Depression and inflammation: Examining the link

Sneezing, coughing, and a sore throat are hallmark symptoms of a common cold, but what keeps you in bed are the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain, and apathetic withdrawal. This “sickness behavior” is induced by inflammatory markers released in response to illness.^1,2 These symptoms are similar to the constellation of symptoms that define depression. Within the inflammatory response to illness, we see the shadow of depression, but the precise relationship remains murky.

Is depression part of a normal somatic inflammatory response run amok? Some researchers have argued that “sickness behavior” is adaptive, forcing the body into a constricted pattern in order to funnel energy into healing.^1,3 If depression and inflammation are related, depression pushes past these adaptive roots and is less a forced pause than a debilitating withdrawal. Perhaps depression, or a subtype, is a sign of inflammation along with heat, pain, redness, and swelling. In some instances, depression may be a sign of an underlying inflammatory process.⁴

In our progression toward understanding depression’s pathophysiology, we see factors that point to a relationship between depression and inflammation:

• depression frequently is comorbid with many inflammatory illnesses

• increased inflammatory biomarkers are associated with major depressive disorder (MDD)

• exposure to immunomodulating agents may increase the risk of developing depression

• stress can activate proinflammatory pathways

• antidepressants can decrease inflammatory response

• inhibition of inflammatory pathways can improve mood.

Exploring these factors and a possible pathway linking inflammation and neurobiologic changes found in depression allows us to look closer at the possible integration of the inflammatory process and depressive symptoms.

Illness and depression rates

Individuals with inflammatory illnesses—autoimmune diseases, cardiovascular disease, diabetes, and cancer—often struggle with depression. Nearly 1 in 5 persons with cardiovascular disease experiences MDD.⁵ A diabetes diagnosis doubles the odds of having depression.⁶ Up to 70% of patients with autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus, experience depression.^7,8 In a large-scale longitudinal study, having a prior autoimmune disease increased the risk of depression by 45% and history of hospitalization with infection increased a patient’s risk by 62%; the risk more than doubled in individuals with both.⁹ Several studies show that 15% to 25% of cancer patients experience depression,¹⁰ compared with 9% in the general population.¹¹

Role of inflammatory markers

During an inflammatory episode the body releases cytokines, which are small, cell-signaling protein molecules. These inflammatory markers launch signaling cascades that incite the immune system into action. Type 1 cytokines (interferon-ã, tumor necrosis factor-á [TNF-á], interleukin [IL]-1) enhance cellular immune responses, and type 2 cytokines (IL-6, IL-10, IL-13) engage antibody responses. These cytokines also induce acute phase proteins, such as C-reactive protein (CRP), which can activate the immune system. Significantly higher levels of inflammatory markers are associated with a range of depressive symptoms, which grants insight into disease severity and treatment response.^3,12,13

Multiple studies have explored the link between depression and inflammatory markers (Table).^14-21 Peripheral inflammatory markers such as IL-6, IL-1â, CRP, and TNF-á are elevated in inflammatory diseases and in otherwise healthy individuals with MDD.¹² In a meta-analysis of 24 studies measuring cytokines in depressed patients, Dowlati et al¹⁴ found individuals with MDD had significantly higher concentrations of TNF-á and IL-6 compared with controls. Increased peripheral inflammatory markers were found among antidepressant nonresponders more often than those who responded to treatment.^15,22

Cytokines and depression risk

Administering immunomodulating agents has been shown to increase the risk of developing depression. Injecting animals with IL-1â or TNF-á causes sickness behavior in a dose- and time-related manner.¹ As these inflammatory signaling proteins increase, sickness behaviors become more pronounced.

In humans, a natural model arises in the use of the cytokine interferon-á (INF-á) for treating hepatitis C, multiple sclerosis, malignant melanoma, and some blood cancers. Patients receiving INF-á have higher rates of depression than those not administered interferon.¹⁶ Patients receiving chronic immunotherapy treatment show long-term changes in monoamine neurotransmitters and along the HPA axis; these changes mimic those seen in depressed individuals.^17,23 Acutely administered immunotherapeutic agents, such as the typhoid vaccine, have led to depressive symptoms with brain changes similar to those seen in MDD.¹⁸ Low levels of IL-6 and CRP independently predicted development of depression over several years.¹⁹

Immunotherapy-induced depression looks similar to any other major depressive episode through our current diagnostic framework and at the molecular and anatomical level.

Stress and inflammation

Depression can develop in the absence of inflammatory illness. Knowing that depressive symptoms may be associated with increased peripheral inflammatory markers, what induces the inflammatory process in some persons who are depressed but medically healthy? One theory is that psychological stress can activate inflammation.