An Open-Label Trial of Divalproex in Children and Adolescents With Bipolar Disorder

doi:10.1097/00004583-200210000-00012

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 41, Issue 10, October 2002, Pages 1224-1230

https://doi.org/10.1097/00004583-200210000-00012 Get rights and content

ABSTRACT

Objective:

This study evaluated the safety and effectiveness of divalproex sodium (Depakote^®) in the treatment of youths with bipolar disorder.

Method:

Forty bipolar disorder patients aged 7 to 19 years, with a manic, hypomanic, or mixed episode, enrolled in an open-label study of divalproex (2–8 weeks), followed by a double-blind, placebo-controlled period (8 weeks).

Results:

Twenty-two subjects (61%) showed ≥50% improvement in Mania Rating Scale (MRS) scores during the open-label period. Significant (p < .001) improvements from baseline were seen for mean scores of all efficacy measures, including the MRS, Manic Syndrome Scale, Behavior and Ideation Scale, Brief Psychiatric Rating Scale, Clinical Global Impressions Severity scale, and Hamilton Rating Scale for Depression. Of the 23 subjects who discontinued the study during the open-label period, 6 (15%) discontinued for ineffectiveness, 6 (15%) for intolerance, 6 (15%) for noncompliance, and 6 (15%) for other reasons. Adverse events were generally mild or moderate in severity, with the most common being headache, nausea, vomiting, diarrhea, and somnolence. Laboratory data results were unremarkable. Too few subjects participated in the double-blind period for statistical analysis.

Conclusions:

This study provides preliminary support for the safety and effectiveness of divalproex in the treatment of bipolar disorder in youths.

Section snippets

Study Design

Child and adolescent inpatients and outpatients were recruited from five academic medical centers for participation in the study. The study was approved by the Institutional Review Boards at each of the sites, and informed consent from the parent and assent from the child were obtained before participation in the study. During a 1-week screening period, subjects were evaluated for eligibility via physical examination, vital signs, hematology tests, blood chemistry tests, medical and psychiatric

Subjects

Forty subjects entered the open-label period of the study. Subject characteristics are presented in Table 1. The mean age of subjects was 12.1 years (SD = 3.62), and median duration of study drug exposure was 33.5 days (range 2–122). The mean divalproex dosage at the final visit was 813 mg/day (SD = 338; 17.5 mg/kg per day [SD = 8.2]), with a mean serum valproate level at the final visit of 83.4 μg/mL (SD = 25.4, n = 37).

Four subjects (10%) began therapy with lithium carbonate on or after day

DISCUSSION

This is the largest open-label study of divalproex treatment for children and adolescents with bipolar disorder. In this study, 61% of the subjects showed a ≥50% improvement from baseline in MRS scores. This response rate is similar to the response rate found by Kowatch et al. (2000) in their open-label comparison of divalproex, lithium, and carbamazepine. The time course of response was fairly rapid, with some improvement shown within the first week of treatment. Symptoms continued to decline

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In the last few decades, scientific evidence has accrued in support of using psychotropics to treat an increasing number of disorders/indications in children and adolescents. This article will present an overview of psychopharmacological treatment of the most common psychiatric conditions in youth, including attention deficit hyperactivity disorder, mood and anxiety disorders, obsessive compulsive disorder, schizophrenia, autism spectrum disorder, and tic disorders. It covers core principles that govern prescribing psychotropics to children and adolescents, reviews some of the scientific data in support of such practice, and lists medications currently used for these conditions.
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Divalproex is approved by the FDA for the treatment of manic and/or mixed episodes in adults, but not in youth. There are several positive open-label studies and a chart review suggesting the benefit of divalproex in the treatment of manic/mixed states.12–14 A double-blind study compared divalproex with quetiapine in treating acute mania and showed higher response with quetiapine.12
Pharmacological treatment of bipolar disorder in children and adolescents
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Depuis une vingtaine d’années, les travaux sur le traitement pharmacologique du trouble bipolaire chez l’enfant et l’adolescent se sont multipliés. Plusieurs études contrôlées ont ainsi démontré que les antipsychotiques étaient significativement plus efficaces que les thymorégulateurs dans le traitement des épisodes maniaques ou mixtes. En revanche, peu d’études se sont intéressées au traitement des épisodes dépressifs (seule la quétiapine a fait l’objet d’études contrôlées contre placebo dans cette indication démontrant son absence d’efficacité). Les données concernant les effets des traitements antimaniaques sur les troubles comorbides, dont la présence complique souvent la prise en charge, sont aussi rares et peu concluantes. Enfin, malgré son importance, force est de constater que le traitement de maintenance reste à ce jour peu documenté, seules deux études contrôlées contre placebo ayant démontré l’efficacité de l’aripiprazole dans le maintien de la réduction des symptômes et la prévention des rechutes. Par ailleurs, si les antipsychotiques apparaissent en règle générale mieux tolérés que les thymorégulateurs, se pose aussi la question de l’impact à long terme des traitements pharmacologiques sur les altérations neuropsychologiques associées au trouble bipolaire. À ce titre, les quelques études disponibles suggèrent que les thymorégulateurs pourraient aussi avoir un effet délétère sur le développement des fonctions cognitives.
To review the options for acute and maintenance pharmacological treatment of bipolar disorder in children and adolescents.
A comprehensive literature review of randomized clinical trials and open-label studies was conducted.
Published data from randomized controlled trials show that antipsychotics are significantly more effective than mood stabilizers in the treatment of manic or mixed episodes. Few data are available related to the treatment of depressive episodes. No trials of selective serotonin reuptake inhibitors have been conducted. Only open trials suggest that lithium and lamotrigine may be effective, whereas quetiapine did not demonstrate efficacy relative to placebo in two studies. Studies regarding the effectiveness of antipsychotics and mood stabilizers for the comorbid disorders are also few and inconclusive. Although long-term treatment is a core aspect of the management of children and adolescents with bipolar disorder, there is a lack of consistent efficacy data. If non-controlled trials suggest that lithium, lamotrigine, quetiapine, ziprazidone, and the combination of risperidone and divalproex or lithium may be useful in some conditions, only aripiprazole has shown efficacy relative to placebo for long-term symptom reduction and relapse prevention. Safety data show that the most frequently reported adverse events in children and adolescents treated with mood stabilizers are gastrointestinal and neurological, whereas use of antipsychotics is mainly related to weight gain and sedation. Lastly, while results from studies having evaluated the impact of pharmacological treatment on neuropsychological functioning are inconsistent, some of them nevertheless suggest that treatment with mood stabilizers may be associated with specific impairments.
Despite recent developments in identifying effective pharmacological interventions, numerous critical gaps remain.
Pharmacologic Treatment of Bipolar Disorder in Children and Adolescents
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Important limitations of this preliminary study include a small sample size, discontinuation before recovery, and rapid discontinuation. Small, open-label trials of DVPX in acute pediatric mania have reported response rates ranging from 53% to 75%.50–52 A large (N = 150; 10–17 years old) 4-week industry-sponsored multicenter study found a similar response rate for DVPX (24%) and placebo (23%).53
Risperidone and divalproex differentially engage the fronto-striato- temporal circuitry in pediatric mania: A pharmacological functional magnetic resonance imaging study
2012, Journal of the American Academy of Child and Adolescent Psychiatry
The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD).
This was a six-week, double-blind, randomized trial of risperidone plus placebo versus divalproex plus placebo for patients with mania (n = 21; 13.6 ± 2.5 years of age). Functional magnetic resonance imaging (fMRI) outcomes were measured using a block design, affective, N-back task with angry, happy, and neutral face stimuli at baseline and at 6-week follow-up. Matched healthy controls (HC; n = 15, 14.5 ± 2.8 years) were also scanned twice.
In post hoc analyses on the significant interaction in a 3×2×2 analysis of variance (ANOVA) that included patient groups and HC, the risperidone group showed greater activation after treatment in response to the angry face condition in the left subgenual anterior cingulate cortex (ACC) and striatum relative to the divalproex group. The divalproex group showed greater activation relative to the risperidone group in the left inferior frontal gyrus and right middle temporal gyrus. Over the treatment course, the risperidone group showed greater change in activation in the left ventral striatum than the divalproex group, and the divalproex group showed greater activation change in left inferior frontal gyrus and right middle temporal gyrus than the risperidone group. Furthermore, each patient group showed increased activation relative to HC in fronto-striato-temporal regions over time. The happy face condition was potentially less emotionally challenging in this study and did not elicit notable findings.
When patients performed a working memory task under emotional duress inherent in the paradigm, divalproex enhanced activation in a fronto-temporal circuit whereas risperidone increased activation in the dopamine (D₂) receptor–rich ventral striatum. Clinical trial registration information—Risperidone and Divalproex Sodium With MRI Assessment in Pediatric Bipolar; http://www.clinicaltrials.gov; NCT00176202.

View all citing articles on Scopus

: Support for this study was provided by Abbott Laboratories.

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ARTICLESAn Open-Label Trial of Divalproex in Children and Adolescents With Bipolar Disorder

ABSTRACT

Objective:

Method:

Results:

Conclusions:

Section snippets

Study Design

Subjects

DISCUSSION

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Diagnostic and Statistical Manual of Mental Disorders

Efficacy of divalproex vs lithium and placebo in the treatment of mania

JAMA

Lithium in hospitalized children at 4 and 8 weeks: mood, behavior and cognitive effects

J Child Psychol Psychiatry

A diagnostic interview for the Schedule for Affective Disorders and Schizophrenia

Arch Gen Psychiatry

The Global Assessment Scale: a procedure for measuring overall psychiatric disturbance

Arch Gen Psychiatry

ARTICLES
An Open-Label Trial of Divalproex in Children and Adolescents With Bipolar Disorder