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Background Several psychotropic drugs can induce weight gain and metabolic alterations. The authors compared metabolic evolutions of patients switching versus continuing psychotropic treatments with different risk profiles. Methods Patients either switched from a high- to a medium- (N  = 36) or low-risk drug (N  = 27), from a medium- to a low-risk drug (N  = 71), or to a same-risk drug (N  = 61). Controls were kept using either a high- (N  = 35), medium- (N  = 155), or low-risk drug (N  = 47). The evolution over 2 years of weight and metabolic parameters was analyzed using linear mixed-effect models, also examining the influence of polygenic risk scores for body mass index (BMI) or BMI and psychiatric disorders. Study Results High-, medium-, or low-risk controls gained on average 1.32%, 0.42%, and 0.36% more weight per month than patients switching from or within these risk categories (P  < .001, P  < .001, and P  = .003, respectively). High-to-high or high-to-medium switches resulted in a greater weight increase than switching to lower-risk categories (+0.77% and + 0.39% respectively, P  < .001). No difference was found between switching medium-to-medium and medium-to-low (P  ≈ 1). Switching high-to-low resulted in 10% weight loss after 2 years, with the greatest loss occurring the first 6 months after the switch. Compared with high-risk controls, lower total cholesterol (−0.27 mmol/l, P  = .043) in the high-to-low group, and lower glucose (−0.44 mmol/l, P  = .032) and systolic blood pressure (−5.50 mmHg, P  = .034) in the low-to-low group were found. Polygenic scores were not associated with weight changes in controls or after switching. Conclusion Psychotropic switches to a lower- or same-risk drug can attenuate weight gain, with only switching high to low resulting in weight loss. [ABSTRACT FROM AUTHOR]