Earlier this week at Psych Congress 2023 (September 6-10, 2023; Nashville, TN), Charles Raison, MD, presented evidence to show how inflammation promotes depression, generating a unique theory of major depressive disorder (MDD).
Dr Raison shared the first indications of a link between inflammation and depression stemming from early data for patients treated with interferon-alpha, a medication composed of the natural inflammatory cytokine. Studies showed that the percentages of patients free of major depression decreased with increasing weeks on interferon-alpha, indicating that depression increases with prolonged use of interferon-alpha. Indeed, with the addition of antidepressants, the number of patients free of major depression improved.
Inflammation causes several abnormalities observed in depression, such as glucocorticoid resistance, increased tumor necrosis factor-alpha, and reduced sleep efficiency. Biomarker studies show that MDD is associated with increased inflammatory biomarkers such as interleukin-6 and C-reactive protein.
With these concepts in mind, researchers set out to more accurately define this correlation. If inflammation causes depression, it would follow that blocking inflammation could treat depression. Interestingly, double-blind placebo-controlled experiments with twice weekly etanercept, a known anti-inflammatory, did show at least a 50% improvement in depression scores. However, further experiments with infliximab, a specific and powerful anti-inflammatory agent, showed nearly indistinguishable results in depressive symptom scores to placebo.
Further investigations provided more clarity on the specific relationship between inflammation and depression. It appears that inflammation predisposes patients to depression through multiple effects on behavior and brain function. However, the relationship is not directly causal in all cases. Inflammation should be considered one of several risk factors for depression development, but MDD is not an inflammatory condition. Anti-inflammatory medications thus only provide antidepressant effects in MDD patients who also present with increased inflammation, while they may be counter-productive in patients without increased inflammation.
Research also shows that inflammatory biomarkers may provide insight into the predicted response to standard antidepressants. For example, higher levels of inflammation appear to correlate with a reduced response to selective serotonin reuptake inhibitors (SSRIs) and a potentially enhanced response to dopaminergic medications.
The precise mechanisms directing the interactions between inflammatory and depressive pathways remain unclear. Research continues to dive into this interesting yet complex system. Ideally, new findings will result in more effective treatment strategies to optimize patient outcomes.
Raison C. Making the connection between inflammation and depression. Presented at: Psych Congress; September 6-10, 2023; Nashville, TN.