Immunoinflammatory and oxidative alterations in subjects with schizophrenia under clozapine: A meta-analysis

Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced by clozapine and its relationship with the drug's clinical response and compare it with other antipsychotics. Our systematic review has selected nineteen studies meeting the inclusion criteria, from which eleven were included in the meta-analysis, totalizing 689 subjects distributed over three different comparisons. The results revealed that clozapine treatment activates the compensatory immune-regulatory system (CIRS) (Hedges's g = + 1.049; CI + 0.62 - + 1.47, p < 0.001) but has no effects on the immune-Inflammatory Response System (IRS) (Hedges's g = -0.27; CI -1.76 - + 1.22, p = 0.71), M1 macrophage (Hedges's g = -0.32; CI -1.78 - + 1.14, p = 0.65) and Th1 (Hedge's g = 0.86; CI-0.93 - + 1.814, p = 0.07) profiles. Comparing clozapine-treated pa-tients with other anti-psychotics-treated, plasma levels of interleukin (IL)-6 were greater in the clozapine group (Hedge's g = 0.75; CI 0.35 -1.15, p < 0.001). In addition, higher IL-6 plasma levels after four weeks of clozapine treatment were related to the development of clozapine-induced fever; however, IL-6 levels recovered to baseline in 6-10 weeks due to an unexplained compensatory mechanism. In conclusion, our results show that clozapine treatment causes a time-dependent mixed immune profile characterized by increased IL-6 levels and CIRS acti-vation, which may contribute to this drug mechanism of action and adverse effects. Future studies must be designed to investigate the relationship between clozapine-induced immune alterations and symptom remission, treatment resistance, and adverse effects, given the im-portance of this drug for treating resistant schizophrenia. (c) 2023 Elsevier B.V. and ECNP. All rights reserved.

Automated summary

This systematic review evaluated the immune alterations induced by clozapine and its relationship with clinical response. The results showed that clozapine treatment activates the compensatory immune-regulatory system and increases plasma levels of interleukin-6. Clozapine-induced immune alterations may contribute to the drug's mechanism of action and adverse effects.