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A Randomized Controlled Trial of Risperidone, Lithium, or Divalproex Sodium for Initial Treatment of Bipolar I Disorder, Manic or Mixed Phase, in Children and Adolescents

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Geller, Barbara·2012·Archives of General Psychiatry
DOI 10.1001/archgenpsychiatry.2011.1508PMC PMC3581342
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Abstract

CONTEXT: There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. OBJECTIVE: To investigate which medication to administer first to antimanic medication-naive subjects. DESIGN, SETTING, AND PARTICIPANTS: The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments. INTERVENTIONS: Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg). MAIN OUTCOME MEASURES: Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents. RESULTS: There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; χ(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; χ(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (χ(2)(1) = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F(1,212) = 45.5, P < .001; F(1,212) = 39.1, P < .001; and F(1,213) = 191.4, P < .001, respectively) and vs divalproex sodium (F(1,212) = 34.7, P < .001; F(1,212) = 45.3, P < .001; and F(1,213) = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001). CONCLUSIONS: Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00057681

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  • Other studies have suggested the efficacy of combination therapy (risperidone plus lithium or divalproex and lithium plus divalproex or carbamazepine) to achieve and maintain remission.

    “Further, other studies have also suggested the efficacy of combination therapy (eg, risperidone plus lithium or divalproex584 and lithium plus divalproex or carbamazepine606) to achieve and maintain remission.”

    From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [584]

    The Abstract’s Interventions section describes separate risperidone, lithium, and divalproex treatment groups, and the Comment reports risperidone’s efficacy for initial treatment compared with the other drugs. Neither passage addresses whether risperidone combined with lithium or divalproex achieves or maintains remission; searches for combination and adjunctive treatment found no such passage in our copy. (LLM, conf=0.76)

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Authors
Geller, B.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Geller, Barbara
Venue
Archives of General Psychiatry
Publisher
American Medical Association (AMA)
Published
2012-05-01
Volume
69
Issue
5
Pages
515
ISSN
0003-990X (ISSN-L)
DOI
10.1001/archgenpsychiatry.2011.1508
PMC
PMC3581342
OpenAlex
W2155569717
Cited by
281
References
38
Citations by year
2026: 1 · 2025: 6 · 2024: 25 · 2023: 8 · 2022: 8 · 2021: 14 · 2020: 11 · 2019: 43 · 2018: 20 · 2017: 34 · 2016: 18 · 2015: 27 · 2014: 26 · 2013: 31 · 2012: 9
FWCI
21.17
Type
journal article
Language
en
Open access
Locations
  • Archives of General Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders
National Institute of Mental Health (U01MH064869, U01MH064868, U01MH064846, U01MH064850, U01MH064851, R01MH051481, U01MH064911, U01MH064887)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Social Sciences › Psychology › Clinical Psychology › Personality Disorders and Psychopathology
Keywords
bipolar I disorder, manic phase, mixed phase, children and adolescents, risperidone, lithium, divalproex sodium, initial treatment, rapid cycling, treatment response, adverse effects, mood stabilizers, antipsychotic drugs
MeSH terms
Adolescent, Bipolar Disorder, Child, Female, Humans, Male, Psychiatric Status Rating Scales, Valproic Acid, Lithium Carbonate, Treatment Outcome, Antimanic Agents, Risperidone

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