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Eur Child Adolesc Psychiatry (2011) 20:127–135 Open-label study comparing the efficacy and tolerabilityof aripiprazole and haloperidol in the treatmentof pediatric tic disorders Hanik K. Yoo • Joong-Sun Lee • Kyoung-Won Paik •Soon-Ho Choi • Sujung J. Yoon • Jieun E. Kim •Jin Pyo Hong Received: 29 March 2010 / Accepted: 15 December 2010 / Published online: 28 December 2010Ó The Author(s) 2010. This article is published with open access at Springerlink.com Due to its unique pharmacodynamic properties during the 4 weeks after commencement of medication of dopamine partial agonist activity, and its association (p 0.05). These results indicate that aripiprazole may be with few and mild side effects, aripiprazole is a candidate a promising drug in the treatment of children and adoles- atypical antipsychotic for patients with tic disorders. This cents with tic disorders. Further controlled studies are open-label study compared the efficacy and tolerability of needed to determine the efficacy and tolerability of ari- aripiprazole with haloperidol, a typical antipsychotic piprazole in these patients.
widely used to treat patients with tic disorders. Forty-eightchildren and adolescents with tic disorders were recruited Aripiprazole
Tic disorders
Tourette from the outpatient clinic at South Korea and treated disorder
Children
Adolescents
Haloperidol with aripiprazole (initial dose, 5.0 mg/d; maximum dose20 mg/d) or haloperidol (initial dose, 0.75 mg/d; maximumdose, 4.5 mg/d) for 8 weeks. Treatment efficacy was measured using the yale global tic severity scale (YGTSS),and tolerability was measured using the extrapyramidal Typical antipsychotics such as haloperidol and pimozide symptom rating scale (ESRS) and an adverse effects have been prescribed to control tic symptoms as first-line checklist. Total tic scores as measured by the YGTSS agent []. More recently, clinical experience with atypical decreased over time in both groups (p 0.001) with- neuroleptics have increased owing to the efficacy and the out any significant differences between groups. ESRS more tolerable adverse effects relative to some classical scores were significantly higher in the haloperidol group antipsychotics [–Some drugs such as risperidonequetiapine ], and olanzapine , ], how-ever, may cause unwanted metabolic side effects, which H. K. Yoo (&)
J.-S. Lee
S.-H. Choi
J. P. Hong may worsen patient quality of life as well as general Department of Psychiatry, University of Ulsan Collegeof Medicine, Asan Medical Center, 388-1 Pungnap-2 dong, medical health status.
Songpa-gu, Seoul 138-736, South Korea Aripiprazole is another candidate atypical antipsychotic agent for patients with tic disorders. This drug has a lowerrisk of metabolic side effects than other atypical neuro- K.-W. PaikDepartment of Psychiatry, Hanyang University Medical Center, leptics. In addition, aripiprazole has a unique pharmaco- Seoul, South Korea dynamic property, namely dopamine partial agonistactivity [Because abnormalities in the brain dopamine system may be closely related to the pathology of tic dis- Department of Psychiatry, Catholic University Medical College,St. Paul Hospital, Seoul, South Korea orders ], we hypothesized that aripiprazole may havetherapeutic effects on tic manifestations. Several clinical trials, including our previous studies, have revealed that Department of Psychiatry, Seoul National University College aripiprazole may be successful in treating patients with tic of Medicine, Seoul National University Hospital,Seoul, South Korea disorders, due to its high efficacy and tolerability – Eur Child Adolesc Psychiatry (2011) 20:127–135 No study to date, however, has compared the efficacy and 5.0–10.0 mg/d increments every 2 weeks as tolerated tolerability of aripiprazole and typical antipsychotics in , ]. Doses were reduced in 2.5–5.0 mg/d steps when these patients. We therefore compared the efficacy and intolerable side effects emerged. The maximum allowable tolerability of aripprazole with haloperidol, a typical anti- dose was 20 mg/d and patients were treated for 8 weeks.
psychotic agent widely used to treat children and adoles- Patients in the haloperidol group were started at a dose of cents with tic disorders.
0.75 mg/d and increased in 1.5–3.0 mg/day incrementsevery 2 weeks to a maximum tolerated dose of 4.5 mg/d]. Psychotropic drugs to control comorbid psychiatric symptoms were not prescribed during the study period.
Patients were assessed every other week, with the final assessment 8 weeks after the start of study medications.
Forty-eight children and adolescents with tic disorders (33 males, 15 females; mean ± SD age = 10.3 ± 3.5 years;range, 6–15 years) were recruited at an outpatient clinic at The YGTSS is a semi-structured clinical interview a general hospital in Seoul, South Korea, from August designed to assess current tic severity; this scale yields 2005 to March 2007. Before determining eligibility, we three summary scores; total motor (0–25), total phonic obtained informed consent and assent from both the study (0–25), and total tic (sum of motor and phonic) scores. The subject and the child's primary caregiver. The study pro- YGTTS also contains an impairment scale (0–50), which tocol was approved by our local Institutional Review evaluates the global level of functional impairment arising from tics [Because this study was designed to compare Patients were deemed eligible if they had DSM-IV efficacy in reducing tic symptoms, the primary outcome diagnosis of tic disorders, as described in the Korean ver- measure was total tic score. The YGTSS was administered sion of the Kiddie-Schedule for Affective Disorders and to each subject at each visit.
Schizophrenia-Present and Lifetime Version (KSADS-PL Secondary outcome measures included the Clinical [and Total Tic scores C22 on the Korean version of Global Impressions-Improvement scale (CGI-I [and the yale global tic severity scale (YGTSS [cor- the CGI-Severity of Illness scale (CGI-S [Scores of 1 responding to at least moderate tic severity. Each patient (very much improved) or 2 (much improved) in the CGI-I was subsequently examined by a board-certified child were regarded as positive responses. Both of these tests were administered at every visit.
Exclusion criteria included current mood disorders, Adverse effects associated with these drugs were assessed psychotic symptoms, and anxiety disorders, except for using an in-house adverse effect checklist, which included obsessive–compulsive disorder, the most common comor- the most commonly encountered side effects of aripiprazole bid anxiety disorder in tic patients. Subjects with an and haloperidol, as well as general questions on health IQ B 70 on the Korean version of the Wechsler Intelli- issues, current illnesses or injuries, and concomitant medical gence Scale for Children-Revised (WISC-R ]) were also treatments. The Extrapyramidal Symptom (EPS) Rating excluded, as were patients with previous or current seizure Scale (ESRS) was also used to rate the severity of Parkin- episodes, electroencephalogram (EEG) abnormalities, and sonism, akathisia, dystonia, and dyskinesia [We mea- those who had used aripiprazole previously. Subjects who sured height and weight at every visit. At the study endpoint, had taken psychotropic medications must have been drug- physical and neurological examinations, laboratory tests, free for at least 2 weeks before study entry and had to be and ECG assessments were repeated.
devoid of any significant medical problems.
All tests were admitted by a single psychiatrist, who was blinded to dose changes but not to the drug of choice.
Statistical analyses This was an open, non-randomized, parallel-group clinicaltrial. All subjects were evaluated at baseline by routine We used intent-to-treat analyses, based on patients assessed laboratory tests, electrocardiogram (ECG), resting pulse at least once after baseline. Multiple linear regression and rate and blood pressure while sitting, height and weight generalized estimation equation (GEE) regression model- measurement, medical history, and physical and neuro- ing were used to identify medication efficacy and the sig- logical examinations. Choice of treatment was based on nificance of changes in ESRS scores. Age, gender, duration patient's preference. Patients in the aripiprazole group of illness, and baseline scores of each outcome were started at a dose of 5.0 mg/d, which was increased in covariates for each analysis. Fisher's exact test and the Eur Child Adolesc Psychiatry (2011) 20:127–135 Mann–Whitney U test were used as appropriate for reducing tic symptoms (Table After 8 weeks of between-group comparisons. All analyses were two-sided, treatment, 54.3% of the aripiprazole and 63.4% of the with statistical significance defined at an a level of 0.05.
haloperidol group showed reductions in total tic scores.
Total tic score decreased over time in both groups (Z =-9.60, p 0.001) (Table ). This reduction was particu- larly marked at the first follow-up visit (week 2) in bothgroups (p 0.001) and was sustained throughout the study period (Fig. There were no significant between-groupeffects or interactions.
Of the 48 children and adolescents with tic disorders, 31 At baseline, the mean motor tic score was higher in the were prescribed aripiprazole and 17 were prescribed halo- haloperidol than in the aripiprazole group (20.5 ± 3.1 vs.
peridol. Twenty-six patients (54.1%) had Tourette's disorder 17.5 ± 5.3; Z = -1.87, p = 0.06), but the difference did and 11 (21.9%) had chronic motor and vocal tic disorders.
not reach statistical significance. Aripiprazole reduced Eighteen participants (37.5%) had other comorbid psychi- motor tic scores 54.3% and phonic tic scores 50.0%, atric disorders, the most common being attention-deficit whereas haloperidol reduced these scores by 58.5 and hyperactivity disorder (31.3%). The mean duration of illness 66.2%, respectively. Motor (Z = -8.29, p 0.001) and was 3.0 ± 2.7 years and 18 subjects (37.5%) had a history of phonic (Z = -5.59, p 0.001) tic scores decreased over previous medication to control tic symptoms.
time in both groups (Table Fig. c), but there were no Although gender ratio, total IQ, type of tic disorders, significant between-group effects or interaction terms.
comorbid conditions, duration of illness, and study medi-cations did not differ between the two groups, the mean age Efficacy of aripiprazole and haloperidol: clinical global was significantly higher in the aripiprazole than in the haloperidol group (11.2 ± 3.5 years vs. 8.6 ± 2.9 years;Z = 2.68, p 0.01). The mean dose and duration of ari- The CGI-S scores of both groups decreased over time piprazole were 10.6 ± 5.2 mg/d and 51.7 ± 12.6 d, (Z = -8.83, p 0.001) without group or interaction respectively, whereas the mean dose and duration of hal- effects. Twenty-two children and adolescents (71.0%) in operidol were 1.9 ± 1.1 mg/d and 46.3 ± 15.8 d, respec- the aripiprazole group and ten (58.8%) in the haloperidol group were ‘‘much improved'' or ‘‘very much improved''on the CGI-I measurement after 8 weeks of medication.
Efficacy of aripiprazole and haloperidol: yale global ticseverity scale At baseline and at each follow-up visit, there were no Although 25 children and adolescents in the aripiprazole significant between-group differences in tic scores, indi- group (80.6%) experienced one or more unwanted side cating that these two drugs were similarly efficacious in effects, only five (16.1%) patients in this group discontinued Table 1 Demographic and Aripiprazole group Haloperidol group clinical characteristics of the 48 children and adolescents withtic disorders Age meana (SD), years 11.2 (3.5) (range: 6–18) 8.6 (2.9) (range: 6–16) Type of tic disorders Tourette's disorder, n (%) Chronic motor and vocal tic disorder, n (%) Transient tic disorder, n (%) Attention deficit hyperactivity disorder, n (%) 9 (29.0) Oppositional defiant disorder, n (%) Obsessive compulsive disorder, n (%) Duration of tic disorders mean (SD), years a p 0.01 by the Mann– Dose/day mean (SD), mg 10.6 (5.2) (range: 2.5–20.0) 1.9 (1.1) (range: 0.75–4.5) Duration of study medication mean (SD), days 51.7 (12.6) (range: 14–60) 46.3 (15.8) (range: 15–61) IQ intelligence quotient Eur Child Adolesc Psychiatry (2011) 20:127–135 Table 2 Efficacy of aripiprazole and haloperidol in the treatment of tic disorders Aripiprazole group Haloperidol group Statistical valuea Group 9 timeInteraction effect Phonic tic scores Very much improved Minimally improved Minimally aggravated Extremely severely ill a To examine the group and time effects for each outcome variable, generalized estimation equation (GEE) modeling was adopted, with age,gender, duration of illness, and baseline scores for each outcome variable included as covariatesb Calculating patients who dropped-out YGTSS yale global tic severity scale, CGI-I clinical global impression-improvement, CGI-S clinical global impression-severity of illness medication prematurely owing to intolerability. In contrast, respectively), but increased significantly in the haloperidol all 17 subjects in the haloperidol group experienced unex- group between 2 and 4 weeks (1.4 ± 2.1 and 2.8 ± 2.6, pected side effects and 6 (35.3%) were not able to continue respectively); these interaction effects were statistically medication owing to unbearable adverse events. Although significant (Z = -2.083, p = 0.037) (Fig. ). In addition, frequencies of side effects between two groups during study the subscale scores for Parkinsonism, akathisia and, dys- period were not different (v2 = 2.08, p = 0.15), rates of tonia were higher in the haloperidol group at 8 weeks. The drug discontinuation were lower in the aripiprazole group Parkinsonism subscale of the ESRS showed an interaction relative to the haloperidol group (v2 = 7.17, p = 0.007).
effect between group and time Z = -2.06, p = 0.04). No The major intolerable side effects included nausea (2 subjects experienced dyskinesia in this study (Table patients), headache (2 patients) and sedation (1 patient) inthe aripiprazole group, and sedation (4 patients) and head- General adverse events ache (2 patients) in the haloperidol group.
The most common side effects of aripiprazole were hyper- Extrapyramidal symptom rating scale somnia (58.1%), nausea/vomiting (29.0%), EPS (19.4%),and headache (16.1%), whereas the most common side The total ESRS score at study endpoint was higher in the effects of haloperidol included hypersomnia (82.4%), haloperidol than in the aripiprazole group. There were headache (58.8%), EPS (41.2%), nausea/vomiting (23.5%), interaction effects between groups and a time effect of the gastrointestinal disturbances (11.8%), emotional hypersen- total ESRS score (Z = -2.17, p = 0.03). Total ESRS sitivity (11.8%), dizziness (11.8%), and chest discomfort scores did not change significantly in the aripiprazole (11.8%) (Table Hypersomnia (v2 = 4.17, p = 0.04), group between 2 and 4 weeks (1.1 ± 1.7 and 1.1 ± 1.8, EPS (v2 = 7.84, p = 0.005), and headache (v2 = 24.34, Eur Child Adolesc Psychiatry (2011) 20:127–135 Fig. 2 Changes in ESRS scores over time in the aripiprazole andhaloperidol treatment groups. Abbreviations ESRS extrapyramidalsymptom rating scale. The error bars refer to standard deviation results of the ECGs including QTc changes were observedbefore and after treatment. Between baseline and 8 weeks,the mean body weight of the subjects in the aripiprazoleand haloperidol groups increased 0.16 kg/week and0.21 kg/week, respectively, but these increases did not differbetween the two groups (Mann–Whitney U test, Z = 0.291,p = 0.771).
To our knowledge, this study is the first to directlycompare the efficacy and tolerability of aripiprazole andhaloperidol in the treatment of children and adolescentswith tic disorders. We found that aripiprazole was aseffective as haloperidol in reducing tic symptoms, as wellas being better tolerated. The mean dose of aripiprazoleused in this study, 10.6 mg/d, was similar to that used inour previous studies in which children and adolescentswith tic disorders were treated with aripiprazole [], and to doses used in previous studies of youths withdevelopmental disabilities [], delusional disorder], and bipolar disorders [In contrast, higher dosesof aripiprazole have been used to treat children and ado-lescents with bipolar disorders , catatonia [ Fig. 1 a Percentage changes in total tic scores over time in the and generalized anxiety disorder ], as well as in psy- aripiprazole and haloperidol treatment groups. b Percentage changes chiatric inpatients ]. The aripiprazole dose used in this in motor tic scores over time in the aripiprazole and haloperidol study was lower than that used in adults with Tourette treatment groups. c Percentage changes in phonic tic scores over time in the aripiprazole and haloperidol treatment groups The error barsrefer to standard deviation Although various atypical antipsychotics are widely used to treat tic disorders, they had weaker efficacy than typical p 0.001) were observed less frequently in the aripiprazole neuroleptics such as haloperidol and pimozide, which can group. All laboratory results before, during and after treat- decrease tic symptoms by more than 60% [Even the first ment were within normal limits. Any abnormalities in the atypical antipsychotic, clozapine, was not able to sufficiently Eur Child Adolesc Psychiatry (2011) 20:127–135 Table 3 Extrapyramidal symptom rating scale scores at study endpoint in the aripiprazole and haloperidol groups Extrapyramidal symptom rating Statistical valuea scale scores mean (SD) Group 9 time interaction effect a Group and time effects on the adverse effect outcome variables were evaluated using generalized estimation equation (GEE) modeling, withage, gender, duration of illness, and baseline scores for each outcome variable included as covariates 36% –, A double-blind, randomized trial on the Table 4 Adverse effects of aripiprazole and haloperidol in the cur-rent study efficacy of ziprasidone in reducing tic symptoms showedthat it reduced tic symptoms by 35%, although side effects, most of which were tolerable, developed in more than 80% of patients ].
Aripiprazole may be more potent than other atypical antipsychotics, reducing tic symptoms by 40–53% , Aripiprazole was also found to be effective in treating Extrapyramidal symptoms antipsychotic-resistant patients with Tourette disorder [ ]. In the current study, 15 subjects (48.4%) in the ari-piprazole group and 3 (17.6%) in the haloperidol group had histories of previous ineffective treatment with antipsy- chotic medication; nevertheless, the efficacy of aripipraz- ole 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 Increased appetite Total Tic Score attained within 2 weeks after the start of treatment ]. 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 abate tic symptoms Although olanzapine showed con- tic symptoms who need prompt symptom improvement.
siderable efficacy, its adverse effects, such as weight gain More than 80% of youths taking aripiprazole experi- and sedation, limits its use for tic control [, ]. Uses of enced one or more unwanted side effects. This high inci- quetiapine have been reported in several case reports dence may have been due to the starting dose of 5 mg, [–and open-label trials [] to decrease tic which may be too high in children and adolescents with tic symptoms. However, in two open-label trials testing que- disorders. Nineteen subjects (61.3%) in the aripiprazole tiapine as an anti-tic drug in children and adolescents with group experienced side effects after their first dose, with Tourette disorder, its efficacy and tolerability were ques- the side effects experienced by four patients (21.1%) dis- tionable. Risperidone is one of the most widely used and appearing spontaneously without any management or dose best-studied atypical antipsychotics in the treatment of tic reduction at the next visit. Further clinical studies using symptoms. Although relatively safe and effective in tic lower initial doses of aripiprazole are required to confirm reduction, risperidone diminishes tic symptoms by less than this possibility.
Eur Child Adolesc Psychiatry (2011) 20:127–135 In addition to the higher dropout rate seen in the halo- randomized trials should be performed to overcome these peridol group, the rate of EPS during the 4 weeks after limitations and determine whether aripiprazole improves tic starting treatment was higher in the haloperidol than in the symptoms or if our findings reflect the natural progression of aripiprazole group. This may be associated with differences tic disorders.
in receptor profiles of the two drugs. Haloperidol has a strongantagonistic affinity to dopamine 2 receptors in the nigro-striatal dopamine pathway, causing EPS [whereas ari- piprazole has partial agonistic activity at the postsynapticdopamine 2 receptors, reducing EPS development ].
Our findings indicate that aripiprazole may be effective and Aripiprazole may be a more ideal anti-tic drug owing to tolerable in the treatment of children and adolescents with its unique pharmacodynamic profile, including both tic disorders. Additional controlled studies are needed to antagonistic and agonistic dopamine activities, depending determine the efficacy and tolerability of aripiprazole in on the environment of the local dopamine system [ patients with tic disorders.
This activity is strongly associated with the pathologicalmechanism of tic disorders. Dopamine receptor hypersen- Conflict of interest We have no disclosures. We report no financial affiliation or other relationship relevant to the subject of this article.
sitivity may be an underlying pathology of tic disorders[Although several studies have confirmed the super- This article is distributed under the terms of the sensitivity of the dopamine system in tic disorders, these Creative Commons Attribution Noncommercial License which per- studies did not consider the anti-dopaminergic drug effects mits any noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source are credited.
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