¹Seoul National University Bundang Hospital, Neuropsychiatry, Gyeonggi-do, Korea, Republic of, ²King's College London, Neuroimaging, London, United Kingdom, ³University of Padua, Information Engineering, Padova, Italy, ⁴Seoul National University Bundang Hospital, Nuclear Medicine, Gyeonggi-do, Korea, Republic of, ⁵College of Medicine, Seoul National University, Nuclear Medicine, Seoul, Korea, Republic of, ⁶Institute of Psychiatry, Psychology, and Neuroscience, King's College London, Psychosis Studies, London, United Kingdom, ⁷Faculty of Medicine, Imperial College London, Institute of Clinical Sciences, London, United Kingdom, ⁸Seoul National University College of Medicine, Psychiatry, Seoul, Korea, Republic of

Background: Schizophrenia and related psychotic disorders are associated with elevated striatal dopamine synthesis from the first episode. While antipsychotics primarily improve symptoms through dopamine D₂ receptor blockade, it remains unclear whether they affect presynaptic dopamine synthesis due to mixed findings in prior studies. Amisulpride’s D₂/D₃ selectivity makes it ideal for studying dopaminergic changes in FEP under controlled conditions. In contrast, aripiprazole’s D₂ partial agonism may influence dopamine synthesis differently.

Aims & Objectives: This study prospectively investigated one-year changes in striatal dopamine synthesis capacity during amisulpride monotherapy in antipsychotic-naïve first-episode psychosis (FEP) and examined associations with clinical outcomes. In a subset, the effect of switching to aripiprazole was also assessed.

Method: We enrolled 23 antipsychotic-naïve patients with FEP and 35 healthy controls. Patients underwent [¹⁸F]DOPA PET and MRI before treatment, and at 6 and 52 weeks after starting amisulpride. A subset who switched to aripiprazole after one year of amisulpride treatment completed an additional PET scan after at least 3 months on the new medication. Clinical symptoms were assessed repeatedly using Positive and Negative Syndrome Scale (PANSS).

Results: Amisulpride monotherapy produced significant symptomatic improvement, with reductions in PANSS total scores over one year (F(3,47.591)=103.738, p<0.001). In contrast, striatal influx rate constant (Kicer) values increased from baseline to 6 weeks, remained elevated at 1 year, and rose further after switching to aripiprazole, despite maintained clinical stability (F(3,307.669)=4.237, p=0.006). A significant correlation was observed between the PANSS Marder positive symptoms dimension and Kicer values in the limbic striatum (R²=0.1900, F(1,21)=4.926, p=0.0376). Healthy controls showed consistent Kicer values without significant longitudinal change (F(2,299.732)=0.636, p=0.530).

Discussion & Conclusions: These findings indicate that dopamine synthesis capacity but increases during one year of selective D2/D3 receptor blockade with amisulpride, with further elevation after transition to partial agonist treatment with aripiprazole. This persistent increase in dopamine synthesis capacity during antipsychotic treatment may underlie relapse vulnerability and emphasizes the importance of sustained receptor blockade.