We tested the hypothesis that long-term treatment with pomaglumetad methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either pomaglumetad methionil ( ) or aripiprazole ( ). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The pomaglumetad methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group (？2.8？±？0.4 versus 0.4？±？0.6; ). However, change in Positive and Negative Syndrome Scale (PANSS) total scores for aripiprazole was significantly greater than for pomaglumetad methionil (？15.58？±？1.58 versus ？12.03？±？0.99; ). The incidences of SAEs (8.2% versus 3.1%; ) and discontinuation due to AEs (16.2% versus 8.7%; ) were significantly higher for pomaglumetad methionil compared with aripiprazole. No statistically significant differences in the incidence of TEAEs, EPS, or suicidal ideation or behavior were noted between treatment groups. In conclusion, long-term treatment with pomaglumetad methionil resulted in significantly less weight gain than aripiprazole. This trial is registered with ClinicalTrials.gov NCT01328093. 1. Introduction All of the current antipsychotics target dopamine receptors as their common mechanism of action [1, 2]. Due to differences in the affinities to the dopamine receptors and interactions with other biogenic monoamine receptors, therapeutic profiles and limitations of individual drugs vary [1]. The conventional/typical antipsychotic drugs are effective in treating positive symptoms of schizophrenia [3, 4]. However, they are associated with extrapyramidal symptoms (EPS) and hyperprolactinemia [3, 4]. The newer generation atypical antipsychotics not only improve positive and, to some extent, negative symptoms of schizophrenia [5, 6] but also have a lower propensity to cause EPS [3, 4, 7, 8] and hyperprolactinemia [3, 4]. However, these agents may still be associated with other adverse events (AEs), such as body weight gain, lipid abnormalities [9, 10], and glucose dysregulation [3, 4] in some patients. Furthermore, drug-induced weight gain may affect long-term compliance, which directly influences the likelihood of successfully managing the course of disease [11, 12]. Hence, a
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