Abstract
Rationale and objectiveClozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders.MethodsWe measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue.ResultsFollowing clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients’ BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α.ConclusionFindings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.
Highlights
The effect of clozapine on proinflammatory cytokines levels in the peripheral blood To demonstrate whether the effect of clozapine treatment altered immune function, the levels of three proinflammatory cytokines, namely IL-1β, IL-6, and tumornecrosis factor-α (TNF-α), were examined in the circulating blood of mice after the experiment
Our results show that murine serum glucagon levels were significantly decreased, serum amylase and proinflammatory cytokine IL-β levels markedly enhanced after clozapine administration
BMI, blood glucose, and proinflammatory cytokines (IL-β, IL-6, and TNF-α) levels increased significantly in clozapine-treated patients compared with healthy controls
Summary
Schizophrenia is a serious mental disease that causes obstacles in thinking, emotion, and behavior, affecting approximately 1% of the world’s population (Insel 2010). More than 30% of individuals diagnosed with schizophrenia have treatmentresistant schizophrenia (Lally and MacCabe 2015). Secondgeneration antipsychotics (SGAs) are currently the first-line treatment for schizophrenia. Clozapine is the only antipsychotic drug approved for the treatment of treatment-resistant schizophrenia and is one of the most effective antipsychotics (Tiihonen et al 2017). Numerous clinical reports have linked SGAs, especially clozapine, to severe metabolic side effects, including weight gain, obesity, and diabetes mellitus (Melkersson and Dahl 2003). The mechanisms by which clozapine induces glycometabolism disorders remain unclear and debatable, which, in turn, largely restricts
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