Effectiveness of Long-Acting Injectable Antipsychotics Versus Oral Antipsychotics in People With Bipolar Disorder: A Systematic Review and Meta-Analysis of Observational Studies: Efficacité des antipsychotiques injectables à action prolongée par rapport aux antipsychotiques oraux chez les personnes atteintes de troubles bipolaires : revue systématique et méta-analyse d'études observationnelles

Abstract

Background Randomised trials suggest long-acting injectable antipsychotics (LAIs) may outperform oral antipsychotics (OAPs) regarding adherence and relapse prevention in bipolar disorder (BD). We aimed to compare the effectiveness and tolerability of LAIs versus OAPs in observational studies. Methods Searching MEDLINE/Embase/PsycINFO until March-25-2025, we conducted a systematic review and random-effects meta-analysis (pre-registered protocol: https://osf.io/gkwrp) of observational studies comparing LAIs versus OAPs in people with BD (primary outcome = study-defined relapse/psychiatric hospitalisation). Results Seventeen studies (4 = cohort, 13 = mirror-image studies; 6186/3676 participants with BD, respectively, high-quality per Newcastle-Ottawa Scale Score >= 7 = 47.1%) were included. The relative risk (RR) for study-defined relapse/psychiatric hospitalisation was significantly lower with LAIs versus OAPs in cohort (k = 4, RR = 0.63, 95% confidence interval (CI) = 0.44;0.90, P = 0.026) and mirror-image studies (k = 5, RR = 0.46, 95% CI = 0.28;0.77, P = 0.013). LAIs were not significantly superior to OAPs in high-quality cohort studies (k = 3, P = 0.78) but in those adjusted for >5 factors (k = 2, RR = 0.56, 95% CI = 0.37;0.84, P = 0.006) nor in high-quality mirror-image studies (k = 2, P = 0.38), but in each second-generation antipsychotic-LAIs study (aripiprazole-LAI: k = 2, risperidone-LAI: k = 1) (k = 3, RR = 0.40, 95% CI = 0.20;0.80, P = 0.03). In cohort studies, LAIs and OAPs did not differ regarding psychiatric hospitalisations (k = 3, P = 0.078) but data on discontinuation and mortality risk were lacking/not meta-analysable. In mirror-image studies, LAIs were associated with significantly lower psychiatric (k = 4, RR = 0.50, 95% CI = 0.25;0.99, P = 0.048) and depression-related (k = 2, RR = 0.46, 95% CI = 0.24;0.86, P = 0.014), but not mania-related hospitalisation risk (k = 2, P = 0.075). LAIs were associated with fewer psychiatric hospitalisations (k = 7, SMD = -1.73, 95% CI = -2.88;-0.57, P = 0.011), hospitalisation days (k = 9, SMD = -1.35, 95% CI = -2.19;-0.52, P = 0.006), mania-related hospitalisations (k = 3, SMD = -0.87, 95% CI = -1.19;-0.56, P < 0.001) and manic episodes (k = 3, SMD = -1.13, 95% CI = -2.00;-0.26, P = 0.03), but not any mood (k = 4, P = 0.13) or depressive episodes (k = 3, P = 0.14). Tolerability outcomes were missing, and GRADE certainty-of-evidence was "low" to "very low". Discussion LAIs were superior versus OAPs in preventing relapse/hospitalisation in cohort and mirror-image studies, in the latter particularly for mania-related outcomes. More robust mirror-image and controlled cohort studies are needed to better assess the effectiveness and tolerability of LAI antipsychotics in BD.