Immune System Contributions to the Pathophysiology of Depression

Major depression is a devastating disorder that represents a major public health concern. Of special relevance is the high percentage of patients whose depression does not respond to or who are unable to tolerate conventional antidepressant medications, which primarily target monoamine neurotransmission. Recent data indicate that the immune system may play a role in the pathophysiology of depression, representing a novel pathway for therapeutic development. Patients with major depression have been found to exhibit evidence of an activated innate immune response as reflected by increased biomarkers of inflammation, including innate immune cytokines, acute-phase proteins, chemokines, and adhesion molecules. In addition, administration of innate immune cytokines to laboratory animals and humans has been shown to induce behavioral changes that significantly overlap with the symptom criteria of major depression. Treatment of patients with inflammatory disorders using anticytokine therapies has also been found to reduce depressive symptoms. Interestingly, psychosocial stress, a well-known precipitant of depressive disorders, has been shown to activate the innate immune response. Finally, innate immune cytokines have been shown to influence virtually every pathophysiological domain relevant to depression including monoamine neurotransmission, neuroendocrine function, synaptic plasticity, and regional brain metabolism. Of note, a response to conventional antidepressant medications is associated with a decrease in inflammatory biomarkers, whereas patients with treatment-resistant depression are more likely to exhibit evidence of increased inflammation. Taken together, these data provide the foundation for considering an activated innate immune response as a potential target for further study and therapeutic development in mood disorders, especially in the context of treatment resistance.