Lessons From Clinical Trials of Immunomodulatory Drugs in Psychiatric Disorders

Immune dysregulation has been implicated in the pathophysiology of psychiatric disorders, with peripheral inflammatory markers correlating with symptom severity, treatment refractoriness, and neural circuit dysfunction. This has led to growing interest in immunomodulatory drugs as potential treatments. Several clinical trials have explored the efficacy of anticytokine treatments (monoclonal antibodies [mAbs]), nonsteroidal anti-inflammatory drugs, and minocycline, among other agents. While there have been some promising results, such as improvement in depression with infliximab among subgroups with peripherally elevated inflammation, overall results have been mixed. Several key lessons have emerged from these studies that can guide future research and clinical care. While most immunomodulatory trials were small and did not utilize biomarker-based enrichment, some recent studies of mAbs have started to use inflammatory markers to guide subgroup analyses and/or enrollment. Outcome measures in many trials relied on broad symptom scales that did not focus on neuroimmune-related psychiatric phenotypes, such as anhedonia. While immunomodulatory drugs for most medical conditions are used as long-term treatments, the trials in psychiatric disorders assessed their effects over short durations, limiting insights into their long-term efficacy, safety, and potential for sustained psychiatric benefits. Absence of large, multicenter, well-powered studies limits the generalizability. Translational research on neuroimmune interactions is needed to refine therapeutic targets and optimize study designs. These lessons highlight the potential of immunomodulatory drugs in psychiatric disorders while emphasizing the need for larger, well-powered trials; biomarker-driven treatment selection; and long-term monitoring. With a targeted approach, immunomodulatory drugs represent an important step toward precision medicine in psychiatry.