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

Barbara Geller*, Joan L. Luby, Paramjit Joshi, Karen Dineen Wagner, Graham Emslie, John T. Walkup, David A. Axelson, Kristine Bolhofner, Adelaide Robb, Dwight V. Wolf, Mark A. Riddle, Boris Birmaher, Nasima Nusrat, Neal D. Ryan, Benedetto Vitiello, Rebecca Tillman, Philip Lavori

*Corresponding author for this work

Research output: Contribution to journalArticle

122 Citations (Scopus)

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-patientchoice, 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%; X 1 2 1=16.9, P<.001) and vs divalproex sodium (68.5% vs 24.0%; X 1 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 (X 1 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.

Original languageEnglish (US)
Pages (from-to)515-528
Number of pages14
JournalArchives of general psychiatry
Volume69
Issue number5
DOIs
StatePublished - May 1 2012

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Risperidone
Valproic Acid
Bipolar Disorder
Lithium
Randomized Controlled Trials
Antimanic Agents
Therapeutics
Outcome Assessment (Health Care)
Lithium Carbonate
Mania
Randomized Controlled Trial
Thyrotropin
Diagnostic and Statistical Manual of Mental Disorders
Prolactin
Psychotic Disorders
Medication
Weight Gain
Appointments and Schedules
Body Mass Index
Pharmacology

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

Cite this

Geller, Barbara ; Luby, Joan L. ; Joshi, Paramjit ; Wagner, Karen Dineen ; Emslie, Graham ; Walkup, John T. ; Axelson, David A. ; Bolhofner, Kristine ; Robb, Adelaide ; Wolf, Dwight V. ; Riddle, Mark A. ; Birmaher, Boris ; Nusrat, Nasima ; Ryan, Neal D. ; Vitiello, Benedetto ; Tillman, Rebecca ; Lavori, Philip. / 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. In: Archives of general psychiatry. 2012 ; Vol. 69, No. 5. pp. 515-528.
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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-patientchoice, 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{\%}; X 1 2 1=16.9, P<.001) and vs divalproex sodium (68.5{\%} vs 24.0{\%}; X 1 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 (X 1 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.",
author = "Barbara Geller and Luby, {Joan L.} and Paramjit Joshi and Wagner, {Karen Dineen} and Graham Emslie and Walkup, {John T.} and Axelson, {David A.} and Kristine Bolhofner and Adelaide Robb and Wolf, {Dwight V.} and Riddle, {Mark A.} and Boris Birmaher and Nasima Nusrat and Ryan, {Neal D.} and Benedetto Vitiello and Rebecca Tillman and Philip Lavori",
year = "2012",
month = "5",
day = "1",
doi = "10.1001/archgenpsychiatry.2011.1508",
language = "English (US)",
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pages = "515--528",
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Geller, B, Luby, JL, Joshi, P, Wagner, KD, Emslie, G, Walkup, JT, Axelson, DA, Bolhofner, K, Robb, A, Wolf, DV, Riddle, MA, Birmaher, B, Nusrat, N, Ryan, ND, Vitiello, B, Tillman, R & Lavori, P 2012, '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', Archives of general psychiatry, vol. 69, no. 5, pp. 515-528. https://doi.org/10.1001/archgenpsychiatry.2011.1508

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. / Geller, Barbara; Luby, Joan L.; Joshi, Paramjit; Wagner, Karen Dineen; Emslie, Graham; Walkup, John T.; Axelson, David A.; Bolhofner, Kristine; Robb, Adelaide; Wolf, Dwight V.; Riddle, Mark A.; Birmaher, Boris; Nusrat, Nasima; Ryan, Neal D.; Vitiello, Benedetto; Tillman, Rebecca; Lavori, Philip.

In: Archives of general psychiatry, Vol. 69, No. 5, 01.05.2012, p. 515-528.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Geller, Barbara

AU - Luby, Joan L.

AU - Joshi, Paramjit

AU - Wagner, Karen Dineen

AU - Emslie, Graham

AU - Walkup, John T.

AU - Axelson, David A.

AU - Bolhofner, Kristine

AU - Robb, Adelaide

AU - Wolf, Dwight V.

AU - Riddle, Mark A.

AU - Birmaher, Boris

AU - Nusrat, Nasima

AU - Ryan, Neal D.

AU - Vitiello, Benedetto

AU - Tillman, Rebecca

AU - Lavori, Philip

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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-patientchoice, 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%; X 1 2 1=16.9, P<.001) and vs divalproex sodium (68.5% vs 24.0%; X 1 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 (X 1 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.

AB - 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-patientchoice, 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%; X 1 2 1=16.9, P<.001) and vs divalproex sodium (68.5% vs 24.0%; X 1 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 (X 1 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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U2 - 10.1001/archgenpsychiatry.2011.1508

DO - 10.1001/archgenpsychiatry.2011.1508

M3 - Article

VL - 69

SP - 515

EP - 528

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 5

ER -