Relapse After Antipsychotic Discontinuation in Schizophrenia as a Withdrawal Phenomenon vs Illness Recurrence: A Post Hoc Analysis of a Randomized Placebo-Controlled Study

J Clin Psychiatry. 2018 Jun 19;79(4):17m11874. doi: 10.4088/JCP.17m11874.


Background: It has been proposed that relapse rates after antipsychotic discontinuation may be artificially inflated and that some of these symptom recurrences may be due to rebound or withdrawal phenomena rather than due to illness recurrence.

Methods: Post hoc analysis of data from a relapse-prevention study (conducted from March 2005 to February 2007) of paliperidone palmitate once-monthly (PP1M) versus placebo was conducted to compare the nature of operationally defined relapse events in schizophrenia patients (diagnosed by DSM-IV criteria) experiencing relapses after randomization to placebo (n = 97) with those in patients receiving maintenance PP1M treatment (n = 36). These 2 groups were compared for onset and severity of recurrence symptoms, symptom profiles at relapse, and postrelapse treatment response. Psychological and physiological signs of discontinuation and signs of antipsychotic tolerance, dyskinesia, and prolactin elevation that might indicate dopamine receptor supersensitivity were compared.

Results: Both groups were similar in terms of relapse symptom profiles, onset and severity of relapse symptoms, and postrelapse treatment response. The Positive and Negative Syndrome Scale total score (mean ± SD) for placebo versus maintenance treatment group at baseline was 54.5 ± 11.74 vs 54.1 ± 11.64 and at relapse was 75.6 ± 16.79 vs 75.2 ± 17.23 (P = .9). No elevated blood pressure or heart rate, dyskinesia, antipsychotic tolerance, or elevated prolactin in the patients relapsing after antipsychotic discontinuation was noted.

Conclusions: Findings suggest that relapses after treatment discontinuation reflect recurrence of the underlying illness and may be consistent with a hypothesis of direct relationship between dopamine and psychosis. No evidence was obtained for withdrawal-related phenomena contributing to the high relapse rates after treatment discontinuation.

Trial registration: identifier: NCT00111189.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antipsychotic Agents / therapeutic use
  • Double-Blind Method
  • Drug Tolerance
  • Dyskinesia, Drug-Induced / diagnosis
  • Female
  • Humans
  • Male
  • Middle Aged
  • Paliperidone Palmitate / administration & dosage*
  • Paliperidone Palmitate / therapeutic use*
  • Prolactin / blood
  • Recurrence*
  • Schizophrenia / blood
  • Schizophrenia / diagnosis*
  • Schizophrenia / drug therapy*
  • Withholding Treatment*
  • Young Adult


  • Antipsychotic Agents
  • Prolactin
  • Paliperidone Palmitate

Associated data