Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials

Abstract

Background: While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs).

Methods: Systematic review/meta-analysis of RCTs that lasted ≥ 6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy (ie, relapse + discontinuation due to inefficacy), hospitalization, and nonadherence.

Results: Across 21 RCTs (n = 5176), LAIs were similar to OAPs for relapse prevention at the longest time point (studies = 21, n = 4950, relative risk [RR] = 0.93, 95% confidence interval [CI]: 0.80-1.08, P = .35). The finding was confirmed restricting the analysis to outpatient studies lasting ≥ 1 year (studies = 12, RR = 0.93, 95% CI:0.71-1.07, P = .31). However, studies using first-generation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82, 95% CI:0.69-0.97, P = .02) and those published ≤ 1991 (consisting exclusively of all 8 fluphenazine-LAI studies; RR = 0.79, 95% CI: 0.65-0.96, P = 0.02) were superior to OAPs regarding the primary outcome. Pooled LAIs also did not separate from OAPs regarding any secondary outcomes. Again, studies using FGA-LAIs and those published ≤ 1991 were associated with LAI superiority over OAPs, eg, hospitalization and drug inefficacy.

Conclusions: In RCTs, which are less representative of real-world patients than naturalistic studies, pooled LAIs did not reduce relapse compared with OAPs in schizophrenia patients. The exceptions were FGA-LAIs, mostly consisting of fluphenazine-LAI studies, which were all conducted through 1991. Because this finding is vulnerable to a cohort bias, studies comparing FGA-LAI vs second-generation antipsychotics-LAI and LAI vs OAP RCTs in real-world patients are needed.

Keywords: adherence; antipsychotics; depot; long-acting injection; meta-analysis; relapse; schizophrenia; treatment discontinuation.

Fig. 1.

Relapse rate-estimated rate preferred, longest time point (safety/efficacy population).

Fig. 2.

All-cause discontinuation (safety/efficacy population).

Fig. 3.

Subgroup analysis comparing (1) FGA-LAI studies published ≤1991, (2) FGA-LAI studies published ≥2005, (3) SGA-LAI studies published ≥2005. When FGA-LAIs (combining the top two groups) and second-generation antipsychotics (SGA)-LAIs (bottom group) were analyzed separately, FGA-LAIs were significantly superior to OAPs in preventing relapse (Studies = 10, n = 897, RR = 0.82, 95% CI: 0.69–0.97, P = 0.02, NNT = 15, heterogeneity: τ² = 0.01, I² = 15%, Q = 10.62, df = 9, P = 0.30), but SGA-LAIs were not (Studies = 11, n = 4053, RR = 1.00, 95% CI: 0.81–1.23, P = 0.99, heterogeneity: τ² = 0.07, I² = 70%, Q = 32.93, df = 10, P = 0.0003). When older randomized controlled trials (RCTs) (<1991) (top group) and the remaining newer RCTs (>2005) (combining the bottom two groups) were analyzed separately, LAIs had lower relapse rates in older RCTs (Studies = 8, n = 826, RR = 0.79, 95% CI: 0.65–0.96, P = 0.02, NNT = 13, heterogeneity: τ² = 0.02, I² = 23%, Q = 9.06, df = 7, P = 0.25), but not in the remaining newer RCTs (Studies = 13, n = 4950, RR = 1.01, 95% CI: 0.83–1.08, P = 0.95, heterogeneity: τ² = 0.06, I² = 64%, Q = 33.39, df = 12, P = 0.0008).