Drug Efficacy in the Treatment of Antipsychotic-Induced Akathisia: A Systematic Review and Network Meta-Analysis

Abstract

Importance: Antipsychotic-induced akathisia (AIA) occurs in 14% to 35% of patients treated with antipsychotics and is associated with increased suicide and decreased adherence in patients with schizophrenia. However, no comprehensive review and network meta-analysis has been conducted to compare the efficacy of treatments for AIA.

Objective: To compare the efficacy associated with AIA treatments.

Data sources: Three databases (MEDLINE, Web of Science, and Google Scholar) were systematically searched by multiple researchers for double-blind randomized clinical trials (RCTs) comparing active drugs for the treatment of AIA with placebo or another treatment between May 30 and June 18, 2023.

Study selection: Selected studies were RCTs that compared adjunctive drugs for AIA vs placebo or adjunctive treatment in patients treated with antipsychotics fulfilling the criteria for akathisia, RCTs with sample size of 10 patients or more, only trials in which no additional drugs were administered during the study, and RCTs that used a validated akathisia score. Trials with missing data for the main outcome (akathisia score at the end points) were excluded.

Data extraction and synthesis: Data extraction and synthesis were performed, estimating standardized mean differences (SMDs) through pairwise and network meta-analysis with a random-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.

Main outcomes and measures: The primary outcome was the severity of akathisia measured by a validated scale at the last available end point.

Results: Fifteen trials involving 492 participants compared 10 treatments with placebo. Mirtazapine (15 mg/d for ≥5 days; SMD, -1.20; 95% CI, -1.83 to -0.58), biperiden (6 mg/d for ≥14 days; SMD, -1.01; 95% CI, -1.69 to -0.34), vitamin B6 (600-1200 mg/d for ≥5 days; SMD, -0.92; 95% CI, -1.57 to -0.26), trazodone (50 mg/d for ≥5 days; SMD, -0.84; 95% CI, -1.54 to -0.14), mianserin (15 mg/d for ≥5 days; SMD, -0.81; 95% CI, -1.44 to -0.19), and propranolol (20 mg/d for ≥6 days; SMD, -0.78; 95% CI, -1.35 to -0.22) were associated with greater efficacy than placebo, with low to moderate heterogeneity (I2 = 34.6%; 95% CI, 0.0%-71.1%). Cyproheptadine, clonazepam, zolmitriptan, and valproate did not yield significant effects. Eight trials were rated as having low risk of bias; 2, moderate risk; and 5, high risk. Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found.

Conclusions and relevance: In this systematic review and network meta-analysis, mirtazapine, biperiden, and vitamin B6 were associated with the greatest efficacy for AIA, with vitamin B6 having the best efficacy and tolerance profile. Trazodone, mianserin, and propranolol appeared as effective alternatives with slightly less favorable efficacy and tolerance profiles. These findings should assist prescribers in selecting an appropriate medication for treating AIA.

Figure 1.. Study Selection Process

Overall, 15 double-blind randomized clinical trials corresponding to 12 interventions were included.

Figure 2.. Risk of Bias Assessment for the 15 Studies Included in the Network Meta-Analysis

Figure 3.. Network Graph for Main Results of Meta-Analysis

Node size is proportional to the total number of patients for each intervention. Line thickness is proportional to weight from the random-effects model. The number overlying the lines is equal to the number of studies corresponding to the comparison. Triangles represent comparisons for 3-arm studies. Colors of the nodes represent the therapeutic classes of intervention: β-blocker (propranolol), antidepressant (mirtazapine, mianserin, and trazodone), mood stabilizer (valproate), anticholinergic (biperiden), antihistaminic (cyproheptadine), benzodiazepine (clonazepam), and triptan (zolmitriptan).

Figure 4.. Ranked Forest Plot of Network Meta-Analysis for Efficacy of Treatments in Antipsychotic-Induced Akathisia

The different treatments are compared with placebo (the reference group). The more negative the standardized mean difference (SMD) is, the higher the reduction in akathisia scale score for intervention compared with placebo. Weight represents the sum of the inverse variance of all effect sizes in the pairwise comparison model for respective intervention. Square size is proportional to weight.

Figure 5.. Head-to-Head Comparisons for Efficacy of the 10 Treatments in Antipsychotic-Induced Akathisia

Drugs are reported by decreasing rank order. Data are standardized mean differences (SMDs) (95% CIs). Comparisons should be read from left to right. For the lower triangle that reports network estimates, column-defining treatment is compared with row-defining treatment. For the upper triangle that reports direct treatment estimates, row-defining treatment is compared with column-defining treatment. The SMDs above 0 favor the column-defining treatment in the lower triangle, whereas they favor the row-defining treatment in the upper triangle. NA indicates not applicable.