The effect of switching antipsychotics to aripiprazole versus paliperidone on weight/cardiometabolic parameters: 18-month follow-up findings from the European Long-acting Antipsychotics in Schizophrenia Trial (EULAST)

Antipsychotic-induced weight gain (AiWG) is a common, burdensome adverse effect. Switching to antipsychotics with lower metabolic risks, such as aripiprazole, is recommended, but long-term data is limited. Long-acting injectables (LAIs) may offer metabolic benefits over oral formulations, yet evidence is inconsistent. We compared long-term effects of switching to aripiprazole versus paliperidone on bodyweight, considering administration route and smoking. To that end, we analyzed data from 241 participants (mean age = 31.0; 32 % female) in the European Long-acting Antipsychotics in Schizophrenia Trial (EULAST), a multicentre, open-label, randomized trial. Participants received aripiprazole (n = 119) or paliperidone (n = 122), orally or as LAIs. Bodyweight was assessed over 18 months. Secondary outcomes included changes in BMI and cardiometabolic parameters. Both groups showed progressive weight gain: over 18 months, body weight increased by 4.7 kgs (95 % CI 3.0-6.5). Weight gain was 4.5 kgs with aripiprazole (95 % CI 2.1-7.0) and 4.9 kgs with paliperidone (95 % CI 2.3-7.4). Clinically significant weight gain (≥5 %) occurred in 41.1 % and 58.7 % of users, respectively (NNH = 5; p = 0.06). Weight gain was more pronounced among participants receiving LAIs (difference of 5.57 kgs; 95 % CI: 0.8-10.4; p = 0.02). Smoking was associated with greater weight gain (+2.3 kgs; 95 % CI: 0.9-3.6; p = 0.001). In conclusion, switching to aripiprazole or paliperidone did not prevent AiWG and LAIs showed no metabolic advantage relative to oral counterparts. The association between smoking and increased weight gain suggests smoking may represent a modifiable risk factor, warranting further investigation of smoking cessation as a potential intervention in AiWG management.