Systematic review: pharmacological treatment of tic disorders--efficacy of antipsychotic and alpha-2 adrenergic agonist agents

Abstract

We conducted a meta-analysis of randomized, placebo-controlled trials to determine the efficacy of antipsychotic and alpha-2 agonists in the treatment of chronic tic disorders and examine moderators of treatment effect. Meta-analysis demonstrated a significant benefit of antipsychotics compared to placebo (standardized mean difference (SMD)=0.58 (95% confidence interval (CI): 0.36-0.80). Stratified subgroup analysis found no significant difference in the efficacy of the 4 antipsychotic agents tested (risperidone, pimozide, haloperidol and ziprasidone). Meta-analysis also demonstrated a benefit of alpha-2 agonists compared to placebo (SMD=0.31 (95% confidence interval CI: 0.15-0.48). Stratified subgroup analysis and meta-regression demonstrated a significant moderating effect of co-occurring ADHD. Trials which enrolled subjects with tics and ADHD demonstrated a medium-to-large effect (SMD=0.68 (95%CI: 0.36-1.01) whereas trials that excluded subjects with ADHD demonstrated a small, non-significant benefit (SMD=0.15 (95%CI: -0.06 to 0.36). Our findings demonstrated significant benefit of both antipsychotics and alpha-2 agonists in treating tics but suggest alpha-2 agonists may have minimal benefit in tic patients without ADHD.

Published by Elsevier Ltd.

Figures

Figure 1. Selection of Studies for Meta-analysis of Antipsychotic Agents in the Treatment of Tics

Flow diagram depicting reasons for exclusion of several trials identified in our search but not included in meta-analysis.

Figure 2. Efficacy of Antipsychotic Agents Compared to Placebo for the Treatment of Tics

Meta-analysis demonstrated a significant, medium-to-large treatment effect of antipsychotic agents in improving tic symptoms compared to placebo (standardized mean difference (SMD)= 0.61 (95% confidence interval (CI): 0.36–0.86), z=4.80, p=0.00001). There was also a no significant heterogeneity between trials (Q=4.51, df=6, p=0.61, I2=0%).

Figure 3. Efficacy of Other Antipsychotic Agents Compared to Pimozide for the Treatment of Tics

Five trials compared the efficacy of FDA approved antipsychotic agents to pimozide. Meta-analysis demonstrated no evidence that other antipsychotics differed in efficacy from pimozide.

Figure 4. Selection of Trials for Alpha-2 Agonists for the Treatment of Tics

A flow diagram depicting reasons for exclusion of 6 articles identified by our search strategy. One trial was excluded because the journal editorial staff retracted the article after there was evidence that the trial and its data was plagiarized from an earlier included trial.

Figure 5. Alpha-2 Agonists for the Treatment of Tics

Meta-analysis of 6 trials demonstrated a significant effect of alpha-2 agonists in reducing tic severity (standardized mean difference (SMD)=0.31 (95% confidence interval (CI): 0.15–0.48), z=3.64, p

Figure 6. Funnel Plot Depicting Publication Bias in Alpha-2 Agonist Trials in the Treatment of Tics

Visual inspection of the funnel plot and the meta-regression of the association between effect size and sample size demonstrated significant evidence of publication bias (α=−0.0012 (95%CI: −0.0021–(−0.0003)), z=−2.65, p=0.008). When publication bias was adjusted for using the Duval and Tweedie trim-and-fill method, alpha-2 agonists still demonstrated a significant benefit compared to placebo (SMD=0.18 (95%CI: 0.03–0.33)).

Figure 7

A: Efficacy of Alpha2-Agonists for the Treatment of Tics in Trials Stratified by ADHD Comorbidity. Trials that required tic patients to have comorbid ADHD (SMD=0.68 (95%CI: 0.36–1.01), z=4.10, p<0.001) demonstrated a significantly greater effect (Test for subgroup differences α2=7.27, df=1, p=0.007) of alpha-2 agonists in reducing tic symptoms than trials that excluded subjects with comorbid ADHD (SMD=0.15 (95%CI: −0.06–0.36), z=1.40, p=0.16). B: Meta-Regression of Alpha-2 Agonist Efficacy in Treating Tics versus Percent of Subjects with Comorbid ADHD in Trial. Meta-regression demonstrated that trials enrolling a larger proportion of subjects with comorbid ADHD reported a greater efficacy of alpha-2 agonists in treating tics. (α=0.0053 (95%CI: 0.0015–0.0091), z=−2.72, p=0.006).

Figure 7

A: Efficacy of Alpha2-Agonists for the Treatment of Tics in Trials Stratified by ADHD Comorbidity. Trials that required tic patients to have comorbid ADHD (SMD=0.68 (95%CI: 0.36–1.01), z=4.10, p<0.001) demonstrated a significantly greater effect (Test for subgroup differences α2=7.27, df=1, p=0.007) of alpha-2 agonists in reducing tic symptoms than trials that excluded subjects with comorbid ADHD (SMD=0.15 (95%CI: −0.06–0.36), z=1.40, p=0.16). B: Meta-Regression of Alpha-2 Agonist Efficacy in Treating Tics versus Percent of Subjects with Comorbid ADHD in Trial. Meta-regression demonstrated that trials enrolling a larger proportion of subjects with comorbid ADHD reported a greater efficacy of alpha-2 agonists in treating tics. (α=0.0053 (95%CI: 0.0015–0.0091), z=−2.72, p=0.006).