Oral versus depot antipsychotic drugs for schizophrenia A critical systematic review and meta-analysis of randomised long-term trials
ABSTRACT Non-adherence is a major problem in the treatment of schizophrenia. Depot antipsychotic drugs are thought to reduce relapse rates by improving adherence, but a systematic review of long-term studies in outpatients is not available.
We searched the Cochrane Schizophrenia Group's register, ClinicalTrials.gov, Cochrane reviews on depot medication, and the reference sections of included studies for randomised controlled trials lasting at least 12 months in outpatients that compared depot with oral antipsychotics in schizophrenia. Data on relapse (primary outcome), rehospitalisation, non-adherence, and dropout due to any reason, inefficacy of treatment and adverse events were summarised in a meta-analysis using a random-effects model. Study quality was assessed with the Cochrane collaboration's risk of bias tool, and publication bias with funnel plots.
Ten studies with 1700 participants met the inclusion criteria. Depot formulations significantly reduced relapses with relative and absolute risk reductions of 30% and 10%, respectively (RR 0.70, CI 0.57-0.87, NNT 10, CI 6-25, P=0.0009), and dropout due to inefficacy (RR 0.71, CI 0.57-0.89). Limited data on non-adherence, rehospitalisation and dropout due to any reason and adverse events revealed no significant differences. There were several potential sources of bias such as limited information on randomisation methods, problems of blinding and different medications in the depot and oral groups. Other studies reduced a potential superiority of depot by excluding non-adherent patients.
Depot antipsychotic drugs significantly reduced relapse. Due to a number of methodological problems in the single trials the evidence is, nonetheless, subject to possible bias.
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ABSTRACT: While 65%-80% occupancy of dopamine D2 receptors with antipsychotics has been proposed to achieve optimal therapeutic response during acute treatment of schizophrenia, it remains unclear as to whether it is also necessary to maintain D2 receptor occupancy within this "safe" window for ongoing maintenance treatment. The data are especially scarce for long-acting antipsychotic formulations. Clinically stable patients with schizophrenia (DSM-IV) receiving a stable dose of risperidone long-acting injectable (LAI) as antipsychotic monotherapy for at least 3 months and free of any psychiatric hospitalization over the past 6 months were included. Dopamine D2 receptor occupancy levels at trough were estimated from plasma concentrations of risperidone plus 9-hydroxyrisperidone immediately before the intramuscular injection of risperidone LAI, using a 1-site binding model derived from our previous positron emission tomography data. This study was conducted from October to December 2011. 36 patients were included in this study (mean ± SD age, 49.3 ± 14.0 years; mean ± SD dose and interval of injections, 38.2 ± 11.6 mg and 16.5 ± 14.0 days, respectively). Mean ± SD D2 receptor occupancy was 62.1% ± 15.4%; 52.8% of the subjects (n = 19) did not demonstrate an occupancy of ≥ 65%. On the other hand, 13.9% (n = 5) showed a D2 occupancy as high as over 80% at the estimated trough. More than half of patients taking risperidone LAI maintained clinical stability without achieving continuous blockade of dopamine D2 receptors ≥ 65% in real-world clinical settings. Results suggest that sustained dopamine D2 receptor occupancy levels of ≥ 65% may not be necessary for maintenance treatment with risperidone LAI in schizophrenia.The Journal of Clinical Psychiatry 08/2012; 73(8):1147-52. DOI:10.4088/JCP.12m07638 · 5.14 Impact Factor
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ABSTRACT: Because long-acting injectable (LAI) antipsychotics are largely reserved for persistently ill patients, little is known about the use of LAIs early in the course of illness for first-episode outpatients. A prospective, open-label, randomized controlled trial was conducted in which outpatients with first-episode DSM-IV schizophreniform disorder, schizophrenia, or schizoaffective disorder were enrolled from December 2004 to March 2007. Participants were randomly assigned at a 2:1 ratio to a recommendation of changing to LAI risperidone microspheres (RLAI) (n = 26) or continuing oral antipsychotic treatment (n = 11) for up to 104 weeks. Primary outcomes were time until initial nonadherence (medication gap of ≥ 14 days) and medication attitudes as assessed with the Rating of Medication Influences scale. Patients randomly assigned to an RLAI recommendation could decline the recommendation, so analysis defined treatment groups by intent-to-treat and as-actually-treated. Eighty-one percent of patients (30/37) stopped medication within 104 weeks. There was a trend toward an initial adherence benefit favoring RLAI acceptors at 12 weeks (P = .058), but no significant difference between RLAI and oral antipsychotic treatment in time to initial nonadherence during the overall study (P = .188). Medication attitudes did not differ between groups. Acceptance of RLAI was associated with an initial adherence benefit that was not sustained over time. Early introduction of LAI therapy did not adversely affect adherence attitudes. The small size of the study and low power limit interpretation, but the few patients who remained adherent into a second year were all receiving RLAI. Nonadherence was almost universal in our first-episode cohort, but nonadherence was more easily detected among first-episode patients treated with LAI therapy than it was with oral antipsychotics. ClinicalTrials.gov identifier: NCT00220714.The Journal of Clinical Psychiatry 08/2012; 73(9):1224-33. DOI:10.4088/JCP.11m06905 · 5.14 Impact Factor
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ABSTRACT: To evaluate the efficacy and tolerability of a once-monthly intramuscular (IM) depot formulation of the dopamine partial agonist aripiprazole as maintenance treatment in adults meeting DSM-IV-TR schizophrenia criteria. The study was conducted from July 2008 until February 2011. Subjects requiring chronic treatment with an antipsychotic entered a 4- to 12-week oral stabilization phase and received oral aripiprazole (10-30 mg/d). Subjects meeting stability criteria for 4 weeks entered an IM-depot stabilization phase in which they received 400-mg aripiprazole-IM-depot injections every 4 weeks (single decrease to 300 mg permitted) with coadministration of oral aripiprazole tablets in the first 2 weeks. Subjects meeting stability criteria for 12 consecutive weeks were randomly assigned (2:1) to aripiprazole-IM-depot or placebo during a 52-week, double-blind maintenance phase. The primary outcome measure was time to exacerbation of psychotic symptoms/impending relapse (event). Safety and tolerability were also assessed. 710 patients entered oral stabilization, 576 progressed to IM-depot stabilization, and 403 were randomly assigned to double-blind treatment. The study was terminated early because efficacy was demonstrated by the preplanned interim analysis (conducted after 64 events). Time to impending relapse was significantly delayed with aripiprazole-IM-depot treatment compared with placebo in both the interim analysis and the final analysis (P < .0001, log-rank test). The hazard ratio (placebo/aripiprazole-IM-depot) at final analysis was 5.03 (95% CI, 3.15-8.02). The rate of impending relapse was significantly lower with aripiprazole-IM-depot than placebo at endpoint (final analysis, 10.0% [n = 27/269] vs 39.6% [n = 53/134]). Improvements in Clinical Global Impressions-Severity of Illness scale and Positive and Negative Syndrome Scale total scores were maintained with aripiprazole-IM-depot treatment but showed significant worsening with placebo (change from double-blind baseline, P < .0001 for aripiprazole-IM-depot vs placebo). The most common treatment-emergent adverse events (occurring in ≥ 5% of aripiprazole-IM-depot subjects and greater than placebo) were insomnia, tremor, and headache. Aripiprazole-IM-depot significantly delayed time to impending relapse compared with placebo and appears to be a well-tolerated maintenance treatment option for schizophrenia. ClinicalTrials.gov identifier: NCT00705783.The Journal of Clinical Psychiatry 05/2012; 73(5):617-24. DOI:10.4088/JCP.11m07530 · 5.14 Impact Factor