Geller 2012.
| Methods |
Study design: parallel, randomised controlled study |
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| Participants |
Diagnosis: DSM‐IV diagnosis of bipolar I disorder, manic or mixed episode, for at least 4 consecutive weeks Method of diagnosis: CGAS 15 score of 60 or less Age: for lithium, median = 9.7 (SD = 2.7) years; for risperidone, median = 11.0 (SD = 3.0) years; for divalproex sodium, median = 9.7 (SD = 2.4) years; range = 6.0 to 15.11 years Sex: lithium 37 girls; 53 boys, risperidone 47 girls; 42 boys, valproate 56 girls; 44 boys. Location: 5 sites participated: the Children’s National Medical Center in Washington, DC; the Johns Hopkins Medical Institutions in Baltimore, Maryland; the University of Pitts‐ burgh in Pennsylvania; the University of Texas Medical Branch in Galveston and the University of Texas Southwestern in Dallas; and Washington University in St Louis, Missouri. Co‐morbidities: disruptive disorders, anxiety disorders, sleep disorders and elimination disorders Adjunctive medication: ten doses of chlorpromazine at 25 mg each were allowed as rescue medications during weeks 1 to 4. |
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| Interventions | Participants were randomly assigned to either: Experimental arm ‐ lithium N = 93 Duration: 8 weeks Treatment protocol: titration schedules for twice‐a‐day dosing, which included lithium at 1.1‐1.3 mEq/L (to convert to millimoles/L, multiply by 1.0). Blood levels were obtained 10‐12 h after the dose and were titrated (Table 1) using weekly Clinical Global Impressions for Bipolar Illness Improvement–Mania (CGI‐BP‐IM) and adverse events scores. Therapist/face‐to‐face contact: not described Comparator arm ‐ risperidone N = 93 Duration: 8 weeks Treatment protocol: titration schedules for twice‐a‐day dosing, which included risperidone at 4 to 6 mg. Therapist/face‐to‐face contact: not described Comparator arm ‐ divalproex sodium N = 104 Duration: 8 weeks Treatment protocol: titration schedules for twice‐a‐day dosing, which included divalproex sodium at 111 to 125 μg/mL (to convert to micromoles/L, multiply by 6.934) blood levels were obtained 10 to 12 hours after the dose and were titrated (Table 1) using weekly Clinical Global Impressions for Bipolar Illness Improvement–Mania (CGI‐BP‐IM) and adverse events scores. Therapist/face‐to‐face contact: not described |
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| Outcomes |
Timepoints for assessment: baseline and endpoint Primary outcome:
Secondary outcome:
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| Notes |
Date of study: 2003‐2008 Funding source: This work was supported by NIMH grants U01 MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, U01 MH064887, U01 MH064911, and R01 MH051481. Role of Sponsor: The NIMH program staff participated in the conception and design of the study, in the analysis and interpretation of data, in the critical revision of the manuscript for important intellectual content, and in administrative, technical, and material support. During the first 2 years of study, Abbott supplied Depakote but had no other input and no knowledge of study data or conduct. There were 2 sites at Washington University in St Louis. One was the data coordinating, management, and statistical analysis site (principal investigator (PI): Dr Geller). The data coordinating site did not participate in data collection and, therefore, did not receive study medication from Abbott. The second site at Washington University in St Louis was a data collection site (PI: Dr Luby). Declarations of interest among the primary researchers: Financial Disclosure: Dr Geller reports the following for the work under consideration: a grant from NIMH; sup‐ port for travel to meetings from NIMH; payment for writ‐ ing or reviewing the manuscript from NIMH; and pro‐ vision of writing assistance, equipment, or administrative support from NIMH. Dr Geller also reports the follow‐ ing from outside the submitted work: consultancy for NIMH and the US Food and Drug Administration (FDA) Federal Advisory Committees; employment at Washing‐ ton University in St Louis, Missouri; grants from NIMH; payment for lectures from Vanderbilt University and the International Review of Bipolar Disorder; payment for manuscript preparation from NIMH; royalties from Guil‐ ford Press; travel, accommodations, and meeting expenses from NIMH and FDA for service on Federal Advisory Committees; payment from Massachusetts Medical Society for Journal Watch in Psychiatry Associate Editorship. Dr Luby reports the following for the work un‐ der consideration: grant from NIMH and provision of medicines from Abbott. Dr Luby also reports the follow‐ ing from outside the submitted work: employment at Washington University School of Medicine in St Louis, Missouri; grants/grants pending from NIMH, National Alliance for Research on Schizophrenia and Depression, and CHADS; and royalties from Guilford Press. Dr Joshi re‐ ports the following from the work under consideration: a grant from NIMH; support for travel to meetings from NIMH; provision of medicines from Abbott. Dr Joshi also... etc |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomization was stratified by age group (6‐12 vs 13‐15 years) and by the presence or absence of the following characteristics: mixed mania, psychosis, and daily rapid cycling. A separate random list of medication assignments was created for each site based on these stratifiers. |
| Allocation concealment (selection bias) | Unclear risk | Randomization was performed at the co‐ordinating site, and a form identifying the randomised medication was e‐mailed to the site’s non‐blinded staff members |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Participants, family members, and treating clinicians were aware of treatment assignment. Independent evaluators (IEs) who were blinded to medication status administered baseline and end‐ point assessments. Masking of the treatment assignment to the IEs was strictly enforced by using staff who were totally uninvolved with the participants’ treatment. Families were instructed not to reveal either the medication or adverse events to the blinded end‐point raters |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 80 withdrawals/290 randomised |
| Selective reporting (reporting bias) | Low risk | Data comprehensively reported |
| Other bias | Low risk | None identified |