Open Label Aripiprazole in the Treatment of Youth with Tic Disorders

Abstract

Background:

Primarily safe and efficacious treatments for chronic tic disorders are needed. Also needed are such treatments that target co-morbid conditions. Aripiprazole, a dopaminergic/serotonergic agent with partial agonist properties at the D2 dopamine receptor and 5-hydrdoxytryptamine 1A (5-HT_1A) receptor and antagonist properties at the 5-HT_2A receptor, holds promise in both regards.

Objective:

This was an open-label, flexible-dose study to evaluate the safety of aripiprazole in children and adolescents with a primary diagnosis of a chronic tic disorder with/without co-morbid disorder(s).

Method:

Sixteen children (15 males) aged 8–17 years participated in the 6-week trial. Ratings for tic, obsessive compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and side effects were administered weekly. Baseline and exit laboratory measures, electrocardiograms (ECGs), weight, and height were obtained.

Results:

The average daily aripiprazole dose was 3.3 mg (range 1.25–7.5 mg). Significant pre-and posttreatment differences were ascertained for the Yale Global Tic Severity Scale motor (p ≤ 0.0001), phonic (p ≤ 0.0001), and total tic (p ≤ 0.0001) scores. Results of other rating scales suggested significant improvements in co-morbid disorders as well, including OCD, ADHD, and depressive disorders. Although aripiprazole was well tolerated, increases in weight were found.

Conclusion:

In this preliminary open-label trial, aripiprazole was a well-tolerated treatment for tics and co-morbid OCD and ADHD symptoms. Improvements in co-morbid conditions may be secondary to tic reduction or to specific to aripiprazole therapy; however, further study is warranted.

Introduction

T ics are sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations that can be transient or chronic. Transient tics affect from 6–20% of school-aged children, with chronic tics and Tourette's syndrome (TS) affecting between 0.5% and 1% of children (Robertson 2003; Swain et al. 2007). TS is characterized by both multiple motor and one or more vocal tics occurring nearly every day for more than 1 year. Although some cases will remit, TS often persists into adulthood and may negatively influence the individuals' ability to develop and maintain healthy interpersonal and social relationships, autonomy, and academic success (Chang et al. 2004; Storch et al. 2007). Co-morbid psychopathology is common among TS patients and may include attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders, obsessive compulsive disorder (OCD), and depressive disorders (Robertson et al. 2002). Often these co-morbid disorders contribute largely to functional impairment; for example, children and adolescents with TS who are also affected by ADHD may experience increased academic, social, and family difficulties, whereas those who have co-morbid OCD or depressive disorders may experience increased emotional and adaptive impairment (Swain et al. 2007).

The decision to treat tic disorders is dependent upon several variables, including severity of the tics, co-morbid psychiatric disorders, and functional impairment. Nonpharmacologic treatments such as behavioral therapy show mixed results. Habit reversal training has worked well to improve tics with long-term effects (Wilhelm et al. 2003; Deckersbach et al. 2006); however, other behavioral techniques, such as biofeedback and awareness training, have not been studied adequately. Furthermore, while relaxation training was found to improve tics (Bergin et al. 1998), it only did so for the short-term. Furthermore, pharmacologic treatment is regarded as “symptomatic” at best (Singer 2005) . For nearly three decades, dopamine-2 (D2) receptor antagonists such as haloperidol and pimozide have been the mainstay of TS treatment (e.g., Uhr et al. 1986). Approximately 70% of patients with TS initially exhibit clinically meaningful suppression of tics with these agents. However, these medications have significant adverse effects, including fatigue, dulling of cognition, memory problems, weight gain, sexual dysfunction, dysphoria, akathisia, parkinsonism, neuroleptic malignant syndrome, and, after chronic use, tardive dyskinesia (Bruun 1988).

The α₂ receptor agonist clonidine has become the first-line treatment by many clinicians because it does not produce adverse neurologic effects. However, only partial benefit has been seen in placebo-controlled trials with this agent, and many patients cannot tolerate clonidine-induced sedation (Goetz 1992). Limited effectiveness and problematic side effects associated with currently available medications have led to a search for better treatments for TS. Risperidone has been found equally efficacious in treatment of TS when compared to clonidine or pimozide (Bruggeman et al. 2001), and ziprasidone was superior to placebo (Sallee et al. 2000). The most common side effect was sedation. Other agents also show efficacy, but with significant side effects, as reported with olanzapine therapy (Budman et al. 2001) and nicotine/haloperidol therapy (Silver et al. 2001; Bowles and Levin 2003).

One of the newest atypical antipsychotics, aripiprazole, is Food and Drug Administration (FDA)-approved for the treatment of schizophrenia and bipolar disorder in adolescents and may provide a new option for the treatment of pediatric tic disorders. Aripiprazole is a unique agent with its mechanism of action as a partial agonist on D₂ and 5-hydroxytryptamine 1A (5-HT_1A) receptors and an antagonist on 5-HT_2A receptors (Bowles and Levin 2003). The upregulation of D₂ receptors in the striatum seen with typical antipsychotics such as haloperidol has been minimal. Rather, in animal models, aripiprazole has been shown to decrease the synthesis, release, and firing rate of mesolimbic dopamine neurons. Furthermore, the effect of dopamine activation is at least in part determined by the state of the activated membrane (Hernandez-Lopez et al. 1997), such that aripiprazole acts as an apparent modulator of dopamine responsive neural substrates. Compared to other antipsychotics, aripiprazole reveals a lower liability for extrapyramidal symptoms, weight gain, QT_c interval prolongation, or hyperprolactinemia in adults (McQuade et al. 2004; Chrzanowski et al. 2006). Nausea, postural dizziness, and somnolence are the most common reported adverse effects in children (Yoo et al. 2007).

Along with a variety of specific cortical and basal ganglia changes, dysregulation of dopamine responsive/dependent circuits has been associated with the pathophysiology of tics and TS (Costa et al. 2006). While there is growing support that a dopamine-modulating agent like aripiprazole may hold promise for treatment of tic disorders (including TS) and associated co-morbid disorders, limited data exist on the efficacy and safety of aripiprazole in treating pediatric disorders (Murphy et al. 2005; Davies et al. 2006; Duane 2006; Storch et al. 2008; Yoo et al. 2007). With this in mind, we report an investigator-initiated, open-label study to evaluate the safety and efficacy of aripiprazole in pediatric chronic tic disorders.

Method

Participants

Sixteen children (15 males, 1 female) between the ages of 8 and 17 years (mean = 12.0 ± 2.8; see Table 1) with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994) primary diagnosis of TS or chronic tic disorder of at least moderate severity (≥4 on the Clinical Global Impression–Severity [CGI-S]) (Guy 1976) and meeting study criteria were enrolled in a 6-week, open-label, flexible-dose trial of aripiprazole; there were 4 screen failures in the 20 subjects screened. Twelve of 16 subjects had co-morbid OCD; 4 had co-morbid ADHD; and 3 subjects had depressive disorders (one with major depression and two with dysthymia, as determined through consensus of the the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version [K-SADS-PL] interview and clinical opinion) (Kaufman et al. 1997). Subjects for this investigator-initiated, Western Institutional Review Board (WIRB)-approved clinical trial were recruited through advertisement and the typical flow at a Tourette Disorder Specialty Clinic.

Table 1.

Individual Subject Titrated Dose, Weight Change, and Medication Status

Participant	Gender	Age	EOW 6 dose (mg)	Concomitant medication	PNT	Weight change (kg)
1	Male	13.6	7.5	None	Yes	−0.1
2	Male	10.5	5.0	Methylphenidate, 54 mg	Yes	+0.5
3	Male	8.6	1.25	None	No	+0.7
4	Male	12.0	5.0	Venlafaxine, 262.5 mg	No	+6.8
				Clonazepam, 1.5 mg
5	Male	13.6	1.5	Sertraline, 75 mg	No	+4.8
6	Male	17.8	5.0	Citalopram, 20 mg	Yes	+5.9
				Methylphenidate, 72 mg
				Valproate, 100 mg
7	Male	14.2	2.5	Clonazepam, 0.75 mg	No	0.0
8	Male	13.2	2.5	Citalopram, 20 mg	No	+3.1
9	Male	11.9	2.5	Citalopram, 20 mg	No	+3.3
10	Male	15.4	7.5	None	Yes	+3.9
11	Female	8.6	2.5	None	No	0.0
12	Male	8.8	1.25	Clonazepam, 0.25 mg	No	+0.4
				Trazodone, 25 mg
13	Male	11.8	2.5	Montelukast, 10 mg	No	+4.8
				Sertraline, 100 mg
14	Male	9.8	2.5	Bupropion, 150 mg	No	+0.3
15	Male	8.2	1.25	Escitalopram, 15 mg	No	+2.5
				Atomoxetine, 40 mg
16	Male	14.8	2.5	None	No	−0.2

Abbreviations: EOW 6 = end of week 6; PNT = prior neuroleptic trial.

In the Institutional Review Board (IRB) application, reviewers were informed of the potential for individual discontinuation of previous medications. Prior to participation in the screening process and clinical trial, procedures and assessments for the study were thoroughly explained to participants and their parents/legal guardians. Written consent and assent were obtained. Subjects enrolling were aware of the potential for discontinuation of study exclusive medications. Diagnoses were determined by the K-SADS-PL administered by a trained nurse and confirmed by a clinical interview with the first author (a board-certified child/adolescent psychiatrist). During this interview, the absence of suicidality was confirmed. Illness severity was determined by use of the CGI-S

Exclusion criteria for the study included DSM-IV criteria for schizophrenia, schizoaffective disorder, delusional disorder, or psychotic disorder not otherwise specified (NOS), substance abuse/dependence, seizure disorder, a history of seizures or conditions that lower the seizure threshold, and those with known allergy or hypersensitivity to aripiprazole. Those who had clinically significant abnormalities based on physical examination, medical history, electrocardiogram (ECG), or laboratory tests were also excluded. Therapy with a depot neuroleptic within one treatment cycle or any other changes in psychoactive medications in 1 month (2 months for antidepressants) prior to clinical trial entry were other reasons for exclusion, as were medications that posed drug interaction potential with aripiprazole, such as carbamazepine, ketoconazole, paroxetine, and fluoxetine. Four subjects were excluded: One subject had not made the time duration for TS diagnosis, 1 had a positive urine drug screen, 1 subject was on paroxetine, and 1 subject was on fluoxetine.

Procedure

Subjects who were medication naïve (n = 5) at trial entry were started on aripiprazole after successfully completing the baseline screening and confirmation of qualifying laboratory assay, physical exam, and ECG results. All results were examined by both the trained psychiatric nurse and the first author. To qualify for trial entry, results had to be within normal limits; if any abnormality was discovered, it was necessary that the finding be considered clinically insignificant for the subject to enter the clinical trial. Those subjects who were on neuroleptic or α₂ agonist medications and chose to discontinue these medications to qualify for the clinical trial (4 individuals) were placed in a supervised medication taper of 7–14 days. Specifically, 2 subjects had a 7-day taper (due to small initial doses of tapered medications) followed by 2 weeks on no medication prior to baseline, while another 2 individuals had a 14-day taper followed by 1 week on no medication prior to baseline. Subjects who completed the washout period and fulfilled the selection criteria then received treatment with aripiprazole for 6 weeks. (See Table 1 for a list of subjects' other medications.) Stable doses of aripiprazole were maintained for 14 subjects; the other 2 subjects maintained a final dose for only 2 weeks, because medication decreases were needed due to side effects. Subjects returned weekly for efficacy ratings and medication titration.

Aripiprazole titration and compliance

For the first week, 1.25 mg for titration once daily was used and, in the absence of efficacy and of dose-limiting side effects, subjects were gradually titrated weekly (1.25–2.5 mg) based on efficacy and tolerability to a maximum not to exceed 15 mg. On the basis of clinical experience, it was anticipated that most subjects would achieve efficacy at 5–15 mg, or approximately 0.2 mg/kg. Parents were required to bring the aripiprazole container with them to each visit. If the pill count on the returned medication indicated noncompliance, the parent was counseled about the importance of compliance and the proper manner of taking study medication as prescribed. Compliance was high throughout the trial (>90% for all subjects), and no families were removed from the study due to medication noncompliance.

Outcome measures

The following efficacy evaluations (administered weekly) were the primary outcome measures:

The Yale Global Tic Severity Scale (YGTSS) (Leckman et al. 1989), a clinician-rated, semistructured interview, was administered to assess tic severity (0–50 scale range, impairment score not included). Motor and phonic tics were rated separately according to number, frequency, intensity, complexity, and interference.

The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (Scahill et al. 1997) was used to measure OCD symptom severity (0–40 scale range for total score of obsessions and compulsions).

The Clinical Global Impressions–Severity and –Improvement (CGI-S and CGI-I) scales were used to assess current functioning along with changes from previous visits (Guy 1976). At baseline, an initial clinician-rated CGI–Severity of Illness score was determined on a 7-point scale ranging from 1 (no symptoms) to 7 (severe symptoms). A rating of 4 is indicative of moderate severity. At subsequent visits, the clinician rated the patient's improvement relative to the symptoms at baseline on a CGI-I assessment, a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The physician and clinicians reviewed completed efficacy ratings at the conclusion of each subject visit; consensus severity and improvement scores were assigned for both tic and OCD symptoms.

Staff responsible for conducting clinician ratings had all received extensive training by the first author in the primary outcome measures and satisfactory interrater reliability had been documented. Pre- and posttreatment data were also collected using the Children's Depression Rating Scale (CDRS) (Poznanski et al. 1979) to measure the presence and severity of depression symptoms; Conners' Abbreviated Symptom Questionnaire for Parents (ASQ-P) (Conners 1989) to measure ADHD symptoms; and a set of continuous performance tasks to measure vigilance, distractibility, and impersistence.

Safety analyses

Safety assessments consisted of the Extrapyradimal Symptom Rating Scale (ESRS), adverse event (AE) recording, clinical laboratory assays, vital signs, physical examinations, and ECGs. AEs were monitored and recorded at all postbaseline study visits. In addition, parents/legal guardians were encouraged to contact us if they experienced any concerns between study visits. For each AE, severity (mild, moderate, severe) and relation to study medication (not related, possibly related, related) were to be noted. Blood and urine samples were collected for laboratory analysis at baseline and at the end of week 6 on aripiprazole. The assays included a complete blood count (CBC) with differential and platelet count, a metabolic panel, a cholesterol/lipid panel, thyroid-stimulating hormone (TSH), total triiodothyronine (T3), hemoglobin A1c, and urinalysis. At baseline screening, before clinical trial entry, a urine toxicology screen was performed to rule out current substance abuse. A comprehensive physical examination was performed by the first author at baseline and the end of week 6 on aripiprazole. At baseline, end of week 3, and end of week 6, the ESRS was administered and a 12-lead ECG was performed. In addition, orthostatic blood pressure and pulse rate assessments were taken each visit, and body weight and body mass index (BMI) were calculated.

Statistical analysis

Paired t-tests were performed to compare pretreatment and posttreatment scores on all outcome measures. Pearson correlations were performed to assess the change in symptom severity. Two-tailed significance levels reported as p values are given in Table 2. Because we were testing 15 comparisons simultaneously, any p value less than 0.003 was considered significant at the 0.05 familywise control level (i.e., using a Bonferroni correction). In other words, we are 95% confident that all significant differences found are true.

Table 2.

Pre- and Posttreatment Symptom Severity

Variable	Pretreatment mean ± SD	Posttreatment mean ± SD	Change mean ± SD	p value
YGTSS (n = 16)
Motor tic	17.9 ± 4.3	8.9 ± 4.8	−8.9 ± 4.6	<0.0001
Phonic tic	14.1 ± 5.3	5.8 ± 5.0	−8.6 ± 4.5	<0.0001
Total tic	32.0 ± 7.8	14.7 ± 7.6	−17.5 ± 6.2	<0.0001
CGI - Tic (n = 16)
Severity	4.9 ± 0.7	3.2 ± 0.5	−1.75 ± 0.8	<0.0001
Improvement	3.0 ± 0.0	5.5 ± 0.5	2.50 ± 0.5	<0.0001
CY-BOCS (n = 12)
Obsessions	10.2 ± 5.1	4.3 ± 5.1	−5.4 ± 4.8	0.002
Compulsions	11.2 ± 4.6	5.9 ± 5.5	−6.8 ± 5.7	0.001
Total OCD	22.6 ± 8.3	10.3 ± 8.9	−12.2 ± 9.3	0.001
CGI - OCD (n = 12)
Severity	2.8 ± 0.8	1.7 ± 0.5	−1.1 ± 0.7	<0.0001
Improvement	3.0 ± 0.0	5.0 ± 0.9	2.0 ± 0.9	<0.0001
ASQ-P (n = 16)
Attention T-scores	63.8 ± 17.7	53.3 ± 13.2	−10.4 ± 14.5	0.012
CDRS (n = 16)
Depression T-scores	55.6 ± 7.2	48.0 ± 5.4	−7.7 ± 7.9	0.002
Continuous Performance Tasks (n = 14)
Efficiency z-scores	−0.8 ± 1.0	−0.3 ± 0.9	0.4 ± 1.3	N.S.
Vigilance error z-scores	1.5 ± 4.6	−0.1 ± 0.8	−1.6 ± 3.9	N.S.
Distractibility error z-scores	2.2 ± 3.5	0.6 ± 1.7	−1.6 ± 2.2	0.019
Weight (kg)
All subjects	43.7 ± 14.6	46.0 ± 15.8	2.3 ± 2.4
SSRI subjects	45.8 ± 13.7	49.9 ± 14.3	4.1 ± 1.3

Abbreviations: SD = Standard deviation; YGTSS = Yale Global Tic Severity Scale; CGI = Clinical Global Impressions; CY-BOCS = Children's Yale-Brown Obsessive Compulsive Scale; OCD = obsessive compulsive disorder; ASQ-P = Abbreviated Symptom Questionnaire for Parents; CDRS = Children's Depression Rating Scale; SSRI = selective serotonin reuptake inhibitor.

Results

Efficacy

At study completion, the average daily dose of aripiprazole was 3.3 mg ± 2.1 (range 1.25–7.5 mg). Statistically significant improvements at posttreatment were found in YGTSS motor tics (p < 0.003), phonic tics (p < 0.003), and total tics (p < 0.003), as well as CYBOCS obsessions (p < 0.002), compulsions (p < 0.003), and total scores (p < 0.003). Further significance was found in the severity and improvement scores of both tics and OCD as measured by the CGI (tic severity p < 0.003, OCD severity p < 0.003), and CGI-I (all 16 subjects had a tic CGI of much improved/very much improved and 10 of the 13 subjects who had co-morbid OCD had an OCD CGI of much improved/very much improved). Table 2 is illustrative of the decrease in YGTSS and CYBOCS scores indicating fewer and less severe symptoms (motor/phonic tics, obsessions/compulsions).

On the end of week 6 Continuous Performance Tasks, 9 of 14 subjects (64%) increased in their task efficiency, 11 of 14 subjects (79%) made fewer anticipatory errors in standard vigilance, and 9 of 14 subjects (64%) made fewer anticipatory errors in vigilance when a visual distracter was present. A significant pre- to posttreatment difference in the CDRS (p < 0.003) was found (see Table 2).

Safety

Treatment-emergent side effects were reported by 11 subjects (1 headache, 3 with mild nausea, 4 with increased irritability, 5 with excitability /restlessness, 3 with inattention, 2 with frequent urination). All side effects were mild or moderate in severity; none was severe enough to cause aripiprazole discontinuation or early study termination. The majority of side effects resolved spontaneously over a few days; in 3 cases, side effects emerged with a dosage increase and promptly decreased with lowered dosage. Results on the ESRS indicated 1 subject exhibited mild Parkinsonian symptoms at one visit following a dosage increase.

Although aripiprazole was generally well tolerated, there was a significant weight gain from baseline to end of week 6 (t = −3.83, degrees of freedom [df] = 15, p < 0.003). Specifically, 8 of 16 subjects (50%) experienced a weight gain equal to or greater than 2.5 kg (see Table 1), whereas weight remained relatively stable in the other eight subjects. Weight gain did not differ between those who were treatment-naïve, those subjects on concomitant antidepressants, and those who had a prior neuroleptic trial (F_(2,12) = 3.70, p > 0.05). (Note: One subject was not included in this analysis, due to membership in both the antidepressant and prior neuroleptic trial groups.) Interestingly, the prior neuroleptic trial subjects ended the 6-week trial on a higher aripiprazole titrated dose than did either the treatment-naïve subjects or the concomitant selective serotonin reuptake inhibitor (SSRI) subjects (F_(2,13) =17.14, p < 0.001).

No statistically significant changes in metabolic test results or ECG readings were found. For example, lipid and cholesterol levels did not change from baseline to the end of week 6 on aripiprazole. And, while T3 levels increased in 11 of 16 subjects (mean increase 31.5 ± 16.1), all levels remained within the normal range. The same held true for the machine-read readings on the ECG: 5 of 16 subjects had QTc interval increases (mean increase 10.0 ± 8.2 milliseconds); however, these increases were considered nonsignificant, as readings <440 are considered to be normal in children (Moss 1993). The mean QTc interval at baseline was 402 ± 16.6 and, at the end of week 6, was 398.2 ± 9.1. It should be noted that there have been problems of poor agreement (Blair et al. 2005) between manual- and machine-generated calculations of QTc, with the machine generated ones underrepresenting the changes. Thus, the reliance on machine-generated calculations marks a limitation of the present study.

Discussion

Aripiprazole was generally well tolerated and associated with a significant decrease in total tic severity. Co-morbid obsessive-compulsive symptoms, attention-deficit symptoms, and depressive symptoms also decreased, although it is not clear whether the effects were direct (i.e., aripiprazole had a direct effect on co-morbid conditions) or whether these symptoms were auxiliary to the tics and, thus, their reduction was an indirect result of tic management. To date, the treatment of OCD with atypical antipsychoatics has resulted in equivocal findings. Quetiapine and olanzapine, for instance, have been found to both significantly ameliorate and worsen symptoms (Tranulis et al. 2005; Gao et al. 2006; Diniz et al. 2009). However, the study of aripiprazole has offered preliminary support for its use in treating OCD (Szechtman et al. 1999; Connor et al. 2005; Murphy et al. 2005; Schneier et al. 2008; Storch et al. 2008). While aripiprazole treatment of OCD in adults has been reported (Connor et al. 2005), little evidence exists on aripiprazole treatment for OCD in children and adolescents (Murphy et al. 2005; Storch et al. 2008). Aripiprazole as an augmentation agent for treating OCD should be at least similar to other agents with D₂ antagonist properties. The distinctive property of aripiprazole as a dopamine–serotonin system modulator may contribute to the treatment response seen in the children with co-morbid OCD. A recent animal model of marble burying suggest that aripiprazole's (Matsushita 2005) 5-HT_1A agonist effect is specific for OCD. Whereas atypicals with lower D₂ but higher 5-HT_2A antagonist properties may worsen OCD symptoms (Tranulis et al. 2005; Gao et al. 2006). Further study of the potential efficacy of aripiprazole in pediatric OCD patients who have not responded to first-line treatments is warranted.

Many of the children gained weight while on aripiprazole during this 6-week study. Because weight gain is common with atypical antipsychotics, and tends to persist for a few months (or perhaps longer), our finding that half of the subjects gained at least 2.5 kg in a 6-week span is a matter of concern. However, to draw firm conclusions regarding weight gain, further research using a larger sample size and longer treatment period is clearly needed. A possible contributing factor includes the difficult nature of weight gain assessment in children who are in formative growth stages. In addition, while medications were not changed during the time period of the study, most subjects were taking other medications (primarily antidepressants) and, thus, an additive or interactive effect is probable considering that the treatment-naïve subjects gained less weight and required a lower titrated dose of aripiprazole. A second concern was transient behavioral activation, noted in a few subjects. However, most patients were satisfied with their treatment response and all subjects elected to stay on the medication at the time of study completion.

In summary, aripiprazole appears not to worsen (and may even improve upon) the symptoms of OCD/attention/mood disorders that are frequently seen in children with tic disorders. Weight gain was seen in over half the children, but no significant metabolic changes were noted, offering an advantage over other atypical antipsychotics that may be used for treating TS (Dehning et al. 2005). Whereas these results are promising, the following limitations must be kept in mind: We employed an open-label trial design, clinicians and raters were unblinded, and not all youths were on aripiprazole monotherapy. Given this, we suggest that while aripiprazole appears to have been effective and well tolerated in the treatment of TS and co-morbid conditions in these 16 children, a larger double-blind placebo-controlled trial is needed.

Footnotes

Disclosures

This submission marks an investigator-initiated study supported by grant funding from Bristol-Myers Squibb (to the first author). The study's authors do not promote for any pharmaceutical companies; and there are no other conflicts of interest.

The statistician for this study was Mark Yang, Ph.D.

This investigator-initiated study was supported by a grant from Bristol-Myers Squibb.

References

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders 4 ^th edition (DMS-IV)Washington (DC): American Psychiatric Association, 1994.

Bergin

, Waranch

, Brown

, Carson

, Singer

. Relaxation therapy in Tourette syndrome: A pilot study. Pediatric Neurol, 18:136–142. 1998.

Blair

, Scahill

, State

, Martin

. Electrocardiographic changes in children and adolescents treated with ziprasidone: A prospective study. J Am Acad Child Adolesc Psychiatry, 44:73–79. 2005.

Bowles

, Levin

. Aripiprazole: A new atypical antipsychotic drug. Ann Pharmacother, 37:687–694. 2003.

Bruggeman

, van der Linden

, Buitelaar

, Gericke

, Hawkridge

, Temlett

. Risperidone versus pimozide in Tourette's disorder: A comparative double-blind parallel-group study. J ClinPsychiatry, 62:50–56. 2001.

Bruun

. Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette's disorder. Am J Psychiatry, 145:621–624. 1988.

Budman

, Gayer

, Lesser

, Shi

, Bruun

. An open-label study of the treatment efficacy of olanzapine for Tourette's disorder. J Clin Psychiatry, 62:290–294. 2001.

Budman

, Rockmore

, Stokes

, Sossin

. Clinical phenomenology of episodic rage in children with Tourette syndrome. J Psychosomat Res, 55:59–65. 2003.

Chang

, Tu

, Wang

. Tourette's syndrome: Psychopathology in adolescents. Psychiatry Clin Neurosci, 58:353–358. 2004.

10.

Chrzanowski

, Marcus

, Torbeyns

, Nyilas

, McQuade

. Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: A 52-week, open-label comparison with olanzapine. Psychopharmacology, 189:259–266. 2006.

11.

Conners

. The Conners rating scales: Instruments for the Assessment of Childhood Psychopathology. Toronto: Multi-Health Systems, 1989.

12.

Connor

, Payne

, Gadde

, Zhang

, Davidson

. The use of aripiprazole in obsessive-compulsive disorder: Preliminary observations in 8 patients. J Clin Psychiatry, 66:49–51. 2005.

13.

Costa

, Lin

, Sotnikova

, Cyr

, Gainetdinov

, Caron

, Nicolelis

. Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction. Neuron, 52:359–369. 2006.

14.

Davies

, Stern

, Agrawal

, Robertson

. A case series of patients with Tourette's syndrome in the United Kingdom treated with aripiprazole. Hum Psychopharmacol, 21:447–453. 2006.

15.

Deckersbach

, Rauch

, Buhlmann

, Wilhelm

. Habit reversal versus supportive psychotherapy in Tourette's disorder: A randomized controlled trial and predictors of treatment response. Behav Res Ther, 44:1079–1090. 2006.

16.

Dehning

, Riedel

, Muller

. Aripiprazole in a patient vulnerable to side effects. Am J Psychiatry, 162:625. 2005.

17.

Duane

. Aripiprazole in childhood and adolescence for Tourette syndrome. J Child Neurol, 21:358. 2006.

18.

Gao

, Muzina

, Gajwani

, Calabrese

. Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review. J Clin Psychiatry, 67:1327–1340. 2006.

19.

Goetz

. Clonidine and clonazepam in Tourette syndrome. Adv Neurol, 58:245–251. 1992.

20.

Guy

. Assessment Manual for Psychopharmacology, revised edition. Rockville (Maryland): National Institute of Mental Health, 1976.

21.

Hernandez-Lopez

, Bargas

, Surmeier

, Reyes

, Galarraga

. D1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca2+ conductance. J Neurosci, 17:3334–3342. 1997.

22.

Kaufman

, Birmaher

, Brent

, Rao

, Flynn

, Moreci

, Williamson

, Ryan

. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL):I reliability and validity data. J Am Acad Child Adolesc Psychiatry, 36:980–988. 1997.

23.

Leckman

, Riddle

, Hardin

, Ort

, Swartz

, Stevenson

, Cohen

. The Yale Global Tic Severity Scale: Initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry, 28:566–573. 1989.

24.

Matsushita

, Egashira

, Harada

, Okuno

, Mishima

, Iwasaki

, Nishimura

, Fujiwara

. Perospirone, a novel antipsychotic drug, inhibits marble-burying behavior via 5-HT1A receptor in mice: implications for obsessive-compulsive disorder. J Pharmacol Sci, 99:154–159. 2005.

25.

McQuade

, Stock

, Marcus

, Jody

, Gharbia

, Vanveggel

, Archibald

, Carson

. A comparison of weight change during treatment with olanzapine or aripiprazole: Results from a randomized, double-blind study. J Clin Psychiatry, 65,Suppl 18:47–56. 2004.

26.

Moss

. Measurement of the QT interval and the risk associated with QTc interval prolongation: A review. Am J Cardiol, 72:23B–25B. 1993.

27.

Murphy

, Bengtson

, Soto

, Edge

, Sajid

, Shapira

, Yang

. Case series on the use of aripiprazole for Tourette syndrome. Int J Neuropsychopharmacol, 8:489–490. 2005.

28.

Poznanski

, Cook

, Carroll

. A depression rating scale for children. Pediatrics, 64:442–450. 1979.

29.

Robertson

. Diagnosing Tourette syndrome. Is it a common disorder? J Psychosomat Res, 55:3–6. 2003.

30.

Robertson

, Banerjee

, Eapen

, Fox-Hiley

. Obsessive compulsive behaviour and depressive symptoms in young people with Tourette syndrome. A controlled study. Eur Child Adolesc Psychiatry, 11:261–265. 2002.

31.

Sallee

, Kurlan

, Goetz

, Singer

, Scahill

, Law

, Dittman

, Chappell

. Ziprasidone treatment of children and adolescents with Tourette's syndrome: A pilot study. J Am Acad Child Adolesc Psychiatry, 39:292–299. 2000.

32.

Scahill

, Riddle

, McSwiggin-Hardin

, Ort

, King

, Goodman

, Cicchetti

, Leckman

. Children's Yale-Brown Obsessive Compulsive Scale: Reliability and validity. J Am Acad Child Adolesc Psychiatry, 36:844–852. 1997.

33.

Schneier

, Martinez

, Abi-Dargham

, Zea-Ponce

, Simpson

, Liebowitz

, Laruelle

. Striatal dopamine D(2) receptor availability in OCD with and without comorbid social anxiety disorder: preliminary findings. Depress Anxiety, 25:1–7. 2008.

34.

Silver

, Shytle

, Philipp

, Wilkinson

, McConville

, Sanberg

. Transdermal nicotine and haloperidol in Tourette's disorder: A double-blind placebo-controlled study. J Clin Psychiatry, 62:707–714. 2001.

35.

Storch

, Lack

, Simons

, Goodman

, Murphy

, Geffken

. A measure of functional impairment in youth with Tourette's syndrome. J Pediatr Psychol, 32:950–959. 2007.

36.

Storch

, Lehmkuhl

, Geffken

, Touchton

, Murphy

. Aripiprazole augmentation of incomplete treatment response in an adolescent male with obsessive-compulsive disorder. Depress Anxiety, 2008.

37.

Swain

, Scahill

, Lombroso

, King

, Leckman

. Tourette syndrome and tic disorders: A decade of progress. J Am Acad Child Adolesc Psychiatry, 46:947–968. 2007b.

38.

Szechtman

, Culver

, Eilam

. Role of dopamine systems in obsessive-compulsive disorder (OCD): Implications from a novel psychostimulant-induced animal model. Pol J Pharmacol, 51:55–61. 1999.

39.

Tranulis

, Potvin

, Gourgue

, Leblanc

, Mancini-Marie

, Stip

. The paradox of quetiapine in obsessive-compulsive disorder. CNS Spectr, 10:356–361. 2005.

40.

Uhr

, Pruitt

, Berger

, Stahl

. Improvement of symptoms in Tourette syndrome by piquindone, a novel dopamine-2 receptor antagonist. Int Clin Psychopharmacol, 1:216–220. 1986.

41.

Wilhelm

, Deckersbach

, Coffey

, Bohne

, Peterson

, Baer

. Habit reversal versus supportive psychotherapy for Tourette's disorder: A randomized controlled trial. Am J Psychiatry, 160:1175–1177. 2003.

42.

Yoo

, Choi

, Park

, Wang

, Hong

, Kim

. An open-label study of the efficacy and tolerability of aripiprazole for children and adolescents with tic disorders. J Clin Psychiatry, 68:1088–1093. 2007.