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Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis

Abstract

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as Kicer value using [18F]DOPA PET before and 6 weeks after antipsychotic discontinuation. The D2/3 receptor availability was measured as BPND using [11C]raclopride PET after antipsychotic discontinuation. Healthy controls also underwent PET scans according to the corresponding schedule of the patients. Patients were monitored for psychotic relapse during 12 weeks after antipsychotic discontinuation. 40% of the patients showed psychotic relapse after antipsychotic discontinuation. The change in Kicer value over time significantly differed between relapsed, non-relapsed patients and healthy controls (Week*Group: F = 4.827, df = 2,253.193, p = 0.009). In relapsed patients, a significant correlation was found between baseline striatal Kicer values and time to relapse after antipsychotic discontinuation (R2 = 0.518, p = 0.018). BPND were not significantly different between relapsed, non-relapsed patients and healthy controls (F = 1.402, df = 2,32.000, p = 0.261). These results suggest that dysfunctional dopamine autoregulation might precipitate psychotic relapse after antipsychotic discontinuation in FEP. This finding could be used for developing a strategy for the prevention of psychotic relapse related to antipsychotic discontinuation.

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Fig. 1: Diagram illustrating the study design.
Fig. 2: The PANSS total scores according to patient relapse statuses.
Fig. 3: Changes in Kicer values in patients with first-episode psychosis (FEP) and healthy controls.
Fig. 4: Relationship between Kicer values at baseline and the time taken to psychotic relapse after antipsychotic discontinuation in patients with first-episode psychosis.

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Acknowledgements

This work was supported by the National Research Foundation of Korea(NRF) grants funded by the Korea government(MSIT) (No. NRF-2019R1A2C2005500, NRF-2019M3C7A1032472)

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Dr Euitae Kim has participated in advisory/speaker meetings organized by Janssen Korea, Otsuka Korea, and Bukwang Pharm Company. Professor. Oliver D. Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Astra-Zeneca, Autifony, Biogen, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Sunovion, Rand, Recordati, and Roche. Professor Jun Soo Kwon has received honorarium from Bukwang Pharm Company, Pfizer Korea, Ostuka Korea and participated in advisory meetings for Boehringer Ingelheim. Professor Jun Soo Kwon was the principal investigator of research projects from Otsuka company and Janssen Korea. The other authors have nothing to declare. Neither authors nor their families have been employed by or have holdings/a financial stake in any biomedical company.

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Kim, S., Shin, S.H., Santangelo, B. et al. Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis. Mol Psychiatry 26, 3476–3488 (2021). https://doi.org/10.1038/s41380-020-00879-0

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