Chapter 7:

Immunological Evidence Supporting The Immune-Cytokine Model of Depression

The Immune-Cytokine Model of Depression (ICMD) is an entirely new concept for understanding the riddle of depression. This is the only model of depression to bridge the conceptual and diagnostic gap between physical and mental disorders.1,2 ICMD views depression to be any number of chronic physical-biological disorders that have mental-emotional symptoms. From the perspective of ICMD, depression isn't really a disease, but rather a multifaceted sign of chronic immune system activation. During chronic immune system activation, greater than normal amounts of various cytokines are secreted. The cytokines produce the multifaceted signs and symptoms of depression. This chapter summarizes the extensive immunological evidence supporting ICMD. Chapter 7 reviews the evidence from biological psychiatry supporting ICMD.

Cytokines Cause The Symptoms Of Depression

Cytokines are at the heart of the immunological basis of depression since they provoke a wide spectrum of neuropsychiatric symptoms when given to human volunteers. The profound effects of cytokines on mood, thought and behavior were first discovered in the early 1980's. For the first time in history, physicians had found molecules made by the human body which, when given to humans, produced all the symptoms necessary for the diagnosis of depression.

These discoveries are of monumental importance. They should have dazzled every psychiatrist and psychologist in the world, but quite surprisingly, mental health professionals had meager interest in these discoveries. Most psychologists and psychiatrists were (and still seem to be) engrossed in their own theories of psychopathology and had little time or interest in psychiatric discoveries coming from other disciplines, especially when they came from something as seemingly unrelated as immunology.

Interferon-alpha Interferon-alpha (INFα) is a cytokine released by activated monocytes and macrophages. It has a number of beneficial effects on various immune cells3, but it also has many very debilitating neuropsychiatric consequences.4 Priestman5 in 1980 was one of the first to report some of INFα's neuropsychiatric effects. A few year later Rohatiner et al.6 published a more detailed study. They gave INFα intravenously for seven days to eleven volunteers and observed the effects. All volunteers became feverish, fatigued and lacked appetite. They were socially withdrawn, slow to answer questions, lost interest in their surroundings and slept most of the day. In one week, these volunteers developed nearly all the symptoms necessary for the diagnosis of major depressive episode. Their brain waves also became abnormal and were suggestive of a brain degenerative disease.

A year later, Adams et al.7 did a longer term (four week, ten patient) study on the effects of INFα. For the first few days fever, headache, aching muscles and other flu like symptoms occurred, but they did not persist. They were replaced by symptoms of severe depression. From the end of the first week to the end the fourth week, eight of the patients:

"experienced psychomotor retardation with unequivocal impoverishment of spontaneous movements, gestures, expressions, speech and thought. They displayed varying degrees of bradykinesia (slowed movement and thought), and social withdrawal consonant with their complaints of decreased energy and signs of a disinclination to act or think. .........They frequently, however, ignored eating, various aspects of grooming, and regular daily activities. ............. Cognitively, while they remained fully oriented, all patients appeared duller, inattentive and disinterested within the first week of interferon therapy. Those who had noted memory and concentration difficulties before therapy now said that these problems were worse. Five patients were bothered by memory and concentration problems during treatment. Two patients had thought blocking and said that they occasionally stopped thinking altogether. Half of the patients exhibited speech stoppage, interrupting sentences with periods of silence and vacant staring, either claiming that they had lost interest in continuing or failing to notice that they had stopped talking. Four patients reported slowed thinking. One patient complained of a constant disquieting sensation of detachment and unreality, even while asleep."

These patients exhibited and experienced the symptoms necessary for the diagnosis of major depressive episode. Surprisingly, depressed mood was not a prominent symptom even though these volunteers became seriously depressed! This is one of the paradoxes of depression we already noted in DSM-IV that is, according to DSM-IV, a patient can be diagnosed with depression without having a pronounced depressed mood. Thus, INFα not only provokes the symptoms which fulfill the criteria for the diagnosis of depression, but it also fits with the curious diagnostic paradoxes of depression.

In a more recent clinical study, Niiranen et al.8 gave high dose intravenous INFα to nine cancer patients for five days, followed by a lower intra muscular dose three times a week. None of the patients had prior neurological or psychiatric disease and just prior to treatment with interferon all patients were judged to be mentally healthy. After initiating INFα therapy, neuropsychiatric abnormalities developed gradually. Very interestingly, on the second day, "a short-lasting but clear euphoric phase was seen. Patients were in a heightened mood and abnormally hopeful, resembling mania."

The depressive symptoms begin appearing on the third day. All volunteers exhibited fatigue, lack of appetite, lack of interest, slowed movement and thought, clumsiness, excessive sleep and all but one was irritable (two very severely) and confused. Very severe depressed mood affected five out of nine and anxiety was reported by three volunteers. This clinical study confirmed the ability of INFα to produce all the symptoms necessary for the diagnosis of major depressive episode. Notable in this trial was the irritability and depressed mood exhibited by the majority of the patients. The symptoms of depression vanished two weeks after discontinuing INFα.

The mild euphoria experienced by all the volunteers on the second day was particularly interesting. Many depressed persons do experience varying periods of euphoria. Also, mood change from fatigue and depression to euphoria is a defining characteristic of bipolar disorders (i.e. cyclothymia, manic-depressive disorder). This suggests that INFα, in addition to being a key cytokine for depression, may also be an important factor in bipolar disorders.

McDonald, Mann and Thomas9 published a paper in 1987 in the Lancet titled 'Interferons as Mediators of Psychiatric Morbidity'. This was a controlled trial of 43 hepatitis B patients, in which 29 patients were given INFα three times weekly for up to six months. Most of the patients on INFα reported fatigue, loss of interest, lack of concentration, anxiety and depression. Control patients not given INFα did not report these symptoms. An amazing 63% of the volunteers on interferon became psychiatric patients! Depressive symptoms did not remit immediately after discontinuing INFα. Symptoms usually lingered with reduced intensity for one to three weeks. There are other human trials documenting INFα's ability to provoke the symptoms of depression.10,11

Tumor Necrosis Factor (TNF) TNF is another powerful cytokine secreted by monocytes, macrophages and lymphocytes. It was named many years ago for its ability to destroy tumors (necrosis=tissue death). TNF has many properties in addition to its capacity to necrotize tumors. It is similar to IL-1 in its ability to regulate a wide variety of tissues and organs, including brain.12

Human volunteers given TNF intravenously develop many neuropsychiatric symptoms. Fatigue, anorexia, headache, muscle ache and malaise were the most common symptoms reported13,14,15 Essentially TNF makes a person feel lousy, just like someone with major depression feels.

Headache has been called a 'mask' for depression16 because most depressed patients suffer from headaches. A number of cytokines can provoke headache, but it occurs more severely and often with TNF than with any other cytokine. Migraine patients have high rates of depression and produce more TNF than normal controls.17 Cytokines are probably key factors causing most headaches.18,19 (notice how often headaches occur with acute illnesses like the flu or respiratory tract infections). The close relationship between cytokines, headache and depression is further support for ICMD.

Interleukin1 (IL1) IL1 is primarily secreted by monocytes and macrophages. The effects of IL1 on behavior has only been studied in laboratory animals. Laboratory animals exhibit "sickness behavior" when given IL1. Sickness behavior includes symptoms like anorexia, reduced activity, loss of interest in usual activities, malaise, increased sleep, lack of body-care activities, reduced social exploration and less food-motivated behavior.20 These behaviors are considered an adaptive response to infection and they are very similar to the behaviors found in human depression.

Recently, monkeys were given IL1 in a quiet setting followed later by an experimenter entering the room and having direct eye contact with the monkey.21 During the quiet setting, without the experimenter in the room, the monkeys showed typical sickness behavior, that is, less activity, less exploration, fewer vocalizations and more sleep. Then the experimenter entered the room and made direct eye contact with the monkeys. This is considered a socially stressful situation for the monkeys. Very interestingly, the monkeys given IL1 exhibited more agitation, more threatening behavior and more anxiety when the experimenter made eye contact than the animals not given IL1. Therefore, under non-stressful social conditions, IL1 produces sickness behavior. But under stressful social conditions, IL1 produces anxious, irritable and hostile behavior. This is very significant, because anxious, irritible and hostile behavior is very common in depressed persons. In fact, irritability is a DSM-IV symptom of depression.

Interleukin-2 (IL2) and Interferon-Gamma (INFγ) INFγ and IL2 are primarily secreted by T-lymphocytes. Low doses of IL-2 produce symptoms of depression. Severe lethargy, impaired memory, slowed responses, impaired attention, anorexia, lack of interest and irritability are found with most volunteers after receiving low doses of IL2. High doses of IL2 provoke very severe symptoms of schizophrenia, including hallucinations, delusions, disorientation in time, place or person.22 These observations have prompted the development of a macrophage-lymphocyte model of schizophrenia.23,24,25

INFγ given to humans usually provokes fatigue, malaise, headache, lack of appetite, weight loss, weakness, lethargy and decreased concentration.26,27 All of these are common symptoms of depression.

Some Comments Cytokines like INFα, INFγ, TNF and IL2 can routinely produce the symptoms of depression in a large percentage of subjects, but certainly not all subjects. Many volunteers have very mild to almost no symptoms, depending on the size and length of time the cytokines are given. The fact that cytokines don't produce depression in all volunteers is consistent with the actual incidence of depression, namely, not everyone in this world develops depression. The majority of people in the United States and Europe will not develop depression during their lifetimes.

If cytokines produced depression in all volunteers, then according to our immune-cytokine model of depression, we should have much, much higher rates of depression than we actually do. Thus, the inability of cytokines to produce depression in all volunteers is consistent with the known incidence of depression and is supportive of ICMD. Why some people are very susceptible to the neuropsychiatric effects of cytokines while many others are not, is not understood at the present time. The ability to resist the neuropsychiatric effects of cytokines is an extremely important trait. Insight into this intriguing ability will have to await future research.

The monkey experiments testing IL1 under socially stressful and nonstressful conditions was of special interest. Under socially stressful conditions, the monkeys did not exhibit sleepy, lethargic behavior, but instead, they were anxious, irritable and hostile. In contrast, under socially nonstressful conditions, the monkeys were sleepy, lethargic and inactive.

We need to emphasize again that cytokines are not exotic chemicals invented by chemists or extracted from plants. Cytokines are made by every living human being. Chronic, high level cytokine secretion occurs in everyone at various times in their lives, whenever chronic immune system activation occurs.

In the experiments using cytokines on humans or animals, usually only one cytokine is administered. This certainly differs from natural immune activation, where a large number of different cytokines will be secreted. Hence, during natural immune activation, it is even more likely that depressive symptoms will appear, since multiple cytokines are being released.

When immune cells begin secreting cytokines, bells don't ring and whistles don't blow. Cytokine secretion is a silent, invisible, unconscious process. After a few days of constant exposure to internally secreted cytokines, a person begins to feel lousy and behave like a sick person. Typically a sick patient is fatigued, irritable, loses appetite, loses interest in things, has a harder time concentrating, has various aches and pains and sleeps more. Indeed feeling lousy is a silent, insidious sign of chronic immune system activation. In general, depressed persons also 'feel lousy'.

Depressed Patients Secrete Greater Amounts Of Cytokines

We now know that cytokines can produce the symptoms of depression in a large percentage of people. The next step is to compare cytokine secretion in depressed patients to healthy controls. If depressed patients were found to secrete greater quantities of cytokines than normals, then a much stronger case can be made for cytokines as important mediators of depression.

Dr. Michael Maes and colleagues from AZ Stuivenberg University, Antwerp, Belgium, and Vanderbilt University, Nashville, Tennessee over the past six years have found extensive evidence of excess cytokine secretion in depressed patients. They have published over forty landmark papers demonstrating that immune system activation, including increased cytokine secretion, is a characteristic of depression. Dr. Maes and colleagues are doing some of the most important biomedical research on depression in the world. His work is quietly revolutionizing the biomedical understanding of depression.

Prior to 1991, no scientists had ever investigated cytokine secretion in depressed patients. At the present time, Dr. Maes and colleagues plus six or so other biomedical research groups are making these important measurements. They have not measured all of the cytokines. So far reports have appeared on interleukin1, interleukin1 receptor antagonists, interleukin6, interleukin6 receptors, INFγ, interleukin2 and interleukin2 receptors.

Interleukin-1 Interleukin-1 is possibly the most powerful, broad spectrum regulatory chemical in the human body. It can control nearly every tissue and organ in the body. IL1 is also one of the supreme commanders of the immune system. Immune cells, for example, cannot be activated without IL1 being present. This remarkable cytokine, which is made by activated monocytes and macrophages, stimulates immune cells, including monocytes and macrophages, to secrete other cytokines such as tumor necrosis factor, IL2, IL6, interferon alpha and interferon gamma. Consequently, elevated levels of IL1 invariably means there are increased quantities of other cytokines being secreted by monocytes, macrophages and lymphocytes.

Maes et al have published two momentous papers on IL1 secretion in depressed patients.28,29 They discovered that monocytes from depressed patients secreted more IL1 than monocytes from healthy controls. The more severe the depression, the greater the IL1 secretion. Patients with severe depression secreted almost three times as much IL1 as healthy subjects.

In another part of the experiment, subjects were given an extremely potent antiinflammatory, immunosuppresive drug called dexamethasone. (Dexamethasone is an analog of cortisol, but it is 25 times more immunosuppressive than cortisol.) The next day, blood samples were taken and monocyte secretion of IL1 was measured. As expected, IL1 production was significantly reduced by dexamethasone in healthy controls. In sharp contrast, IL1 production was not suppressed by dexamethasone in depressed patients! IL1 secretion continued at very high levels even in the presence of a powerful immunosuppressive drug like dexamethasone. Indeed after dexamethasone, both moderately and severely depressed patients secreted almost six times more IL1 than healthy controls! This crucial experiment shows that even a potent immunosuppressive drug can't calm down depressed patients' overactive immune systems.

Seidel et al.30 recently reported on cytokine production during and after acute clinical stage of depression in 39 hospitalized patients. Production of various cytokines, including IL1, was significantly elevated in depressed patients compared to controls. Six weeks later, after the acute clinical stage, IL1 production was reduced towards control values.

Interleukin1 Receptor Antagonist Very recently, Dr. Maes31 and colleagues found increased serum interleukin1 receptor antagonist (IL1ra) concentrations in patients with major depression. And what is IL1ra? Well, for one thing, IL1ra is not an immune system activator. It is an immune system suppressor, but paradoxically it is only released by an activated immune system. IL1ra is released by activated monocytes at the same time they release IL1. The primary function of IL1ra is to block the action of IL1.

Why would activated monocytes release IL1 and at the same time release a molecule that opposes the action of IL1? Answer: This is one of the immune system's many self-regulating mechanisms. IL1ra prevents IL1 from activating too many immune cells at too many sites throughout the body. It helps keep inflammation and immune mediated tissue destruction under control.

An elevated level of IL1ra is a reliable sign of an activated immune system.32 Thus Dr. Maes report on IL1ra is another key piece of clinical evidence demonstrating that depressed persons have activated immune systems.

Interleukin-6 This cytokine is similar to IL-1 in its ability to stimulate the immune system and regulate many organs and systems in the body, including the brain. Monocytes and macrophages are the prime producers of IL-1 and IL-6. Both of these cytokines work together to reinforce and complement each others actions. Maes and colleagues in two studies have measured IL-6 production in depressed patients.33,34 In the first study, the most severely depressed patients had significantly higher IL-6 production than healthy controls, in fact it was over twice as high. The second study confirmed the elevated levels of IL6 in depression. They found high levels before and after treatment with antidepressant medications. In addition, soluble IL6 receptors were elevated, which is another sign of increased IL6 secretion.

In a recent report from Poland, Sluzewska35 and colleagues found IL6 levels thirteen times higher than controls in 6 of 22 depressed patients. The patients with normal IL6 levels also had other blood signs of immune activation. After treatment with the antidepressant Prozac for eight weeks, IL6 along with the other blood signs of immune activation returned to normal. Two other independent clinical studies from different laboratories have found elevated IL6 in depressed patients.36,37

Interferon-gamma INFγ is made by activated T-lymphocytes. It has a variety of effects on the immune system, including stimulating monocytes and macrophages to secrete more interleukin1, interleukin6, tumor necrosis factor and interferonalpha. In a recent investigation by Maes et al.38 , lymphocytes from severely depressed subjects secreted three times more INFγ than lymphocytes from healthy controls. This is further strong evidence of immune activation in depressed patients.

Interleukin-2 and Soluble IL2 Receptors Seidel et al.39 reported that Tlymphocytes from acutely depressed patients secreted significantly more interleukin2 than controls. As these patients improved, their interleukin2 secretion returned to normal.

When Tlymphocytes secrete interleukin2, they also release soluble interleukin2 receptors (sIL2Rs). Due to various technical reasons, measurements of sIL2r's are easier and more reliable than for IL2. Consequently, sIL2Rs are often measured instead of interleukin2.

Three clinical investigations by Maes et al.40,41,42 have revealed significantly greater amounts of sIL2Rs in depressed patients than in healthy subjects. Depressed persons had almost double the concentration of sIL2Rs compared to healthy persons. Increased production of sIL2Rs has been confirmed in two other controlled clinical studies43,44, which means there are now five independent clinical trials reporting high levels of sIL2R in the blood of depressed patients. The reports on sIL2Rs are strong evidence that depressed patients have an activated immune system that is secreting excessive amounts of interleukin2.

Tumor Necrosis Factor and Interferon-alpha As mentioned at the beginning of this chapter, TNF and INFα provokes depressive symptoms in a large percentage of human volunteers. Unfortunately, these cytokines have yet to be measured in depressed subjects. TNF has been measured in chronic fatigue syndrome45 and migraine headache46, two syndromes which are closely linked with depression. TNF was elevated in both chronic fatigue syndrome and migraine headache.

A variety of cytokines, including IL1, IL2, IL6 and INFγ, enhance the production of TNF and INFγ. Since we have seen that IL1, IL2, IL6 and INFγ are elevated in depression, it is reasonable to assume that TNF and INFα are elevated also.

Further Evidence Of An Activated Immune System With Depression

In addition to their pioneering investigations on cytokines, Dr. Michael Maes and several other laboratories have reported on other aspects of the immune system in depression. The following are summaries of the additional immunological discoveries made by biomedical scientists throughout the world.

Leukocytosis Depressed patients, compared to healthy controls, have an elevated white blood cell count. A high white count is called leukocytosis. The white blood cells (leukocytes) include all of the immune cells found in the blood, consequently, leukocytosis is a reliable sign of an activated immune system.

Maes et al.47 in a sophisticated immunological study of 109 depressed patients, found the most severely depressed patients had the highest white count. Patients with minor depression had milder leukocytosis. Similar immune activation in depressed patients was reported in an earlier paper by Maes et al.48 Irwin et al.49 and Kronfol and House50 also detected leukocytosis in depressed patients. A recent report by Müller et al.51 found very striking functional leukocytosis in 37 severely depressed patients. Hence, immune system activation, as evidenced by leukocytosis, is now a well established phenomena in depressed patients.

Monocytosis Increased numbers of monocytes in the blood (called monocytosis) of depressed patients was first reported by Maes et al.52,53 and recently confirmed by Seidel et al.54 Monocytes are found in the blood, which makes them easy to sample and measure. They are the chief source of IL1, IL6, TNF and INFα in the blood.

Monocytes migrate from the blood into solid tissues where they are transformed into macrophages. Macrophages never return to the blood. This means they are rarely evaluated in humans because almost all immune system analyses are done on blood. Nevertheless, in animal experiments, whenever there is monocytosis, there is macrophage activation someplace in the body. Thus, the monocytosis exhibited by depressed patients indicates that macrophages are activated someplace in their bodies..

Neutrophilia Maes two papers on monocytes cited above also found high levels of neutrophils (a condition called neutrophilia) in the blood of depressed patients. The most severely depressed individuals had the highest numbers of neutrophils. Neutrophils, the most plentiful of the white blood cells, are members of the inflammatory arm of the immune system. Neutrophilia is a well established sign of immune system activation. Thus the discovery of neutrophilia in depression is another persuasive piece of evidence showing that depressed individuals have activated immune systems.

B-Lymphocytes The total number of lymphocytes does not appear to be increased in depressed patients. Nevertheless, within the various types of lymphocytes, there are very important changes. In a recent study by Maes et al.55 of 106 subjects, there was a significantly increased number and percentage of B-lymphocytes in depressed subjects compared to controls. This was confirmed in another study of depressed patients.56 B-lymphocytes are the antibody producing cells. (They are called B-lymphocytes because they are matured in bone.) Increased numbers and percentages of B-lymphocytes are clear signs of immune system activation.

T-Lymphocytes The T stands for the fact that these lymphocytes mature in the thymus. By secreting regulatory cytokines like IL-2 and INFγ, T-lymphocytes exert remarkable control over immune system activity. Immunologists have identified many different types of T-lymphocytes. Two of the most important are the T-helper lymphocytes (these are identified by the so called CD4 antigen on their cell surface) and the T-suppressor lymphocytes (these are identified by the so called CD8 antigen on their cell surface).

Maes et al.57, in one of his many landmark papers on depression, reported extraordinarily consistent evidence of Tlymphocyte activation in depressed patients. Healthy controls were compared to 101 depressed inpatients consecutively admitted to the Psychiatric Ward of the University Hospital of Antwerp. Depressed patients had significantly higher percentages of T-helper lymphocytes and lower percentages of T-suppressor lymphocytes than healthy controls. The Thelper/Tsuppressor ratio was significantly elevated in depressed patients. The patients with the most severe depression had the highest percentage of T-helper lymphocytes and the highest Thelper/Tsuppressor ratio.

A high percentage of T-helper lymphocytes combined with the finding of monocytosis in depression, means that both the lymphocyte and the macrophage arms of the immune system are activated. The reduced percentage of Tsuppressor lymphocytes is another clear sign the immune system is energized. The high Thelper/Tsuppressor ratio is a reliable indicator of immune system activation. In the same paper, Maes et al provided additional evidence of lymphocyte activation.

Recently Müller et al.58 investigated the lymphocyte subsets of severely depressed patients. Their results were very similar to Maes et al's findings. Müller et al's paper provided independent confirmation of over-active immune systems in severely depressed patients. Several earlier papers by other scientists have also reported a high Thelper/Tsupressor ratio in depressed patients.59,60

Another reliable sign of lymphocyte activation is the presence of interleukin2 receptors on the outer surfaces of lymphocytes. Maes et al.61 reported that increased interleukin2 receptors on lymphocytes is a hallmark for major depression. This is further independent evidence of immune activation with depression.

Autoantibodies The usual antibodies made by activated B-lymphocytes will clump and identify foreign proteins. As soon as a foreign protein is tagged with an antibody, it will be devoured by macrophages and killer lymphocytes. In this way, the immune system can quickly identify and destroy foreign invaders.

In sharp contrast, autoantibodies, clump and identify self proteins (that is, proteins which are an integral part of your own body). Self-proteins, after they are tagged with autoantibodies, will be attacked and devoured by macrophages and killer lymphocytes. In other words, when autoantibodies are produced, the immune system begins attacking the very body it is supposed to defend. Diseases which are caused by the immune system attacking the body are called autoimmune diseases.

Autoantibodies are routinely found in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis. The inflammation, pain and tissue destruction in autoimmune diseases are a result of activated macrophages and lymphocytes attacking tissues which are tagged with autoantibodies.

As early as 1976 a paper was published proposing a model of depression as an autoimmune disease.62 The model was based on the discovery of a high incidence of elevated autoantibodies in depressed patients. Two recent papers by Maes and colleagues63,64 have confirmed the presence of elevated titers of autoantibodies in up to 72% of depressed patients compared to none for healthy controls. The levels were not as high as those found in systemic lupus erythematosus(SLE) or rheumatoid arthritis, but they were significantly higher than healthy controls. High levels of autoantibodies in depressed patients is another unmistakable sign of macrophage and lymphocyte activation.

It is too complicated to discuss here, but depressed patients have many other signs of immune activation which are also found in autoimmune diseases like SLE.65,66 Another profound similarity between depression and autoimmune disease is the very high incidence of depression with autoimmune diseases. Lots of rheumatoid arthritis patients are depressed (over 40%).67 Depression with SLE68 is common also, but at even higher rates (up to 70%) than with rheumatoid arthritis.

Typically, biomedical scientists either have no explanation for the high rates of depression occurring with autoimmune diseases or very convoluted explanations. In sharp contrast, the immune-cytokine model of depression has a clear and direct explanation, i.e.: the activated immune systems in persons with autoimmune disease secrete excessive amounts of cytokines. Excessive cytokines provoke the symptoms and signs of depression.

Neopterin Monocytes and macrophages, when activated, release a chemical called neopterin. Plasma neopterin levels are elevated in numerous diseases where monocyte-macrophage activation is know to occur, such as cancer, viral and bacterial infections, AIDS, rheumatoid arthritis and other inflammatory disorders. Elevated plasma or urinary concentrations of neopterin are sensitive and reliable indicators of immune system activation.69

Several reports of raised neopterin concentrations in depressed patients were published in the 1980's.70,71 Maes et al.72 recently investigated 47 depressed subjects and reported elevated plasma neopterin, which confirmed the earlier studies. Severely depressed patients had the highest concentrations of neopterin, which means they had the most activated immune systems.

Interferon-gamma, which is made by Tlymphocytes, is the principal inducer of neopterin secretion.73 Interferon-gamma instructs monocytes and macrophages to make more neopterin. Therefore, the high levels of neopterin in depressed patients, in addition to indicating energized monocytes and macrophages, also testifies to activated Tlymphocytes and increased secretion of interferon-gamma.

Tryptophan and Interferongamma Tryptophan is an essential amino acid. Our bodies cannot make it and we can't live without it. Thus, a small amount of tryptophan, only one quarter of a gram per day, is a required part of the human diet.74

Tryptophan has received a great amount of psychiatric attention because the neurotransmitter serotonin is made from it. Low brain levels of serotonin are believed to be one of the main neurotransmitter defects underlying depression. This concept is supported by the effectiveness of Prozac and other recently marketed serotonin enhancing antidepressant drugs.

Since tryptophan is a precursor to serotonin and low serotonin may underlie depression, it is easy to see how low availability of tryptophan could be related to depression. A large amount of clinical research suggests low tryptophan is a factor in depression.75 First, patients with depression have low blood levels of tryptophan. Second, patients with the lowest tryptophan levels respond the best to serotonin raising antidepressants like prozac. Third, healthy volunteers given experimental diets designed to deplete the body of tryptophan, developed depressed moods. When the tryptophan depleted volunteers were given tryptophan supplements, their mood returned to normal. Fourth, tryptophan supplements given to depressed patients appears to help their moods.

During the 1980's, due to the clinical reports of benefit, tryptophan supplements became popular in the United States. (They were taken off the market in 1990 because of disease causing impurities found in some of the supplements.) Diets designed to raise blood levels of tryptophan were also in vogue. Nevertheless, there are difficulties with the dietary tryptophan-depression linkage. The three most important are: 1). Diets low in tryptophan are very rare in the United States and Europe. Our average intake of tryptophan is three to four times higher than required.76 2). Depressed persons do not have diets deficient in tryptophan. 3). Except for frank malnutrition, blood levels of tryptophan are independent of diet.77

If not diet, what then controls blood levels of tryptophan? This question has received a great deal of scientific attention. Many factors have been investigated, such as, stress hormones, insulin, sex hormones, thyroid hormone, fatty acid metabolism and diet, but none of them can explain the low blood levels of tryptophan in depressed persons.

Recently, Maes and colleagues explored the tryptophan-depression connection and they discovered that the immune system is a major player here.78,79 In their ground breaking research, the low tryptophan in depressed patients was powerfully linked with the patients activated immune system. The more activated the immune system, the lower the tryptophan levels. These discoveries suggest that the immune system is an important regulator of blood tryptophan levels.

How does the immune system control tryptophan levels? An important mechanism appears to involve interferon-gamma. We previously mentioned that INFγ is elevated in depressed patients. INFγ does many things, including the induction of an enzyme called indoleamine 2,3dioxygenase. A main function of indoleamine 2,3dioxygenase is to rapidly metabolize tryptophan, thereby depleting blood levels of tryptophan. Thus, the high levels of INFγ in depressed patients is the likely cause of their low blood levels of tryptophan.

Two other cytokines, IL1 and IL6 also play a role in lowering tryptophan levels. Both these cytokines are elevated in depression and they both stimulate the liver to make a variety of proteins. Since proteins are made from amino acids, including tryptophan, the liver's increased production of protein helps to deplete tryptophan availability.

Acute Phase Proteins During acute illnesses (i.e. infection, cancer, trauma, surgery, inflammation etc.), the liver makes a special set of proteins, called acute phase proteins. At the same time, the liver reduces its production of standard blood proteins like albumin and transferrin. Acute phase proteins assist the immune system in repairing tissue and fighting infection. A combination of low albumin and transferrin along with elevated blood titers of acute phase proteins is a reliable indicator of serious physical illness.80

The mechanism controlling the change in protein levels during acute illness was a mystery for many years. The discovery of cytokines, in particular IL-1 and IL-6, cleared up the mystery. IL-1 and IL-6, which are released by activated monocytes and macrophages, force the liver to make more acute phase proteins and less albumin and transferrin. Therefore, a high level of acute phase proteins is a reliable sign of monocyte-macrophage activation and increased cytokine secretion.

Dr. Maes and colleagues, in an important series of papers81,82,83 have found significant reductions in albumin and transferrin along with very significant elevations of acute phase proteins in depressed patients. The most seriously depressed patients have the highest levels of acute phase proteins and the lowest values for albumin. Maes' work has been confirmed by a number of other independent laboratories.84,85,86 The discovery of elevated titers of acute phase proteins in depressed patients is unmistakable evidence of monocyte-macrophage activation during depression. It is truly stunning support for the immune-cytokine model of depression.

Polymorphonuclear Elastase This substance with a forbidding name is an enzyme released by activated neutrophils. Neutrophils are part of the inflammatory arm of the immune system. Extensive work during the 1970's and 1980's has revealed that an elevated polymorphonuclear elastase (PMNE) level is a reliable indicator of inflammatory disease.87 In a recent controlled study of 108 people, PMNE levels in patients with major depression were two to six times higher than in healthy controls.88 Patients with dysthymic disorder, a milder form of depression, only had modest elevations in PMNE. This report is further independent evidence of immune activation in serious depression.

Zinc Several studies have reported low serum zinc (hypozincemia) in depressed patients.89,90 Maes et al.91, in another landmark paper, have also found hypozincemia in depressed subjects. They were able to rule out diet, medications or concurrent illness as the cause of the low serum zinc, but they did discover an immunological explanation for the phenomena.

The depressed patients with hypozincemia had high neopterin levels. In fact, there was a very strong inverse correlation between serum zinc and serum neopterin. In other words, patients with the lowest zinc had the highest neopterin levels. Neopterin is a sensitive indicator of immune activation, thus, patients with the greatest immune activation had the lowest zinc. Immune activation was the only variable that was linked with low zinc.

Can an activated immune system lower serum zinc? Yes it can. Indeed, one of the characteristics of immune activation is a rapid fall in serum zinc.92 Increased secretion of IL1 and IL6 during immune activation is the main reason for the fall in serum zinc. IL1 and IL6 instruct the liver to make more metallothionein, a complex molecule which removes zinc from the blood. This, of course, reduces the amount of zinc in the blood and puts more of it into the liver. The liver needs the extra zinc in order to accelerate its production of proteins required by an activated immune system. Therefore, low serum zinc in depression is another sign of immune activation.

Thyroid Stimulating Hormone

Immunosuppression We have reviewed a massive amount of scientific evidence showing that depressed patients have activated immune systems with increased cytokine secretion. Nevertheless, many scientific papers continue to report just the opposite. The notion of depression causing immunosuppression is subscribed to by many medical professionals and lay persons. So what gives here? Could both views be correct? Yes they could, but we need to do some explaining.

Evidence of immunosuppression in depression was first reported in the early 1980's93 and since that time a continual stream of scientific publications have confirmed the initial reports The most consistent findings are the impaired ability of lymphocytes to proliferate (i.e. divide and make daughter cells) when stimulated by certain chemicals and the reduced activity of natural killer cells (a type of lymphocyte).94

The discovery of immunosuppression in depressed patients was widely publicized by medical professionals and the lay press. Immunosuppression fit very nicely with the view of the immune-brain connection as a one way communications pathway from the brain to the immune system (i.e. brain→immune system). It seemed natural to speculate on a depressed brain sending suppressive messages to the immune system. And why not? Depressed persons appear to be sending suppressive messages to their whole being, so why not to their immune system?

This notion appeared to make sense on many levels. Psychotherapists, especially those with psychoanalytical underpinnings, were attracted to it. Every day they thought they could see the power of the 'unconscious' mind on their patients lives. They reasoned that if the 'unconscious' mind could make a mess of someones life, then it seemed reasonable that it should be able to mess up their immune system also. Psychoneuroimmunologists, mind-body practitioners, writers and lecturers liked it because it gave them something deep, profound and mysterious to say.

Epidemiologists and ordinary physicians could subscribe to it, because they were aware of the statistics on depression, namely, depressed persons have more physical illnesses, more physical illnesses of greater severity and have higher death rates from physical illnesses than persons without depression.95,96,97 These statistics could be interpreted as being the effects of an impaired immune system. Thus the dogma that depression is linked with an impaired immune system and depression probably causes immunosuppression became firmly established in the minds of both the public and medical professionals.

Unfortunately, a critically important aspect of immunosuppression was not considered, namely, immunosuppression is very often caused by an activated immune system. We have talked about this paradox before. It is worth repeating- an activated immune system usually suppresses certain parts of the immune system. This paradoxical action prevents the immune system from running wild and attacking all parts of the body. One of the keys to the paradox is cortisol. Blood levels of cortisol always rise with immune activation. IL1 and IL6 released by activated macrophages, stimulate the hypothalamic-pituitary-adrenal axis to secrete copious amounts of cortisol. Cortisol is immunosuppressive. It helps to control energized immune cells.

We have mentioned two other factors that help to control an activated immune system- interleukin1 receptor antagonists (IL1Ra) and soluble interleukin2 receptors (sIL2R). Both of these substances are elevated in depressed patients. Both IL1Ra and sIL2R are released by activated macrophages and lymphocytes. They are reliable signs of immune activation, yet one of their main functions is to suppress the immune system.

Dr. Maes and colleagues are aware of immune impairment in depression. In fact, their first studies investigated immunosuppression with depression.98 In these first studies they accidentally discovered (most great discoveries are by accident) that their depressed patients had signs of immune activation along with signs of immunosuppression.99 Dr. Maes has shown that immune activation can account for the impaired lymphocyte proliferation in depression. For example, excessive IL1 in depressed patients elevates their cortisol level100, which in turn, impairs their lymphocyte proliferation.101) The blunted natural killer cell activity in depressed patients is also a consequence of immune activation.102

In conclusion, both immune activation and immune suppression co-exist in depression. Investigators looking for immunosuppression in depressed patients will find it. They will also find plenty of immune activation if they look for it. The key finding is this: immune activation is the cause of the immunosuppression in depression. The primary immune process in depression is immune activation and concurrent immunosuppression is secondary.

Summary

There is considerable immunological evidence supporting immune activation and cytokine secretion as important processes underlying depression. First, cytokines given chronically to human volunteers can produced all the symptoms necessary for the diagnosis of depression. Second, depressed patients secrete more cytokine than normal controls. The level of cytokine secretion is closely linked with the severity of the depression. Third, depressed patients have activated immune systems. The most severely depressed patients have the most activated immune systems. Furthermore, immune activation is the cause of the concurrent immunosuppression reported with depression.

Next chapter: Evidence From Biological Psychiatry


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