Dopamine and Mood in Psychotic Disorders: An 18F-DOPA PET Study

TY - JOUR

T1 - Dopamine and Mood in Psychotic Disorders

T2 - An 18F-DOPA PET Study

AU - Jauhar, Sameer

AU - McCutcheon, Robert A.

AU - Nour, Matthew M.

AU - Veronese, Mattia

AU - Rogdaki, Maria

AU - Bonoldi, Ilaria

AU - Azis, Matilda

AU - Whitehurst, Thomas

AU - Arumuham, Atheeshaan

AU - Onwordi, Ellis

AU - Turkheimer, Federico

AU - McGuire, Philip

AU - Young, Allan H.

AU - Howes, Oliver D.

N1 - Publisher Copyright: © 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.

PY - 2025/8/13

Y1 - 2025/8/13

N2 - 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 (Ki cer) 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 Ki cer measured by 18F-DOPA PET. MAIN OUTCOMES AND MEASURES Striatal Ki cer 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). Ki cer (controlling for age and sex) was significant across groups in whole striatum (F 2,71 = 4.04; P = .02; R 2 = 0.13). People with psychosis and MDE had lower Ki cer 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 Ki cer was associated with greater positive psychotic symptoms (R 2 = 0.13; β [SE], 0.000066 [0.000030]; P = .03), notably in the associative striatum (R 2 = 0.15; P = .02). No significant association was found in the limbic striatum. CONCLUSIONS AND RELEVANCE Ki cer was lower in psychosis and comorbid MDE than mixed/mania syndromes, and transdiagnostically, greater positive psychotic symptoms were associated with higher Ki cer in the associative, but not limbic, striatum. This subregion dopamine dysregulation has relevance for dopamine-modulating therapeutic agents and drug discovery.

AB - 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 (Ki cer) 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 Ki cer measured by 18F-DOPA PET. MAIN OUTCOMES AND MEASURES Striatal Ki cer 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). Ki cer (controlling for age and sex) was significant across groups in whole striatum (F 2,71 = 4.04; P = .02; R 2 = 0.13). People with psychosis and MDE had lower Ki cer 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 Ki cer was associated with greater positive psychotic symptoms (R 2 = 0.13; β [SE], 0.000066 [0.000030]; P = .03), notably in the associative striatum (R 2 = 0.15; P = .02). No significant association was found in the limbic striatum. CONCLUSIONS AND RELEVANCE Ki cer was lower in psychosis and comorbid MDE than mixed/mania syndromes, and transdiagnostically, greater positive psychotic symptoms were associated with higher Ki cer in the associative, but not limbic, striatum. This subregion dopamine dysregulation has relevance for dopamine-modulating therapeutic agents and drug discovery.

UR - https://www.scopus.com/pages/publications/105020271379

U2 - 10.1001/jamapsychiatry.2025.1811

DO - 10.1001/jamapsychiatry.2025.1811

M3 - Article

C2 - 40802251

SN - 2168-622X

VL - 82

SP - 1009

EP - 1014

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 10

ER -