Abstract
Second-generation antipsychotics (SGAs) are the cornerstone of treatment for schizophrenia because of their high clinical efficacy. However, SGA treatment is associated with severe metabolic alterations and body weight gain, which can increase the risk of type 2 diabetes and cardiovascular disease, and greatly accelerate mortality. Several underlying mechanisms have been proposed for antipsychotic-induced weight gain (AIWG), but some studies suggest that metabolic changes in insulin-sensitive tissues can be triggered before the onset of AIWG. In this review, we give an outlook on current research about the metabolic disturbances provoked by SGAs, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances. Specifically, we discuss the mechanistic insights gleamed from cellular and preclinical animal studies that have reported on the impact of SGAs on insulin signaling, endogenous glucose production, glucose uptake and insulin secretion in the liver, skeletal muscle and the endocrine pancreas. Finally, we discuss some of the genetic and epigenetic changes that might explain the different susceptibilities of SGA-treated patients to the metabolic side-effects of antipsychotics.
Highlights
A cross-sectional analysis of more than 3000 articles published on antipsychotic-induced weight gain (AIWG) in first-episode, drug-naïve patients with schizophrenia found an average increase of 5.3 kg in weight and 1.86 kg/m2 in body-mass index in second-generation (atypical) antipsychotics (SGAs)-treated patients compared with patients receiving placebo in treatments longer than 12 weeks; the highest weight gain was found with olanzapine and clozapine, followed by quetiapine and risperidone
Despite this review focuses on SGAs-mediated glucose dysregulation independently of body weight gain, it is noteworthy to mention that both AIWG and dyslipidemia are major metabolic side-effects [28,50,51]
While AIWG is associated with glucose dysregulation, evidence points to a direct effect of SGAs on glucose metabolism
Summary
Antipsychotic drugs (APDs) are the cornerstone of treatment for schizophrenia and other mental diseases, including bipolar disorders, dementia, autism-related irritability and severe mental illness [1,2,3]. A cross-sectional analysis of more than 3000 articles published on antipsychotic-induced weight gain (AIWG) in first-episode, drug-naïve patients with schizophrenia found an average increase of 5.3 kg in weight and 1.86 kg/m2 in body-mass index in SGA-treated patients compared with patients receiving placebo in treatments longer than 12 weeks; the highest weight gain was found with olanzapine and clozapine, followed by quetiapine and risperidone This meta-analysis found that aripiprazole, often associated with fewer metabolic side-effects, led to weight gain after short-term periods of treatment [53]. As we will discuss below, cellular and preclinical animal models have provided valuable knowledge about the main targets and molecular pathways disrupted by SGAs (for instance, the intracellular insulin signaling pathways) that can predict long-term metabolic outcomes
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