Absolute Receptor Occupancy, Not Rate of Decline, Predicts Relapse

Journal article : Review

Relapse following antipsychotic discontinuation is consistently associated with reduction in dopamine D2 receptor occupancy, but available evidence does not support the view that relapse risk is determined by the speed of receptor-occupancy decline. Meta-analytic findings indicate that, within discontinuation studies, abrupt and gradual discontinuation do not significantly differ in relative relapse risk. Apparent advantages of slower dose reduction in some studies are difficult to interpret, as they often reflect continued therapeutic exposure rather than a specific protective effect of tapering itself. Similarly, the non-linear relationship between antipsychotic dose, receptor occupancy, and relapse risk is consistent with a threshold model of therapeutic protection, but does not provide evidence that hyperbolic tapering schedules independently reduce relapse risk. Comparisons of relapse rates across oral and long-acting injectable discontinuation arms from different trials are also methodologically problematic, because substantial trial-level differences affect both discontinuation and maintenance groups. Recent analyses further show that early rapid relapse occurs not only after discontinuation but also in patients maintained on treatment, and that its clinical profile does not resemble a stereotyped withdrawal syndrome. Taken together, the available trial data support the interpretation that relapse risk after discontinuation is primarily determined by whether antipsychotic exposure falls below a therapeutic threshold, rather than by withdrawal kinetics. Although gradual discontinuation may offer pragmatic clinical advantages, there is currently no robust evidence that tapering schedule independently reduces relapse risk.

Authors: McCutcheon, RA; Pillinger, T; Rubio, JM; Taylor, D; Jauhar, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Schizophrenia Bulletin: The Journal of Psychoses and Related Disorders
• Volume: 52
• Issue: 3
• Pages: sbag057
• Article number: sbag057
• Publication date: 2026-04-01
• Acceptance date: 2026-03-24
• DOI: 10.1093/schbul/sbag057
• EISSN: 1745-1701
• ISSN: 1787-9965, 0586-7614
• Pmid: 42241484
• Language: English
• Keywords: Antipsychotic; Schizophrenia; Clinical Trials; Antipsychotic Agents; Humans; Psychosis; Receptors, Dopamine D2; Discontinuation; Relapse; Recurrence
• Subtype: Review