Recent evidence and potential mechanisms underlying weight gain and insulin resistance due to atypical antipsychotics

Abstract

Objective: Atypical antipsychotics (AAPs) promote obesity and insulin resistance. In this regard, the main objective of this study was to present potential mechanisms and evidence concerning side effects of atypical antipsychotics in humans and rodents. Method: A systematic review of the literature was performed using the MEDLINE database. We checked the references of selected articles, review articles, and books on the subject. Results: This review provides consistent results concerning the side effects of olanzapine (OL) and clozapine (CLZ), whereas we found conflicting results related to other AAPs. Most studies involving humans describe the effects on body weight, adiposity, lipid profile, and blood glucose levels. However, it seems difficult to identify an animal model replicating the wide range of changes observed in humans. Animal lineage, route of administration, dose, and duration of treatment should be carefully chosen for the replication of the findings in humans. Conclusions: Patients undergoing treatment with AAPs are at higher risk of developing adverse metabolic changes. This increased risk must be taken into account when making decisions about treatment. The influence of AAPs on multiple systems is certainly the cause of such effects. Specifically, muscarinic and histaminergic pathways seem to play important roles.

Effectiveness of a risk-minimization activity involving physician education on metabolic monitoring of patients receiving quetiapine

“…Therapeutic use of atypical antipsychotics has been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk (including hyperglycemia, dyslipidemia, and weight gain). Although all atypical antipsychotics may produce some metabolic changes, each drug has its own specific risk profile (Newcomer, 2007;Volpato et al, 2013).…”

Leptin and psychiatric illnesses: does leptin play a role in antipsychotic-induced weight gain?

“…Greater leptin elevation with olanzapine, clozapine, and quetiapine can be explained by the higher affinity of these drugs for muscarinic M3 receptors, which are known to be the underlying source of large differences concerning weight gain and other side effects [72]. Indeed, SGA-induced weight gain could be due to the stimulation of muscarinic M3 receptors as well as of 5-HT1a, 5-HT6, and adrenergic α2 receptors, and also the blockade of serotonin 5-HT2c and 5-HT1b, adrenergic α1, dopamine D2 and histamine H1 receptors [14,75,76]. The inhibitory effect on hypothalamic H1Rs includes activation of AMP-activated protein kinase (AMPK), a well-known feeding regulator [22][23][24]76].…”

“…Indeed, SGA-induced weight gain could be due to the stimulation of muscarinic M3 receptors as well as of 5-HT1a, 5-HT6, and adrenergic α2 receptors, and also the blockade of serotonin 5-HT2c and 5-HT1b, adrenergic α1, dopamine D2 and histamine H1 receptors [14,75,76]. The inhibitory effect on hypothalamic H1Rs includes activation of AMP-activated protein kinase (AMPK), a well-known feeding regulator [22][23][24]76]. Noteworthy, suppressing effect on dopamine D 2 receptors with and impact on reward processing and physical activity is also the mechanism by which FGAs can induce weight gain [4,10].…”

Haloperidol affects bones while clozapine alters metabolic parameters - sex specific effects in rats perinatally treated with phencyclidine

“…Although, there are several studies describing the effects of antipsychotics on bone [38–40] and metabolic parameters [41–43] in animals, there is a lack of investigations concerning effects of antipsychotics on these parameters in experimental animal model of SCH. Since our recent investigation has revealed reduced bone mass in male rats in PCP animal model of SCH and protective effect of atypical antipsychotic risperidone [44], the aim of this study was to assess the effects of chronic haloperidol (belonging to PR antipsychotics) and clozapine (belonging to PS antipsychotics) treatment on bone mass, body composition, corticosterone, IL-6 and TNF-α concentrations and metabolic parameters in male and female rats perinatally treated with PCP.…”