A Double-Blind, Randomized, Placebo-Controlled Trial of Oxcarbazepine in the Treatment of Bipolar Disorder in Children and Adolescents

Patients were recruited from 20 centers in the United States. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki (1996). The protocol and statement of informed consent were approved by the institutional review board at each center before the study was initiated. Written informed consent was obtained from each study subject’s parent or legal guardian, as was consent or assent from the study subject prior to participation in the study.

To be eligible for the study, subjects had to be outpatients 7 to 18 years of age and have a diagnosis of bipolar I disorder, manic or mixed episode, as defined in DSM-IV and confirmed by the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL) (19) . A total score of 20 or above on the Young Mania Rating Scale (YMRS) (20) was required at the baseline visit; patients who did not qualify could repeat the measure within 3 days.

Exclusion criteria included a current primary DSM-IV axis I diagnosis of schizophrenia, delirium, anorexia nervosa, autism, bulimia, or substance-induced mood disorder; a need for inpatient or partial psychiatric hospitalization among psychotic patients and patients experiencing an extreme manic episode; a history of seizure disorders; an IQ below 70; or a history of psychogenic polydipsia. Patients whom the investigator judged to be at risk of suicide or homicide and patients who were acutely suicidal or homicidal at the time of screening were excluded. Female patients of childbearing potential who had a positive serum pregnancy test, were not practicing reliable contraception, or were nursing were excluded. Other exclusion criteria included a history of symptomatic hyponatremia or serum sodium levels <135 meq/liter, current treatment with oxcarbazepine, or a previous failure to respond to oxcarbazepine. Patients who were taking or planning to take other investigational drugs during the study period or within 1 month before entering the study, who were receiving antimanic medications that could not be tapered, or who had a known hypersensitivity to oxcarbazepine or carbamazepine were also excluded from the study. Patients were required to be free of psychotropic medications, with the exception of stimulants and diphenhydramine, before entering the study. For patients taking fluoxetine or other medications with a long half-life, a washout period based on the half-life of the medication was required before participation in the study. Patients with comorbid attention deficit hyperactivity disorder (ADHD) were permitted to continue treatment with a stimulant during the course of the trial if they had been on a stable dose of the stimulant for at least 3 months before participating in the trial. Diphenhydramine was permitted for the control of agitation and aggression, starting at 0.5 mg/kg of body weight or 25 mg per dose, to a maximum of 100 mg/day. However, diphenhydramine was to be avoided for at least 8 hours prior to the administration of any efficacy assessments.

This was a prospective, multicenter, double-blind, randomized, placebo-controlled trial of oxcarbazepine as monotherapy in the outpatient treatment of children and adolescents with a diagnosis of bipolar I disorder. The study consisted of a 3- to 14-day baseline phase and a 7-week double-blind phase. The double-blind phase consisted of three periods: a 2-week titration period, a 4-week maintenance period, and a 1-week down-titration period. During the baseline phase, patients underwent the following assessments for eligibility screening: DSM-IV diagnosis of bipolar I disorder, manic or mixed episode, confirmed by K-SADS-PL and clinical history; symptom severity, assessed by the YMRS; physical and neurological examination, including the Mini-Mental State Examination (21) ; laboratory evaluations; and an ECG. Current medications and use of alcohol and/or illicit drugs were also recorded. Patients who met all eligibility criteria were randomly assigned to receive either oxcarbazepine or placebo. During the 2-week titration period, the oxcarbazepine dose was titrated upward by 300 mg every 2 days to a maximum dose level of 900–2400 mg/day based on body weight or to the maximum dose tolerated. At the investigator’s discretion, the dose could be tapered downward by 300 mg/day if the patient experienced intolerable adverse effects. The patient could be maintained at that dose level for the remainder of the titration phase or could have the dose titrated up later in the titration period to reach a maximum tolerated dose. No upward dose adjustments were permitted after the titration period.

A clinician such as a psychiatrist, clinical psychologist, or psychometrician with at least 2 years’ experience in treating pediatric patients conducted all efficacy assessments. For consistency, each patient was assessed by the same clinician throughout the study where possible. A prestudy investigators’ meeting was held to review the study protocol, the case report form, and all aspects of how the study would be conducted. Training in YMRS rating was provided at the prestudy meeting. All raters who conducted interviews using the YMRS were required to pass a certification test. K-SADS-PL training was also provided at the prestudy meeting, although staff at the study sites were familiar with the use of the instrument. Any raters who joined the study after the prestudy meeting received the same rater training individually.

Efficacy assessments were conducted at the end of each of the first 6 weeks or on early discontinuation. The primary efficacy measure was the change from baseline in the YMRS total score at the end of the study, using the last-observation-carried-forward method. Secondary efficacy measures (also based on last observation carried forward) included the percentage of patients who demonstrated a reduction ≥50% in the YMRS score relative to baseline; the mean change from baseline to end of study in the Children’s Depression Rating Scale (22) ; the mean change from baseline to end of study in the Clinical Global Impression scale modified for bipolar disorder (CGI) (23) ; and the mean change from baseline to end of study in quality of life as measured by the Child Health Questionnaire (24) domain scores.

Safety was assessed by monitoring adverse events, vital signs such as pulse and blood pressure, laboratory test results, and findings on ECG and physical and neurological examinations. Assessments were conducted at each study visit and at the end of the down-titration period. Clinical laboratory tests, which included hematology, serum chemistry, dipstick urinalysis, and serum pregnancy test for females of childbearing potential, were performed at screening, at weeks 2 and 6, and at the end of the down-titration period. Physical and neurological examinations and ECGs were performed at screening and at week 6. In addition, a urine pregnancy test was performed at week 4 and a urine drug screen at weeks 2, 4, and 6.

It was estimated that 55 patients per treatment group would be sufficient to detect a mean difference of eight between oxcarbazepine and placebo in the change from baseline to end of study in the YMRS total score, based on a standard deviation of 13 (24) . This mean difference is detectable with a power of 90%, given a significance level of 5% using a two-sided t test.

A computer-generated randomization list, stratified by age subgroup (children 7–12 years old and adolescents 13–18 years old) and comorbid ADHD diagnosis, was used to assign patients to each treatment group. A 1:1 randomization to oxcarbazepine or placebo was used.

The safety population consisted of all patients who underwent random assignment into the treatment phase and received at least one dose of study drug. All patients who entered the treatment phase, received at least one dose of study drug, and had at least one efficacy assessment after baseline were included in the intent-to-treat population.

Statistical analyses of the efficacy of oxcarbazepine were conducted with the data set from visit 8 (day 42, final assessment before the down-titration period) or from the last-observation-carried-forward data set, based on the intent-to-treat population. All hypothesis tests were two-sided and assessed at the 5% significance level.

For continuous efficacy variables, an analysis of covariance (ANCOVA) model was used, with corresponding baseline measurement, age group (7–12 years versus 13–18 years), and ADHD diagnosis as covariates and treatment group and study center as factors. Confidence intervals and point estimates for treatment differences in changes from baseline and within-group changes from baseline were provided. If the parametric assumptions were not met, Wilcoxon rank sum tests were used to analyze the primary efficacy variable.

The YMRS 50% response rate at each visit and at end of study was compared for the two treatment groups using the Cochran-Mantel-Haenszel test with study center as a blocking factor. This procedure tests for the association between treatment groups and the number of responders, adjusting for study center. For the remaining secondary categorical efficacy variables, between-treatment comparisons were made using a modified ridit transformation with the Cochran-Mantel-Haenszel procedure, adjusting for age group and ADHD diagnosis. This is a distribution-free nonparametric test used to compare the changes in scores on the 7-point modified CGI scale between treatment groups. In addition, post hoc analyses evaluated differences between the two age groups.

As shown in Figure 2 and Table 2, mean YMRS scores decreased among patients in both the oxcarbazepine and placebo groups from baseline for the intent-to-treat population, using the last-observation-carried-forward method. The difference between groups was not statistically significant at any time point. At endpoint, the adjusted mean change from baseline in YMRS scores was –10.90 for the oxcarbazepine group and –9.79 for the placebo group. Age group was not a significant covariate in the model. Decreases from baseline to endpoint were also noted for both the oxcarbazepine and placebo groups in mean total scores on the Children’s Depression Rating Scale and the modified CGI, and global health and global behavior scores on the Child Health Questionnaire ( Table 2 ); again, the differences between groups were not statistically significant.

There were no statistically significant differences between the oxcarbazepine and placebo groups in study completion, age at diagnosis, duration of illness, and treatment response. No statistically significant differences were observed between treatment groups, for either age group, in total Children’s Depression Rating Scale scores or global behavior scores on the Child Health Questionnaire.

For the total population at the study endpoint, using the Cochran-Mantel-Haenszel test between treatment groups, 42% of the oxcarbazepine group and 26% of the placebo group achieved at least a 50% reduction in YMRS scores relative to baseline, although the difference between groups was not statistically significant. Results on this measure for the two age groups were also compared. Forty-one percent of the children in the oxcarbazepine group and 17% of those in the placebo group achieved at least a 50% reduction in YMRS scores. Among adolescents, the results on this measure were similar for oxcarbazepine and placebo (43% and 40%, respectively). The response rates were similar for children and adolescents treated with oxcarbazepine.

Overall, 84% of the patients experienced one or more adverse events; the incidence of adverse events was higher in the oxcarbazepine group (90%) than in the placebo group (79%). For the total sample, six adverse events met the criteria of occurring in at least 5% of the oxcarbazepine group with an incidence of at least twice that in the placebo group: dizziness, nausea, somnolence, diplopia, fatigue, and rash ( Table 3 ). For the 7–12-year-old subgroup, in addition to these adverse events, blurred vision, increased appetite, toothache, and insect bite also met the criteria, whereas for the 13–18-year-old subgroup, vomiting and exacerbation of bipolar disorder additionally met the criteria, although fatigue did not.

The majority of adverse events were mild to moderate in severity and were transient, occurring early in the study. For the oxcarbazepine group, the incidences of diplopia, dizziness, and nausea were highest during the 2-week titration phase and decreased through the end of the study: on day 7, diplopia was reported in 6% of the subjects, dizziness in 22%, and nausea in 20%; on day 14, diplopia was reported in 17%, dizziness in 28%, and nausea in 21%; on day 21, diplopia was reported in 9%, dizziness in 28%, and nausea in 16%; on day 28, diplopia was reported in 10%, dizziness in 20%, and nausea in 10%; on day 35, diplopia was reported in 8%, dizziness in 18%, and nausea in 5%; and at endpoint, diplopia was reported in 2%, dizziness in 10%, and nausea in 7%). More discontinuations due to adverse events occurred in the oxcarbazepine group (N=11, 19%) than in the placebo group (N=2, 4%, including one patient who discontinued during the down-titration period). The mean duration of treatment before discontinuation was similar for the oxcarbazepine and placebo groups (21 days and 23 days, respectively).

The incidence of psychiatric adverse events was similar between treatment groups: 12 (20%) in the oxcarbazepine group and 10 (18%) in the placebo group. Six patients in the oxcarbazepine group and none in the placebo group experienced adverse events that met criteria for serious adverse events, and all required hospitalization. The serious adverse events were exacerbation of bipolar disorder (N=3), aggressive outburst (N=1), suicide attempt (N=1), and inappropriate sexual behavior (N=1). The investigators at the sites where these adverse events occurred used their clinical judgment to determine whether the event was related to the study medication. Three of the serious adverse events were suspected to be related to the oxcarbazepine (one instance each of exacerbation of bipolar disorder, aggressive behavior, and suicide attempt), and three were judged to be unrelated to the oxcarbazepine (two instances of exacerbation of bipolar disorder and one instance of inappropriate sexual behavior). Two of these six patients completed the study. The other four patients discontinued the study within 6 days of their first dose of oxcarbazepine, and no postrandomization YMRS scores were obtained for them.

No clinically significant differences were noted between treatment groups in vital signs, laboratory tests, or findings on physical examination or ECG. None of the patients developed hyponatremia. The mean change in body weight from baseline to end of study was 0.83 kg for the oxcarbazepine group and –0.13 kg for placebo group (F=5.18, df=1, p=0.025).