Beyond the acute episode: D2 receptor pharmacology and risk-stratified antipsychotic decisions in acute and transient psychotic disorder

Introduction

Acute and transient psychotic disorder (ATPD) is characterized by abrupt onset of psychotic symptoms with rapid remission, representing up to 6% of first-episode psychoses with an incidence of approximately 4–5 per 100,000 per year. [1] Despite favorable short-term outcomes, over 50% of patients experience relapse, and 44% shift to other diagnoses within 4.5 years, most commonly schizophrenia (21%). [1] No antipsychotic is formally licensed for ATPD, and no evidence-based guidelines exist specifically for its pharmacological management, leaving clinicians to extrapolate from first-episode psychosis (FEP) protocols. [2] The role of substance exposure, particularly serotonergic hallucinogens such as ayahuasca, acting as a potent 5-HT2A agonist, adds further diagnostic and therapeutic complexity. [3] We illustrate this clinical dilemma with the case of a 47-year-old woman with no prior psychiatric history, admitted following acute-onset of auditory hallucinations, persecutory ideation, behavioral disorganization, and affective instability, preceded by psychosocial stressors and intermittent cannabis and ayahuasca use. Brain MRI and EEG were unremarkable. Treatment with aripiprazole 15 mg/day and sodium valproate 1000 mg/day achieved full remission within four days.

Aims

This narrative review aims to synthesize evidence on: (1) recurrence risk and prognostic factors in ATPD; (2) antipsychotic maintenance versus discontinuation after remission; (3) the influence of serotonergic hallucinogen and cannabis exposure on prognosis and diagnostic trajectory.

Methods

Narrative review of peer-reviewed literature, meta-analyses, and clinical guidelines (2000–2026) from PubMed and Cochrane Library using terms including “acute and transient psychotic disorder,” “brief psychotic disorder,” “antipsychotic maintenance,” “antipsychotic discontinuation,” “ayahuasca psychosis,” and “hallucinogen-induced psychosis.” Data were extracted and synthesized narratively; statistical results are reported as published in the original studies.

Results

Meta-analytical data (82 studies, n=11,133) demonstrate significantly lower psychotic recurrence in ATPD compared with first-episode schizophrenia (39% vs. 78% at 24 months), with 76% of ATPD patients antipsychotic-free at follow-up. [1] A recent randomized trial (n=227) found that early dose reduction/discontinuation after FEP remission led to more relapses at 12 months but significantly better functioning at 36–48 months, suggesting long-term functional benefits of guided tapering. [4] Partial D2 agonism, as with aripiprazole, was associated with lower relapse risk than full D2 antagonism, independent of tapering speed. [4] Psychotic relapse is an independent risk factor for diagnostic shift (RR=1.67), particularly in non-polymorphic subtypes. [5] Hallucinogen-induced psychosis carries a 26% pooled transition rate to schizophrenia, and cannabis-induced psychosis 34%, warranting sustained monitoring in substance-exposed patients. [3]

Conclusions

The evidence supports individualized, risk-stratified antipsychotic management after ATPD rather than uniform prolonged maintenance. Patients achieving rapid remission without polymorphic features, as in the present case, may be candidates for guided dose reduction using partial D2 agonists, with close monitoring for at least 3 years. [1,5] Substance exposure history, particularly serotonergic hallucinogens including ayahuasca and cannabis, should critically inform both diagnostic classification and duration of pharmacological treatment, given the substantial risk of transition to schizophrenia spectrum disorders. [3]

References

1-Provenzani U, Salazar de Pablo G, Arribas M, Pillmann F, Fusar-Poli P. Clinical outcomes in brief psychotic episodes: a systematic review and meta-analysis. Epidemiol Psychiatr Sci. 2021;30:e71. 2-Fusar-Poli P, Salazar de Pablo G, Rajkumar RP, et al. Diagnosis, prognosis, and treatment of brief psychotic episodes: a review and research agenda. Lancet Psychiatry. 2022;9(1):72–83. 3- B, Lappin J, Large M, Sara G. Transition of substance-induced, brief, and atypical psychoses to schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2020;46(3):505–516. 4-Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy. JAMA Psychiatry. 2013;70(9):913–920. 5-Castagnini AC, Foldager L, Bertelsen A. Prognostic significance of psychotic relapse in patients with first-episode acute and transient psychosis: new empirical support for ICD-11. J Psychiatr Res. 2021;138:1–6.