Compelling evidence suggests that subgroups of major depressive disorder may be associated with an inflammatory state.¹ Findings include elevated levels of cytokines^2,3 and an increased susceptibility for autoimmune diseases and infections.⁴ Furthermore, treatment with proinflammatory agents induces symptoms of depression.⁵

Comorbidity, defined as the presence of 1 or more disorders in relation to an index disorder,¹ has been the focus of a substantial body of research during the 5 decades since the term was introduced.² In the mental health field, it is widely acknowledged that individuals treated for incident mental disorders are at increased risk of subsequently developing other mental disorders.³ Based on a survey of mental health among adolescents 13 to 17 years of age, Kessler et al⁴ reported that 27.9% of respondents met criteria for 2 or more disorders. Several community surveys have reported that, among respondents with at least 1 mental disorder, 45% to 54% have 1 or more additional lifetime diagnoses.^3,5,6

Mood disorders frequently co-occur with medical illnesses that involve inflammatory pathophysiologic mechanisms, such as cancer and cardiovascular diseases.^1-3 The development of mood disorders has recently been linked to inflammation,^4,5 and experimental activation of inflammatory reactions has been demonstrated to induce symptoms of mood disorders in human and animal studies.^5-9 Immune components, such as proinflammatory cytokines and brain-reactive antibodies, can induce changes in neurotransmitter and neuroendocrine function related to psychiatric disorders.^5,10,11 In addition, several studies¹² have identified diverse immune alterations in subgroups of persons with mood disorders without other known somatic comorbidities.

Accumulating evidence supports an association between depression and inflammatory processes, a connection that seems to be bidirectional. Clinical trials have indicated antidepressant treatment effects for anti-inflammatory agents, both as add-on treatment and as monotherapy. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity of the inflammatory cascade, limited clinical evidence, and the risk for side effects stress cautiousness before clinical application. Thus, despite proof-of-concept studies of anti-inflammatory treatment effects in depression, important challenges remain to be investigated. Within this paper, we review the association between inflammation and depression together with the current evidence on use of anti-inflammatory treatment in depression. Based on this, we address the questions and challenges that seem most important and relevant to future studies, such as timing, most effective treatment lengths and identification of subgroups of patients potentially responding better to different anti-inflammatory treatment regimens.