Chapter 1


In 1991 I wrote a speculative biomedical paper suggesting that the immune system is the key to understanding a broad range of mental illnesses, including depression, schizophrenia, hyperactivity, anxiety and manic-depressive disorder.1 The basic idea was this: the immune system, when activated, secretes potent hormone-like substances called cytokines. These cytokines have powerful effects on the brain: they alter brain function and behavior. Indeed, cytokines, based on many scientific reports, can cause all the symptoms and signs of at least two mental illnesses: depression2 and schizophrenia3,4.

Considerable biomedical research has been published recently showing that the immune system is profoundly involved in psychiatric diseases, especially depression. The discoveries on the role of the immune system in mental illness form the basis for a new understanding of the nature of mental illness, especially depression. These discoveries have remarkable implications for the treatment, prevention and cure of mental disease. Yet few people know about these developments. The public is completely oblivious. Even practicing psychiatrists and psychologists are unaware of the growing revolution in their own field. Only a select group of immunologists and biological psychiatrists who are knowledgeable in both disciplines are aware of these important scientific advances. This book is an attempt to inform both the public and medical professionals of these fundamental advances in our understanding of mental illness.

The Present Situation

The problem with our present understanding of mental illness is our lack of understanding. After 100 years of research, the major mental illnesses remain draped in mystery. Scientists have yet to discover the cause (etiology) of any psychiatric disease, whether it be depression, schizophrenia, obsessive-compulsive disorder or attention deficit disorder. The fundamental nature of mental disease is poorly understood. For example, it isn't known if schizophrenia is one disease or many different diseases with similar symptoms. Depression has the same problem. There are many types and subtypes of depression along with various mixtures of depression with other diseases. So the question, 'what is depression?' is essentially unanswerable.

Since the causes of mental illnesses are unknown, there are no known methods for their prevention. The notion of preventing depression or schizophrenia remains a very distant dream. In the case of depression, our inability to prevent is underscored by the dramatic rise in the incidence of depression this century. The incidence of depression continues to rise every decade.

The possibility of curing a mental illness is also a distant dream, a very long way from reality. In order to cure an illness, there has to be some understanding of the cause. In the case of mental illnesses, the causes are unknown.

There are no blood tests, urine tests, X-ray methods, biopsies or any other physical methods for the objective diagnosis of any mental illness. There are no blood tests or physical measurements which can distinguish a depressed person from a schizophrenic patient or from a healthy person. The complete lack of objective physical methods to diagnose mental illnesses is a reflection of the lack of scientific understanding of these diseases. Instead of objective physical tests, psychiatrists rely on non-specific symptoms (e.g. fatigue, hopelessness, sadness), non-specific signs (e.g. weight change, sleep problems, slowed movement) and patient self-report for diagnosing a mental illness.

Barriers to Progress

The poor progress in the scientific understanding of mental illness stands in sharp contrast to the remarkable advances in the understanding of the causes and pathophysiology of physical diseases. The lack of insight into mental disease is often attributed to the enormous complexity and inaccessibility of the human brain. On the other hand, over 100 years of unsuccessful research on the etiology and pathophysiology of mental illness could be telling us there is something wrong with our research.

What could be wrong with the research? Of course there are many possibilities. The thesis of this book is that there are two major flaws with mainstream psychiatric research. One major flaw is the division of diseases into mental and physical. The physical illness model is the only medical research model that has yielded results this century. The mental model has been a flop and for good reason. The immunological and pharmacological discoveries to be discussed in this book have revealed that mental illnesses are actually physical diseases.

The common assumption that the brain is the prime place to look for answers to mental disease is the other fundamental flaw. Certainly brain research is important and has provided vital information for the drug treatment of psychiatric diseases. But after 45 years of brain-drug research, we are no closer to understanding the nature or causes of mental illness. The revolutionary immunological discoveries made during the last decade suggest that the immune system is the place to look for answers to psychiatric diseases. And why not, since the immune system is a key interface between the environment and the body, including the brain. It plays a crucial role in every major physical disease, including atherosclerosis, cancer, diabetes, infection, rheumatoid diseases, osteoporosis and many others. Indeed, it would be highly unusual if the immune system didn't have a crucial in psychiatric diseases also.

Physical vs Mental Disease

For much of this century human diseases have been classified as either physical or mental. Diseases classified as physical are quite familiar to us and include the common cold, influenza, infections of all types, cancer, diabetes and heart disease. They also include a multitude of less familiar pathologies of the heart, arteries, lung, liver, kidney, skin, pancreas, stomach, intestines, bone, joints, blood, nerves, brain, spleen, lymph, immune system, endocrine system and various other sites. Physical diseases are presumed to have physical causes which can range from infection, trauma and biochemical abnormalities to inherited genetic diseases.

Illnesses such as schizophrenia, depression, manic-depressive disorder (bipolar disease), anxiety disorders, conduct and character disorders and phobias represent the bulk of the mental illnesses. Mental diseases are presumed to have mental causes, just as physical diseases are assumed to have physical causes. Pathological thoughts and fantasies, emotional conflicts, repressed anger, psychological and emotional trauma, psychological stress and emotional depravation are thought to be the keys to finding the causes, cures and preventive methods for mental disorders. Consequently, for many years severe, chronic illnesses like schizophrenia, major depression, anxiety and manic-depressive disorder were presumed to be caused by various combinations of psychological, emotional and mental stressors but not by any physical causes. Indeed, schizophrenia, one of the most debilitating diseases known to man, was widely accepted, prior to 1950, to be caused by bad mothering, 'malevolent' mothers, or mothers who consistently communicated 'double-bind' messages to their children.

Due to the limited biomedical knowledge before 1950, the bifurcation of diseases into mental and physical was a rational, reasonable concept during the first half of this century. In 1952, with the monumental discovery of the beneficial effects of the antipsychotic drug chlorpromazine on schizophrenia, serious problems developed in continuing to classify diseases as either mental or physical. Before the discovery of chlorpromazine (trade name Thorazine), there were no effective drug therapies for schizophrenia or any other psychiatric disease. Furthermore, psychotherapy didn't work on schizophrenia then and it still doesn't today. Hence, a great dilemma surfaced, namely, that the mental disease schizophrenia was responding very favorably to a physical treatment (i.e. chlorpromazine), whereas patients with schizophrenia rarely if ever benefited from mental therapies (i.e. psychotherapy). This, of course, provoked an obvious question: is schizophrenia really a 'mental' disorder or is it in fact a physical disease? Forty years ago the answer was unclear, but today there is a mountain of evidence demonstrating that schizophrenia is a physical disease.

The discovery of the anti-schizophrenic effects of chlorpromazine in 1952 was a watershed event in the history of psychiatry and mental illness. Chlorpromazine triggered a vast amount of biological and pharmaceutical research on the physical nature of mental illness. This research has resulted in a massive and continually growing body of biomedical evidence demonstrating that serious psychiatric illnesses are basically physical diseases.

Another result of the drug research has been a plethora of effective medications to treat (but not cure) serious diseases like depression, manic-depressive disorder, anxiety, schizophrenia and obsessive-compulsive disorder. Most of the psychoactive medications affect neurotransmitter systems in the brain, which has led to the widely accepted notion that neurotransmitter dysfunctions are the key pathologies underlying mental illnesses. Some of the neurotransmitters affected by these medicines are serotonin, norepinephrine, acetylcholine, dopamine and gamma-amino-butyric acid (GABA).

Nevertheless, here we are in 1997, forty-five years after the discovery of chlorpromazine and the medical world is still burdened with the antiquated system of classifying diseases as either mental or physical. The antiquated system has generated a great deal of conceptual confusion along with a number of fundamental barriers to progress in solving the baffling nature of psychiatric diseases. One consequence of the mental classification of psychiatric disease is illustrated by the fact that after almost 100 years of research on mental illnesses, there is literally no understanding of the cause or basic pathophysiology of any 'mental' disease. Schizophrenia, for example, during the 1920's, 30's and 40's was thought to be caused by bad mothering. We now know that those ideas were incorrect. Today, after much intensive research on one of the most chronic and debilitating diseases known to man, we are left without a clue as to the cause or fundamental pathophysiology of schizophrenia. Moderately successful drug treatments (i.e. chlorpromazine and other drugs) do exist for schizophrenia, but the possibility of finding methods to prevent or cure schizophrenia remains a very distant prospect.

The situation for depression is similar. There are many effective drug treatments for depressive disorders but the cause or causes of depressive disorders are unsolved riddles. There are no known cures or preventive methods for depression and the pathophysiology of depression is poorly understood. The same sad state of affairs exists for obsessive-compulsive disorders, anxiety and manic-depressive disorder.

It is true that neurotransmitter abnormalities are pathologies found with depression and schizophrenia. Some would say the neurotransmitter dysfunctions are the cause of depression and schizophrenia. However the real question of cause remains, that is, what causes the neurotransmitter dysfunctions? So far, none of the drug or neurotransmitter research has discovered what causes the neurotransmitter dysfunctions.

Mental Classification as a Barrier to Progress

The poor progress of mental illness research stands in glaring contrast to the swift progress in understanding the causes and methods to prevent and/or cure many physical diseases. The acquired immune deficiency syndrome (AIDS) is a good example to illustrate the rapid advances in understanding the causes of physical diseases. AIDS was first reported in the medical literature in 1981. It was given the name AIDS in 1982. By 1984 the infective agent causing AIDS was discovered (i.e. HIV-human immunodeficiency virus). In 1985 a successful blood test to detect HIV was developed, which made it possible to positively diagnose AIDS. These remarkable advances have made it possible to prevent AIDS. The proven methods for prevention (safe sex, sterile needles, carefully screened blood) when implemented have sharply reduced the rate of HIV infection and demonstrate that AIDS is a preventable disease. Pharmaceutical companies have developed treatments for AIDS and are working on vaccines to prevent AIDS. The treatments are becoming so effective that some researchers are talking about being able to cure AIDS in the not too distant future.

Why have advances in understanding causes and implementing methods for preventing and curing physical diseases been so rapid while progress is almost non existent in understanding the causes or devising methods to prevent or cure mental diseases? Of course no one knows the whole answer, but a good part of the answer may have to do with classifying diseases as mental. If, for example, AIDS had been classified as a mental disease (and it is very possible it could have been because psychiatric symptoms usually occur with AIDS), then researchers would have been looking for mental (i.e. psychological, emotional) causes of AIDS. Stressful lifestyles, abusive parents, emotional stressors, intense psychological stresses and various psychosocial stressors would have been searched and researched and then embellished with statistical significance and sophisticated mind-body jargon. Statements like "studies have shown that emotional stressors along with intense psychological stresses have conspired in these patients to cause their minds to suppress their immune systems" could have become commonplace buzzwords. A great deal of research, speculative concepts and confusing debate would have been produced. Nothing medically useful for preventing or treating AIDS would have resulted. The only general consensus would have been that more money was needed for research.

Peptic ulcer is a textbook example of a disease with physical and emotional symptoms that was assumed to have a mental cause (i.e. emotional and psychological stress). Mental stressors were believed to be causing excess stomach acid secretion. The excess stomach acid was thought to be the cause of the ulcers. The standard treatment for many years was a life of reduced mental and emotional stress along with a bland diet and copious amounts of antacids. In the 1970's medicines were discovered (Zantac, Pepcid) which blocked the secretion of stomach acid (acid blockers). These medications are very effective treatments for peptic ulcers but they are not cures. Peptic ulcer patients were told they would be taking acid blockers for the rest of their lives.

In 1982, Dr. Barry Marshall discovered an important link between the bacteria Helicobacter pylori and peptic ulcers. He proposed that peptic ulcers were caused by Helicobacter pylori infecting the lining of the stomach rather than mental stress. His work was met with ridicule because everyone already 'knew' that ulcers were caused by worry, anger and mental stress. Furthermore, everyone 'knew' that bacteria could not grow in the lining of the stomach and if they could, they would have been discovered already. Thus, for another 10 years the medical establishment rejected the growing mountain of evidence on Helicobacter pylori as the cause ulcers. Finally, in 1994 the evidence became so massive and convincing that the medical establishment agreed with Dr. Marshall. Indeed, over 90% of all peptic ulcers are caused by Helicobacter pylori. Peptic ulcers are now being cured using antibiotics.

Peptic ulcer is a classic modern case of psychiatric dogma (i.e. diseases have mental causes) interfering with the discovery of the physical cause of a disease. Physicians, especially psychiatrists, were so sure that worry and mental stress caused ulcers that it was thought foolish and unnecessary to look for physical causes. Over 25 million Americans suffered with peptic ulcers, yet for nearly 50 years almost all the studies investigating the cause of peptic ulcers looked at mental factors. Except for research on the blockade of stomach acid, there were few if any studies on physical causes of ulcers. For half a century no one believed ulcers were caused by an infection, so no one looked for an infective agent. Thanks to the unorthodox work of Dr. Barry Marshall, we now know that the bacteria Helicobacter pylori is the cause of ulcers rather than worry or mental stress. Ulcers can now be cured with one intensive course of antibiotics instead of being treated for a lifetime with acid blockers, antacids, a bland diet and a variety of emotional, psychological and psychiatric treatments.

Compare the rapid progress on AIDS and peptic ulcer (after the dogma of mental cause was overcome) with the situation for a 'mental' disease like depression. After a century of research on depression, the basic cause or causes are unknown. In the face of legions of psychotherapists applying the results of a century of research, we actually have increased incidence of depression every year. Incidence rates for depression are ten times higher now than at the turn of the century and they keep going up. Many medical researchers characterize this as an ongoing and escalating epidemic of depression. Furthermore, depression strikes at younger ages than ever before. For example, childhood depression was almost unknown at the turn of the century, whereas now it is a common disorder. The highest rates of depression for females used to be after menopause, but depression now occurs in women most often between ages 18 and 44. Clearly, the billions of dollars spent on research and the vast number of papers, books, and theories published on depression have not led to anything remotely resembling useful methods for prevention or any understanding of the cause of depression. The high rates of recurrence of depression demonstrates that we don't have a cure for depression either.

Immunology and Disease

During the past twenty years there have been many landmark discoveries on the role of the immune system in physical diseases. These discoveries have led to two fundamental insights into virtually all physical diseases. First, the immune system is profoundly involved in all physical diseases, including diabetes, cancer atherosclerosis, Alzheimer's Disease, multiple sclerosis and Parkinson's Disease. Second, the symptoms and signs of physical illnesses are actually the result of immune system activities. For example, fever, which is a very reliable sign of acute infection (or other serious pathologies) is not caused by the infective agent (i.e. bacteria, virus or fungi), but rather by the immune system itself. The same is true of inflammation, tenderness, aches, pains, rash, loss of appetite, muscle wasting, weight loss, nausea, fatigue, malaise, depressed mood, rash and a variety of hormone, blood, biochemical and organ system abnormalities.

Symptoms, Signs and Cytokines

How does the immune system produce the symptoms and signs of disease? There are many steps and processes in the production of symptoms and signs, but by far the most important step is the release of cytokines by activated immune cells. Cytokines are chemical messengers (ie hormones) made by immune cells and certain other cells. When they are released into the blood, cytokines can affect the function of every tissue and organ in the body, including the brain. Extensive animal and human studies have clearly demonstrated that cytokines cause the symptoms and signs of disease.

Cytokines were officially recognized at an international meeting of immunologists in 1979. Prior to 1979, immunologists believed that immune cells could not and did not secrete chemical messengers. Before 1979 there was no understanding of fever or other symptoms and signs of disease. No one believed that the immune system was the cause of symptoms and sign of disease, because there was no known mechanism for the immune system to produce them. Thus, the discovery of cytokines created a revolution in immunology and medicine. Since that time, an enormous amount of research has been devoted to cytokines. Many of the names of cytokines have become well known. The chemicals known as interferons are cytokines, so are the interleukins, the colony stimulating factors and tumor necrosis factor.

Cytokines and Mental Disease

Research on cytokines has recently been applied to mental diseases and it looks like cytokines will revolutionize our understanding of psychiatric diseases. There are many aspects of cytokines which make their application to mental illness obvious. First, in addition to producing all the symptoms and signs of physical illness, cytokines can provoke most, if not all, the symptoms of mental diseases, especially depression and schizophrenia. Second, in addition to producing the mental symptoms of depression and schizophrenia, cytokines produce the physical signs commonly associated with depression or schizophrenia, such as, inflammation, hormone abnormalities, headache, and biochemical abnormalities. Third, cytokines can pass from the blood to the brain. Also, they can be made by immune cells residing in the brain and there are receptors for cytokines throughout the brain. Fourth, cytokines have powerful effects on neurotransmitter activities, including those linked with depression and schizophrenia, such as norepinephrine, serotonin and dopamine. Current research indicates that cytokines can account for the neurotransmitter abnormalities found with psychiatric diseases.

A basic assumption of biological psychiatry is that the brain is the place to look for the causes of depression, schizophrenia and other mental diseases. The recent revelations on cytokines point to the immune system as the place to look for the causes of depression, schizophrenia and other mental diseases.


In this book, the recent research supporting a completely new way of looking at primary psychiatric diseases will be presented. At the heart of the model are the recent discoveries on the powerful effects the immune system and cytokines have on the brain, mood and behavior. The revolutionary model of psychiatric disease proposed in this book is:

  • All diseases are physical, including psychiatric diseases.
  • Prevalent diseases, whether they be psychiatric or traditional physical diseases, have physical causes.
  • The symptoms and signs of traditional physical illnesses are due to cytokines secreted by an activated immune system. In a similar manner, the symptoms and signs of most psychiatric diseases are due to cytokines chronically secreted by an activated immune system. Thus, the fundamental mediator of most psychiatric diseases is an activated immune system secreting various cytokines.
  • Finding the causes of the immune activation and chronic cytokine secretion in psychiatric diseases will be the keys to unraveling the mysteries of 'mental' illness.

Cytokines are secreted in the course of every disease, where they provoke a wide spectrum of both mental and physical symptoms. This discovery makes it very understandable as to why 'mental' pathology is not only found in 'mental' diseases, but also in traditional physical diseases. In addition, the discoveries on cytokines explain the mystery of the high coincidence of traditional physical illnesses and 'mental' illnesses.

The immune model of mental illness solves other fundamental problems of psychiatric diseases, one of which is the bifurcation of diseases into mental and physical. The rationale for classifying diseases as either mental or physical is completely eliminated by the discovery of cytokines since cytokines produce both mental and physical symptoms. The immune model puts psychiatric diseases solidly in the framework of physical diseases, exactly where they should have been for the past forty-four years. No longer will researchers be burdened with the impossible task of finding the 'mental' causes of psychiatric diseases. The powerful and very successful scientific research methods used on physical diseases can be applied directly to depression, schizophrenia and other 'mental' illnesses by using this model. Essentially the search for cause of these illnesses will be transformed into a search for the cause of the immune system activation underlying depression, schizophrenia, mania, obsessive-compulsive disorder and other 'mental' illnesses.

The label "mental cause" has a profoundly negative effect on patients. Think for a moment about the message the physician is giving to his patient. The physician is actually saying, "We haven't been able to find a real cause of your illness, so that means your own mind and nervous system in causing your disease. To be a little more blunt, you are the cause of your disease. It's your fault you are sick. It's your anger, your impatience, bad moods, thoughts and emotions combined with your explosive irritability that is at the root of your problems. Frankly, inside that brain of yours lies such an odious, unpleasant person that your own body can't stand you! Your body has become diseased because it has to carry such an awful person inside."

We now know that almost all the physical and mental changes that occur with physical diseases are due to the actions of cytokines. Most of the changes have a well understood purpose, namely, to save your life. We have already mentioned the benefits of fever, but what about inflammation? How could inflammation save your life? Here again the answer is quite simple. During inflammation, immune cells, responding to cytokines, surround the site of infection (or tissue damage site), forming a wall around the site. The wall prevents the spread of infection to the rest of the body. Thus, almost all infections remain localized. Before the era of antibiotics, a bacterial infection which broke through the wall and spread throughout the body, meant death was immanent. Even with antibiotics, an infection which breaks through the inflammatory walls is extremely dangerous and life threatening. Nevertheless, standard medical practice continues to advocate anti-inflammatory medications during acute illnesses.

What about muscle wasting? How do cytokines cause muscle wasting? Immune cytokines, when released into the blood, travel to every tissue and organ in the body, including muscles. Certain cytokines stimulate enzymes which break muscle down into amino acids. So the muscles waste away, but why would the immune system want to do this? The answer is simple, to save your life. The activated immune cells need high amounts of certain amino acids for energy and to carry out their war against the invading bacteria. Also, amino acids are the building blocks to make antibodies. Antibodies are vital in the war against the invading bacteria. Thus, muscles are a reservoir of vital foods and building materials for an immune system engaged in warfare against invading bacteria.

Cytokines trigger many hormone changes during illness. One important change is the remarkable rise in the steroid hormone named cortisol. Cortisol is a well known anti-inflammatory, immunosuppressive hormone. Why would an activated immune system raise the level of an immunosuppressive hormone? Again the answer is quite simple. Cortisol helps protect the body against the powerful immune soldiers mobilized during immune activation. Without necessary restraints like cortisol, the lethal immune soldiers released during the war against bacteria can severely damage tissues and organs throughout the body.

Cytokines can go to the brain and cause tremendous changes in mood, behavior and attitude. Fatigue, depressed mood and lack of interest in people and events is an all to common occurrence during serious illness. ("I felt so bad I wanted to die" is a typical description of a bout with the flu.) OK, explain to me, what could be good about feeling bad? Well, by feeling terrible, fatigued and asocial, the infected person lies down, rests, sleeps, does nothing and keeps away from people. This conserves energy needed by the immune system to fight the infection and helps prevent the spread of disease to other people.

Cytokines do many other things to the body, but this brief look should be enough to let the reader know that cytokines are extraordinarily important molecules. They were first discovered in 1979 and since that time, cytokines have revolutionized our understanding of physical diseases.

Next chapter: An Overview

Chapter 1 References

1. Smith RS. The immune system is a key factor in the etiology of psychosocial disease. Medical Hypotheses 34:49-57, 1991.

2. Smith RS. The macrophage theory of depression. Medical Hypotheses 35:298-305, 1991.

3. Smith RS. A Comprehensive Macrophage-T-Lymphocyte Theory of Schizophrenia. Medical Hypotheses 39:248-257, 1992.

4. Smith RS, Maes M. The Macrophage-T-Lymphocyte Theory of Schizophrenia: Additional Evidence. Medical Hypotheses 45:135-141, 1995.