LAUSR

Importance There is limited neurobiological or trial evidence guiding treatment of co-morbid affective syndromes in psychotic disorders. Given use of dopamine blocking antipsychotics, understanding dopamine function, across these mood states, is warranted. Objectives To test for differences in dopamine synthesis capacity (Kicer) between affective syndromes across psychotic disorders, and association with psychotic symptom severity. Design, setting and participants In this cross-sectional 18F-DOPA PET study 38 individuals with first-episode psychosis and comorbid affective syndromes (MDE: n= 25; mixed/mania: n= 13) and 38 matched controls were recruited from early intervention services in inner-city London. Data were collected from March 2013 to February 2022. Main outcome and measures Striatal Kicer, Positive and Negative Syndrome Scale, Hamilton Depression Rating Scale, Montgomery Asperg Depression Rating Scale, Young Mania Rating Scale. Results Mean (SD) age was 27.15 (8.89); MDE: 30.7 (12.83), mixed/mania: 23.7 (3.12), controls 25.99 (6.01). Sex distribution did not differ (male: depression 52%, mixed/mania 61.5%, controls 65.8%; p = .56). Kicer (controlling for age and sex) was significant across groups in whole striatum (F (2, 73) = 4.04, p=.02, R2 =0.13). People with psychosis and MDE had lower Kicer compared to those with psychosis and mixed/mania (β =0.014, SE=0.001, p=0.02), largest difference observed in limbic striatum (Cohen’s d=1.57, p<.001.) In the overall psychosis sample, higher striatal Kicer was associated with greater positive psychotic symptoms (R2 = .13, β = 0.011, SE = 0.001, p= .03), notably in associative striatum (R2= .15, p = .02). No significant association was found in the limbic striatum (p = .19). Conclusion and relevance Dopamine synthesis capacity is lower in psychosis and co-morbid MDE than mixed/mania. Trans-diagnostically, greater positive psychotic symptoms are associated with higher dopamine synthesis capacity in associative, though not limbic striatum. This sub-region dopamine dysregulation has relevance for dopamine modulating therapeutic agents and drug discovery.