Importance: Weight gain is a common and serious adverse effect of antipsychotic treatment. A variable individual predisposition to development of metabolic disturbances calls for predictive biological markers.

Objectives: To investigate whether attenuated striatal activity during reward anticipation is associated with amisulpride-induced weight change in antipsychotic-naive patients with schizophrenia undergoing initial treatment and to examine the association between weight change and changes in reward anticipation activity after treatment.

Design, Setting, and Participants: Sixty-nine antipsychotic-naive inpatients and outpatients with schizophrenia were included in a multimodal longitudinal cohort study from December 16, 2008, to December 11, 2013. Fifty-eight patients underwent functional magnetic resonance imaging (fMRI) while performing a monetary reward task. After 6 weeks of treatment with amisulpride, a relatively selective dopamine D2 antagonist, 39 patients underwent a second fMRI scan and measurement of change in body weight. Final follow-up was completed on January 14, 2014, and data were analyzed from October 25, 2014, to June 15, 2015 and August 31 to September 19, 2015.

Exposures: Six weeks of individually dosed amisulpride treatment.

Main Outcomes and Measures: Reward-anticipation activity in the striatum before and after treatment and weight change.

Results: Of the 69 patients who consented to the study, 39 underwent the follow-up fMRI and weight measurement (age range, 18-45 years; 17 women and 22 men). The mean (SD) daily dose of amisulpride was 272 (168; range, 50-800) mg, and patients gained a mean (SD) of 2.3 (2.8; range, -4 to 8) kg in body weight. Improvement from baseline to follow-up was found on the mean (SD) positive (19.9 [4.1] to 14.3 [3.8]), general (39.7 [7.7] to 30.5 [7.7]), and total (78.5 [15.3] to 63.2 [13.9]) scores on the Positive and Negative Syndrome Scale (P < .001). Weight gain was predicted by low mean (SD) baseline reward-related activity in the right-sided putamen (0.20 [0.93]; F35,3 = 5.64; P = .003). After 6 weeks, weight gain was associated with an increase in mean (SD) reward activity in the same region during treatment (0.28 [0.74]; F37,1 = 4.48; P = .04).

Conclusions and Relevance: Activity in striatal regions of the reward system appears to be associated with the individual variability in the predisposition for antipsychotic-associated weight gain. Moreover, pharmacologic modulation of the reward system may play a role in antipsychotic-associated weight gain.