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Individual randomized controlled trials (RCTs) of habit reversal training and a Comprehensive Behavioral Intervention for Tics (collectively referred to as behavior therapy, BT) have demonstrated efficacy in reducing tic severity for individuals with Tourette Syndrome and Chronic Tic Disorders (collectively referred to as TS), with no examination of treatment moderators. The present meta-analysis synthesized the treatment effect sizes (ES) of BT relative to comparison conditions, and examined moderators of treatment. A comprehensive literature search identified eight RCTs that met inclusion criteria, and produced a total sample of 438 participants. A random effects meta-analysis found a medium to large ES for BT relative to comparison conditions. Participant mean age, average number of therapy sessions, and the percentage of participants with co-occurring attention deficit hyperactivity disorder (ADHD) were found to moderate treatment effects. Participants receiving BT were more likely to exhibit a treatment response compared to control interventions, and identified a number needed to treat (NNT) of three. Sensitivity analyses failed to identify publication bias. Overall, BT trials yield medium to large effects for TS that are comparable to treatment effects identified by meta-analyses of antipsychotic medication RCTs. Larger treatment effects may be observed among BT trials with older participants, more therapeutic contact, and less co-occurring ADHD.

Chronic Tic Disorders and Tourette Syndrome (afterward collectively referred to as TS), are characterized by the presence of sudden motor movements and/or vocalizations (referred to as tics) that persist for more than a year. Tourette Syndrome commonly begins in childhood, increases in severity into early adolescence, and may persist into adulthood (Bloch and Leckman, 2009). Tic symptoms show little difference between youth and adults with TS, with common tics including eye blinking, head jerk movements, mouth movements, and simple vocalizations (McGuire et al., 2013). The estimated prevalence rate for TS in children ranges from three to eight per 1000 (Centers for Disease Control and Prevention, 2009). Individuals with TS frequently experience co-occurring obsessive compulsive disorder (OCD), non-OCD anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and/or disruptive behaviors (Freeman et al., 2000). Tics and co-occurring conditions have been associated with functional impairment (Conelea et al., 2011 and Conelea et al., 2013), and a diminished quality of life (Jalenques et al., 2012 and Storch et al., 2007). Traditionally, TS has been managed with psychotropic medications such as antipsychotics and alpha-2 agonists (Scahill et al., 2006). A meta-analysis of five randomized controlled trials (RCTs) of antipsychotic medications identified a significant reduction in tic severity relative to placebo [standard mean difference (SMD) = 0.58], with no significant difference between medications (Weisman et al., 2012). Despite their efficacy, antipsychotics may be associated with side effects that may limit tolerability (Scahill et al., 2006). Alpha-2 agonists present another treatment option, with a meta-analysis of six RCTs indentifying a more modest (SMD = 0.31), yet still significant benefit relative to placebo (Weisman et al., 2012). As a result, these medications are commonly recommended as a first-line treatment by professional organizations due to less severe side effects (Murphy et al., 2013). Behavioral interventions have also demonstrated success in reducing tic severity (Verdellen et al., 2011). Among these interventions, only habit reversal training (HRT) has consistently demonstrated efficacy in RCTs. The core components of HRT are considered to be awareness training and competing response training (Miltenberger et al., 1998), with adjunctive therapeutic components including self-monitoring, relaxation training, contingency management, motivational procedures, and generalization training (Piacentini and Chang, 2006). Awareness training involves the detection of premonitory urges and/or early tic movements that precede a tic. Competing response training involves the identification of behaviors that are physically incompatible with a targeted tic, which are implemented upon early tic detection (e.g., premonitory urges, early tic movements). Habit reversal training serves as the principle therapeutic component in the Comprehensive Behavioral Intervention for Tics (CBIT) (Woods et al., 2008), which integrates HRT with functional assessment and function-based intervention procedures designed to mitigate influences of daily life that worsen tics. A related behavioral intervention called exposure and response prevention (ERP) involves exposure to sensations/urges that precede tics with response prevention of tics (Verdellen et al., 2004). These two treatments share similarities in terms of procedure (tic prevention) and mechanisms of change (habituation to urges), but are distinguished by the use of competing responses. The efficacy of HRT and CBIT (afterward collectively referred to as behavior therapy, BT) has been supported across several RCTs with two noted exceptions (Azrin and Peterson, 1990, Deckersbach et al., 2006, O'Connor et al., 2001, Piacentini et al., 2002, Piacentini et al., 2010, Wilhelm et al., 2003 and Wilhelm et al., 2012). One exception is a comparison trial of HRT to ERP. Participants in the ERP condition experienced greater reductions in tic severity that trended toward significance (Verdellen et al., 2004). Difference in duration of therapeutic contact hours may account for discrepancies as ERP participants received 24 therapeutic contact hours, whereas HRT participants received only 10. The other exception is a comparison trial of HRT to awareness training (a component of HRT), with results indicating only a minimal benefit of HRT above awareness training (Piacentini et al., 2002). While both of these trials compared BT to another active behavioral intervention, the remaining RCTs utilized waitlist or non-directive therapy as control conditions. When making treatment recommendations, it is important to synthesize empirical evidence to guide clinical decisions (Murad and Montori, 2013). Meta-analyses provide a quantitative synthesis of treatment trials, and can examine moderators of treatment effects across studies. To date, only two meta-analyses have examined the efficacy of behavioral interventions for tics, albeit with noted limitations (Bate et al., 2011 and Wile and Pringsheim, 2013). Bate et al., 2011 examined the efficacy of HRT across multiple habit disorders (e.g., TS, trichotillomania, nail biting, thumb sucking, stuttering, teeth grinding). While Bate et al. found HRT to have a large effect for TS (Cohen's d = 0.78), this examination had several limitations. For instance, Bate and colleagues excluded RCTs that used core BT components alongside adjunctive therapeutic components ( O'Connor et al., 2001), and did not include a large trial of BT for TS ( Wilhelm et al., 2012) or the comparison trial of HRT to awareness training ( Piacentini et al., 2002). Furthermore, Bate and colleagues did not identify the measures used to extract treatment effects. As the psychometric properties of tic severity ratings scales differ from one another ( McGuire et al., 2012), preference should be given to clinician-administered scales that have demonstrated reliability and validity. Wile and Pringsheim (2013) examined the efficacy of BT for individuals with TS in two meta-analyses that each included two RCTs. On the clinician-rated Yale Global Tic Severity Scale (YGTSS; Leckman et al., 1989), Wile and Pringsheim (2013) found a difference in YGTSS Total Tic Scores between behavior therapy groups and comparison groups of 3.66 and 10.52 for blinded and unblinded trials, respectively. Their examination of treatment response in two RCTs on the Clinical Global Impression of Improvement (CGI-Improvement; Guy and Bonato, 1970) identified an odds ratio in favor of BT. Despite its noteworthy contributions, this report had limitations that included a small sample size, utilization of a fixed effect model, and did not explore treatment moderators. Given the collective limitations of existent meta-analyses, further investigation is needed to comprehensively quantify treatment effects of BT, and explore moderators of treatment. A systematic approach to quantifying BT treatment effect is important because it facilitates comparison with existing pharmacotherapy meta-analyses for TS, and provides an informative comparison in the absence of a head-to-head RCT. Similarly, an examination of BT treatment moderators may inform clinical recommendations. The present meta-analysis examined RCTs of BT to determine its efficacy in reducing tic severity and identify the odds ratio of treatment response. Additionally, this meta-analysis examined moderators of BT treatment effects that included: co-occurring OCD and ADHD; number of 1-h therapy sessions; participant age; methodological quality; and tic medication status.

3. Results 3.1. Included studies Initial search strategies produced 507 potential abstracts/citations, with 14 abstracts/citations being retrieved for detailed review (see Fig. 1). Table 1 displays the eight RCTs that met inclusion criteria, which produced a total sample of 438 participants. Two trials compared BT to a wait-list condition (Azrin and Peterson, 1990 and O'Connor et al., 2001), and six trials compared a BT to an active comparison condition [e.g., awareness training (Piacentini et al., 2002), supportive therapy (Deckersbach et al., 2006 and Wilhelm et al., 2003), psychoeducation and supportive therapy (Piacentini et al., 2010 and Wilhelm et al., 2012), and ERP (Verdellen et al., 2004)]. Full-size image (51 K) Fig. 1. Study selection and rationale for exclusion. Figure options Table 1. Study characteristics and coded variables for studies included in meta-analysis. Author Control N Mean age % With ADHD % With OCD % On tic medication # Of sessions Study quality Effect size Outcome measure Treatment response Azrin and Peterson, 1990 WL 10 18 NA NA 30% 7 25 0.48 Video observations of tic frequency NA O′Connor et al., 2001 WL 50a 37 2% 10% 2% 13 17 1.41b Video observations of tic frequency and severity (0–100) NA Piacentini et al., 2002 BTC 25 11 20% 28% 48% 8 25 0.09 YGTSS HRT: 6/13 AT: 3/12 Wilhelm et al., 2003 ND 32 35 NA NA 48% 14 19 1.38 YGTSSc NA Verdellen et al., 2004 BTC 43 21 30% 14% 40% 10 21 −0.52 YGTSS NA Deckersbach et al., 2006 ND 30 35 NA 30% 33% 14 26 1.67 YGTSSc HRT: 10/15 SP: 2/15 Piacentini et al., 2010 ND 126 12 26% 19% 37% 8 40 0.57 YGTSS CBIT: 32/61 PST: 12/65 Wilhelm et al., 2012 ND 122 32 28% 18% 25% 8 38 0.53 YGTSS CBIT: 24/63 PST: 4/59 Note: WL = Waitlist, BTC = Contains active BT components, ND = Nondirective, ADHD = Attention Deficit Hyperactivity Disorder, OCD = Obsessive Compulsive Disorder, YGTSS = Yale Global Tic Severity Scale, HRT = Habit Reversal Training, AT = Awareness Training, SP = Supportive Psychotherapy, CBIT = Comprehensive Behavioral Intervention for Tics, PST = Psychoeducation and Supportive Therapy, NA = Not Available or Not Applicable. a Although 69 participants with TS participated in the trial, video observation of frequently and severity data available for only 50 participants (40 HRT/CBT, 10 Waitlist control). b Combined effect size for video ratings of frequency and severity. c Evaluator/rater not blind to treatment condition. Table options 3.2. Reliability of coding study characteristics There was excellent inter-rater agreement between the two raters on categorical and continuous study characteristics (100% agreement), as well as overall study methodological quality (ICC = 0.98, 95% CI = 0.91, 0.99). 3.3. Treatment effects of BT As seen in Fig. 2, a random effects meta-analysis identified a medium to large treatment effect of BT compared to all control conditions (SMD = 0.67, 95% CI: 0.22, 1.12, z = 2.91, p = 0.004). Visual inspection of the forest plot, Q statistic, and I2 statistic identified the presence of significant heterogeneity [Q(7) = 29.32, p < 0.001, I2 = 76.13%]. As Verdellen et al., 2004 and Piacentini et al., 2002 used behavioral interventions as comparison conditions, the summary effect was re-calculated with these two trials excluded. Results identified a large treatment effect (SMD = 0.94, 95% CI: 0.54, 1.34, z = 4.58, p < 0.001), with less heterogeneity observed [Q(5) = 12.61, p = 0.03, I2 = 60.34%]. Full-size image (42 K) Fig. 2. Efficacy of BT compared to wait-list and active comparison control conditions for the treatment of tics. Figure options 3.4. Treatment response from BT As seen in Fig. 3, there was a high OR in favor of participants receiving BT experiencing a treatment response (OR = 5.77, 95% CI: 3.23, 10.30, z = 5.92, p < 0.001), with little heterogeneity observed across trials [Q(3) = 2.23, p = 0.53, I2 = 0.00%]. Treatment response on the CGI-Improvement produced a NNT of three across trials (95% CI: 2.3, 4.2). Full-size image (29 K) Fig. 3. Treatment Response of BT compared to active comparison conditions. Figure options 3.5. Moderators of BT First, when examining comorbidity, no significant association was identified between the percent of study participants with OCD and ES (B = 0.02, p = 0.64). However, a small negative association existed between the percent of study participants with ADHD and ES (B = −0.05, 95% CI: −0.09,−0.002, z = −2.07, p = 0.04). Second, when examining the therapeutic contact, a small positive association between the average number of therapy sessions and ES was identified (B = 0.18, 95% CI: 0.03, 0.33, z = 2.36, p = 0.02). Third, a small positive association was found between the average participant age in each trial and ES (B = 0.05, 95% CI: 0.001, 0.09, z = 2.05, p = 0.04). Fourth, no significant association was found between methodological quality and ES (B = −0.01, p = 0.64). Finally, no significant association was identified between the percent of study participants on tic-influencing medications and ES (B = −0.02, p = 0.26). 3.6. Publication bias and sensitivity analyses Although visual inspection of the funnel plot suggested publication bias may exist, Egger's test for bias indicated that publication bias was not significant (p = 0.57). When Duval and Tweedie's trim-and-fill method was applied, no studies were trimmed and BT still exhibited a medium to large effect (SMD = 0.67, p = 0.004). Rosenthal's Fail-safe N calculations identified that at least 62 unretrieved studies with an effect size of zero were needed to reduce the summary ES of BT to a non-significant level. Meanwhile, Orwin's Fail-safe N calculations identified that only 21 unretrieved studies with a mean effect of zero were needed to bring the summary ES to under 0.16. The analog to ANOVA revealed that heterogeneous ES were observed between trials using WL (SMD = 1.09), ND (SMD = 0.90) and BTC (SMD = −0.27) [Q(2) = 10.12, p = 0.004]. Follow-up pair-wise comparisons revealed heterogeneous ES between BTC and ND [Q(1) = 9.18, p = 0.002] and BTC and WL [Q(1) = 6.39, p = 0.012], but not between ND and WL [Q(1) = 0.15, p = 0.700].