Antipsychotic treatment in clinical high risk for psychosis: Iatrogenesis related to dopamine supersensitivity psychosis?

To the Editor

Zhang et al. (2020) conducted a 3-year longitudinal study of the effectiveness of antipsychotics (AP) on preventing transition for clinical high risk (CHR) for psychosis patients in developing psychosis. Their findings showed AP had no benefit in preventing transition in this CHR population. In fact, among the 450 follow-up CHR patients, those who had received antipsychotic medication (n = 309) had significantly higher psychosis transition rates compared to those who had not (26.9% vs 17.7%). The psychosis transition rate for mild, but not severe CHR cases was significantly elevated. Antipsychotic treatment (APT) predicted transition independent of symptoms, despite similar functional levels of CHR patients with and without AP. Thus, the results do not support the hypothesis raised by Raballo et al. (2021) that CHR patients commenced on APT may be more vulnerable for transition to psychosis on the basis of poorer levels of functioning.

Zhang et al. (2020) observed that for CHR patients with mild symptoms, those on continuous APT were more likely to transition to psychosis than those who ceased APT. CHR patients on higher doses of APT were also more likely to transition to psychosis compared with those on lower dosage. These results suggest that dopamine supersensitivity is a plausible pathogenic mechanism for the effect of APT within the CHR population. Howes and Kapur (2009) hypothesised that excessive synthesis of presynaptic dopamine may be a final common pathway for developing schizophrenia, and prolonged blockade of the D2-receptor by APT leads to D2-receptor upregulation, thereby increasing the risk of supersensitivity states. In the CHR population, this process may contribute to the worsening of the primary abnormality of psychosis, leading to symptom onset or re-emergence.

The dopamine system being the likely final common pathway for the pathogenesis of psychosis, combined with the dopamine supersensitivity process resulting from prolonged D2-receptor blockade, may explain the significantly higher rates of transition to psychosis in CHR patients exposed to AP. Higher antipsychotic doses and longer treatment duration likely increase this risk. Accordingly, further studies of APT should explore the specific in vivo human positron emission tomography imaging changes within D2-receptors (possible upregulation of D2-receptors) and their effect on psychosis transition. Such studies would better characterise the risk/benefit balance of APT in CHR patients. In the interim, clinicians should heed the caveat that APT may be potentially hazardous for CHR patients and particularly for those with mild presentations (Zhang et al., 2020).