Young Mania Rating Scale Line Item Analysis in Pediatric Subjects with Bipolar I Disorder Treated with Aripiprazole in a Short-Term,Double-Blind,Randomized Study

Introduction

I ndividuals with early-onset bipolar disorder (defined as onset of symptoms before 18 years of age) seem to have worse psychosocial outcomes than those who have later-onset bipolar disorder, with increased substance abuse, suicide attempts, and rapid cycling (Carter et al. 2003; Lin et al. 2006; Leverich et al. 2007). The long-term consequences of this illness greatly impact the ability of these youths to carry out normal daily functions, with devastating effects on social interactions, school performance, and family relationships and dynamics (Post and Kowatch 2006). These pediatric patients therefore require careful treatment to prevent further mood episodes and relapse (Chang 2008).

The need for safe and effective therapies for bipolar I disorder has been well recognized. Psychotherapeutic, psychosocial, educational, and pharmacotherapeutic interventions are currently available for the treatment of bipolar I disorder in pediatric patients (Chang 2008). Indeed, with the rise in recognition of pediatric bipolar disorder, there is an increase in the need for validated treatment approaches. Among pharmacotherapeutic options, atypical antipsychotics have been recognized as having a role in treatment, and there are currently four FDA-approved medications for this population: aripiprazole, olanzapine, quetiapine, and risperidone (Abilify 2009; Seroquel 2009; Risperdal 2010; Zyprexa 2010).

Aripiprazole is an atypical antipsychotic with a novel mechanism of action, exerting partial agonist activity at dopamine D₂ and D₃ and serotonin 5-HT_1A receptors and antagonist activity at 5-HT_2A receptors (Burris et al. 2002; Jordan et al. 2002; Shapiro et al. 2003; Jordan et al. 2004; Tadori et al. 2008). Aripiprazole has shown efficacy in reducing Young Mania Rating Scale (YMRS) total scores in pediatric subjects in multiple studies (Biederman et al. 2007; Findling et al. 2009; Tramontina et al. 2009).

This report describes a post hoc analysis of results from a pivotal trial (Findling et al. 2009) evaluating aripiprazole for the treatment of an acute manic or mixed episode associated with bipolar I disorder in pediatric patients aged 10–17 years. The primary efficacy outcome measure in that trial was the total score of the 11-item YMRS, a validated measure recommended for the evaluation of treatment effects on mania symptom severity (Tohen et al. 2009). Because the YMRS total score represents a collection of several different discrete symptoms, which may themselves have a varying response to treatment, we conducted a post hoc analysis of the individual YMRS line items to better understand which particular symptoms of mania are affected (or not) by aripiprazole treatment.

Methods

This is a post hoc analysis of the YMRS line item data from a multicenter, randomized, double-blind, placebo-controlled, 4-week study. The study compared aripiprazole (10 or 30 mg/day) versus placebo for the treatment of outpatient and hospitalized, or partially hospitalized, pediatric subjects (10–17 years) with bipolar I disorder experiencing a manic or mixed episode. Full methodology has been previously described (Findling et al. 2009).

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of bipolar disorder, manic or mixed episode, with or without psychotic features for each subject was made by a board-certified or eligible child and adolescent psychiatrist. The diagnosis was then confirmed using the Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version at the time of screening. A five-member, independent Data Safety Monitoring Board provided frequent assessment of subject safety.

After screening and medication washout, subjects were randomly assigned to target doses of aripiprazole (10 or 30 mg/day) or matching placebo once daily for 4 weeks. Study medication could be administered at any time of day without regard to meals. Aripiprazole dosing started at 2 mg/day (days 1 and 2), 5 mg/day (days 3 and 4), and 10 mg/day (day 5). Subjects in the 10 mg/day group remained at that target dose, and titration continued for the 30 mg/day group with 10 mg/day (days 5 and 6), 15 mg/day (days 7 and 8), 20 mg/day (days 9 and 10), and 25 mg/day (days 11 and 12) and concluded with the target dose of 30 mg/day on day 13. Matching placebo was administered according to the same titration schedule. Study medication was dispensed at weekly visits in child-resistant blister cards containing a 1-week supply.

The primary endpoint was the mean change in YMRS total scores to week 4. Mean changes from baseline to endpoint in the YMRS total score and individual items, in both aripiprazole treatment arms combined and each treatment arm versus placebo, were compared using analysis of covariance (ANOVA) using the last observation carried forward for dataset, with baseline measurements as a covariate and treatment arms as main effects. Treatment effect was calculated as the difference between the aripiprazole (10 or 30 mg/day) arms and placebo arm on those measures. Cohen's d effect sizes at week 4 were calculated using the following formula: 2*t/(d.f.), where t is the t statistic derived from an ANOVA model with treatment as a factor and d.f. is the degrees of freedom. Safety assessments included the frequency and severity of treatment-emergent adverse events (TEAEs) and discontinuation due to TEAEs, among others.

Results

Line item analyses

Mean change from baseline to week 4 by treatment group (10 or 30 mg/day) versus placebo for individual YMRS line items are shown in Figure 1A. Seven of the 11 line items showed a statistically significant improvement in both the aripiprazole treatment groups (10 and 30 mg/day) compared with placebo. The seven items showing improvement were elevated mood, increased motor activity/energy, sleep, irritability, speech, language/thought disorder, and aggressive behavior. The YMRS line item abnormal thought content also showed statistically significant improvement with aripiprazole 30 mg/day compared with placebo. Effect sizes by treatment group (10 or 30 mg/day) compared with placebo are shown in Figure 1B.

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FIG. 1.

Young Mania Rating Scale line item analysis of (A) least square mean change from baseline to week 4; (B) effect size. Mean (SD) baseline values for individual Young Mania Rating Scale line items for 10 mg/day, 30 mg/day, and placebo, respectively: elevated mood: 2.8 (1.0), 2.7 (1.1), 2.8 (0.9); increased motor activity: 2.8 (1.1), 3.0 (0.9), 2.9 (0.9); sexual interest: 1.0 (1.2), 0.9 (1.2), 1.0 (1.2); sleep: 1.9 (1.1), 1.7 (1.2), 1.9 (1.1); irritability: 5.1 (1.5), 4.9 (1.7), 5.2 (1.5); speech: 4.0 (1.9), 4.5 (1.8), 4.7 (1.7); language/thought disorder: 2.2 (0.7), 2.2 (0.7), 2.2 (0.9); abnormal thought content: 3.2 (2.2), 3.2 (2.2), 2.9 (2.1); disruptive/aggressive behavior: 4.5 (1.9), 4.4 (1.6), 4.8 (1.8); appearance: 0.9 (0.9), 0.9 (0.9), 1.1 (1.0); insight: 1.4 (1.4), 1.2 (1.3), 1.5 (1.4). *p < 0.05 vs. placebo; **p < 0.01 vs. placebo; ***p < 0.001 vs. placebo.

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With the pooled aripiprazole dataset, significant improvements versus placebo were seen on the following individual YMRS line items at week 4: elevated mood (−1.5 vs. −0.9, p < 0.001), increased motor activity/energy (−1.6 vs. −0.7, p < 0.001), sleep (−1.2 vs. −0.7, p < 0.001), irritability (−2.4 vs. −0.9, p < 0.001), speech (−2.4 vs. −1.3, p < 0.001), language/thought disorder (−1.0 vs. −0.6, p < 0.001), content (−1.6 vs. −1.2, p < 0.05), and aggressive behavior (−2.3 vs. −0.9, p < 0.001). The three YMRS line items with the greatest effect size with the pooled aripiprazole group at week 4 were irritability (effect size = 0.7), aggressive behavior (effect size = 0.7), and increased motor activity/energy (effect size = 0.6). Nonsignificant improvements with the pooled aripiprazole group versus placebo on individual YMRS line items at week 4 were seen on sexual interest (−0.4 vs. −0.3, p = 0.105), appearance (−0.4 vs. −0.3, p = 0.182), and insight (−0.5 vs. −0.3, p = 0.067).

Discussion

The purpose of this post hoc analysis was to evaluate systematically the effects of aripiprazole on individual YMRS line items in pediatric subjects with a manic or mixed episode associated with bipolar I disorder. Aripiprazole treatment resulted in statistically significant improvements in the majority of YMRS line items at week 4 and often sooner episodes. Symptoms of irritability, aggressive behavior, and increased motor activity/energy appeared to be the most responsive to treatment. Thus, aripiprazole may confer favorable outcomes for patients in whom these symptoms predominate. It has been proposed that severe irritability constitutes one of the cardinal symptoms of mania in children and adolescents, and irritability and aggressive behavior can be among the most worrisome and disruptive of symptoms for patients and caregivers. Improvements in other line items were of variable magnitude, and although there was only a trend toward improvement in insight, it is interesting to speculate whether this could be improved further with longer-term treatment, which would also include psychosocial therapies. Sustained improvements in insight are particularly important as these may be directly affecting adherence to therapy.

The findings in this pediatric cohort are consistent with those observed by Frye at al. in an adult population (Frye et al. 2008). Irritability and disruptive aggressiveness were most improved in terms of effect sizes in adults; this was seen across all subgroups: manic, mixed, those with psychosis, and those with rapid cycling (Frye et al. 2008). It is important to note, however, that psychiatric disorders in pediatric subjects may present with variable symptom profiles that are not always congruent with typical adult presentations.

Although other atypical antipsychotics have been previously shown to be effective in the treatment of pediatric subjects with bipolar I disorder, this analysis is of clinical interest because it specifically addresses the effects of specific individual mania symptoms as assessed by YMRS. It is also important, from a clinical standpoint, to understand the tolerability profile that may be expected with this treatment option; the safety and tolerability of aripiprazole in this patient population has been previously described (Findling et al. 2009). Briefly, it is worth noting that the most common TEAEs reported were somnolence, extrapyramidal disorder, and fatigue.

Limitations of this study include the fact that it was a post hoc analysis; because of the exploratory nature of the analysis, adjustments were not made for multiple comparisons. Further, the study duration was 4 weeks; more information from long-term data on specific symptom improvements is warranted.

In conclusion, pediatric subjects experiencing an acute manic or mixed episode associated with bipolar I disorder demonstrated an early, sustained, statistically significant improvement with aripiprazole compared with placebo. Aripiprazole improved a broad spectrum of symptoms across the YMRS scale, most notably irritability, aggressive behavior, and increased motor activity/energy.