Role of Cytokines in depression

Cytokines in depression hypothesis

Cytokines in depression has recently been postulated that cause depressive illness in man. This hypothesis is based on the following observations:
1. Treatment of patients with cytokines can produce depression symptoms;
2. Activation of the immune system is observed in many depressed patients;
3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction;
4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with antidepressants has been shown to inhibit sickness behavior induced by LPS;
5. Several cytokines can activate the hypothalamo–pituitary–adrenocortical axis (HPAA), which is commonly activated in depressed patients;
6. Some cytokines activates cerebral noradrenergic systems, also commonly observed in depressed patients;
7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment.

The role of proinflammatory cytokines, such as interleukin (IL)-1, tumournecrosis factor (TNF)-α and interferon (IFN)-γ, in the aetiology and pathophysiology of major depression, is discussed. The "cytokine hypothesis of depression" implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders.(table 1)

Experimental evidence cited for a cytokine hypothesis of depression

Evidence of cytokine in depression Principal cytokines implicated
Treatment of patients with cytokines induces symptoms of major depression IL-2, IFNα
Activation of the immune system is observed in many depressed patients. This may be reflected in elevated circulating concentrations of cytokines IL-6
Activation of the immune system, and administration of LPS or cytokines to animals induces sickness behavior, which resembles major depressive disorder. Chronic treatment with antidepressants inhibits LPS-induced sickness behavior IL-1
Cytokines can activate the HPA axis. Elevated plasma cortisol is commonely observed in depressed patients. IL-1, IL-6,TNFα, IFNα
Cytokines activated brain noradrenergic systems. Elevated NE and its catabolites are commonly observed in the CSF of depressed patients. IL-1, TNFα
Cytokines activate brain serotonergic systems. Abnormalities of brain serotonin have been implicated in major depression and its treatment. IL-1, IL-6, TNFα

Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules. In addition, therapeutic administration of the cytokine interferon-α leads to depression in up to 50% of patients. Moreover, proinflammatory cytokines have been found to interact with many of the pathophysio-logical domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and behavior. Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and para-sympathetic nervous system pathways. Finally, depression might be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation. These findings suggest that targeting proinflammatory cytokines and their signaling path-ways might represent a novel strategy to treat depression.(figure 1)

cytokines in depression

It is now known that cytokines have effects on cells outside the immune system, and that non-immune cells can synthesize and secrete cytokines. Thus cytokines can be regarded as classical hormones that can function locally or systemically to orchestrate immune responses, and can also coordinate immune responses with those of other physiological systems in the body, including the nervous system. The cytokine hypothesis of depression derives from both clinical and experimental observations. The clinical observations were made on patients treated with interferons (IFN's) and interleukin-2 (IL-2). Such patients often displayed influenza-like symptoms and nonspecific neuropsychiatric symptoms, some of which are characteristics of depression. Whereas the flu - like side effects tend to attenuae as cytokine treatment continues, the neuropsychiatric adverse effects may only disapp ear after termination of cytokine administration, or treatment with anti depressants, e.g. the selective serotonin re-uptake inhibitor (SSRI) paroxetine.

Cytokines have been shown to be effective in the treatment of medical conditions, such as hepatitis C, multiple sclerosis, some infections, leukemia, Kaposi's sarcoma, melanoma, myeloma, renal carcinoma and other forms of cancer. The cytokines most commonly used are IFNα, IFNβ, IFNγ and IL-2. Each of these cytokines has been reported to produce side effects such as asthenia, myalgia, confusion and influenza-like symptoms. Depression is most commonly associated with treatment with IFNα and IL-2, and occasionally with IFNβ but not with IFNγ. (table 2)

Neuropsychiatric side effects of immunotherapies based on the administration of proinflammatory cytokines

Immunotherapy Neuropsychiatric side effects Clinical condition treated
IFN-α Fatigue, Psychomotor slowing, Depressed mood, Anxiety, Social withdrawal, Irritability, Anorexia, Cognitive disturbances Cancer, Multiple sclerosis, Chronic hepatitis C, other viral infections
IFN-β Fatigue, Depressed mood, Cognitive impairment Multiple sclerosis, Cancer
IL-1 Cognitive impairment Cancer
IL-2 Fatigue, Anhedonia, Dysphoria, Cognitive impairment  
TNF-α Fatigue, Anorexia Cancer

The cytokine hypothesis of depression suggests a key role for cytokines in the mdiation of the pathophysio logical characteristics of major depression. From this perspective, it is tempting to assume that the efficacy of antidepressants in the treatment of depressive disorders may, at least in part, rely on down regulation of pro-inflammatory cytokine synthesis.

Cytokine molecules related

IFN Receptor

IL10 Family Receptor

TGF beta Family Receptor


1, Aye-Mu Myint, et al. Th1, Th2, and Th3 cytokine alteration s in major depression.Journal of Affective Disorders 88 (2005) 167 – 173.
2,Jan Pieter Konsman, et al. Cytokine-induced sickness behaviour: mechanisms and implications.TRENDS in Neurosciences Vol.25 No.3 March 2002
3, Olga J.G. Schiepers, et al. Cytokines and major depression.Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 201 – 217
4, Rob er t Dant zer, et al. Cytokine, Sickness Behavior, and depression.Immunol Allergy Clin N Am 29 (2009) 247–264
5, Charles L. Raison, et al. Cytokines sing the blues: inflammation and the pathogenesis of depression.TRENDS in Immunology Vol.27 No.1 January 2006
6, Levent Sutcigil, et al. Pro- and Anti-Inflammatory Cytokine Balance in Major Depression: Effect of Sertraline Therapy.Clinical and Developmental Immunology.Volume 2007