as they do so. Their speech, behavior, mood, and feeling states may be quite disparate and incongruent. Schizophrenia is the most severe mental disorder that humans experience. It is most often a progressive disorder, the course slowly increasing downhill throughout the lifetime of the individual. They may end up being very, very disabled after a few years.

The brain scans show that while resting, the brains of normal subjects and schizophrenics look very much alike. But they differ considerably when we ask each individual to perform a specific task that requires an ability to abstract, an ability to solve problems, and an ability to remember. In the brains of normal individuals the prefrontal cortex “lights up,” indicating that there has been a major influx of blood into that particular region. This shift of blood flow arises from the need to support increased neuronal activities required to carry out those challenging thinking processes.

In the schizophrenic patients, however, there is essentially no change in blood flow to that region. This quantitative information about regional blood flow allows us to focus on a specific region of the brain of schizophrenics that appears to be highly dysfunctional.

That is just an example. There are hundreds of studies of this nature that have established, we believe irrefutably, that the seat of the schizophrenic problem, and many other major mental disorders, resides in the brain.

CLASSIFYING MENTAL ILLNESSES

Another major step in clinical research that has been advanced in part by findings in the neurosciences has been the attempt to develop a detailed, accurate classification system, based upon empirical observations and accurate diagnostic criteria, to differentiate each of the many discrete expressions of mental disorders. This thick bookcontains detailed descriptions of mental disorders as conceptualized in the West, along with the various clinical characteristics, signs, and symptoms that one must identify in order to make a specific diagnosis of one type of mental disorder or another.

Mental disorders are discrete. In pure form, they do not closely resemble one another. They differ systematically and manifest their own identifying characteristics. For example, here is a description of major depression. Perhaps the second most common group of mental disorders is what we call “mood disorders,” of which the most important one is major depression. Let us suppose that a clinician who is well trained sees someone who tells him or her, “I am profoundly sad, blue, and dysphoric. I have been so for several weeks. It doesn’t change. I have problems in sleeping. I go to sleep, but I wake up every morning at two or three o’clock, and can’t get back to sleep. I have lost my appetite. I have lost considerable weight, up to, say, 15 percent of my normal weight. I am unable to think and concentrate at the level that I used to. It is a problem every day. I have low energy. I can’t accomplish anything. I am besieged with thoughts of death and dying and suicide.”

The clinician knows almost immediately that, according to this accumulated cluster of symptoms, this individual suffers from major depression. This classification system helps him to confirm that diagnosis, and it tells him, in addition, once the diagnosis is made, what means he has by which to respond. This disorder, like so many other mental disorders, won’t go away rapidly by itself. Major depression, if untreated, lasts about nine or ten months. If major depression is treated appropriately, the physician can usually bring relief rather quickly. So this diagnostic codification has made, we believe, a major contribution to our understanding and ability to respond to a spectrum of mental disorders.

Because of the accuracy of classification, and because we can thereby better train people to diagnose accurately and recognize various mental disorders, three years ago the NIMH conducted a major national survey of mental disorders existing in the U.S. population. We examined door-to-door a sample of adults in all age brackets, representative of both urban and rural areas. A total of 18,000 persons participated in specific research-structured diagnostic interviews. What we found was something that I think those of us who are clinicians already knew. Mental disorders, rather than being rare diseases, are very common, perhaps the most common category of diseases that mankind experiences. We found that between 12 and 13 percent of those interviewed had already experienced some recognizable mental disorder. They were, or had been, or should have been patients. So the scope of mental disorders in the United States has now been estimated quantitatively for the first time. Since this was a household survey, it defines a major public health problem.

DALAI LAMA: I am impressed by the numbers. The percentage seems quite high. Perhaps I should have been included in that survey!

LEWIS JUDD: One in ten, approximately. Moreover, we found that in terms of projecting lifetime risks, that percentage actually rises to 20 percent. That indicates that one in five persons, at least in the United States, will have a serious, diagnosable, and treatable mental disorder some time during their lifetime. These are serious, common mental disorders that are of major public health importance. We are beginning to move forward to address that problem full scale.

ADVANCES IN PSYCHOPHARMACOLOGY

In addition, paralleling this advance, there have been developments in the field of psychopharmacology, which is my area of research. It involves attempting to find medications that can help treat and improve mental conditions. For example, we now have available in the West more than thirty medications that are effective antidepressants, useful in treating people. This spectrum of medications is so broad, effective, and fundamentally sophisticated, that we can now manage to treat effectively 85 percent of all depressive disorders that gain the attention of trained clinicians.

DALAI LAMA: In the case of people who are depressed, are there not occasionally valid reasons why they are depressed, as when they reflect on certain tragedies and misfortunes, whether true or untrue? If as a result of their reflections or for some other reason, they get depressed, would this medication really help to reduce their depression?

LEWIS JUDD: First of all, antidepressants don’t treat unhappiness. Antidepressants are highly specific to correct major depression, the syndrome I described that, in our view, is a clinically significant depressive disorder with a variety of well-defined characteristics.

DALAI LAMA: Isn’t it possible that a mental affliction clinically identified as depression could arise from sustained thinking on some unfortunate circumstance? Doesn’t that happen?

LEWIS JUDD: Absolutely, but it doesn’t matter. We are looking at a continuum of biological vulnerabilities. We believe that virtually anybody can develop a major clinical depression. We know, or at least strongly suspect, that some people who develop depressive disorders inherit a genetic vulnerability to do so. In these susceptible cases, it doesn’t take much provocation in the environment to trigger a major depression. There are others who don’t have that vulnerability, who almost seem almost immune to depression. They may be exposed to all kinds of terrible things without becoming depressed, but still they can become depressed if there is an enormous accumulation of untoward, unprecedented, or tragic events in their lives.

What we are finding is that once you develop a clinical manifestation of a major depression, it doesn’t matter much what has caused it. Once a person becomes depressed, then that condition needs to be treated specifically or it will persist for nine or ten months, or longer.

DALAI LAMA: Does major depression arise initially from some external cause that brings about a harmful change in the brain, leading to the symptoms, or, alternatively, is the original cause found in the brain and the illness is just triggered by something from the environment?

LEWIS JUDD: There probably is room in the model for both types. However, conceptually, I think we are looking at this as a genetic/environmental interaction. Let us suppose that someone has a very, very high genetic propensity for developing depression. It may look as though the depression is being triggered from within, independent of what is happening in their environment. However, if you go back and look carefully at what happened to the person just before he or she began to show symptoms, you can always find some type of an “assault,” perhaps subtle things, that may have triggered the depression. Because that person’s threshold for developing depression is so low, it doesn’t take much. So I would say, it takes two to tango—a genetic vulnerability and an environmental stressor. Major depression is a complex interaction between one’s inherited constitutional givens and environmental events that elaborate and precipitate manifestations of the depressive disorder.

ROBERT LIVINGSTON: Lew, if I understood you correctly, you said you had something like thirty different kinds of medications that are helpful in coping with this syndrome of depression.

LEWIS JUDD: That’s correct. There have really been almost three generations of antidepressants developed. Each of these generations has been more sophisticated and specific than the others. So, as I say, we can now manage about 85 percent of all depressive disorders. Certainly, in this country, you need not suffer long from a depressive disorder. We can absolutely manage this problem for the vast majority of cases.

LARRY SQUIRE: It might help to clarify to what extent Western science says that the drug is the treatment of choice, as opposed to improved understanding as the form of treatment.

LEWIS JUDD: First of all, I have been talking this far exclusively about medications that help specific disorders. But many medications are given to patients as a part of an interactive healing relationship between physician and patient. Any dispensing of medications has to be couched as part of a credible and caring transactional education about the illness from the patient to the physician and from the physician to the patient. Also, for some cases of depression, it is appropriate that we apply certain forms of psychotherapy that have been designed specifically to deal with individuals who have depressive disorders.

We are finding that if you give a patient with severe major depression psychotherapy only, it is often not very effective. But, psychotherapy can be very helpful for less severely ill patients with clinical depression. If you give medications only to severely depressed patients, it will help more than 60 percent of such patients. But, if you combine psychotherapy of a specific nature with the dispensing of appropriate medication, you raise that rate of relief even further. This is evidence that there may be a synergistic effect between psychopharmacology and specific forms of psychotherapy.

At present, we are convinced that this should not be an either/or therapeutic approach: either an appropriate medication or an appropriate kind of psychotherapeutic/educational transaction. Therapy often works best when these are combined. Certainly there is a tendency in this disorder for symptom recurrence. A high proportion of those who develop a depression will have at least one other depression. With patients who suffer repeated recurrences of depression, psychotherapy during the interval when symptoms are in abeyance will reduce the likelihood of further recurrence.

DALAI LAMA: Is continuing the medication by itself not helpful for lowering the repeat rate?

LEWIS JUDD: Medication maintained at the appropriate dose level is also very helpful. But, in addition, patients can be educated to avoid certain kinds of circumstances that are especially problematic for them or to manage such circumstances better so that they don’t find themselves being stressed and psychologically assaulted in ways that may bring on depression.

DALAI LAMA: Of the two causes—physical disorder of the brain and exposure to distressing circumstances—which tends to be the initial cause? Is thinking about tragic circumstances the dominant cause?

LEWIS JUDD: Yes, it might be so. I think our experience indicates that depressive disorders can be created and sustained and potentially prevented by means of influential techniques that might be applied with respect to managing one’s environment.

DALAI LAMA: Leaving aside the question of moral and ethical values, have there been cases where someone has had one brain image taken at the initial onset of depression and another at a later time without receiving medications? Has it been possible to observe brain changes while the depression is developing?

LEWIS JUDD: That has at this point not been done.

DALAI LAMA: You can do this with animals?

LEWIS JUDD: There are models for depression in animals that are experimentally manipulated. The best one that we use right now, which we think is analogous to depression in humans, is called “learned helplessness.” You put the animal into a situation where basically it can’t win, and then soon the animal gives up and looks very lethargic, as if it were depressed. We have studied the brain chemistry of animals in such states and found some highly specific things. However, it is not clear whether this is exactly equivalent to a depressive disorder in humans

THE GENETIC INHERITANCE OF MENTAL ILLNESS

Let me now present an example of a disorder that appears to be more regulated by inheritance than necessarily by environmental interaction. There is a very serious disease that has, according to virtually every study that’s been done in other cultures and in other countries, a prevalence rate that is almost identical with what we are finding in the United States. Even though no other country has done the extensive epidemiological study that we have done nationally, the fact is that smaller studies elsewhere provide data that are very similar.

The disorder I’m talking about is manic-depressive illness, which attacks around 1 to 2 percent of the adult population. In the United States there are probably two and half million people with manic-depressive disorder. These are individuals for whom it runs in their family. There are very clear genetic factors in this disorder.

People with manic-depressive illness experience intense periods of depression, lasting anywhere from six to eight months, followed by a period of symptom quiescence, and then maybe a period of what we call manic behavior, which is the opposite of depression. This involves an intense agitated elation, euphoria, grandiosity, irritability, lack of need for sleep, boundless energy, and very poor social judgment.

These manic-depressive individuals have an average of five to eight episodes lasting from six to nine months each time throughout their lifetime. Sometimes they may have as many as fifty to sixty episodes in total. These episodes appear to attack people almost out of the blue. Once initiated, symptoms appear to be locked in, lasting for a roughly predictable period of time.

We have discovered a medication that is highly specific for this disorder: lithium, one of the trace elements found in the human body. Now, if you trace the natural course of the manic-depressive disorder in a patient before and after they have undertaken a course of lithium treatment, there is a phenomenal difference. Before we had lithium, manic-depressive patients spent approximately 25 percent of their adult lives in hospitals. They spent an additional 25 percent of their lives going into and coming out of those episodes. So it cost them roughly half their adult lives. Lithium was introduced as a medication in this country relatively recently, being approved by the Food and Drug Administration in 1969. We have calculated that the introduction of that one drug alone, in this country has saved $39 billion in costs over the last twenty years: $12 billion in elimination of the need for hospitalization, and $27 billion in recovered productivity among individuals who were previously highly disordered and disabled and who are now living very productive lives. What we have discovered through studies on manic-depressive psychosis is a tight linkage—for the first time—between a highly specific diagnosis, a specific medication, and a predictable clinical benefit.

One of the most exciting areas of genetics has been discovered from population genetics and family pedigree studies, for example, from twin studies. This relates to both manic-depressive illness and to schizophrenia, both being mental disorders that run in families. If one identical twin has schizophrenia, the likelihood of the other twin having schizophrenia is about 35 to 45 percent. It is at least thirty-five times more likely to occur in the twin of a person who has schizophrenia than it would in the normal population, so there is a strong genetic preponderance.

We have been looking for families in which there is a genetic concentration of disorders. We are beginning to develop family pedigrees to track the offspring of parents with schizophrenia. In one family, for example, where one of the parents had schizophrenia, among their eleven offspring there were five with schizophrenia. Among their grandchildren, there were two. We are now on the lookout for families of this kind, to study their genetics, to analyze their chromosomes, and to find out whether we can identify the location of the chromosomes that are potentially responsible for at least a predisposition to these illnesses.

DALAI LAMA: In terms of hereditary diseases, if the illness is on the father’s side, is there evidence that the boy or the girl from the family will be more likely to inherit that disease?

LEWIS JUDD: It depends on whether the inheritance is sex-linked. If it is linked to the sex or X chromosome, then it would reveal a preponderance effect on the son or daughter. For example, in major depression there is a two to one preponderance of women over men. In manic-depressive disorder, women are slightly more affected than men, but it is almost even. In schizophrenia, it is evenly divided between the sexes.

We know in manic-depressive illness that it is genetically transmitted. We strongly suspect that this is also true in schizophrenia. There may be other disorders that we are now finding that may be genetically linked, like obsessive-compulsive disorders and certain forms of anxiety disorder.

LEWIS JUDD: I have a question. The way we in the West presently think about mental disorders is fairly deterministic. For example, in an extreme case, with a high genetic tendency, in an environment filled with elaborate stresses, it is inevitable that someone will develop a mental disorder at some point. On this account, we are becoming increasingly less judgmental about the appearance of mental disorders and are disinclined to attribute them to past failures or to emotional weaknesses and various other factors.

What are the Buddhist conceptions of mental disorders? Is there attribution to some type of failure of self, or failure of enlightenment, or failure of centeredness, that would result in a mental disorder such as an increase of wind or whatever other humor might be involved?

DALAI LAMA: As I mentioned previously, from a Buddhist perspective we think of consciousness and energy as they are subjectively experienced. Within this context, then, if a person is experiencing some kind of mental dysfunction, it is frequently understood that the mind itself has become too withdrawn in upon itself and that there is a corresponding physiological process involving the energies themselves, which are closely associated with consciousness, also entering into a dysfunctional state.

So, in the Buddhist view, it can happen, for example, that one’s mind will become depressed because of some environmental event. As a result of the mind becoming depressed, there is a chemical, maybe an electrochemical, transformation in the brain that has now occurred. The mental dysfunction will then be aggravated. When that happens, there is a further chemical response, which then avalanches upon itself. This is the Buddhist view, simply stated. It was with this in mind that I was asking previously, which has the greater dominance, external circumstances or internal ones?

Additionally, in the Buddhist view—and similarly in Western interpretations—on occasion, without any special external event taking place, there can simply be a dysfunction or disruption in the balance of the elements within the body. In that event, the internal circumstances are the dominant, principal cause. In dependence upon this physiological cause then, the mind can become depressed.

LEWIS JUDD: I was inquiring about something else as well. In Western society, having a mental disorder is still highly stigmatized. Someone is essentially at fault. They have presumably done something wrong. Because of this cultural attitude, oftentimes people are ashamed, and unable or unwilling to seek help. Is there a similar kind of pejorative social conception that affects the mentally ill in Tibet or India?

DALAI LAMA: It is more an individual matter. In a Buddhist culture, you have some who respond with compassion, and you have others who do not respond with compassion.