Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial

Abstract

Importance: Long-acting, injectable, second-generation antipsychotic medication has tremendous potential to bring clinical stability to persons with schizophrenia. However, long-acting medications are rarely used following a first episode of schizophrenia.

Objective: To compare the clinical efficacy of the long-acting injectable formulation of risperidone with the oral formulation in the early course of schizophrenia.

Design, setting, and participants: A randomized clinical trial performed at a university-based research clinic, between 2005 and 2012. Eighty-six patients with recent onset of schizophrenia were randomized to receive long-acting injectable risperidone or oral risperidone. Half of each group was simultaneously randomized to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being. An intent-to-treat analysis was performed between October 4, 2012, and November 12, 2014.

Interventions: A 12-month trial comparing the long-acting injectable vs oral risperidone and cognitive remediation vs healthy-behaviors training.

Main outcomes and measures: Psychotic relapse and control of breakthrough psychotic symptoms.

Results: Of the 86 patients randomized, 3 refused treatment in the long-acting injectable risperidone group. The psychotic exacerbation and/or relapse rate was lower for the long-acting risperidone group compared with the oral group (5% vs 33%; χ21 = 11.1; P < .001; relative risk reduction, 84.7%). Long-acting injectable risperidone better controlled mean levels of hallucinations and delusions throughout follow-up (β = -0.30; t68 = -2.6, P = .01). The cognitive remediation and healthy-behaviors training groups did not differ significantly regarding psychotic relapse, psychotic symptom control, or hospitalization rates, and there were no significant interactions between the 2 medications and the 2 psychosocial treatments. Discontinuations owing to inadequate clinical response were more common in the oral group than in the long-acting risperidone group (χ21 = 6.1; P = .01). Adherence to oral risperidone did not appear to differ before randomization but was better for the long-acting risperidone group compared with the oral group (t80 = 5.3; P < .001). Medication adherence was associated with prevention of exacerbation and/or relapse (χ21 =11.1; P = .003) and control of breakthrough psychotic symptoms (β = 0.2; t79 = 2.1; P = .04).

Conclusions and relevance: The use of long-acting injectable risperidone after a first episode of schizophrenia has notable advantages for clinical outcomes. The key clinical advantages are apparently owing to the more consistent administration of the long-acting injectable. Such formulations should be offered earlier in the course of illness.

Trial registration: clinicaltrials.gov Identifier: NCT00333177.

Trial registration: ClinicalTrials.gov NCT00330551 NCT00333177.

Conflict of interest statement

Disclosures: Dr Subotnik reports serving as a consultant to Janssen Scientific Affairs, LLC; being on the speaker’s bureau for Otsuka America Pharmaceutical, Inc; and receiving research support from Janssen Scientific Affairs, LLC, and Genentech Inc, through grants to Drs Nuechterlein and Ventura. Dr Ventura reports serving as a consultant to Posit Science Corporation and Boehringer-Ingelheim GmbH and receiving research support from Janssen Scientific Affairs, LLC, Posit Science Corporation, and Genentech Inc. Dr Marder reports receiving consulting fees from AbbVie, Pfizer, Lundbeck, Boeringer Ingelheim GmbH, Shire Plc, Roche, Genentech Inc, Takeda Pharmaceutical Company Ltd, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Inc, Targacept, and FORUM Pharmaceuticals and grant support from Amgen, Synchroneuron, and Sunovion. Dr Nuechterlein reports serving as a consultant to Genentech Inc, Janssen Scientific Affairs, LLC, Otsuka America Pharmaceutical, Inc, and Janssen-Cilag and receiving support from Janssen Scientific Affairs, LLC, Posit Science Corporation, and Genentech Inc. No other disclosures were reported.

Figures

Figure 1. CONSORT Flow Diagram of Progress Through the Randomized Controlled Trial Phases

CR indicates cognitive remediation; HBT, healthy-behaviors training.

Figure 2. Time to First Psychotic Exacerbation and/or Relapse as a Function of Form of Medication Administration in 83 Patients

The risk of exacerbation and/or relapse over time was significantly lower for the long-acting injectable risperidone group than for the oral risperidone group. x Indicates censored data.