Cytokine Blockade Attenuates Inflammation and Improves Depressive Psychopathology After COVID-19: A Naturalistic Observational Study

Current insight on inflammation in psychiatry suggests that perturbation of inflammatory set points could foster psychopathology and recent evidence support immune-inflammatory mechanisms as targets for antidepressant pharmacology. In the present naturalistic observational study we evaluated the possible effect of the cytokine-blocking agents in preventing the development of post-COVID depression in a large sample of survivors also exploring the relationship between post-COVID depressive risk, treatment with cytokine-blocking agents, and innate immune response markers. 588 COVID-19 survivors were included, of them 374 received the best available treatment at the time and 131 received standard treatment combined with cytokine-blocking agents (anakinra, tocilizumab, sarilumab, reparixin and mavrilimumab). Post-COVID depressive psychopathology was evaluated at short (34.6 ± 17.39 days) and long term (126.76 ± 61.4 days) follow-ups. The systemic inflammation index as (neutrophils*platelets)/lymphocytes was computed in a subgroup of 274 patients. COVID-19 survivors who were treated with cytokine-blocking agents experienced less severe depressive symptomatology and, simultaneously, less susceptibility to develop clinically relevant depression. Moreover, the longitudinal investigations, revealed that patients treated with cytokine-blocking agents underwent a spontaneous symptoms relief over time. Systemic inflammation index decrease over hospitalization was found to affect the susceptibility to long-term depression. Finally, we observed that cytokine-blocking agents’ impact on depression was mediated by lowering of systemic inflammation. Our findings indicate potential efficacy of cytokine-blocking agent treatment during the early stages of COVID-19, mitigating post-COVID depressive symptoms by attenuating systemic inflammation. Further investigation through preclinical and clinical studies is warranted to elucidate immune-inflammatory pathways as viable targets for antidepressant psychopharmacology.