Antipsychotic-Induced Weight Gain: Dose-Response Meta-Analysis of Randomized Controlled Trials

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.

Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine

“…According to this hypothesis, it was reasonable that the therapeutically relevant concentration of QTP enhanced AMPK signalling due to the high-affinity H1R antagonistic action of QTP (Ki = 11 nM). With regard to the biphasically concentration-dependent stimulatory effects of QTP on AMPK signalling (bell-shaped pattern), the therapeutically relevant concentration (3 μM) enhanced AMPK signalling but the stimulatory effects of the higher concentrations (10 and 30 μM) were attenuated compared to the therapeutically relevant concentration, which is consistent with the dose dependency of QTP on weight gain [ 14 ]. Exploring the mechanism by which the activation of AMPK at higher concentrations of QTP diminishes compared to that of the therapeutic concentration of QTP is clinically important for appropriate dose determination.…”

“…Both lurasidone and brexpiprazole have been evaluated as the safest options in patients with the risk of developing metabolic complications and weight gain, since these antipsychotics are listed among the best atypical antipsychotics associated with metabolic outcomes [ 14 , 42 ]. Lurasidone has the lowest affinity to H1R antipsychotics (Ki = >1000 nM); however, brexpiprazole is a H1R antagonist (Ki = 19 nM), but is a low-risk antipsychotic for metabolic complications [ 14 , 42 ]. Therefore, the contradiction between lurasidone and brexpiprazole regarding the low risk for metabolic complications cannot be fully explained by their affinity to H1R.…”

“…This attenuation is possibly associated with similar mechanisms, namely the downregulation of 5-HT7R and attenuation of cAMP synthesis observed in astrocytes. Therefore, the results from the in vitro experiment using cultured astrocytes can be used to interpret the mechanism involved in clinical findings that the 5-HT7R inverse agonistic action of QTP plays important roles in the biphasically dose-dependent effects of QTP (bell-shaped pattern) on weight gain [ 14 ]. In other words, the 5-HT7R inverse agonistic action probably contributes to the prevention of antipsychotic-induced weight gain [ 38 , 39 , 44 ].…”

“…In contrast to the effectiveness of a high dose of QTP, a daily dose of QTP of 300 mg/day was superior to 600 mg/day with respect to quality of life and metabolic complications [ 9 ]. Notably, a dose–response meta-analysis revealed that the dose–response curve of weight gain induced by QTP was approximately bell-shaped and its peak was 1.48 kg at around 600 mg/day [ 14 ].…”

“…Both antidepressive mood-stabilising antipsychotics, lurasidone and brexpiprazole, are evaluated to be the safest option in patients with a risk of developing metabolic complications, since they are listed among the best atypical antipsychotics associated with metabolic outcomes [ 14 , 42 ]. The mechanisms of similar clinical features between lurasidone and brexpiprazole, which are of low risk for the development of metabolic complication, are also probably involved in the 5-HT7R inverse agonistic action of these atypical antipsychotics [ 38 , 39 ].…”