Antipsychotic-Induced Weight Gain

Abstract and Introduction

Abstract

Background: Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis.

Methods: We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain.

Findings: Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses.

Interpretation: Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice.

Introduction

Weight gain is one of the most important side-effects of antipsychotic drugs. It is associated with metabolic disturbances such as increase in glucose, cholesterol, and lipids and may thus contribute to the well-documented excess mortality of people with schizophrenia compared to the general population.^[1] While it is well-known that antipsychotic drugs differ in their propensity to produce weight gain, little is known about the question of whether weight gain is dose-related. To know this would be important for various reasons. We have recently shown that the efficacy dose-response relationships of many antipsychotics have a hyperbolic shape and finally approach a plateau, i.e., beyond a certain threshold higher doses do not lead to more efficacy.^[2] If in contrast higher doses were associated with more weight gain, this would be one more reason to avoid high doses for these drugs. But it is also possible that once the receptors that are responsible for weight gain are fully bound, higher doses of a given drug would not lead to more weight gain, i.e., the dose-response curves would again plateau. It is even conceivable that at higher doses, some antipsychotics have antihyperphagic effects that lead to less weight gain. Such a hypothesis has, for example, been put forward for 5-HT_1A receptor partial agonists such as lurasidone^[3] and ziprasidone.^[4]

We, therefore, conducted a meta-analysis of dose-response studies on weight gain, similar to our previous analysis on the efficacy of antipsychotic drugs.^[5] With this method we explored whether the dose-response relationships of the drugs are monotonic (higher doses are always associated with more weight gain), hyperbolic (weight gain increases with higher doses until a plateau is approached), or bell-shaped (weight gain increases up to certain doses beyond which less weight gain is produced than by lower doses).