Time-dependent effect of antipsychotic discontinuation and dose reduction on social functioning and subjective quality of life–a multilevel meta-analysis

BACKGROUND: Meta-analyses indicate superiority of antipsychotic maintenance treatment over discontinuation within up to 24 months after treatment initiation for patients with schizophrenia-spectrum disorders. In terms of functional recovery, long-term trials show improved functioning after discontinuation, suggesting a time-dependent effect of antipsychotic maintenance. However, these trials were not included in previous meta-analyses. We therefore investigated whether the effect of antipsychotic maintenance treatment vs. discontinuation on social functioning and quality of life varies by trial length. METHODS: The study was preregistered with PROSPERO (CRD42021248933). PubMed, PsycINFO, Web of Science, Embase and trial registers were systematically searched on 8th November 2021 and updated on 25th June, 2023 and 10th August, 2023 for studies that compared antipsychotic maintenance to discontinuation and reported data on social functioning or subjective quality of life in patients with schizophrenia-spectrum disorders. Risk of bias was assessed with the RoB 2, the ROBINS-I and the RoB-ME tools. Quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation approach. FINDINGS. We included k = 35 studies (N = 5924) with follow-ups between one month and 15 years. Overall, maintenance and discontinuation did not differ on social functioning (k = 32; n = 5330; SMD = 0.204; p = 0.65; 95% CI [−0.69, 1.10]) or quality of life (k = 10; n = 943; SMD = −0.004; p = 0.97; 95% CI [−0.22, 0.21]), whilst subgroup analyses of middle- (2–5 years; k = 7; n = 1032; SMD = 0.68; 95% CI [0.06, 1.28]) and long-term follow-ups (>5 years; k = 2; n = 356; SMD = 1.04; 95% CI [0.82, 1.27]) significantly favoured discontinuation. However, the quality of evidence was rated as very low. INTERPRETATION: Although our findings suggest a time-dependent decrease in the effect of maintenance treatment on social functioning, interpretation of these findings is limited by the serious risk of bias in middle- and long-term trials. Therefore, any conclusions regarding the long-term benefits of antipsychotic treatment or discontinuation for functional recovery are premature and more high-quality trials tailored to comparing state of the art maintenance treatment vs. discontinuation are needed. FUNDING: None.