Mechanisms underlying metabolic disturbances associated with psychosis and antipsychotic drug treatment

Abstract

The increase in cardiovascular disease and reduced life expectancy in schizophrenia likely relate to an increased prevalence of metabolic disturbances. Such metabolic risk factors in schizophrenia may result from both symptom-related effects and aetiological factors. However, a major contributory factor is that of treatment with antipsychotic drugs. These drugs differ in effects on body weight; the underlying mechanisms are not fully understood and may vary between drugs, but may include actions at receptors associated with the hypothalamic control of food intake. Evidence supports 5-hydroxytryptamine receptor 2C and dopamine D2 receptor antagonism as well as antagonism at histamine H1 and muscarinic M3 receptors. These M3 receptors may also mediate the effects of some drugs on glucose regulation. Several antipsychotics showing little propensity for weight gain, such as aripiprazole, have protective pharmacological mechanisms, rather than just the absence of a hyperphagic effect. In addition to drug differences, there is large individual variation in antipsychotic drug-induced weight gain. This pharmacogenetic association reflects genetic variation in several drug targets, including the 5-hydroxytryptamine receptor 2C, as well as genes involved in obesity and metabolic disturbances. Thus predictive genetic testing for drug-induced weight gain would represents a first step towards personalised medicine addressing this severe and problematic iatrogenic disease.

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology

“…There are a number of mechanisms by which antipsychotic medication may increase body weight, particularly blockade at D2/3, 5HT2c and histamine 1 receptors (Karr et al, 2019;Reynolds and McGowan, 2017). There is also evidence that antipsychotic medication may disrupt hormones involved in the control of food intake, such as leptin and adiponectin, and evidence that antagonism of muscarinic M3 receptors on pancreatic β-cells may contribute to glucose dysregulation (see Reynolds and McGowan, 2017). Large, multiple-treatments, network meta-analyses of clinical trials of antipsychotic medications have shown that most can lead to significant weight gain (Huhn et al, 2019;Leucht et al, 2013).…”

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

“…SGAs, such as olanzapine (OLZ), have numerous metabolic side effects (Newcomer, 2005). These include weight gain, dyslipidaemia, hyperglycaemia, insulin resistance, and an increased risk for the development of type 2 diabetes and cardiovascular disease (Bergman and Ader, 2005;Newcomer, 2005;Kessing et al, 2010;Lord et al, 2017;Reynolds and McGowan, 2017). Although impairments in glucose homeostasis often accompany weight gain itself, there is evidence that OLZ has direct diabetogenic effects independent of changes in body weight.…”

Progress in Genetic Polymorphisms Related to Lipid Disturbances Induced by Atypical Antipsychotic Drugs

“…Although there have been tremendous reports on the metabolic side effects of atypical antipsychotic drugs, the mechanisms remain elusive (Reynolds and McGowan, 2017). Available evidence has suggested that the clinical responses to antipsychotics and related side effects could vary from patient to patient.…”