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 RESEARCH ARTICLE

An open-label trial of aripiprazole in the treatment of aggression in male adolescents diagnosed with conduct disorder

Samuel Kuperman, MD

Professor of Psychiatry and Head, Division of Child Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA USA

Chadi Calarge, MD

Assistant Professor of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA USA

Anne Kolar, MD

Clinical Assistant Professor of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA USA

Timothy Holman, MA

Clinical Trial Coordinator, Touro University-California, Vallejo, CA, USA

Mitchell Barnett, PharmD, MS

Associate Professor, College of Pharmacy, Touro University-California, Vallejo, CA, USA

Paul Perry, PhD

Professor, College of Pharmacy, Touro University-California, Vallejo, CA, USA, Emeritus Professor, Colleges of Medicine and Pharmacy, University of Iowa, Iowa City, IA, USA

BACKGROUND: The adverse effect profiles of typical and atypical antipsychotics are problematic because of their extrapyramidal and endocrine adverse effects, respectively.

METHODS: Ten adolescent male patients diagnosed with conduct disorder received aripiprazole in doses of ≤20 mg/d in an open-label, intent-to-treat design to establish and characterize the efficacy of the drug in reducing aggressive behavior.

RESULTS: Based on clinician and parent observations, aripiprazole was effective in reducing aggressive behavior in adolescent boys. The change in clinician-observed aggression ratings appears to have been driven by a decrease in physical aggression, whereas the change in parent-observed aggression ratings appears to have been driven by a decrease in verbal aggression and aggression against objects and animals.

CONCLUSIONS: Aripiprazole was an effective and relatively well-tolerated treatment for overall aggression in adolescent males with conduct disorder, in the view of both clinicians and parents. Depending on the observer, aripiprazole improved aggression categorized as physical aggression, verbal aggression, and aggression against objects and animals.

KEYWORDS: aggression, aripiprazole, conduct disorder

ANNALS OF CLINICAL PSYCHIATRY 2011;23(4):270-276

  INTRODUCTION

The use of atypical antipsychotics in children began with clozapine in 1992.1,2 Since then, 5 other atypical agents (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) have been introduced into the US market. These newer agents have a lower risk of agranulocytosis, which has limited the usefulness of clozapine. Among the atypical antipsychotics, risperidone is the most extensively studied in children and adolescents for a range of indications, including schizophrenia,3 bipolar disorder,4 irritability in autistic disorder,5 Tourette syndrome,6 and conduct problems.7 However, weight gain, hyperprolactinemia, and extrapyramidal symptoms are troublesome adverse drug reactions (ADRs) commonly associated with risperidone.8 Aripiprazole, however, is not limited by these ADRs to the same degree.8 Only one other study has described the effectiveness and safety of aripiprazole in younger patients diagnosed with conduct disorder.9 In that study, adverse events were similar to the known profile for aripiprazole in adults.

This study proposes to replicate the finding that aripiprazole is effective in the treatment of aggression associated with adolescent males diagnosed with conduct disorder. However, by using contrasting clinician and parental rating scales that quantify aggression, the study may shed light on the specific types of aggression that might be most amenable to treatment with aripiprazole.

  METHODS

The study was designed as a 6-week, open-label, intent-to-treat (ITT) trial. A priori inclusion criteria were male sex, age 13 to 17, Tanner stage 4 or 5, and diagnosis of conduct disorder based on a clinical interview10 by a board-certified child psychiatrist in an outpatient clinic setting. Exclusion criteria were history of exposure to aripiprazole, elevated prolactin level, abnormal ECG, mental retardation, active drug abuse, suicidal ideation, and preexisting Axis III health condition. The initial aripiprazole dose depended on the weight of the patient: <25 kg = 1 mg/d; 25 to 50 kg = 2 mg/d; 51 to 70 kg = 5 mg/d; >70 kg = 10 mg/d.11 Thereafter the dose was individualized based on the response to and tolerability of the drug, with a maximum aripiprazole dose of 20 mg/d. After the baseline evaluation, enrolled study patients were assessed weekly for the first 2 weeks and then every other week until week 6. Current psychotropic medications, except for other antipsychotics, were allowed due to the exploratory nature of this study. All antipsychotic medications were tapered at least 1 week before enrollment.

The primary outcome efficacy measures were the Overt Aggression Scale–Modified (OAS-M)12 and the Children’s Aggression Scale–Parent Version (CAS-P).13 Using 2 different primary outcome measures of aggression afforded an opportunity to compare changes in study participant behavior from 2 distinct vantage points—clinician and parent. These scales provide ratings of various types of aggressive behavior that range from overall scores of aggressive behavior to subscale scores for specific types of aggression, such as verbal aggression, aggression toward objects, aggression toward property, use of weapons, etc. The secondary outcome measures were the Clinical Global Impression–Severity of Illness (CGI-S) and Clinical Global Impression–Improvement (CGI-I) scales.14 Safety measures for extrapyramidal ADRs included the Abnormal Involuntary Movement Scale (AIMS),15 the Simpson-Angus Scale (SAS),16 and the Barnes Akathisia Scale (BAS).17 The Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale also was used to monitor ADRs.18 This questionnaire divides ADRs into 4 general categories of symptoms: psychic, neurologic, autonomic, and miscellaneous. Height, weight, and body mass index (BMI) measurements, as well as initial and endpoint fasting blood glucose and lipid levels, were used to assess the metabolic effects of the drug. Serum prolactin concentrations, along with galactorrhea, gynecomastia, and changes in libido, were monitored to assess sexual ADRs. Initial and endpoint ECGs were obtained to monitor patients for any changes in the QT-corrected interval. A gamma–glutamyl transpeptidase (gamma-GT) level was collected to monitor liver function.

At screening, a history and physical examination were performed. The physical examination was repeated when the patient exited the study. Additional data collected at the screening and last visit included a urine analysis, screen for drugs of abuse, and a complete blood count. Vital signs and anthropometric measurements were obtained at every visit. The psychometric rating scales (OAS-M, CAS-P, CGI-S, and CGI-I) and the ADR rating scales (AIMS, SAS, BAS, and UKU) were administered at the baseline visit (week –1), at actual enrollment (week 1) and at all subsequent visits (weeks 2, 4, and 6).

An ITT design was used to eliminate the false-positive bias created by nonresponding patients who dropped out of the study because of more serious or refractory illness. In cases where a patient did not complete the entire 6-week trial, the last available observation was carried forward and used for purposes of comparison. For each outcome variable, the ITT population included all patients with at least 1 postenrollment psychometric measurement (ie, patients received at least 1 week of aripiprazole). A within-patient repeated-measures analysis of variance (ANOVA) based on a general linear model (GLM) was used to assess the changes in patient psychometric test scores across the 5 time intervals. The P value associated with Wilks’ lambda was used to determine statistical significance in all repeated-measures tests, a relatively conservative approach not susceptible to violations of the assumption of sphericity. Bivariate comparisons for patient screening and exit variables (ie, vital signs, clinical chemistry values, and extrapyramidal symptoms) were made using paired sample Student t tests. An α value of 0.05 was used to determine statistical significance. All analyses were conducted using SAS version 9.1 (SAS Institute Inc., Cary, NC).

The study received institutional review board (IRB) committee approval from the University of Iowa College of Medicine (IRB Application No. 200306035). All study participants and their adult caregiver(s) reviewed separate information summaries and gave written informed consent or assent.

  RESULTS

Study eligibility was initially assessed in 106 patients (FIGURE). From this screen, a cohort of 12 adolescent males between age 13 and 17 (14.6 ± 1.1 years) were recruited and enrolled for aripiprazole treatment. Two patients dropped out of the study during the first week of treatment and refused to return to the clinic for an exit examination; they were therefore excluded from the analyses. The remaining 10 patients had analyzable data in that they completed at least a week or more on aripiprazole and had at least 1 subsequent follow-up appointment. Eight patients completed the 6-week trial, and 1 each dropped out after 1 week and 5 weeks, respectively. Of the 10 evaluated patients, 6 were taking no other medications at the start of the study. The 4 patients receiving other medications before study entry continued to receive those medications, which were citalopram, 40 mg/d, along with amphetamine mixture 40 mg/d; methylphenidate, 90 mg/d; guanfacine, 2.5 mg/d; or methylphenidate, 60 mg/d. Because these patients were being treated for attention-deficit/hyperactivity disorder (ADHD) in addition to conduct disorder, it was clinically unrealistic to discontinue ADHD medications in the opinion of the investigators and the human subjects committee. Only 2 of the 10 patients had been treated in the past with an antipsychotic (risperidone in both cases).

FIGURE : Patient screening history

All patients initially received either 5 or 10 mg/d (7.0 ± 2.6 mg/d) of aripiprazole. The final dose (9.8 ± 6.1 mg/d) did not differ significantly from the initial dose. Adjusted for weight, the initial aripiprazole dose was 0.10 ± 0.05 mg/kg/d, which was similar to the final dose of 0.13 ± 0.06 mg/kg/d.

TABLE 1 presents the changes in score for the primary outcome measures. Significant improvement was seen in the OAS-M total score. It declined from 11.5 ± 6.5 at baseline to 3.8 ± 8.3 at week 6 (P = .02). The CAS-P total score decreased from 20.8 ± 6.1 to 4.6 ± 5.7 (P < .01). The primary measures OAS-M and the CAS-P further subdivide aggression into specific categories. Specifically, the OAS-M subdivides aggression into 1) verbal aggression, 2) aggression against property, 3) physical aggression against self (autoaggression), and 4) physical aggression. Among the 4 OAS-M subscales (TABLE 1), only OAS-M physical aggression showed a statistically significant improvement (P = .04). The CAS-P, which assesses severity, frequency, pervasiveness, and diversity of aggressive disruptive behaviors, is further subdivided into 5 domains: 1) verbal aggression, 2) aggression against objects and animals, 3) provoked physical aggression, 4) unprovoked physical aggression, and 5) use of weapons. Among the CAS-P subscales, both verbal aggression and aggression against objects and animals showed a significant improvement over the study period (P = .015 and P = .04, respectively).


TABLE 1

Changes in psychometric scale scores assessing aggressive behavior in adolescent patients diagnosed with conduct disorder (N = 10)

Scale Baseline Week 1 Week 2 Week 4 Week 6 P valuea
OAS-M, total 11.5 ± 6.5 4.3 ± 5.4 1.7 ± 2.9 4.3 ± 6.3 3.8 ± 8.3 .023
OAS-M, verbal aggression 2.2 ± 1.2 1.2 ± 0.9 0.7 ± 1.3 1.0 ± 0.9 1.0 ± 1.2 .166
OAS-M, aggression against property 4.2 ± 3.0 0.5 ± 1.3 0.6 ± 1.4 0.6 ± 1.4 0.6 ± 1.9 .157
OAS-M, autoaggression 0.6 ± 1.9 0.6 ± 1.9 0.0 ± 0.0 1.5 ± 3.2 0.6 ± 1.9 .475
OAS-M, physical aggression 4.5 ± 3.9 2.0 ± 4.3 0.4 ± 1.3 1.2 ± 3.8 1.6 ± 3.9 .036
CAS-P, total 20.8 ± 6.1 10.6 ± 9.6 3.3 ± 3.9 4.8 ± 5.3 4.6 ± 5.7 .002
CAS-P, verbal aggression 12.9 ± 4.3 6.2 ± 5.0 2.0 ± 2.0 2.3 ± 2.8 2.7 ± 2.8 .015
CAS-P, aggression against objects and animals 3.8 ± 2.2 1.1 ± 1.1 0.4 ± 0.7 0.5 ± 0.7 0.4 ± 0.8 .038
CAS-P, provoked physical aggression 2.1 ± 2.2 2.2 ± 3.2 0.5 ± 1.1 1.1 ± 1.4 0.8 ± 1.6 .288
CAS-P, unprovoked physical aggression 1.6 ± 2.0 1.0 ± 1.7 0.4 ± 0.9 0.7 ± 1.1 0.6 ± 1.2 .383
CAS-P, use of weapons 0.4 ± 1.0 0.1 ± 0.3 0.0 ± 0.0 0.2 ± 0.4 0.1 ± 0.3 .410
CGI-I 0.0 (baseline) 2.9 ± 0.8 2.1 ± 1.0 3.0 ± 1.7 2.1 ± 1.4 .005
CGI-S 4.5 ± 0.7 3.5 ± 0.7 3.0 ± 0.5 3.1 ± 1.1 3.0 ± 1.5 .029
aWithin-patient repeated-measures ANOVA was used to determine the overall treatment effect.
ANOVA: analysis of variance; CAS-P: Children’s Aggression Scale–Parent Version; CGI-I: Clinical Global Impression–Improvement; CGI-S: Clinical Global Impression–Severity of Illness; OAS-M: Overt Aggression Scale–Modified.

The secondary outcome measures suggest that the severity of the patients’ symptoms decreased from a global rating of moderately to markedly ill to a rating of mildly ill by the end of the study. In fact, the CGI-S score decreased from 4.5 ± 0.7 to 3.0 ± 1.5 (P = .03). Of the 8 patients who completed the entire 6 weeks of treatment, 5 were rated as very much improved on the CGI-I, with the other 3 having minimal improvement.

As presented in TABLE 2, there were no significant changes in the patients’ systolic or diastolic blood pressure, respiratory rate, pulse, weight, and BMI. Because 1 patient dropped out and declined to return to clinic for the final examination, clinical chemistry values were available for only 9 patients. There were no significant changes from study entry to study termination for serum glucose, gamma-GT, cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein concentrations. Prolactin concentrations decreased significantly from 12.8 ± 6.1 mg/dL to 3.7 ± 2.6 mg/dL (P = .02). The ECG parameters of the PR, QT, and QTc intervals were unchanged.


TABLE 2

Changes in scores for vital signs, prolactin concentrations, and extrapyramidal symptoms from baseline to LOCF (N = 10)

  Baseline Study exit P valuea
Systolic blood pressure (mm Hg) 122 ± 11 120 ± 10 .241
Diastolic blood pressure (mm Hg) 68 ± 11 68 ± 6 .369
Respiratory rate (rpm) 17 ± 6 18 ± 6 .329
Heart rate (bpm) 72 ± 12 72 ± 12 .93
Weight (kg) 71.0 ± 22.5 72.6 ± 23.4 .172
Body mass index (kg/m2) 24.3 ± 6.4 24.6 ± 6.6 .347
Prolactin (mg/dL) 12.8 ± 6.1 3.7 ± 2.6 .016
AIMS 0.1 ± 0.3 0.2 ± 0.6 .685
SAS 1.5 ± 2.0 2.1 ± 2.3 .086
BAS 1.2 ± 2.0 0.3 ± 0.9 .363
aPaired-sample t test.
AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale;
LOCF: last observation carried forward; SAS: Simpson-Angus Scale.

The AIMS (dyskinesia), SAS (Parkinsonian movements), and BAS (akathisia) scores did not change significantly after treatment with aripiprazole (TABLE 2). None of the patients who took aripiprazole for at least 1 week discontinued the drug because of ADRs. Of the 36 visits during which the UKU side effect rating scale was administered to 10 patients, there were 3 (8%) instances during which the dose was reduced because of ADRs. The dose of aripiprazole was decreased both at the end of weeks 1 and 2 because of sedation, fatigue, and tension headaches for 1 participant and at week 5 because of sedation and fatigue for another participant. As can be seen in TABLE 3, the most commonly reported ADRs were sleepiness/sedation (90%) and fatigue (80%). However, despite the high percentage of ADRs reported, most complaints were rated as mild—of the 160 ADR UKU reports, 26 (16%) were rated as moderate and none were reported as severe.


TABLE 3

Adverse effects reported by study participants using the UKU side effect rating scalea

AE No. (%) of AE reports during 1 to 4 clinic visits (N = 36 clinic visits) No. (%) of patients reporting AEs (N = 10)
Psychic
Concentration difficulties 2 (6%) 1 (10%)
Increased fatigability 17 (47%) 8 (80%)
Sleepiness/sedation 20 (56%) 9 (90%)
Depression 2 (3%) 2 (20%)
Tension/inner unrest 5 (14%) 2 (20%)
Increased duration of sleep 10 (28%) 3 (30%)
Decreased duration of sleep 6 (17%) 4 (40%)
Increased dream activity 3 (8%) 3 (30%)
Emotional indifference 4 (11%) 2 (20%)
Neurologic
Rigidity 7 (19%) 4 (40%)
Hypokinesia or akinesia 2 (6%) 2 (20%)
Tremor 6 (17%) 4 (40%)
Akathisia 7 (19%) 6 (60%)
Autonomic
Accommodation disturbance 1 (3%) 1 (10%)
Increased salivation 4 (11%) 3 (30%)
Reduced salivation 1 (3%) 1 (10%)
Nausea/vomiting 7 (19%) 5 (50%)
Diarrhea 1 (3%) 1 (10%)
Constipation 1 (3%) 1 (10%)
Polyuria/polydipsia 2 (6%) 2 (20%)
Orthostatic dizziness 3 (8%) 2 (20%)
Palpitations/tachycardia 3 (8%) 2 (20%)
Increased perspiration 10 (28%) 6 (60%)
Miscellaneous
Pruritus 1 (3%) 1 (10%)
Photosensitivity 2 (6%) 2 (20%)
Increased pigmentation 2 (6%) 2 (20%)
Weight gain 11 (31%) 6 (60%)
Weight loss 5 (14%) 2 (20%)
Increased sexual desire 3 (8%) 2 (20%)
Headache
Tension headache 3 (8%) 2 (20%)
Migraine headache 1 (3%) 1 (10%)
Other forms of headache 9 (25%) 5 (50%)
aScale administered at least once for 10 study participants.
AE: adverse effect; UKU: Udvalg for Kliniske Undersøgelser.

  DISCUSSION

In this pilot study, aripiprazole was effective in reducing aggressive behavior in adolescent boys as measured by total score on 2 different primary outcome scales—1 rated by a clinician and 1 rated by a parent. The change in clinician-observed aggression ratings appears to have been driven by a decrease in physical aggression, whereas the change in parent-observed aggression ratings appears to be driven by a decrease in both verbal aggression and aggression against objects and animals. The CAS-P findings are consistent with aripiprazole improving both verbal aggression and aggression against objects and animals during the treatment period.

The CGI ratings also suggest aripiprazole was effective because the severity rating decreased from a global rating of moderately or markedly ill to a rating of mildly ill by the end of the study. Thus, taken in toto, one can conclude aripiprazole appears to reduce total aggression, irrespective of the measure used, although ratings of the specific aggressive behavior attenuated are dependent on the tool used to measure aggressive behavior. Whether longer periods of treatment would result in more significant clinical improvement requires further investigation, because only 5 of the 8 patients who completed all 6 weeks were rated as very much improved, with 3 considered minimally better.

One of the goals of this study was to explore the short-term tolerability of aripiprazole in an adolescent population. Weight gain, hyperprolactinemia, and extrapyramidal ADRs limit the clinical utility of most antipsychotics. Similar to other studies, this study suggests that aripiprazole use has a relative low propensity for weight gain.19 Also consistent with the published literature,9 aripiprazole reduces prolactin, likely because it is a partial dopamine agonist. The effect of low prolactin concentration during development is unknown, but normal concentrations of prolactin may have a positive effect on bone mineral density, particularly during development.20

As summarized in TABLE 3, the use of aripiprazole was associated with a number of ADRs. Although fatigue and sedation were most problematic, nearly all of the participants rated the ADRs as mild, and on only 3 occasions did the ADR lead to a change in clinical management. Specifically, the dose of aripiprazole was reduced to address excessive sedation, fatigue, and, in one case, tension headache. On the other hand, there was no appreciable effect of aripiprazole on vital signs, ECG, and gamma-GT. Interestingly, participants complained of rigidity, tremor, and akathisia on the UKU scale, but these reports did not translate into significant changes in the clinician ratings on the AIMS, SAS, or BAS scales.

Although, the average weight change was a nonsignificant increase of 1.4 kg, the findings of Correll and coworkers21 are worrisome because aripiprazole was associated with a mean increase of 4.4 kg weight change in 41 children and adolescents exposed to an approximate dose of 10 mg/d over 10 weeks. The current study observed a BMI increase of only 0.29 kg/m2, whereas Correll et al21 observed a BMI increase of 1.67 kg/m2. However, 10% of patients in the Correll series were diagnosed with conduct disorder, which begs the question of whether patients with conduct disorder are physiologically predisposed to weight gain.

There were 3 major limitations to the study. First, it was an open-label design and thus at risk for the biases inherent with this type of trial. However, this study was exploratory with regard to establishing the dose response, the frequency of adverse effects, and whether aripiprazole was effective in treating conduct disorder. The second major limitation was the small sample size (10 patients). This is indicative of the multiple challenges the investigators experienced in recruiting and maintaining interest in the study by adolescent males with conduct disorder. A case in point is the patient who terminated participation after being in the study for 5 weeks. Both the patient and his mother independently agreed that aripiprazole was beneficial in decreasing ongoing problems with aggression, but the patient no longer wanted to take the time to return for follow-up visits. Third, because of exploratory nature of this study, patients continued their previous nonantipsychotic medication for the treatment of ADHD, so the results cannot be solely attributed to the use of aripiprazole. Finally, it should be mentioned that the study included only male patients, so generalizability of the findings to female adolescents may be limited.

  Conclusions

This exploratory open-label trial offers preliminary evidence that aripiprazole was an effective and relatively well-tolerated treatment for overall aggression in adolescent males with conduct disorder, in the view of both clinicians and parents. Depending on the observer, the drug improved aggression categorized as physical aggression, verbal aggression, and aggression against animals and objects.

ACKNOWLEDGMENTS: This project, CN138-228, was supported as an independent investigator-initiated trial funded by Bristol-Myers Squibb.

DISCLOSURES: Dr. Calarge receives grant/research support from the National Alliance for Research on Schizophrenia and Depression and the National Institute of Health. Drs. Kolar, Kuperman, Barnett, Perry, and Mr. Holman report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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CORRESPONDENCE: Paul Perry, PhD, Touro University-California, College of Pharmacy, 1310 Club Lane (Mare Island), Vallejo, CA 94592 USA, E-MAIL: paul.perry@tu.edu