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Cytokines and Depression

Chapter 9

Physical Illness and Depression

Chapters 7 and 8 summarized a massive amount of recent biomedical evidence confirming the Immune-Cytokine Paradigm of Depression (ICPOD). Depression can now be conceptualized in a completely new way. Instead of a large set of arbitrary types and subtypes of a mysterious, elusive disease, depression can now be understood to be a multifaceted sign of chronic immune system activation, analogous to fever as a reliable sign of acute immune system activation. The important question is, what is the cause of the chronic immune system activation? One obvious answer is chronic physical disease, because immune system activation and cytokine secretion are integral parts of physical disease. In fact, most of the symptoms, signs and pathology of physical diseases are caused by cytokines (see Chapter 5).

The ICPOD directly predicts a very high incidence of depression with physical illness. Not only does it predict, but it also provides a mechanism, which incorporates the latest concepts and advances of biomedical science, to explain why there is a high incidence of depression with physical illness. No other model of depression can do this.

Biomedical reports over the past 20 years have consistently confirmed ICPOD's prediction In very large studies of physically ill patients, up to 83% have significant depressive symptoms and up to 26% are diagnosed with depression.1,2 The patients with the most severe physical illnesses have the highest incidence of depression. Also fitting beautifully with the immune-cytokine model is the finding that physical illness is the most frequently reported cause of depression in older persons.3

Thus, the biomedical literature shows that physically ill patients have high rates of depression. This, of course, is not surprising since depression is actually a multifaceted sign of chronic immune system activation and physically ill people have activated immune systems. This is no more surprising than having a high incidence of fever in patients with acute physical illnesses, since fever is a reliable sign of acute immune system activation.

Physically ill patients with depression have poorer outcomes compared to patients without depression. For example, one study tracked 285 home-dialysis patients.4 After age, depression was the most important predictor of death in these patients. Depression was more important than any of the physiological variables measured. In addition to higher death rates, depressed patients have many more complications. A recent study of 211 seriously ill hospitalized patients documented a more powerful influence of depression on complications and death.5 Seventy of the physically ill patients were depressed. After one month in hospital, 22% of the depressed patients died compared to less than 4% of the non-depressed patients. Moreover, the depressed patients had four times as many life-threatening complications. These findings were independent of disease severity and age, in fact, the depressed patients were younger. There are many other reports of increased complications and death in depressed physically ill patients.

Having more complications and deaths in depressed physically ill patients is not surprising either, since depression is a sign that the immune system is more activated in these patients, indicating that there is a more violent, desperate war going on in their bodies. Depression is a sign that the patient is sicker, just as high fever is a sign of disease severity in acutely ill patients.

A century ago, when fever was viewed as a disease rather than a sign of disease, fever was blamed for complications and death in sick people. And why not? Patients with the highest temperatures had the highest death rates and most complications. A nice correlation: higher fever, higher death. Blaming fever for deaths based on correlations is an example of flawed scientific thinking, because correlations do not give information on cause and effect. Correlations merely indicate that there may be a relationship between death and fever, but it doesn't reveal the nature of the relationship, if any.

Today, no medical professional would suggest that fever kills patients because we know that fever is not a disease. It is a sign of acute immune system activation, an indicator of the intensity of the war going on inside the body. In like fashion, depression is not a disease, but rather a multifaceted sign of chronic immune system activation, an indicator of disease severity. Nevertheless, medical professionals continue to view depression as a disease, and therefore lay the blame on depression for the higher deaths and increased complications in physically ill patients. Blaming depression is another example of flawed scientific thinking.

Persons diagnosed with depression, but apparently free of physical illness, also have higher death rates, at least four times higher than healthy, non-depressed persons! This comes from an intensive study of 3000 adults age 55 and over living in the New Haven, Connecticut.6 The authors wrote, "Our results indicate that the odds of dying are more than four times greater for individuals with affective disorders (i.e. depression) than for others in the sample, controlling for age, sex, and physical health. There were no suicides or deaths from external causes."

In a study of 11,000 outpatients, the functioning and well-being of subjects with depressive symptoms (but no physical illness) were compared to healthy controls and to persons with chronic physical diseases.7 The functioning and well-being of persons with depressive symptoms were much worse than healthy controls. Somewhat surprising, the functioning and well-being of persons with depressive symptoms were, for the most part, worse than for patients with chronic physical diseases! Patients with both depressive symptoms and a chronic physical disease had the very poorest functioning and well-being.

Of special note: the subjects with depressive symptoms, in general, did not have enough symptoms to qualify for a depressive disorder. In other words, having a few depressive symptoms impairs a person's functioning and well-being as much as heart disease, lung disease or other chronic diseases do. A very recent survey of 2400 subjects confirmed the debilitating effect that a few depressive symptoms have on functioning and well being.8 This is of great importance because the number of people having depressive symptoms (but not enough symptoms to qualify for a diagnosis of depression) is three times greater than the number diagnosed with depression. We are talking about a lot of people here. In this survey, 16% of the people had either depressive symptoms or a depressive disorder. Sixteen percent of the whole population of the United States is 40 million people. Think of it, 40 million people in the US having depressive symptoms that impair functioning and well-being as much as major chronic physical illness do!

Our immune-cytokine model of depression sees the findings this way: 1). Forty million people in the US have chronic immune system activation of unknown cause. 2) Chronic immune system activation impairs functioning and well-being as much as chronic physical illnesses do. 3). These people would be expected to have a high incidence of physical illnesses, because physical disease is a common cause of immune system activation.

Indeed, there are numerous reports of previously undiscovered physical diseases in psychiatric patients. One of the most striking was an intensive medical investigation of 100 consecutive admissions to a state psychiatric hospital.9 An astonishing 80% of the patients had previously undiagnosed physical illness! Almost half the patients had physical illness that were causing the psychiatric symptoms. Twenty eight patients, upon successful treatment of their physical illness, had complete elimination of their psychiatric disease! These authors point out that the great majority of psychiatric patients are not examined for physical diseases and when they are, the exam is usually cursory and superficial. The implications of this study are mind-boggling.

Other investigations have also reported previously undiagnosed physical diseases, but the numbers are not as high. A California study of 529 public mental health patients found almost half had active physical diseases and the majority were undetected before the study.10 Fosythe et al11 reexamined 1100 mental health outpatients. Fifty-six percent had physical diseases, with over half of them previously undiagnosed. In a different report on 2090 mental health outpatients, Koranyi12 found 43% had physical diseases, with almost half of them previously undiagnosed. Almost 75% of the physical diseases were thought to be the cause of the mental health problems. A smaller study of hospitalized psychiatric patients (200 patients) reported 50% had physical illnesses and half of those were causal of their psychiatric diseases.13 Many other studies documenting the physical illness and undiagnosed physical illness in psychiatric patients can be found in reference.14

Even though the incidence of physical disease in these reports is remarkably high, they are most likely an underestimate because many physical diseases are very hard to detect. Remember, it took over 50 years to discover the physical cause (i.e. bacterial infection) of peptic ulcers. Brucellosis (milk fever), a known cause of fatigue and depression, is extremely difficult to identify after the acute stage. Lyme disease has been around a long time, but it was only recently discovered to be a bacterial infection. It was the mysterious cause of severe juvenile arthritis. Lyme disease is a known cause of depression and a schizophrenic like syndrome. Once the infection becomes chronic, it becomes exceedingly difficult to identify. These few examples provide unmistakable evidence that chronic bacterial infections can be exceedingly difficult to uncover. Recent scientific papers reporting evidence of Borna Disease virus infection in depressed patients suggests infection is the cause of their depression.

Early stage cancer is difficult to detect.

ORGANIC BRAIN DISEASE

Multiple sclerosis, Alzheimer's Disease, Parkinson's Disease and stroke are considered organic brain diseases because they exhibit consistent, measurable structural brain pathologies. In contrast, psychiatric diseases like depression, schizophrenia, bipolar disorder, anxiety and obsessive compulsive disorder have traditionally been classified as functional brain diseases because measurable structural brain pathologies were not usually found. Due to more detailed brain pathology studies, the distinction between organic and functional brain disease is not as clear today as it was in the past. For example, brains from schizophrenic and depressed patients often (but not always) have structural abnormalities.

The extensive immunological evidence summarized in this book questions the whole notion of classifying depression as either an organic or functional brain disease. First, we have shown that depression is not a brain disorder, but rather is an activated immune system which sends powerful mood and behavior altering messages (i.e. cytokines) to the brain. Second, we have argued that depression isn't a disease after all. Instead, depression is a multifaceted sign of chronic immune system activation.

Depression is a prominent feature of the organic brain diseases covered in this section. Biological psychiatry remains befuddled by the depression exhibited by the organic brain disease patients. Establishment psychiatry offers no biological mechanisms or theories to explain the high incidence of depression with these diseases. In contrast, the cytokine model of depression provides a direct, consistent and uncluttered mechanism to explain their high incidence of depression.

Multiple Sclerosis Nerve cells have three basic parts: dendrites, the axon and the cell body. Dendrites are fine projections extending from the cell body. They receive messages from other cells and carry the message to the nerve cell body. The axon is a long, fine projection extending from the cell body. It carries messages from the cell body to other cells. Most axons, especially long ones, are wrapped by special cells called oligodendrocytes . These cells are rich in a fatty substance called myelin. Axons wrapped with oligodendrocytes are said to be myelinated. Nerve impulses travel along myelinated axons very rapidly compared to non-myelinated axons.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the brain. In this disease, the oligodentrocytes surrounding axons are destroyed at various random locations in the brain. After the oligodendrocytes are destroyed, the axons are essentially demyelinated. Demyelinated axons carry messages very slowly, hence these nerve cells essentially stop functioning which results in profound muscular dysfunctions and other deficits. The dysfunctions produced by MS vary, depending on the locations in the brain where the oligodendrocytes have been destroyed. Connective tissue is produced at the various sites where the oligodendrocytes have been destroyed, which is the basis for the name multiple sclerosis (sclerosis=hardening).

Over 300,000 people in the United States have MS, the majority are female.15 There have been intensive investigations on the etiology of MS16, but unfortunately the cause or causes remain unknown. Nevertheless, a great deal is known about the steps involved in the destruction of the oligodendrocytes.17

In healthy individuals, activated T-lymphocytes can pass through the blood-brain barrier, survey the brain and then return to the blood. For some unknown reason, in MS patients the activated T-lymphocytes remain in the brain and secrete cytokines to attract and activate other immune cells, including macrophages and lymphocytes. The activated macrophages and lymphocytes begin attacking, destroying and devouring myelin and oligodendrocytes at various random sites. The immune activation and tissue destruction constitutes the active phase of MS.

Usually the active phase is self-limiting and the disease goes into remission, but the tissue damage remains. The disease has a variable course. Some patients experience an active phase only once, others have a continuous cycle of active phase, remission, active phase and remission etc. In these patients muscle dysfunctions and other deficits become more severe and debilitating as the brain damage accumulates.

There are many clinical studies that report significantly increased cytokine concentrations in the cerebrospinal fluid of MS patients. IL-1 and TNF are elevated in MS patients.18 The values for IL-6 have been conflicting, but the most recent careful study did find IL-6 in MS brain.19 Another report showed that macrophages and lymphocytes in the cerebrospinal fluid of MS patients are producing large quantities of TNF and lymphotoxin.20 Soluble and membrane bound interleukin-2 receptors are elevated in MS patients, which is an unmistakable sign of T-lymphocyte activation and increased IL-2 secretion.21,22 A very important observation in these investigations is that cytokine levels are high during the active phase and then fall back to normal during remission.

What about depression and MS? Since there are high cytokine levels in the brains of MS patients, the cytokine model of depression directly predicts high rates of depression in MS, especially during the active phase. Not surprising, there is massive evidence of significant depression in MS. Since Charcot first reported depression with MS in 1881, there has been a continual stream of papers confirming the observation.23 Lifetime incidence of depression in MS patient appears to exceed 50%, but before the disease develops, rates are low in these patients. Most studies did not distinguish between the active phase and remission. Those that did found the severity and incidence of depression higher during the active phase.24 This, of course, fits beautifully with the concept of depression as a multifaceted sign of chronic immune system activation.

A recent paper analyzed (meta-analysis) six controlled studies of depression in MS.25 They concluded that "MS patients are significantly more depressed than comparison groups." Most of the comparison groups were not healthy controls but rather physically ill patients. We already know that physically ill patients have high rates of depression. Thus, depression in MS is significantly higher than for other physical illnesses. Furthermore, the depression in MS "is frequently associated with worsening condition. A more recent clinical report continues to confirm the high rates of depression with MS.26

Parkinson's Disease Parkinson's Disease (PD) is a slowly developing movement disorder caused by the degeneration of a small brain stem structure called the substantia nigra. The cause of the degneration is unknown. PD is usually first diagnosed after age 50 and the incidence increases with advancing age. Over 500,000 people have PD in the United States.

The classical features are tremor, muscle rigidity and slowed movement. Sometimes occuring before the classical symptoms are fatigue, aching limbs, mental slowness and depression.27

Serious depression affects about 40% of PD patients with milder depression affecting even more patients. The depressive symptoms usually occur early in the disease, often preceeding the onset of the movement deficits. This indicates that awareness of disability is not triggering the depression, but rather the mood change is due to the underlying biology of the disease. Furthermore, depression is increased during periods of rapid deterioration in movement ability.28,29

Recently the contents of TNF, IL-1 and IL-6 were shown to be much higher in brain of PD patients than in healthy controls.30 Cerebrospinal fluid levels of IL-2, TNF and IL-6 were also significantly elevated in PD.31

An inherent feature of the cytokine model of depression is the concept that high brain cytokine levels are fundamental mediators of depression. The evidence from PD directly confirms the model. PD has high brain cytokine levels and extraordinarily high rates of depression.

Alzheimer's Disease Alzheimer's disease (AD) is a progressive degenerative disease of the cerebral cortex and various other brain centers of unknown etiology. It is the most common cause of dementia, with an estimated 3 million or more cases in the United States. The incidence goes up rapidly with age, rising to 47% for persons over 85 years old.32

During the past 13 years, an enormous amount of research has shown that AD is an inflammatory brain disease, mediated by activated microglia and lymphocytes.33,34,35,36 Elevated levels of various inflammatory cytokines, acute phase proteins and other markers of immune activation have been confirmed in numerous reports. The elevated cytokines include IL-1, IL-6, TNF and IL-2 receptors. Immune activation and elevated cytokines can account for the cellular pathology occuring in AD. Unfortunately the cause of the immune activation is unknown.

Depression is closely associated with all types of dementias, especially AD.37 Depression is relatively rare in advanced AD, but quite common in the early stages. Indeed, AD is often preceeded by severe depression.38,39 For example, a study of 28 depressed patients reported half of them developed AD after three years.40 Another study of 44 elderly patients with depressive pseudodementia (depression with reversible dementia) found 89% had developed AD after being tracked for an average of 8 years.41 Other studies have also shown that depressive pseudodementia is a powerful predictor of AD.42

A large number of studies have reported high rates of depression occuring with AD. One report on 50 AD patients found that 75% of them were depressed at the beginning of their disease.43 In a review of 30 studies, the highest reported incidence of depressed mood was 87%, although most studies had an incidence of 50%.44 The remarkably high incidence of depression coexisting with AD, especially in light of the high brain cytokine levels reported for AD, is powerful evidence supporting the cytokine model of depression.

AD is not an abrupt development. There is a long silent stage of progressive nerve cell destruction before dementia becomes evident. It is extremely likely that there are high brain cytokine levels during the long silent stage because activated immune cells, along with increased cytokine levels, are the principal mediators of the brain destruction in AD. Therefore the consistent reports of depression preceeding the diagnosis of AD is further evidence that cytokines are fundamentally involved in depression.

Depressive Pseudodementia We have seen that true dementia very often occurs with depression. On the other hand, severe depression in elderly patients commonly occurs with a reversible dementia, called depressive pseudodementia. In these patients when their depression lifts, their intellectual abilities return to normal.

Stroke Very high rates of depression occur in stroke patients.45 Within the first 4 weeks after stroke, Robinson et al46 found 47% of the patients had post-stroke depression. Other studies have found 30% to 60% of stroke patients develop symptoms of major depression, with the symptoms usually lasting more than six months.47

Post-stroke depression is related to poorer outcome. For example, in a short term study, non-depressed stroke patients improved slightly, whereas the condition of depressed stroke patients deteriorated over time.48 Another study found much less recovery in depressed patients after two years compared to non-depressed patients.49

After stroke high cytokine levels are a reasonable expectation, since the damaged tissue incurred by stroke activates the immune system. Indeed in recent experiments, cytokines, including IL-1, IL-6 and TNF, are elevated in animal brain after experimental stroke. In human studies, serum and cerebrospinal fluid levels of IL-1, IL-6, and IL-1 receptor antagonist are elevated in stroke patients, with the cytokine levels much higher in cerebrospinal fluid than in serum. Patients with the greatest brain damage had the highest levels of cytokine.50,51

Clearly, post-stroke depression is another example of cytokines and depression being at the same place at the same time. This evidence provides additional powerful support for the cytokine model of depression.

At the present time, establishment biological psychiatry does not have an explanation for post-stroke depression. The traditional explanation for post-stroke depression is a psychological one, namely, that depression in stroke patients is a psychological reaction to their disability. Folstein et al52 examined this theory and found it wanting. They compared stroke patients to patients with disabilities due to non-neurological causes. Stroke patients had much more depression than non-stroke patients with similar disabilities.

The cytokine model is the only theory that simply and directly explains post-stroke depression, namely, the cytokines in stroke injured brain cause depression. In addition, the cytokine model explains why post-stroke depression predicts poorer outcome since depression identifies those patients with more activated immune cells in the damaged brain, indicating that the tissue injury is continuing and is unresolved.

Traumatic Brain Injury There are almost one million traumatic brain injuries in the United States annually. These injuries are a leading cause of death and disability among people under age 45. Numerous studies have reported high rates of depression following traumatic brain injury. Jorge et al53 found a depression rate of 30%. In other studies, depression ranged from 33 to 50%.54,55

Immune activation would be expected after traumatic brain injury because damaged tissue activates the immune system. Not surprisingly, increased levels of IL-1 and IL-6 were found in serum and brain-ventrical fluid of patients with severe head injury. The amounts in brain-ventrical fluid were much higher than in serum.56,57 Once again, sophisticated neuroimmunological research confirms the cytokine model of depression, namely, cytokines in the brain=high rates of depression.

AIDS The aquired immunodeficiency syndrome (AIDS) was first reported in 1981 and within a few years reached epidemic proportions. The human immunodeficiency virus (HIV) is the cause of AIDS. HIV infection results in a massive immune system response, including immune activation along with concurrent destruction of T-helper lymphocytes. The immune activation produces most of the symptoms and signs of AIDS, whereas the depletion of T-helper lymphocytes leaves the body defenseless against many lethal infections, which results in extremely high death rates for AIDS patients.58

Any infection, including HIV infection, triggers the production of cytokines. Copious amounts of IL-1, IL-6, TNF and IFN-γ are produced by AIDS patients. Normally these cytokines help the immune defenses, but in the perverse case of AIDS, these cytokines stimulate the replication of more virus.59

The brain often becomes infected with HIV at a very early stage of AIDS. There are several probable ways HIV travels through the blood-brain barrier and into the brain: 1). HIV infected monocytes pass through the blood-brain barrier--there is excellent evidence for this mechanism. Once in the brain, the HIV infected monocytes transform themselves into cytokine secreting macrophages. 2) Cells lining the blood-brain barrier become infected with HIV--there is some evidence for this mechanism. 3). Lymphocytes infected with HIV pass through the blood-brain barrier--there is less evidence for this mechanism. Regardless of the mechanism, the brain does become infected with HIV before the clinical signs of AIDS appear. Copious amounts of cytokine are produced in brain by HIV infected macrophages, with high levels of IL-1, IL-6 and TNF reported for HIV infected brain.60,61

Neuropsychiatric pathology is one of the most common and serious complications of HIV infection. Almost 65% of AIDS patients exhibit AIDS dementia complex- a syndrome characterized by psychiatric symptoms, especially depression, movement problems and impaired thinking, memory and understanding.62 Up to 83% of AIDS patients have significant depressive symptoms.63 Depression begins to occur before the symptoms of AIDS appear. Indeed, "there is a dramatic, sustained rise in depressive symtoms as AIDS develops, beginning as early as 18 months before clinical AIDS is diagnosed."64 Clearly, depression is a well-documented, significant problem for AIDS patients.

AIDS depression is another remarkable example of depression and cytokines being at the same place at the same time. The cytokine and depression evidence from AIDS is further powerful support for the cytokine model of depression.

Conclusions We have looked at the six most prevalent organic brain diseases: multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, traumatic brain injury and AIDS dementia complex. Each disease has very high rates of depression, yet establishment biological psychiatry, with all of their remarkable advances in pharmacology, neurotransmitters and brain function, cannot even begin to scientifically explain the depression. To biological psychiatry, depression remains a deep, unfathomable, inexplicable disease. The most they can offer is something like this: "

PHYSICAL ILLNESS

Heart Disease The pathology underlying most heart disease is atherosclerosis, a complicated, chronic inflammatory disease which develops on the inside of arteries. Atherosclerosis can be likened to a series of improperly healing wounds (called fibrous plaque) on the inside of arteries. Like most wounds, a fibrous cap (i.e., scab) forms over it. Underneath the fibrous cap is a complex viscous fluid (like pus) composed of various cell types, dead and dying cells, tissue fluids, inflammatory chemicals, cholesterol and fat.

Occasionally a fibrous cap thins and ruptures, permitting the thick liquid underneath to escape into the blood. The escaping viscous material triggers a clot to form in the rapidly moving blood. Of course, a clot inside an artery blocks the flow of blood. If the clot (called a thrombosis) is in the coronary artery, then heart muscle becomes severely deprived of blood (called ischemia), causing heart muscle to die, dangerous heart rhythms and severe chest pain. This sequence of events is commonly called a 'heart attack" or more properly a myocardial infarction (heart muscle death). Heart attack is a leading cause of death in the United States and most of the Western world.

Persons with heart disease have very high rates of depression.65 After a heart attack, up to 30% of the patients develop major depression and an even larger number have minor depression. Both the depressed and non-depressed patients, according to the standard clinical evaluations, have cardiac illnesses of equivalent severity. Yet, in a tracking study of heart attack patients, the depressed patients had much higher death rates and more complications than the non-depressed patients.66 Another study found a four fold increase in deaths for depressed heart attack patients.67 Depression appears to be a better measure of disease severity than the standard clinical evaluations. Indeed depression can identify those patients with the greatest likelihood of dying or developing complications.

Depression is commonly present in heart attack patients even before their heart attack occurred. Also, depression is prevalent in patients at high risk (due to atherosclerosis in their coronary arteries) of having a heart attack. The depressed high risk patients are twice as likely to have a heart attack as the non-depressed high risk patients.68 The mental precursors of heart attack have been studied by Appels.69 He reports that heart attack is regularly preceded by fatigue, general malaise and minor depression.

Thus, depression is prevalent before and after heart attack. It also identifies the individuals who are most likely to have a heart attack and those who are most likely to have complications and die. The authors of these reports view depression as a disease and accordingly, they all jump to the conclusion that the disease depression is somehow causing the heart attacks, complications and death. Of course, we have a different view, namely, that depression is not a disease, but rather a multifacted sign of chronic immune system activation, just as fever is a sign of acute immune system activation. Depression identifies the patients who are having the greatest ongoing battles between their immune system and their internal cardiac disease. Depression is a powerful indicator (and certainly not a cause) of disease severity, just as fever is a powerful sign of disease severity.

But does the immune system have anything to do with atherosclerosis and heart attack? Yes it does! Atherosclerosis is fundamentally an inflammatory disease mediated by activated macrophages in the arterial wall.70 The activated macrophages secrete cytokines, including IL-1 and TNF, cause growth and inflammation of the fibrous plaque and are directly involved in thinning and rupture of the fibrous cap.71 Numerous animal and human experiments report that atherosclerotic arteries secrete more IL-1 than healthy arteries.72

The IL-1 and TNF secreted by the activated macrophages stimulate the liver to make acute phase proteins. Persons with atherosclerosis and at high risk of heart attack, have elevated levels of acute phase proteins. Patients with the highest levels of acute phase proteins have the most heart attacks and deaths.73,74 Therefore, acute phase proteins, which are reliable signs of immune system activation, can identify the patients who have the highest probability of heart attack, just as depression, which is a sign of immune system activation, identifies patients who proceed to have heart attack or other complications.

After a clot forms in the coronary artery (ie heart attack), there is reduced blood flow to heart muscle and heart muscle begins to die (infarction). The immune system is quickly activated in order to clean up the mess and attempt to repair the tissue. Consequently, the immune system is even more activated after a heart attack than it is before the event.

In heart disease, as we saw with organic brain disease, depression and immune activation are at the same place at the same time. The clinical evidence on heart disease is powerful confirmation of the cytokine model of depression. Furthermore, our model explains why depression occurs with both atherosclerosis and heart attack, and why depression identifies those patients at greatest risk of heart attack, complications and death. The concept is simple: depression is not a disease, rather it is a multifacted sign of chronic immune system activation, just as fever is a sign of acute immune system activation.

Cancer The immune system plays an extraordinarily complex role in cancer. The immune system is constantly on alert for malignant cells. If discovered, malignant cells are attacked and destroyed by activated immune cells. Unfortunately malignant cells occasionally evade detection by the immune system and continue to grow while evading detection. Eventially the tumor will be detectedby the immune system, resulting in immune system activation and increased cytokine secretion. A great number of animal and human studies document increased cytokine secretion by immune cells that are associated with malignant tissue.75 Consequently, cancer patients routinely have activated immune systems and increased cytokine secretion.

Cytokines have conflicting effects on tumor growth and survivial. On the one hand low levels of IL-1 often act as a tumor growth factor, stimulating the growth and spread of the tumor. On the other hand, higher levels of cytokine often inhibit growth and orchestrate tumor destruction.76

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Chapter 9 References

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