title: Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia.
abstract: While placebo-controlled studies continue to be required by regulatory authorities for the licensing of new drugs for schizophrenia to demonstrate maintenance of effect, the long-term risks to participants are largely unknown. We compared the response to treatment with paliperidone palmitate before and after relapse in such a study. This was a post-hoc analysis of 97 patients with schizophrenia who relapsed while receiving placebo in a multinational relapse prevention clinical trial. Patients underwent an initial open-label treatment phase of 33 weeks (comprising a 9-week transition phase to switch patients to paliperidone palmitate, a 12-week flexible-dose phase and a 12-week fixed-dose phase); a double-blind phase of variable duration during which stabilized patients were randomized 1:1 to either continue paliperidone palmitate or receive placebo; and an optional 52-week open-label flexible-dose extension phase. There was a small but significant increase in PANSS total scores after eight months of treatment following relapse (56.7[12.68]) compared with prerelapse endpoint (54.5[11.74]) (p=0.026). Fourteen of 97 (14.4%) patients who had initially responded favorably to treatment met predefined nonresponse criteria in the postrelapse treatment phase, suggesting that treatment refractoriness may evolve in a subset of patients after relapse. However, relapses occurred in 18% of patients randomized to ongoing treatment in the double-blind phase, raising the possibility that treatment failure may also evolve in patients receiving continuous treatment. These findings may help inform decisions regarding the future of placebo-controlled trials in schizophrenia.
authors.affiliation: University of Stellenbosch, Tygerberg 7500, Cape Town, South Africa. rae@sun.ac.za
authors.forename: Robin
authors.initials: R
authors.lastname: Emsley
authors.forename: Isaac
authors.initials: I
authors.lastname: Nuamah
authors.forename: David
authors.initials: D
authors.lastname: Hough
authors.forename: Srihari
authors.initials: S
authors.lastname: Gopal
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000068882:Paliperidone Palmitate; D010168:Palmitates / Q000627:therapeutic use*; D010919:Placebos / Q000009:adverse effects*; D012008:Recurrence; D012559:Schizophrenia / Q000188:drug therapy*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D010168:Palmitates; D010919:Placebos; D000068882:Paliperidone Palmitate