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Original Investigation |

Striatal Reward Activity and Antipsychotic-Associated Weight Change in Patients With Schizophrenia Undergoing Initial Treatment

Mette Ø. Nielsen, PhD1,2; Egill Rostrup, DMSc3; Sanne Wulff, PhD1,2; Birte Glenthøj, DMSc1,2; Bjørn H. Ebdrup, PhD1,2
[+] Author Affiliations
1Centre for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, University of Copenhagen, Copenhagen, Denmark
2Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, University of Copenhagen, Copenhagen, Denmark
3Functional Imaging Unit, Department of Clinical Physiology and Nuclear Medicine, University of Copenhagen, Copenhagen, Denmark
JAMA Psychiatry. 2016;73(2):121-128. doi:10.1001/jamapsychiatry.2015.2582.
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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.

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Figure 1.
Flowchart of Patient Recruitment

fMRI indicates functional magnetic resonance imaging.

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Figure 2.
Study Regions of Interest (ROIs)

The predefined ROIs in the ventral striatum (light blue) are centered in Montreal Neurological Institute (MNI) coordinates ±10, 14, and −6; those in the putamen (dark blue) are centered in MNI coordinates ±22, 4, and 4.

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Figure 3.
Correlation Between Functional Magnetic Resonance Imaging (fMRI) Signal and Weight Change in the Right-Sided Putamen Region of Interest

The correlation between weight gain and baseline fMRI signal (A) and between weight gain and change in fMRI signal (B) after 6 weeks of amisulpride treatment. Patients with the lowest contrast signal during reward anticipation at baseline gained the most weight during antipsychotic treatment. Patients who gained the most weight after amisulpride treatment had the highest signal increase (calculated using linear regression).

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Figure 4.
Whole-Brain Voxelwise Correlations Between Baseline Functional Magnetic Resonance Imaging (fMRI) Signal and Weight Change

There was a partial overlap between voxels showing a significant correlation between baseline fMRI signal and weight change (red) and the predefined region of interest (blue) (P < .001, uncorrected). The figure is centered in Montreal Neurological Institute coordinates 22, 4, and 2.

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