JAMA Psychiatry. 2025 Aug 13. doi: 10.1001/jamapsychiatry.2025.1811. Online ahead of print.
ABSTRACT
IMPORTANCE: There is limited neurobiological or trial evidence guiding treatment of comorbid affective syndromes in psychotic disorders. Given the use of dopamine-blocking antipsychotics, understanding dopamine function across these mood states is warranted.
OBJECTIVE: To test for differences in dopamine synthesis capacity (Kicer) between affective syndromes across psychotic disorders and for association with psychotic symptom severity.
DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study using fluorine F 18-labeled fluorodopa (18F-DOPA) positron emission tomography (PET), individuals with first-episode psychosis and comorbid affective syndromes, including a current major depressive episode (MDE) or mixed/mania syndromes, and matched controls were recruited from early intervention services in inner-city London, United Kingdom. Data were collected from March 2013 to February 2022 and analyzed from October 1, 2023, to January 1, 2025.
EXPOSURE: Striatal Kicer measured by 18F-DOPA PET.
MAIN OUTCOMES AND MEASURES: Striatal Kicer and scores on the Positive and Negative Syndrome Scale, Hamilton Depression Rating Scale, Montgomery-Åsberg Depression Rating Scale, and Young Mania Rating Scale were determined.
RESULTS: The study included a total of 76 individuals (38 with first-episode psychosis and comorbid affective syndromes [25 with MDE and 13 with mixed/mania syndromes] and 38 matched controls). The mean (SD) age was 27.2 (8.9) years overall, 30.7 (12.8) years among those with MDE, 23.7 (3.1) years among those with mixed/mania syndromes, and 26.0 (6.0) years among controls. Sex distribution did not differ (MDE, 13 [52%] male; mixed/mania syndromes, 8 [62%] male; controls, 25 [66%] male; P = .56). Kicer (controlling for age and sex) was significant across groups in whole striatum (F2,71 = 4.04; P = .02; R2 = 0.13). People with psychosis and MDE had lower Kicer compared with those with psychosis and mixed/mania syndromes (β [SE], 0.014 [0.001]; P = .02), with the largest difference observed in the limbic striatum (Cohen d = 1.57; P < .001). In the overall psychosis sample, higher striatal Kicer was associated with greater positive psychotic symptoms (R2 = 0.13; β [SE], 0.000066 [0.000030]; P = .03), notably in the associative striatum (R2 = 0.15; P = .02). No significant association was found in the limbic striatum.
CONCLUSIONS AND RELEVANCE: Kicer was lower in psychosis and comorbid MDE than mixed/mania syndromes, and transdiagnostically, greater positive psychotic symptoms were associated with higher Kicer in the associative, but not limbic, striatum. This subregion dopamine dysregulation has relevance for dopamine-modulating therapeutic agents and drug discovery.
PMID:40802251 | DOI:10.1001/jamapsychiatry.2025.1811
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