Beyond dopamine: Exploring anti-inflammatory mechanisms of antipsychotics

Schizophrenia is increasingly recognized as a disorder with a prominent neuroimmune component. Researchers have observed elevated markers of inflammation (e.g., cytokines, CRP, and NLR) not only during first-episode psychosis but also in chronic stages, suggesting that immune dysregulation may play a key role in the illness's pathophysiology. Yet, current pharmacological treatment mainly targets dopaminergic dysregulation, which is effective in reducing positive symptoms but is ineffective in managing negative symptoms and cognitive decline associated with schizophrenia. Antipsychotics (APs) may exert anti-inflammatory effects, possibly through attenuating glial activation and modulation of the immune pathways, though these effects remain still underexplored. That is why, in this narrative review, we synthesize evidence from in vitro, animal, and human studies to examine whether APs influence inflammatory processes and assess their potential in mitigating the refractory symptoms of schizophrenia through the immune modulation. Despite promising findings, several key uncertainties persist: inflammatory markers exhibit inconsistent patterns across studies, methodological approaches differ considerably, and antipsychotic-induced metabolic alterations further complicate interpretation. To fully understand the anti-inflammatory potential of APs, future research should identify the most effective compounds, determine optimal treatment timing, and rigorously control for confounding factors. Crucially, a paradigm shift is needed: clinical trials must adopt biomarker-guided stratification, and drug development should focus on agents that modulate the innate immunity. These steps are essential for developing more effective treatments for the refractory symptoms of schizophrenia.