Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far?

Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side-effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C-reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets.