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The Inflammatory Theory of Depression

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A role for cytokines in depression?

The similarity between the symptoms of cytokine-induced sickness and depression is striking: in both cases there is a withdrawal from the physical environment and from other people that is accompanied by pain, malaise and decreased reactivity to reward (anhedonia). Moreover, some components of sickness behavior in animals, such as a decreased preference for sweet solutions and reduced social exploration, are improved by antidepressant treatment. In humans, major depression develops in roughly a third of patients who are treated with the cytokines for cancer or hepatitis. In agreement with these findings, depression is more prevalent in people suffering with conditions that lead to chronic inflammation (such as heart diseases, type 2 diabetes and rheumatoid arthritis. Depression could represent a maladaptive version of cytokine-induced sickness, which could occur when activation of the immune response is exacerbated in intensity and/or duration, or that takes place in the context of an increased vulnerability to depression, for example, in individuals who produce excess cortisol.   Of course, chronic stress has all these effects. Pro-inflammatory cytokines cause various clinical aspects of depression, including hyperactivity of the hypothalamus--pituitary--adrenal axis (the source of the stress response), disturbed serotonin metabolism, and the symptoms of reduced activity, libido, appetite, movement, etc.

Vegetative, somatic and psychological symptoms of depression

Investigation of the symptoms that developed in cancer and hepatitis C patients receiving treatment with cytokines confirmed that they were caused by the treatment, and revealed that they fell into two distinct categories: early-onset symptoms of depression, which all patients display and which include flu-like symptoms, fatigue, anorexia, pain and sleep disorders, and late-onset psychological symptoms of depression that are experienced by up to half of patients and include mild impairments in thinking and in memory and depressed mood, sometimes accompanied by anxiety and irritability. Pretreatment with paroxetine, an antidepressant, reduces the psychological symptoms but has little or no effect on the early onset symptoms. The patients who developed psychological symptoms of depression scored higher on a depression scale before cytokine treatment was started and had an enhanced pituitary--adrenal response following the first injection of cytokines, indicating that vulnerability to immunotherapy-induced depression involves both psychological and physiological risk factors.

A role for tryptophan?

Treatment with cytokines alters the biochemistry of patients; the most revealing sign is a pronounced reduction in blood levels of tryptophan, which correlates with the patients' depression scores 3 weeks into the treatment. Tryptophan is an essential amino acid that is actively transported into the brain to make serotonin. The availability of tryptophan determines the rate of serotonin synthesis in the brain. Acute tryptophan depletion decreases mood in vulnerable people who have a familial history of major depressive disorders or are drug-free in remission after an episode of major depression.

Alternative mechanisms for cytokine-induced depression

There is evidence that cytokines might modulate serotonin neurotransmission by mechanisms other than the decrease in tryptophan levels. A hyperactive hypothalamus--pituitary--adrenal axis is often associated with depression. Pro-inflammatory cytokines acutely and potently activate the hypothalamus--pituitary--adrenal axis.   In conditions of chronic inflammation, pro-inflammatory cytokines can cause receptor resistance to stress hormones. In addition, pro-inflammatory cytokines seem to promote expression of a form of the glucocorticoid (stress hormone) receptor that is inactive but still binds stress hormones. At the hypothalamic level, this cytokine-dependent glucocorticoid receptor resistance can explain the reduced ability of high levels of stress hormones to shut down their own production (through turning off the production of corticotrophin releasing factor or CRF). At the level of the immune cells, the normally inhibitory effect of stress hormones on further cytokine production and action would no longer work, setting the stage for a "run-away freight train effect" that would result in an ever increasing production of pro-inflammatory cytokines. This increased inflammatory response in the brain results in a decreased inhibitory feedback on CRF by the stress hormones, thereby ever intensifying the stress-response.

Neuroanatomy of cytokine-induced depression

The search for a possible neuroanatomical basis of cytokine-induced depression has focused on the brain circuits that are involved in emotion processing and psychomotor retardation, both of which are altered in patients with clinical depression. Neuroimaging data of depressed patients show decreased baseline activity in the frontal and temporal cortex and the insula, and increased activity in the cerebellum, subcortical and limbic regions. In agreement with this, cancer patients treated with cytokines display decreased activity in the dorsal prefrontal cortex (which is what occurs in people diagnosed with depression) and increased activity in the cerebellum and basal ganglia (especially in the left putamen and nucleus accumbens where this increased activity is correlated with fatigue and lack of energy. These data These findings are consistent with the greater difficulty of cytokine treated patients to regulate their emotions.

Implications for depression in medically ill people

A growing amount of information points to the importance of the relationship between inflammation and depression in physically ill patients and in conditions that are associated with increased activity of the immune system, including aging and obesity. For instance, the prevalence of depression in patients with coronary heart disease, a disease in which inflammation is now recognized as a major contributing factor, is three times higher than in the general population. Depression has long been known to be a risk factor for subsequent cardiac events and mortality.

Mechanisms of enhanced response to systemic inflammation

Conditions of chronic inflammation exacerbate the sickness and depression-like behaviors that develop in response to acute inflammation. This phenomenon can be seen in mice models of degenerative brain disease, type 2 diabetes, and normal ageing, and might be due to an effect called "priming'. For example, in mice that have previously been exposed to pro-inflammatory cytokines (the priming stimulus), exposure to a triggering stimulus, such as an additional acute stress or an infection, leads to an exaggerated production of pro-inflammatory cytokines.

Future directions

The symptoms of sickness (for example, fatigue, reduced appetite, sleep disorders, altered mood and thought) have a negative impact on the quality of life of patients with chronic inflammatory disorders, but not much can be done to alleviate these symptoms. Activities like physical exercise, hypnosis, and even Reiki could have a beneficial effect on the symptoms of sickness, as could anti-inflammatory diets.

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Lewis Mehl-Madrona graduated from Stanford University School of Medicine and completed residencies in family medicine and in psychiatry at the University of Vermont. He is the author of Coyote Medicine, Coyote Healing, Coyote Wisdom, and (more...)
 
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