The Course of Relapse Following Antipsychotic Discontinuation in Schizophrenia: A Test of the Antipsychotic Withdrawal Syndrome Hypothesis of Relapse

BackgroundAntipsychotics are central to relapse prevention in schizophrenia, but longer-term use is associated with adverse effects that often prompt dose reduction or discontinuation. Although relapse risk increases after discontinuation, the nature of relapse remains unclear. Specifically, it is uncertain whether relapse reflects re-emergence of underlying illness or pharmacological withdrawal. MethodsWe analysed longitudinal symptom data (Positive and Negative Syndrome Scale; PANSS) from 417 individuals with schizophrenia who experienced relapse post-stabilization in five randomized, double-blind, placebo-controlled discontinuation trials of oral and long-acting injectable (LAI) paliperidone. Latent class mixed modelling was used to identify distinct trajectories of symptom change preceding relapse. FindingsTwo latent classes of relapse were identified: rapid and delayed onset. Rapid relapse was associated with more severe positive, negative, and cognitive symptoms at relapse. The proportion of individuals experiencing rapid relapse did not differ between those randomized to placebo (treatment discontinuation) versus treatment continuation in either LAI (p=0.119) or oral trials (p=0.949). No consistent increase in withdrawal-like symptoms (e.g. anxiety, agitation, depression) was found in discontinuation compared to continuation groups. Across formulations, individuals with rapid relapse had significantly higher baseline PANSS scores than those with delayed relapse (p<0.001). InterpretationRelapse following antipsychotic discontinuation follows at least two distinct trajectories that are not specific to treatment withdrawal. The comparable proportions of rapid and delayed relapse trajectories between discontinuation and continuation groups, together with the absence of a distinct symptom profile at relapse, does not support pharmacological withdrawal as a common mechanism of relapse. Instead, higher baseline symptom severity in those who experience rapid relapse may reflect pre-existing vulnerability and/or trial-related measurement artefacts related to baseline symptom rating and trial inclusion criteria. This emphasizes the clinical importance of risk stratification and individual monitoring, and challenge the assumption that relapse risk can be meaningfully reduced through dose tapering strategies alone.