Antipsychotic drugs and obesity

Abstract

Mechanisms underlying antipsychotic cardiometabolic adverse effects are incompletely understood. This hampers the identification of high-risk patients, low-risk antipsychotics and preventive/ameliorative treatments. Recent clinical, molecular and genetic data suggest that: (i) antipsychotic-naïve samples provide the greatest power for mechanistic studies; (ii) weight and metabolic effects can be discordant, pointing to overlapping and distinct mechanisms; (iii) antipsychotics affect satiety and energy homeostasis signaling; (iv) the specific peptides mediating these effects are unknown but probably overlap with those involved in idiopathic obesity; and (v) single nucleotide polymorphisms in genes encoding known neurotransmitter receptors and metabolic proteins are promising pharmacogenomic targets for countering adverse affects. However, sophisticated molecular studies and genome-wide association studies, ideally in antipsychotic-naïve/first episode samples, are needed to further advance the field.

Figure 1

Figure 1a. Effect of prior treatment exposure on BMI increase with risperidone in adults and youth [–11]. The difference in the magnitude of weight gain associated with risperidone depends on patient age and treatment history. In adults and youth, the weight gain in antipsychotic-naïve and first-episode patients (green bar) is far greater than in patients with chronic illness and treatment exposure, either in pooled reviews (blue bars), or prospective studies (red bars). In comparison to adults, the weight gain in youth, and especially in those with no more than seven days of lifetime antipsychotic exposure (green bar on the right), was the greatest. The blue and red bars, respectively, at the left of Figure 1a display data summarized in a recent review [6], and data derived from the large-scale prospective CATIE trial [7]. Figure 1b. Heterogeneity of weight gain in antipsychotic-naïve youth treated with risperidone for three months [11]. The pie chart shows the heterogeneity of three-month weight gain in 135 children and adolescents receiving risperidone who were part of a cohort study of 272 antipsychotic-naïve youth. Despite a mean weight gain of 5.3 kg, weight gain outcomes varied considerably: weight loss occurred in 4.4%; weight gain of 0–6.9% of baseline body weight occurred in 31.1%; of 7–13.9% in 39.6%; of 14–20.9% in 18.5%; and of ≥21% in 6.7% of youth.

Figure 2

Model of antipsychotic-induced weight gain. The heterogeneity of antipsychotic-induced weight gain results from still poorly understood drug-gene-environment interactions. Moderators of antipsychotic-induced weight gain include variables related to patient demographics, treatment setting, illness characteristics, past and baseline antipsychotic and comedication treatments, and baseline diet, activity, and body composition. Mediators include antipsychotic dose, comedications, medication side effects and changes in diet and activity. Taken together, these factors interact in specific ways leading to antipsychotic-induced weight gain via so far incompletely understood mechanisms and pathways.