Chapter 8

Evidence From Biological Psychiatry

Biological psychiatry views mental illness as a physical or "biological" disorder rather than a "mental" disease. For over 45 years biological psychiatrists have searched for physical abnormalities in persons suffering from psychiatric disease. The main research pathway of biological psychiatry has been to investigate the actions of psychoactive medications, such as antidepressants and antipsychotics.

The antipsychotic drug chlorpromazine (Thorazine), discovered in 1952, was the first effective medication for schizophrenia. As we mentioned previously, the discovery of chlorpromazine revolutionized psychiatry. It jolted psychiatry into the world of biomedical research. Suddenly it was possible for biomedical scientists to view schizophrenia as a physical, biological disorder. Thousands of scientists immediately thought the obvious, that is, "if we could uncover the mechanism of chlorpromazine's action, then we could discover the secret to schizophrenia."

After 1952, many other effective psychoactive drugs were discovered- antianxiety (tranquilizers), antidepressant, antimanic and antipsychotic drugs. With these discoveries, all of the serious psychiatric diseases-anxiety, depression, schizophrenia, obsessive-compulsive disorder and manic-depressive disorder-could be viewed as physical-biological physical diseases. Investigating the mechanism of action of psychoactive medications became the main beacon and hope for the new and rapidly expanding field of biological psychiatry.

Elucidating the mechanism of action of a psychoactive drug is no easy task. The brain, of course, is the obvious place to look, but how can you experiment on a living human brain? Well, you can't. Its unethical and anyway, who is going to donate their living brain to scientific research? That leaves the living brains of experimental animals and the dead brains of human corpses. There are several problems here: 1). Even though rat and human brains are very similar, they are not identical. In addition, mental illnesses are distinctly human diseases. There are no animal models for schizophrenia, obsessive-compulsive disorder or manic-depressive disease. Syndromes that look like depression and anxiety can be produced in animals, but we can't be sure if they are the same as the human diseases. 2). Only limited information can be gathered from dead human brains. Obviously no drug action studies can be done because a dead brain has no action. Only analyses of brain structure, neurotransmitter concentrations and neurotransmitter receptor densities can be done. Except for brain structure, these analyses are questionable because brains from depressed persons usually have been exposed to antidepressants for many years. Hence any values from analyses may be revealing the effects of the drugs rather than insights into depression. 3). The brain is horrendously complex. Investigators could easily be looking in the wrong places.

In spite of these difficulties, progress in psychopharmacology has been rapid. We now have so much information on psychoactive drugs that it appears their actions are complex and multifaceted, rather than simple and uncluttered (what can you expect in a complex brain?). Investigating drug action has been the most fruitful area of research in biological psychiatry. Another area of fruitful research has been on hormone abnormalities in psychiatric disease.

Biological Psychiatry's Theories of Depression

Norepinephrine and Depression

Norepinephrine is a neurotransmitter made at sites inside and outside the brain. The locus coeruleus, a very small brain stem structure with direct connections to all the important structures in the brain, is the principal norepinephrine center. Outside the brain, the sympathetic nervous system and the adrenal glands are the main sources of norepinephrine.

In 1958, Tofranil (imipramine), the first modern antidepressant, was discovered. Tofranil, because of its chemical structure, is called a tricyclic antidepressant. In the 1960's it was revealed that Tofranil and the other tricyclic antidepressants block the uptake of norepinephrine into nerve endings.1 Very quickly biological psychiatrists proposed norepinephrine as one of the key factors in depression. The first investigations found that depressed patients appeared to have reduced activity and production of norepinephrine in the brain. Patients with mania appeared to have increased norepinephrine activity. This resulted in a nice uncluttered theory of both depression and mania i.e. depression is associated with a relative deficit of norepinephrine and mania is associated with a relative excess of norepinephrine.

A number of other pharmacologic agents supported the simple theory. For example, amphetamine (speed) and cocaine raise norepinephrine brain levels and also produce euphoria and mania-like symptoms. Conversely, the heart medication reserpine depletes brain norepinephrine and often leads to depression.

More recently, the simple view of excess norepinephrine in mania and reduced norepinephrine in depression has been severely challenged. The speed of action of antidepressants is one of the problems. Antidepressants affect norepinephrine receptors almost immediatly, yet it takes two or three weeks for them to exhibit their antidepressant effects. This suggests that something other than norepinephrine is the key to understanding depression. In addition, many recent human studies have reported increased norephinephrine in many depressed patients rather than decresed norepinephrine. At the present time, the more general notion of a dysregulation of the norepinephrine system is the working hypothesis for norepinephrine in depressed patients.2

The locus coeruleus (LC), the brain's principal norepinephrine center, plays a key role in many important neurobiological regulations, such as, blood pressure, hypothalamic-pituitary secretions and behavior. A great variety of brain chemicals affect locus coeruleus activity, including the neurotransmitters acetylcholine, epinephrine, gamma-aminobutyric acid (GABA) and serotonin. The LC, which receives messages from these psychiatrically important neurotransmitters, helps regulate the cortex, hippocampus, hypothalamus, cerebellum and many other centers profoundly involved in behavior.3 These facts on the LC emphasize the fundamental importance of norepinephrine in behavior.

Recently, further evidence of profound involvement of the locus coeruleus in depression was reported. Nestler4 and colleagues from Yale University tested all the major types of antidepressants on laboratory rats for 21 days and then measured the levels of the enzyme tyrosine hydroxylase in the LC. Every type of antidepressant reduced tyrosine hydroxylase by 40-70%. They also tested electroconvulsive therapy (an effective treatment for severe depression) and discovered that it also lowered tyrosine hydroxylase. Why is this important? Tyrosine hydroxylase is the rate limiting enzyme for the synthesis of norepinephrine. When tyrosine hydroxylase is reduced, norepinephrine is also reduced. Thus, all the effective biological therapies for depression diminish the production of norepinephrine in the LC. This strongly suggests that norepinephrine dysfunction is a key factor in depression.

Cytokines and Norepinephrine

What causes the norepinephrine dysfunction in depressed patients? At the present time, cytokines are the strongest candidates. (Corticotrophin releasing factor (CRF), a hypothalamic hormone, is also a candidate. But cytokines do affect CRF. See chapter 5.). A variety of cytokines, including IFNα, IL-1 and IL-2 have been shown to powerfully affect locus coeruleus activity.5,6,7 Animals challenged with antigens (this activates the immune system and raises cytokine secretion) have increased norepinephrine activity in the locus coeruleus, hippocampus and the hypothalamus.8 The neurotransmitter changes were very similar to those provoked by uncontrollable psychological stressors.

A great many studies have consistently reported that IL-1 given peripherally (that is, outside the brain) to whole animals stimulates the turnover and release of norepinephrine in the hypothalamus.9,10 The neurons releasing the norepinephrine into the hypothalamus actually originate in the locus coeruleus. Thus, the locus coeruleus powerfully influences the output of hypothalamic-pituitary hormones, including the stress hormones. Increased release of norepinephrine in the hypothalamus raises the output of stress hormones. IL-1 also stimulates tyrosine hydroxylase activity in the hypothalamus.11 In addition, IL-2 profoundly raises norepinephrine activity in the hypothalamus.12

What does all this mean? It means that cytokines can account for the norepinephrine abnormalities found with depression. This, of course, is extremely important, because norepinephrine dysfunction is thought to be one of the key factors underlying depression. This is powerful support for the immune-cytokine model of depression.

Serotonin and Depression

Norepinephrine dysregulation isn't the only neurotransmitter problem linked with depression. This is clearly shown by the action of antidepressants, since antidepressants affect many neurotransmitter receptors in the brain, in addition to norepinephrine receptors. In fact, antidepressants have a greater affinity for histamine receptors (histamine acts as a neurotransmitter in the brain) than they do for norepinephrine receptors. Antidepressants also have an affinity for acetylcholine, dopamine and serotonin receptors.13

Brain studies also reveal why norepinephrine couldn't be acting alone as the only neurotransmitter involved with depression. Serotonin, for example, is found in many neurons containing either norepinephrine or GABA. Serotonin and norepinephrine have a particularly close relationship. Serotonin and norepinephrine neurons can take up each other's neurotransmitter, thereby altering each other's function. In addition, serotonin neurons inhibit norepinephrine neurons in the locus coeruleus while norepinephrine neurons help regulate serotonin neurons. Serotonin and dopamine also have a close, mutual influencing relationship.14

The chemical name for serotonin is 5-hydroxytryptamine (5HT), so serotonin is often abbreviated 5HT. The bulk of the serotonin containing nerves are in the brain stem formation called the raphe nuclei. Each serotonin nerve cell puts out over 500,000 terminals to the thinking (cortex) and emotional (limbic system) centers of the brain!15 Due to the enormous number of connections, serotonin is involved in regulating mood, anxiety, arousal, vigilance, impulsivity, aggression, suicidality, obsessive-compulsive behanvior and psychotic thinking. In addition, serotonin containing nerves help regulate appetite, sleep-wake cycle, daily and seasonal biological rythms, pain reception, hormone production and brain development.16 Serotonin dysfunction is implicated in a broad spectrum of psychiatric diseases, including depression, anxiety, obsessive-compulsive disorder, alsoholism, schizophrenia and autism.

For the past ten years serotonin has been at the center of depression research. This has been due to the discovery of very effective antidepressants (i.e. Prozac, Zoloft, Paxil) which primarily affect the reuptake of serotonin. These new drugs (called serotonin selective reuptake inhibitors or SSRI's) for the most part have more powerful benefits and fewer side effects than the older tricyclic antidepressants.

Recent research has found other evidence linking serotonin with depression. Much of it has to do with the amino acid L-tryptophan (LTRP), since serotonin is made from it. When LTRP is in short supply, serotonin production goes down. Several studies show that depressed patients have lower blood levels of LTRP. Also, LTRP deficient diets give to normal men lowers their mood while depressed patients successfully treated with Prozac, have a rapid return of their depressive symptoms when LTRP is eliminated from their diet. A good deal of other research (but too complex to present here) supports reduced serotonin activity as a key factor in depression.17

Cytokines and Serotonin

Low levels of LTRP is one of the best documented abnormalities in depression. Since LTRP is needed for serotonin synthesis, this abnormality can explain some of the reduced serotonin activity in the brain. Yet the cause of the low LTRP has been difficult to explain. Dietary studies, popularized by Wurtman18 , suggested diet may be involved in the low LTRP. High carbohydrate diets, for example, appeared to increase LTRP availability to the brain whereas high protein diets reduced LTRP availability. Nevertheless, the effects of protein vs. carbohydrate diets on LTRP availability are modest and diet cannot account for the low LTRP in depressed patients.

Recently, Dr. Maes19,20 and colleagues provided evidence of profound cytokine involvement in low plasma LTRP. In depressed patients, signs of immune activation were inversely related to LTRP levels. In other words, depressed patients with the greatest immune activation and cytokine secretion had the lowest LTRP levels. The relationship with interferonγ was particularly interesting, because previous workers21 had shown that interferonγ sharply reduces LTRP levels. This is how it lowers LTRP: interferonγ stimulates the production of an enzyme called indoleamine 2,3-dioxygenase. This enzyme degrades LTRP by converting it into another substance. Other cytokines, like IL-1 and IL-6, can also reduce LTRP levels. Thus, low LTRP in depression appears to be caused by immune activation, especially the cytokines interferonγ, IL-1 and IL-6. The low LTRP is an important factor in the low serotonin in depressed patients.

There are now a number of excellent research papers showing that IL-1 and IL-6 have very pronounced effects on serotonin activity in the brain. Zalcman et al22 gave cytokines to whole animals peripherally (i.e. outside the brain rather than inside the brain) and discovered important changes in serotonin activity in the hypothalamus and hippocampus. Serotonin activity increased in both these brain areas which resulted in depleted content of serotonin. Linthorst et. al.23 from the Max Planck Institute applied interleukin-1β directly to the hippocampus of whole animals and observed behavior, serotonin activity and hormone output. There was a significant increase in serotonin activity, hypothalamic-pituitary-adrenal hormone (i.e. stress hormones) output and depression-like behavior. Four other research groups applied interleukin-1β directly to the hypothalamus in whole animals with remarkably powerful effects on serotonin activity.24,25,26,27 These studies confirme and reconfirme IL-1's consistent effects on serotonin activity and stress hormone output. Both serotonin activity and stress hormone output were increased.

These sophisticated experiments show that both IL-1 and IL-6 directly affect the serotonin system in the brain, whether they are give peripherally or applied directly to the brain. These papers along with Dr. Maes remarkable discoveries on LTryp provide very good evidence that immune activation is a key factor in the serotonin abnormalities found in depressed patients. Indeed, at the present time, immune activation is the only known scientific explanation for the serotonin abnormalities in depression.

There is one important serotonin finding that is unresolved. In depressed humans, it appears that serotonin activity is reduced, but in all the animal studies with cytokines, the serotonin activity was increased. What gives here? A key difference is that in the animal studies, all experiments were short term, three or four hours at the most, whereas in humans, depression is a chronic, long term affair. Long-term, chronic animal studies with cytokines are urgently needed. Nevertheless, the really important discovery is that cytokines profoundly affect serotonin activity, since serotonin dysfunction is the best way to describe the serotonin phenomena in depressed humans.

It is possible to extrapolate from these short term animal studies of increased serotonin activity to predict reduced serotonin activity with chronic immune activation. First, Dr. Maes and others have shown that interferonγ depletes LTRP. Chronic depletion of LTRP would naturally lead to reduced serotonin activity, since LTRP is the precursor for serotonin. Second, high serotonin output would eventually lead to depleted serotonin production. Third, it is common for biological systems to compensate for an activated system by slowly down-regulating it. Thus, chronic immune activation and cytokine secretion could easily lead to depleted serotonin along with a down-regulated serotonin system.

Dopamine and Depression

Dopamine is a neurotransmitter with a close relationship to norepinephrine, because norepinephrine is made from dopamine. The steps in the biosynthesis of dopamine are:

Tyrosine → Dopamine → Norepinephrine → Epinephrine

The production rate of both dopamine and norepinephrine is controlled at the first step (tyrosine→DOPA) by the enzyme tyrosine hydroxylase. Previously, in the norepinephrine section, we mentioned that antidepressants reduce the activity of tyrosine hydroxylase28, therefore antidepressants affect the production of dopamine. In addition to reducing the activity of tyrosine hydroxylase, most antidepressants affect the dopamine system in other ways. Bupropion, a unique antidepressant, only modestly affects serotonin and norepinephrine, while its most potent effect is blocking dopamine reuptake.29 Therefore, evidence from antidepressant action suggests that dopamine plays an important role in depression.30

A considerable amount of human evidence shows that a low dopamine turnover rate is linked with depression.31 First, reduced levels of the dopamine metabolite homovanillic acid is found in the cerebrospinal fluid of depressed patients. This is strong evidence of low dopamine turnover. Depressed persons attempting suicide also have low homovanillic acid in cerebrospinal fluid. Second, dopamine receptor binding is increased in depressed patients. This is consistent with low dopamine turnover. Third, psychostimulants like amphetamine and methylphenidate increase dopamine activity and appear to relieve depression. Indeed, amphetamine is still used to treat difficult cases of depression. Fourth, drugs like bromocriptine which increase dopamine activity exclusively, are effective antidepressants. Fifth, high dose anti-psychotic drugs usually worsen depressed mood. High dose anti-psychotics reduce dopamine activity. On the other hand, low dose anti-psychotic drugs usually improve depressed mood. Paradoxically, anti-psychotics at low doses increase dopamine activity. Sixth, patients with Parkinson's Disease have very high rates of depression. Diminished dopamine activity is the main pathology in Parkinson's Disease. Seventh, mania, which seems to be the opposite of depression, has high dopamine activity.

Cytokines and Dopamine

The above evidence suggests dopamine dysfunction plays an important role in depression. Of course, the important question is, what causes the dopamine dysfunction in depression? As with serotonin and norepinephrine, cytokines profoundly affect dopamine activity. All of the cytokine-neurotransmitter animal experiments studies have been short term (i.e. hours) . There have been many experiments with interleukins. Interleukin-1 increases tyrosine hydroxylase activity, the enzyme for the production of dopamine and norepinephrine.32 Several experiments injected interleukin-1 directly into the hypothalamus and found a great increase in dopamine release by the hypothalamus.33,34,35 One experiment administered several different cytokines peripherally, that is, outside the brain rather than inside the brain.36 They reported that IL-1 enhanced dopamine turnover in the prefrontal cortex; IL-6 increased dopamine activity in the hippocampus and prefrontal cortex and IL-2 increased dopamine turnover in the prefrontal cortex. Probably the most interesting experiment was done by a psychiatric group from McGill University.37 They applied IL-2 to brain at several different concentrations. At very low concentration, IL-2 increased dopamine release, but at higher concentrations, IL-2 inhibited dopamine release.

These studies clearly show that various cytokines at physiological concentrations have profound effects on dopamine activities. Most studies showed cytokines increased dopamine release, but one notable study showed decreased dopamine release at higher cytokine concentrations. Unfortunately, all the experiments are over a very short time period, whereas depression and other psychiatric diseases are long-term chronic disorders. Long term experiments which test the effects of cytokines on neurotransmitter activities are urgently needed.

Acetylcholine and Depression

Acetylcholine is a neurotransmitter at three important sites: brain, the autonomic system and the junction between nerves and muscle, called the neuromuscular junction. At the neuromuscular junction, acetylcholine tells the muscle to contract. The neuromuscular junction has been an important target for the development of poisons used against humans and insects. Insects have neuromuscular junctions very similar to the ones in humans, with acetylcholine as the messenger. Most present day insecticides block acetylcholine metabolism at the neuromuscular junctions in insects and in humans. (The trick here, of course, is to follow the instructions on the label so insects will die without killing humans). When acetylcholine metabolism is blocked, muscle function goes haywire, so all vital muscle actions become deranged, including breathing and heart beat. Death ensues quickly. Nerve gas has the same mechanism of action as insecticides, but it is more lethal than insecticides because it is inhaled, gets into the blood more rapidly and then is carried quickly throughout the body until the victim dies.

The autonomic nervous system, which connects the brain to vital organs and structures throughout the body, uses acetylcholine as a neurotransmitter. General body functions, such as heart rate, breathing and gastrointestinal functions are regulated by the autonomic nervous system. This system has two branches: the sympathetic system and the parasympthetic system. These two branches usually have opposing actions: the sympathetic system generally prepares your body for danger and the parasympathetic system prepares your body for safety and relaxation. Thus, sympathetic nerves increase heart rate and decrease gastrointestinal function, while parasympathetic decrease heart rate and increase gastrointestinal function. Sympathetic nerves require acetylcholine at the end closest to the brain and use norepinephrine at the end innervating vital organs and structures. The parasympathetic system uses acetylcholine at both ends. The sympathetic system and the hypothalamic-pituitary-adrenal axis (HPA-axis) work together to prepare the body for danger. We will discuss this relationship further in a later section.

There are various acetylcholine centers throughout the brain. Due of its involvement in Alzheimers Disease, the nucleus basalis in the lower part of the forebrain is the best known acetylcholine center. The nucleus basalis has extensive connections with the cerebral cortex, the thinking part of the brain, and the hippocampus, an important structure for memory and emotion. Severe memory deficits are evident when the nucleus basalis is damaged, as occurs in Alzheimer's Disease.

An acetylcholine theory of depression was first published in 197238 and was recently reviewed.39 Essentially the theory proposes that overactivity of the brain's acetylcholine system is an important dysfunction causing depression. The theory is based on animal models of depression and limited human work. For example, drugs which increase acetylcholine activity provoke behaviors in animals which mimic human depression. They also activate the HPA axis (HPA axis activation is a common finding in depressed persons).

Psychiatrically normal subjects given drugs that increase brain acetylcholine levels, rapidly develop depressed moods. Depressive symptoms worsen in depressed patients given these same drugs. Depressed patients appear to be more sensitive to these drugs than normals. (It should be pointed out that these acetylcholine enhancing drugs function the same as insecticides and nerve gases. It is not surprising that nerve gas like drugs have powerful effects on mood and behavior, but it is quite an extrapolation to suggest that this is the basic pathology of depression.)

Subjects receiving acetylcholine precursors, like choline or lecithin, sometimes report depressed moods. Recently, MRI brain scans revealed higher choline levels (choline is needed to make acetylcholine) in the brains of depressed patients. After successful antidepressant drug therapy, the high choline brain content returns to normal. It is difficult to interpret these precursor studies since choline and lecithin have many actions of their own.

Many antidepressant drugs do affect the acetylcholine system, but there are no pharmacological papers claiming that this is part of their antidepressant of action. Thus, the scientific literature on antidepressant drugs is not very supportive of the acetylcholine theory of depression.

Altogether, there is some support for the acetylcholine theory of depression. But it is very difficult to argue that dysfunction of the acetylcholine system is the fundamental neurotransmitter pathology underlying depression since there is so much independent evidence on serotonin and norepinephrine and little truly direct evidence on acetylcholine. The acetylcholine system influences serotonin and norepinephrine, while the serotonin and norepinephrine systems influence acetylcholine. Therefore if serotonin and norepinephrine are important for depression, then it seems reasonable that the acetylcholine system would have some influence here.

Cytokines and Acetycholine

What causes the acetylcholine dysfunction, if any, in depression? None of the proponents of the acetylcholine theory even suggest a cause, except that other neurotransmitter dysfunctions, like serotonin and norepinephrine, may be causing it. But biological psychiatry has not come up with any explanations for the serotonin or norepinephrine problems either. Once again, cytokines to the rescue.

A number of cytokines have been investigated to see if they affect the acetylcholine neurotransmitter system. Interleukin-140 and interleukin-241 are the only cytokines that appear to influence acetylcholine. IL-1 at low doses, during the first 20 minutes, increased the content of acetylcholine. Higher doses, on the other hand, reduced the acetylcholine content of the hippocampus. IL-2 produced a very similar effect. High doses of IL-2 lowered acetylcholine concentrations, whereas low doses raised acetylcholine concentrations. In humans, according to the authors of the IL-2 paper, low levels of IL-2 would be more realistic and high levels of IL-2 would only be expected under more serious, pathological condition. Therefore, these researchers would expect IL-2 to more commonly raise acetylcholine levels than lower them.

The main conclusion of the cytokine-acetylcholine experiments is this: both IL and IL-2 profoundly affect the acetylcholine neurotransmitter system. More extensive experiments need to be done, especially long term chronic studies and giving cytokines peripherally rather than injecting them directly into the brain. Nevertheless, the cytokine theory of depression is the only model that provides an external explanation for the possible acetylcholine dysfunction in depression.

Antidepressants and Cytokines

We have mentioned several times that antidepressant drugs have been at the center of biological psychiatry's notions on depression. The neurotransmitter theories of depression have come directly from the presumed mechanism of action of antidepressant drugs. Since their inception, there has been a fundamental problem with the neurotransmitter theories of depression, namely, antidepressant drugs affect neurotransmitter systems almost immediately, yet it takes two to three weeks of daily medication for the depressive symptoms to abate. The time lag strongly suggests that antidepressants are affecting something in addition to neurotransmitters. Recent reports indicate that immunosuppressive mechanisms may play key roles in antidepressant drug action.

The antidepressant Rolipram is an important example. Rolipram does not directly affect neurotransmitters in the brain. Instead, it suppresses the production of tumor necrosis factor, interferon-gamma and a cytokine named lymphotoxin.42 Rolipram's actions are remarkable support for the cytokine theory of depression.

The tricyclic imipramine, when given orally for several weeks to rats, caused a huge increase in interleukin-1 receptor antagonist production in widespread areas of their brains.43 Why is this important? Because the main function of interleukin-1 receptor antagonist is to block the action of interleukin-1. Interleukin-1 receptor antagonist is an anticytokine. It helps to control and suppress an activated immune system. Thus, imipramine, which for many years was thought to primarily affect norepinephrine, has now been shown to have immunosuppressive, anticytokine properties. Also, the length of time it takes to induce interleukin-1 receptor antagonist production fits very nicely with the time lag for effective antidepressant action.

In 1996, a landmark investigation by Xia et. al.44 reported immunosuppressive actions for three different tricyclic antidepressants. Monocytes and T-lymphocytes from human blood, when incubated with tricyclics, produced 60% less IL-2, 70% less IL-1 and TNF, and also inhibited IL-6 and interferon-gamma. Thus, tricyclic antidepressants have direct cytokine suppressive properties. This important discovery dramatically supports the cytokine theory of depression.

Very recently, Shirayama et al45 reported that long term antidepressant treatment reduced the production of substance P in rat brain. They used five antidepressants, each one having a different presumed mechanism of action (ie they worked on different neurotransmitter systems). Nevertheless, all of them had one action in common: they reduced substance P in the brain. This discovery does link directly with cytokines, because substance P stimulates monocytes to produce more IL-1, IL-6 and TNF.46 Possibly of greater importance is the ability of substance P to induce astrocyte cells in the brain to produce more cytokine.47 Hence, by reducing substance P, the production of cytokines inside the brain and outside the brain is reduced.

Another action of a broad range of antidepressants is their ability to lower the activity of the enzyme tyrosine hydroxylase.48 (Tyrosine hydroxylase controls the production of norepinephrine and dopamine). In contrast, the cytokine IL-1 raises the activity of tyrosine hydroxylase.49 Consequently, the ability of antidepressants to lower the activity of tyrosine hydroxylase can be viewed as an anticytokine property.

Conclusion The recently discovered anticytokine and cytokine suppressing properties of antidepressants is of fundamental importance to any theory of depression, especially a cytokine theory of depression. In sharp contrast to the rapid effects of antidepressants on neurotransmitter systems, antidepressants have a slow effect on cytokine systems. This fits beautifully with the slow therapuetic action of antidepressants on depressed patients. Indeed, the slow therapuetic action of antidepressants has been the fundamental problem with the neurotransmitter theory of depression.

Hormones and Depression

The Hypothalamic-Pituitary-Adrenal Axis (HPA-Axis)

In a previous section we discussed the HPA-axis. The hypothalamus is one of the key command and control centers of the brain. It releases a variety of hormones that control the pituitary. One of them, corticotrophin releasing factor (CRF) permits the pituitary to release adrenocorticotrophic hormone (ACTH) into the blood stream. ACTH stimulates the adrenal cortex to release cortisol into the blood.

Under normal, benevolent circumstances, the HPA-axis is a self-regulating system, with the various hormones staying in a 'normal' range. The self-regulation is made possible by cortisol exerting feedback control over the hypothalamus. For example, a high blood level of cortisol forces the hypothalamus to reduce its output of CRF, this in turn reduces ACTH which then reduces cortisol output. On the other hand, a low blood level of cortisol permits the hypothalamus to increase its output of CRF, triggering a higher release of ACTH, which goes on to stimulate the release of cortisol. This feedback control keeps cortisol within a 'normal' range.

Many 'abnormal' circumstances can alter the self-regulating scenario. A tumor on the pituitary or the adrenals can push ACTH and cortisol way above normal. This rare condition is called Cushing's Disease. A very high rate of depression occurs with Cushing's Disease, which first suggested to researchers that HPA-axis overactivity could cause depression.

The most common cause of HPA-axis hyperactivity is stress. This has been so extensively confirmed in animal and human experiments that the HPAaxis is called the stress axis.

External stressors (ie. psychological, 'mental', social and economic stressors) activate the HPAaxis and so do internal stressors (ie. infection, trauma, dying tissue, organ dysfunction, cancer, autoimmune disease and other physical diseases.) When external stressors are present (life-threatening danger, for example), the sympathetic nervous system, including the adrenal medulla, participates. The sympathetic system can be profoundly activated by the hypothalamus. The sympathetic system prepares the body for danger by raising heart and breathing rate, blood flow to muscles, glucose availability and alertness. It also stimulates the adrenal medulla to release adrenalin into the blood stream. Adrenalin in the blood reinforces and extends the actions of the sympathetic nervous system. An activated sympathetic-adrenal medulla system makes most people feel nervous with heart pounding anxiety.

HPA-axis hyperactivity along with anxiety is a common finding in depressed patients. Stress is by far the most common cause of HPAaxis hyperactivity, therefore stress has been offered as the main explanation for the HPA-axis hyperactivity in depressed patients. This has resulted in labeling depression a 'stress-induced disease'.

If depression is a stress induced disease, then what are the stressors inducing depression? External stressors (ie psychological, 'mental', social, economic) have been the main factors suggested by psychiatrists, psychologists, popular writers and the public. This leads to statements like, "I am depressed because I have a stressful job." "I am depressed because I have a stressful marriage" "I am depressed because of economic stresses" "I am depressed because I am stressed out" or "The world is so stressful, that's why I am depressed".

There are problems with the these notions on stress and depression. If the notions were correct, then the incidence of depression should be at least ten times higher because the majority of people routinely face significant external stressors. In almost all cases of depression, external stressors cannot account for their illness. If they could, then the etiology of depression would be known, because we would know the cause of most cases of depression. Clearly, this is not the situation in psychiatry today or yesterday. Every textbook of psychiatry and every scholarly review on depression openly admits that the etiology of depression is unknown. For example, The American Psychiatric Association's latest texbook of psychiatry says "The causes of depressive disorder and bipolar disorder are unknown."50

Cytokines and HPAaxis Hyperactivity

HPAaxis hyperactivity in depressed patients is one of the most extensively documented physical abnormalities in biological psychiatry. So what is the cause? This question has been stumping biological psychiatry for years. Since external stessors can only account for a small percentage of HPA overactivity, they have looked elsewhere for the cause. Neurotransmitters are involved in regulating the HPAaxis, so they have been examined.51 It is reasonable to suspect that neurotransmitter dysfunctions could be causing the HPA dysfunction. But then, what causes the neurotransmitter dysfunctions? Biological psychiatry (since they are oblivious to cytokines) draws a blank. So we are back to square one, no known cause. The other area exhaustively searched is the HPAaxis itself.52 The defect or defects in the HPAaxis are sought. And what if they are found? The next question would be, what caused the HPAaxis defects? Again no answer, so back to square one, that is, no known cause.

Cytokines to the rescue. We know that HPAaxis activation is caused by either external or internal stressors. In the case of depression, external stressors have been eliminated as the key factor, so this leaves internal stressors (ie infection, trauma, autoimmune disease, cancer, dying tissue and organ dysfunction) as the cause. Internal stressors are well established causes of immune system activation and activated immune systems secrete much higher amounts of IL-1, IL-2, IL-6 and TNF. These same cytokines profoundly activate the HPAaxis53,54

In 1991, in a published biomedical paper titled "The Macrophage Theory of Depression"55 I suggested that the macrophage cytokine IL-1 was the cause of the HPAaxis hyperactivity. For the past six years Dr. Michael Maes and others have extensively documented immune activation, including excessive secretion of IL-1, IL-2, IL-6 and TNF, in depressed patients (see chapter 6). Dr. Maes also found that the elevated IL-156 and IL-6 in depressed patients accounted for the HPAaxis hyperactivity.

So there you have it. Immune activation and cytokines were proposed as the cause in 1991. Dr. Maes and others from 1991 to 1996 found exceedingly powerful and consistent support for the proposal. For the most part, the HPAaxis activation mystery of depression has been solved by the discovery of immune activation in depression. Now we are in 1997 and where is biological psychiatry on this issue?

We previously covered the extensive evidence showing that depressed patients have activated immune systems, including increased cytokine secretion.

The popular concept of stress as being exclusively psychological or mental is a fundamental defect in the notion of depression as a 'stress' induced disease. The continual emphasis on external stressors (ie mental stressors) as the cause of HPA-axis overactivity has resulted in reinforcing the notion of depression as a 'mental' disease caused by 'mental' stressors. Thus, an important finding of biological psychiatry (ie HPA-axis overactivity in depression), has, paradoxically, led to an overemphasis of a non-biological view of depression (ie that depression is a disease caused by 'mental' or psychological stressors.)

Next chapter: Physical Illness & Depression

Chapter 8 References

1. Richelson E. Biological basis of depression and therapeutic relevance. J Clin Psychiatry 52:6(suppl), 4-10, 1991.

2. Siever LJ. "Role of noradrenergic mechanisms in the etiology of affective disorders" in Psychopharmacology: The Third Generation of Progress. Meltzer HY ed. Raven Press, New York, 1987.

3. Valentino RJ, Aston-Jones GS. "Physiological and anatomical determinants of locus coeruleus discharge." in Psychopharmacology: The Fourth Generation of Progress. Bloom FE, Kupfer DJ, eds. Raven Press, New York, 1995, pp373-385.

4. Nestler EJ, McMahon A, Sabban EL et al. Chronic antidepressant administration decreases the expression of tyrosine hydroxylase in the rat locus coeruleus. Proc Natl Acad Sci (USA) 87:7522-26, 1990.

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