Effect of Long-Acting Injectable Antipsychotics vs Usual Care on Time to First Hospitalization in Early-Phase Schizophrenia: A Randomized Clinical Trial

Abstract

Importance: Long-acting injectable antipsychotics (LAIs) can potentially reduce hospitalization risk by enhancing medication adherence but are rarely considered for early-phase schizophrenia treatment.

Objective: To determine whether encouraging use of a LAI compared with usual care delays the time to first hospitalization with patients with early-phase illness.

Design, setting, and participants: The Prevention of Relapse in Schizophrenia (PRELAPSE) trial was cluster randomized with a follow-up duration of 2 years. The study began in December 2014, was completed in March 2019, and was conducted in 39 mental health centers in 19 US states. Site randomization assigned 19 clinics to encourage treatment with long-acting aripiprazole monohydrate (aripiprazole once monthly [AOM] condition) and 20 to provide treatment as usual (clinician's choice [CC] condition). Participant eligibility criteria included (1) schizophrenia diagnosis confirmed by a structured clinical interview, (2) fewer than 5 years of lifetime antipsychotic use, and (3) age 18 to 35 years. The AOM sites identified 576 potentially eligible participants, of whom 234 (40.6%) enrolled; CC sites identified 685 potentially eligible participants, of whom 255 (37.2%) enrolled.

Interventions: There were no restrictions on treatment at CC sites (including using LAIs) or at AOM sites with the exception that aripiprazole monohydrate had to be prescribed within US Food and Drug Administration-approved guidelines.

Main outcomes and measures: The primary outcome was time to first psychiatric hospitalization based on participant interviews every 2 months, the service use resource form administered every 4 months, and other sources (eg, health records) as available. Potential events were adjudicated by an independent committee masked to treatment assignment.

Results: The 489 participants (368 men [75.3%]) had a mean (SD) age of 25.2 (4.2) years and 225 (46.0%) had 1 year or less lifetime antipsychotic use. Fifty-two AOM (22%) and 91 CC participants (36%) had at least 1 hospitalization. The mean survival time until first hospitalization was 613.7 days (95% CI, 582.3-645.1 days) for AOM participants and 530.6 days (95% CI, 497.3-563.9 days) for CC participants. For time to first hospitalization, the hazard ratio was 0.56 (95% CI, 0.34- 0.92; P = .02), favoring AOM. Survival probabilities were 0.73 (95% CI, 0.65-0.83) for AOM participants and 0.58 (95% CI, 0.50-0.67) for CC participants. The number needed to treat to prevent 1 additional hospitalization was 7 participants treated with AOM compared with CC.

Conclusions and relevance: Long-acting injectable antipsychotic use by patients with early-phase schizophrenia can significantly delay time to hospitalization, a personally and economically important outcome. Clinicians should more broadly consider LAI treatment for patients with early-phase illness.

Trial registration: ClinicalTrials.gov Identifier: NCT02360319.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kane reported grants from Otsuka and Lundbeck; personal fees from Alkermes, Allergan, Intracellular Therapies, Janssen, Lundbeck, Merck, Neurocrine, Newron, Otsuka, Pierre Fabre, Roche, Sumitomo Dainippon, Sunovion, Teva, and Reviva; personal fees from and being a shareholder of LB Pharma; and being a shareholder of Vanguard Research Group outside the submitted work. Dr Schooler reported grants from Otsuka and personal fees from Allergan, Alkermes, Gw/Greenwich Pharmaceuticals, Intracellular Therapies, Lundbeck, and Otsuka. Dr Marcy reported grants from Otsuka, Alkermes, Boehringer-Ingelheim, Janssen, Lundbeck, NeuroRX, Takeda, and Roche and personal fees from Otsuka. Dr Achtyes reported grants from Vanguard Research Group, Otsuka, Takeda, Biogen, Astellas, Pear Therapeutics, Novartis, Boehringer Ingelheim, National Network of Depression Centers, Avanir, Pine Rest Foundation, Janssen, Alkermes, Neurocrine Biosciences, and InnateVR; personal fees and travel support from Janssen, Neurocrine Biosciences, Alkermes, Indivior, Otsuka/Lundbeck; and Sunovion; and personal fees from F Hoffman-La Roche outside the submitted work. Dr Gibbons reported grants from the National Institute of Mental Health, being the founder of Adaptive Testing Technologies, and personal fees from Merck, Glaxo-Smith-Kline, Pfizer, Wyeth, and the US Department of Justice. Dr Robinson reported grants from Otsuka and personal fees from Otsuka, Lundbeck, Janssen, Neurocrine, Neuronix, US WorldMeds, Advocates for Human Potential, the American Psychiatric Association, C4 Innovations, Costello Medical, and Health Analytics. No other disclosures were reported.

Figures

Figure 1.. Site Participant Flow

AOM indicates aripiprazole once monthly.

Figure 2.. Time Remaining Without Having a First Hospitalization

Log rank test χ2 = 11.373; df = 1; P < .001. AOM indicates aripiprazole once monthly; CC, clinician’s choice.