McElroy 2010.
| Methods | Randomized double‐blind trial | |
| Participants |
Number of total participants/type of patients: 62 participants randomised. Outpatient study Inclusion criteria: Sex: male and female Age: 18 years and over Diagnosis: met DSM‐IV‐TR criteria for bipolar I or II disorder or bipolar disorder not otherwise specified and currently experiencing a hypomanic, manic, or mixed episode (as determined by the Structured Clinical Interview for DSM‐IV‐TR33); have a YMRS score ≥ 10 and < 21 at the baseline assessment and at least 1 prior study screening visit at least 3 days, but no longer than 2 weeks, before baseline; had an overall CGI‐BP score ≥ 2 and < 5 Exclusion criteria: Considered severely psychiatrically ill or in need of psychiatric hospitalisation in the judgment of the clinical investigator Baseline YMRS score ≥ 21, CGI‐BP score ≥ 5, or Inventory of Depressive Symptoms (IDS) 35 score ≥ 39 Experiencing clinically significant suicidal ideation, homicidal ideation, or psychotic features Current DSM‐IV‐TR diagnosis of delirium, dementia, or other cognitive disorder or a lifetime DSM‐IV‐TR psychotic disorder DSM‐IV‐TR substance dependence disorder (except for nicotine dependence) within 3 months of study entry, a current DSM‐IV‐TR diagnosis of cocaine, stimulant, or hallucinogen abuse, or a urine drug screen positive for cocaine, stimulants, or hallucinogens Clinically significant finding on medical history, physical examination, electrocardiogram, or laboratory testing History of allergy or hypersensitivity to any valproate or valproate preparation Women were excluded if they were pregnant, lactating, or, if fertile, not practising a form of medically accepted contraception Must be receiving no psychotropics for the 1 week (4 weeks for fluoxetine or depot antipsychotics) before the baseline assessment, except as needed lorazepam (up to 2 mg/d) or zaleplon (up to 10 mg/d) |
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| Interventions |
Location: USA, hospital site in Cincinnati Study duration: October 2003 ‐ November 2007 Treatment groups: 1. Valproate ER administered at an initial dose of 15 mg/kg/day, rounded up or down to the nearest 500 mg, and subsequently adjusted to a dose considered optimal based on the participant’s clinical response and side effects, but not to exceed 30 mg/kg/day 2. Placebo Concomitant medications: as needed use of lorazepam 0.5 – 2.0 mg/day was allowed for the management of affective symptoms for the first 2 weeks of the study; as needed lorazepam 0.5 – 1.0 mg/d was allowed for the next 2 weeks. No lorazepam was permitted for the final 4 weeks. As needed zaleplon (10 – 20 mg/day at bedtime) was allowed for management of insomnia throughout the study Length of study: 8 weeks Randomisation: 31 patients randomised to valproate 31 patients randomised to placebo |
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| Outcomes |
Primary outcome: Changes in YMRS Other outcomes: Adverse events, withdrawal from study and associated reasons, IDS, CGI‐BP , HARS, and GAF scales also collected |
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| Funding | "This investigator‐initiated study was funded in part by a grant from Abbott Laboratories. Abbott Laboratories also partially funded poster production costs and the first author’s travel expenses to present the poster." | |
| Conflict of interest | "Dr McElroy is a consultant to or member of the scientific advisory boards of AstraZeneca, Eli Lilly, Jazz, and Schering‐Plough; is a principal or co‐investigator on research studies sponsored by Abbott, AstraZeneca, Bristol‐Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Jazz, National Institute of Mental Health (NIMH), Marriot Foundation, Orexigen, Shire, and Takeda; is inventor on United States Patent No. 6,323,236 B2: Use of Sulfamate Derivatives for Treating Impulse Control Disorders; and has received payments from Johnson & Johnson. Dr Jefferson has received grant/research support from The Program for Minority Research Training in Psychiatry and The American Psychiatric Institute for Research and Education (5T32 MH 19126‐18). Dr Keck is presently or has been in the past year a principal or co‐investigator on research studies sponsored by AstraZeneca, Cephalon, GlaxoSmithKline, Eli Lilly, Epi‐Q, Jazz, Marriot Foundation, NIMH, Orexigen, and Pfizer; has been reimbursed for consulting, in the past year, to GlaxoSmithKline, Bristol‐Myers Squibb, Pfizer, Quantia MD, Shering‐Plough, and Sepracor; and is inventor on United States Patent No. 6,387,956: Methods of Treating Obsessive‐Compulsive Spectrum Disorder Comprises the Step of Administering an Effective Amount of Tramadol to an Individual. Drs Welge and Guerdjikova and Messrs Martens and Creech have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article." | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomly assigned to receive valproate ER or placebo in a 1:1 ratio according to computer‐generated coding. Randomization was balanced by use of permuted blocks." Comment: Computer‐generated coding is a low‐risk strategy |
| Allocation concealment (selection bias) | Low risk | Quote: "Allocation concealment was achieved by having the research pharmacy perform the randomisation, package the study medication, and maintain the integrity of the blinded information throughout the trial" Comment: Pharmacy ensured randomisation separate from investigators |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "Double blind" Quote: "Unblinded investigators were to be notified only of concentrations ≥150 μg/mL. To maintain the blind, similar notifications were to be given for a placebo patient who was at the same point in the study. No serum valproate levels, however, exceeded 150 μg/mL" Quote: "All study medication was in identical 500‐mg tablets supplied in numbered containers and dispensed to patients according to a predetermined randomisation schedule" Comment: Blinding procedures seem effective |
| Blinding of outcome assessment (detection bias) Efficacy | Unclear risk | Comment: No information on blinding of outcome assessors |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: 17 participants (57%) in the valproate ER group and 15 participants (50%) in the placebo group did not complete all 8 weeks of treatment. This was not a significant difference between group (Fisher exact test, P = 0.796). Thus even though both groups' dropout rates are above 30% they are at low risk of bias |
| Selective reporting (reporting bias) | Unclear risk | Comment: Pre‐published trial protocol, however the publication of primary outcome was only made on 27 December 2007. This is after the study finished recruiting all its participants. This makes it unclear whether the primary outcome was selected before or after some of the results were known, making this outcome at unclear risk. |
| Other bias | Low risk | Comment: None identified |