Typical antipsychotics such as haloperidol and pimozide have been prescribed to control tic symptoms as first-line agent [1]. More recently, clinical experience with atypical neuroleptics have increased owing to the efficacy and the more tolerable adverse effects relative to some classical antipsychotics [1–11]. Some drugs such as risperidone [7, 12], quetiapine [13], and olanzapine [4, 10, 11], however, may cause unwanted metabolic side effects, which may worsen patient quality of life as well as general medical health status.

Aripiprazole is another candidate atypical antipsychotic agent for patients with tic disorders. This drug has a lower risk of metabolic side effects than other atypical neuroleptics. In addition, aripiprazole has a unique pharmacodynamic property, namely dopamine partial agonist activity [14]. Because abnormalities in the brain dopamine system may be closely related to the pathology of tic disorders [15], we hypothesized that aripiprazole may have therapeutic effects on tic manifestations. Several clinical trials, including our previous studies, have revealed that aripiprazole may be successful in treating patients with tic disorders, due to its high efficacy and tolerability [16–24]. No study to date, however, has compared the efficacy and tolerability of aripiprazole and typical antipsychotics in these patients. We therefore compared the efficacy and tolerability of aripprazole with haloperidol, a typical antipsychotic agent widely used to treat children and adolescents with tic disorders.

To our knowledge, this study is the first to directly compare the efficacy and tolerability of aripiprazole and haloperidol in the treatment of children and adolescents with tic disorders. We found that aripiprazole was as effective as haloperidol in reducing tic symptoms, as well as being better tolerated. The mean dose of aripiprazole used in this study, 10.6 mg/d, was similar to that used in our previous studies in which children and adolescents with tic disorders were treated with aripiprazole [16, 23, 24], and to doses used in previous studies of youths with developmental disabilities [33–35], delusional disorder [36], and bipolar disorders [37]. In contrast, higher doses of aripiprazole have been used to treat children and adolescents with bipolar disorders [38, 39], catatonia [40], and generalized anxiety disorder [41], as well as in psychiatric inpatients [42]. The aripiprazole dose used in this study was lower than that used in adults with Tourette disorder [21, 43–45].

Although various atypical antipsychotics are widely used to treat tic disorders, they had weaker efficacy than typical neuroleptics such as haloperidol and pimozide, which can decrease tic symptoms by more than 60% [29]. Even the first atypical antipsychotic, clozapine, was not able to sufficiently abate tic symptoms [5]. Although olanzapine showed considerable efficacy, its adverse effects, such as weight gain and sedation, limits its use for tic control [4, 10]. Uses of quetiapine have been reported in several case reports [12, 46–49] and open-label trials [13, 49] to decrease tic symptoms. However, in two open-label trials testing quetiapine as an anti-tic drug in children and adolescents with Tourette disorder, its efficacy and tolerability were questionable. Risperidone is one of the most widely used and best-studied atypical antipsychotics in the treatment of tic symptoms. Although relatively safe and effective in tic reduction, risperidone diminishes tic symptoms by less than 36% [3, 6–9, 50, 51]. A double-blind, randomized trial on the efficacy of ziprasidone in reducing tic symptoms showed that it reduced tic symptoms by 35%, although side effects, most of which were tolerable, developed in more than 80% of patients [52].

Aripiprazole may be more potent than other atypical antipsychotics, reducing tic symptoms by 40–53% [23, 24]. Aripiprazole was also found to be effective in treating antipsychotic-resistant patients with Tourette disorder [19, 21]. In the current study, 15 subjects (48.4%) in the aripiprazole group and 3 (17.6%) in the haloperidol group had histories of previous ineffective treatment with antipsychotic medication; nevertheless, the efficacy of aripiprazole was equivalent to that of haloperidol, suggesting that aripiprazole may be a drug of choice for drug-resistant tic patients, although further confirmation is required.

In our previous report, aripiprazole was effective at its initial dose, 5 mg, with 62.0% of the total reduction in Total Tic Score attained within 2 weeks after the start of treatment [24]. Although we found that tic severity in the aripiprazole group diminished almost linearly from 2 to 8 weeks, the reduction during the first 2 weeks, during treatment with the initial dose of 5 mg/day, accounted for 60.0% of the total reduction in Total Tic Score, observed in this study. This indicates that aripiprazole may be useful in the treatment of children and adolescents with tic disorders, especially those with unbearable or strongly dysfunctional tic symptoms who need prompt symptom improvement.

More than 80% of youths taking aripiprazole experienced one or more unwanted side effects. This high incidence may have been due to the starting dose of 5 mg, which may be too high in children and adolescents with tic disorders. Nineteen subjects (61.3%) in the aripiprazole group experienced side effects after their first dose, with the side effects experienced by four patients (21.1%) disappearing spontaneously without any management or dose reduction at the next visit. Further clinical studies using lower initial doses of aripiprazole are required to confirm this possibility.

In addition to the higher dropout rate seen in the haloperidol group, the rate of EPS during the 4 weeks after starting treatment was higher in the haloperidol than in the aripiprazole group. This may be associated with differences in receptor profiles of the two drugs. Haloperidol has a strong antagonistic affinity to dopamine 2 receptors in the nigrostriatal dopamine pathway, causing EPS [53], whereas aripiprazole has partial agonistic activity at the postsynaptic dopamine 2 receptors, reducing EPS development [14].

Aripiprazole may be a more ideal anti-tic drug owing to its unique pharmacodynamic profile, including both antagonistic and agonistic dopamine activities, depending on the environment of the local dopamine system [14, 54]. This activity is strongly associated with the pathological mechanism of tic disorders. Dopamine receptor hypersensitivity may be an underlying pathology of tic disorders [15]. Although several studies have confirmed the supersensitivity of the dopamine system in tic disorders, these studies did not consider the anti-dopaminergic drug effects [55–57], and several neuroimaging studies assessing influences of drugs on the dopamine system have yielded conflicting results [58–60]. Significantly, pergolide, a typical dopamine agonist, reduced tic symptoms in two previous randomized, controlled clinical studies [61, 62]. Thus, an imbalance in dopamine systems may be a pivotal cause of tic disorders. The stabilizing action of aripiprazole in an environment of unbalanced dopamine status, therefore, as in tic-affected brain areas, may be more ideal in abating tic symptoms.

Apart from acting as a partial dopamine agonist, aripiprazole has serotonin 2A antagonistic properties, which may also facilitate its ability to stabilize the dopamine system by increasing dopamine release [63]. The serotonin 2A receptor has been associated with tic symptoms, both in animals [64] and humans [65]. In addition, the partial agonistic actions of aripiprazole at the serotonin 1A receptor might improve tic symptoms by decreasing anxiety [66], which occurs frequently in patients with tic disorders and has been associated with tic aggravation [1]. Moreover, the partial agonistic activities of aripiprazole on the dopamine 3 and 4 receptors may be correlated with the effects of this drug on tic disorders, as shown both clinically [61, 62] and genetically [67–69].

Although our findings indicate that aripiprazole has equivalent efficacy but higher tolerability than haloperidol in children and adolescents with tic disorders, our study had several limitations, including the small sample size, open-label approach, and short-term nature of the study. Thus, we cannot confirm the tolerability and long-term efficacy of aripiprazole in these patients. In addition, because the patients chose aripiprazole or haloperidol, it could result in differences such as age and baseline scores among the groups of patients. Double-blind, placebo-controlled, and randomized trials should be performed to overcome these limitations and determine whether aripiprazole improves tic symptoms or if our findings reflect the natural progression of tic disorders.

Our findings indicate that aripiprazole may be effective and tolerable in the treatment of children and adolescents with tic disorders. Additional controlled studies are needed to determine the efficacy and tolerability of aripiprazole in patients with tic disorders.