other randomized controlled trials for bipolar disorder


(Updated 6/14/05; note that placebo-controlled trials have been placed in the right column.)

Walton SA, Berk M, Brook S.
Department of Psychiatry, University of the Witwatersrand Medical School, Johannesburg, South Africa.
Superiority of lithium over verapamil in mania: a randomized, controlled, single-blind trial.
J Clin Psychiatry. 1996 Nov;57(11):543-6.
"BACKGROUND: Both case reports and small controlled studies suggest the efficacy of verapamil in the treatment of mania. METHOD: Forty patients with DSM-IV mania were studied in a 28-day randomized, controlled, single-blind trial of either lithium or verapamil. RESULTS: The patients receiving lithium showed a significant improvement on all rating scales (Brief Psychiatric Rating Scale [BPRS], Mania Rating Scale [MRS], Global Assessment of Functioning [GAF], and Clinical Global Impression [CGI]) compared with those receiving verapamil. The mean MRS score at Day 28 in the lithium group was significantly lower than that in the verapamil group (17.47 vs. 24.43, respectively; F = 6.17, df = 1, p = .018). A similar pattern was seen with the BPRS (12.68 vs. 20.57; F = 10.69, df = 1, p = .002), CGI (2.31 vs. 3.33; F = 6.05, df = 1, p = .019), and GAF (43.52 vs. 52.31; F = 4.36, df = 1, p = .044) (ANCOVA). CONCLUSION: This study suggests that lithium is superior to verapamil in the management of acute mania." [Abstract]


Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB.
Brigham and Women's Hospital, Department of Psychiatry, Harvard Medical School, Boston, Mass, USA. alstoll@mclean.harvard.edu
Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.
Arch Gen Psychiatry. 1999 May;56(5):407-12.
"BACKGROUND: Omega3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega3 fatty acid group performed better than the placebo group. CONCLUSION: Omega3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder." [Abstract]

Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G.
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group.
Bipolar Disord. 2000 Sep;2(3 Pt 2):249-55.
"OHJECTIVES: To assess efficacy and safety of gabapentin in the treatment of bipolar disorder. METHODS: This was a double-blind, placebo-controlled trial of adjunctive gabapentin (dosed flexibly between 900 and 3,600 mg/day). Patients with a lifetime diagnosis of bipolar disorder (type I), and who were currently suffering from symptoms of either mania, hypomania or a mixed state despite ongoing therapy with lithium, valproate, or lithium and valproate in combination were eligible for inclusion. The primary efficacy measures were the baseline to endpoint change in total score on the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HAM-D). RESULTS: Both treatment groups had a decrease in total YMRS from baseline to endpoint, but this decrease was significantly greater in the placebo group (-9) than the gabapentin group (-6) (p < 0.05). No difference between treatments was found for the total score on the HAM-D. Secondary efficacy measures were not different between treatment groups. More patients in the placebo group had changes made to their ongoing lithium therapy (n = 12) compared to the gabapentin group (n = 4). When these patients are removed from the efficacy analysis, the YMRS treatment difference still favors placebo, but is no longer statistically significant. Based on gabapentin plasma levels at termination, some patients did not take the study drug as prescribed. CONCLUSIONS: The findings of this study did not demonstrate that gabapentin is an effective adjunctive treatment when administered to outpatients with bipolar disorder." [Abstract]

Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH.
Stanley Center for Bipolar Research, Ministry of Health Mental Health Center, Ben Gurion University of the Negev, Beersheva, Israel.
Phenytoin as an antimanic anticonvulsant: a controlled study.
Am J Psychiatry. 2000 Mar;157(3):463-5.
"OBJECTIVE: Phenytoin, a classical anticonvulsant, shares with antimanic anticonvulsants the property of blockade of voltage-activated sodium channels. The authors therefore planned a trial of phenytoin for mania. METHOD: Patients with either bipolar I disorder, manic type, or schizoaffective disorder, manic type, entered a 5-week, double-blind controlled trial of haloperidol plus phenytoin versus haloperidol plus placebo. Of 39 patients, 30 completed at least 3 weeks and 25 completed 5 weeks. RESULTS: Significantly more improvement was observed in the patients receiving phenytoin. Added improvement with phenytoin in scores on the Brief Psychiatric Rating Scale and Clinical Global Impression was seen in the patients with bipolar mania but not those with schizoaffective mania. CONCLUSIONS: Blockade of voltage-activated sodium channels may be a common therapeutic mechanism of many anticonvulsants given for mania, and phenytoin may be a therapeutic option for some manic patients." [Abstract]

Janicak PG, Sharma RP, Pandey G, Davis JM.
Psychiatric Institute, University of Illinois at Chicago 60612, USA.
Verapamil for the treatment of acute mania: a double-blind, placebo-controlled trial.
Am J Psychiatry. 1998 Jul;155(7):972-3.
"OBJECTIVE: This study investigated the efficacy of verapamil in acute mania. METHOD: The study was a 3-week double-blind, random-assignment, parallel-group, placebo-controlled inpatient trial of verapamil for patients with acute mania. Of the 32 study patients, 15 were given placebo and 17 were given verapamil. RESULTS: Mean absolute change scores on the Mania Rating Scale at endpoint, with baseline scores as the covariates, did not differ between the verapamil and placebo groups. There were no significant differences between the two groups in age, sex, and presence of psychosis. CONCLUSIONS: The investigators found no benefit of verapamil over placebo in treating acute mania." [Abstract]

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Recent Bipolar Disorder RCT Results

1) Di Tommaso MC
A comparative study of bipolar disorder and attention deficit hyperactivity disorder through the measurement of regional cerebral blood flow.
J Biol Regul Homeost Agents. 2012 Jan-Mar;26(1):1-6.
Attention Deficit Hyperactivity Disorder (ADHD) and Bipolar Disorder (BPD) are two common neuropsychological disorders which are often present in a comorbid state. I used the results of cerebral blood flow studies made with Single Photon Emission Computer Tomography (SPECT), Positron Emission Tomography (PET) and Functional Magnetic Resonance Imaging (fMRI), to investigate a possible relationship between ADHD and BPD. The common areas of the brain involved in both BPD and ADHD appears to be the prefrontal cortex in its various components, the basal ganglia and possibly the cerebellum which, especially in the past, has been little studied by researchers in relation to ADHD and BPD. Among the differences the blood flow lateralization, present in BPD in states of altered mood, is evident with left hypoperfusion and right hyperperfusion during depression, the opposite in the case of manic state; in ADHD, the lateralization is less constant and of questionable interpretation. In BPD the involvement of a greater number of brain areas, especially the temporal lobe, is common. I advance the hypothesis that BPD progresses from ADHD secondary to expansion of perturbation in cerebral blood flow. [PubMed Citation] [Order full text from Infotrieve]

2) Camm AJ, Karayal ON, Meltzer H, Kolluri S, O'Gorman C, Miceli J, Tensfeldt T, Kane JM
Ziprasidone and the corrected QT interval: a comprehensive summary of clinical data.
CNS Drugs. 2012 Apr 1;26(4):351-65.
[PubMed Citation] [Order full text from Infotrieve]

3) Dauphinais DR, Rosenthal JZ, Terman M, DiFebo HM, Tuggle C, Rosenthal NE
Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression.
Psychiatry Res. 2012 Mar 30;196(1):57-61.
Treatment of bipolar disorder often results in patients taking several drugs in an attempt to alleviate residual depressive symptoms, which can lead to an accumulation of side effects. New treatments for bipolar depression that do not increase the side effect burden are needed. One nonpharmacological treatment with few side effects, bright light therapy, has been shown to be an effective therapy for seasonal affective disorder, yet has not been extensively studied for other forms of depression. Forty-four adults with bipolar disorder, depressed phase were randomized to treatment with bright light therapy, low-density or high-density negative ion generator for 8 weeks. The primary measure of efficacy was the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS). Adverse events were assessed using the Young Mania Rating Scale (YMRS) and Systematic Assessment for Treatment Emergent effects (SAFTEE). All outcome variables were statistically analyzed using a mixed model repeated measure analysis of variance (ANOVA). The results showed no statistically significant differences between groups in any outcome measures at study end point; adverse events, including switches into hypomania, were rare. Further research is needed to determine the efficacy of bright light therapy in this population. [PubMed Citation] [Order full text from Infotrieve]

4) Swartz HA, Frank E, Cheng Y
A randomized pilot study of psychotherapy and quetiapine for the acute treatment of bipolar II depression.
Bipolar Disord. 2012 Mar;14(2):211-6.
[PubMed Citation] [Order full text from Infotrieve]

5) Fan A, Berg A, Bresee C, Glassman LH, Rapaport MH
Allopurinol augmentation in the outpatient treatment of bipolar mania: a pilot study.
Bipolar Disord. 2012 Mar;14(2):206-10.
[PubMed Citation] [Order full text from Infotrieve]

6) Dierckx B, Heijnen WT, van den Broek WW, Birkenhäger TK
Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta-analysis.
Bipolar Disord. 2012 Mar;14(2):146-50.
[PubMed Citation] [Order full text from Infotrieve]

7) Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TF, Nugent AC, Scherk H, Gruber O, Chen X, Sachdev PS, Dickstein DP, Malhi GS, Ha TH, Ha K, Phillips ML, McIntosh AM
Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies.
Bipolar Disord. 2012 Mar;14(2):135-45.
[PubMed Citation] [Order full text from Infotrieve]

8) Kilbourne AM, Neumann MS, Waxmonsky J, Bauer MS, Kim HM, Pincus HA, Thomas M
Public-academic partnerships: evidence-based implementation: the role of sustained community-based practice and research partnerships.
Psychiatr Serv. 2012 Mar;63(3):205-7.
This column describes a process for adapting an evidence-based practice in community clinics in which researchers and community providers participated and the resulting framework for implementation of the practice-Replicating Effective Programs-Facilitation. A two-day meeting for the Recovery-Oriented Collaborative Care study was conducted to elicit input from more than 50 stakeholders, including community providers, health care administrators, and implementation researchers. The process illustrates an effective researcher-community partnership in which stakeholders worked together not only to adapt the evidence-based practice to the needs of the clinical settings but also to develop the implementation strategy. [PubMed Citation] [Order full text from Infotrieve]

9) McElroy SL, Winstanley E, Mori N, Martens B, McCoy J, Moeller D, Guerdjikova AI, Keck PE
A randomized, placebo-controlled study of zonisamide to prevent olanzapine-associated weight gain.
J Clin Psychopharmacol. 2012 Apr;32(2):165-72.
Weight gain is commonly observed with olanzapine treatment. Zonisamide is an antiepileptic drug associated with weight loss. This study examined the effectiveness of zonisamide in preventing weight gain in 42 patients beginning olanzapine for bipolar disorder or schizophrenia. Each patient had a body mass index of 22 mg/kg or greater and was randomized to taking olanzapine with either zonisamide (n = 20) or placebo (n = 22) for 16 weeks. The primary outcome measure was change in body weight in kilograms from baseline. In the primary analysis using longitudinal regression, patients who received zonisamide had a significantly slower rate of weight gain and increase in body mass index than those who received placebo. The patients treated with zonisamide gained a mean (SD) of 0.9 (3.3) kg, whereas those treated with placebo gained a mean (SD) of 5.0 (5.5) kg; P = 0.01. None of the patients in the zonisamide group, compared with 7 patients (33%) in the placebo group, gained 7% of body weight or greater from baseline (Fisher exact test, P = 0.009). The zonisamide group, however, reported significantly more cognitive impairment as an adverse event than the placebo group (25% vs 0, respectively; P = 0.02). Zonisamide was effective for mitigating weight gain in patients with bipolar disorder or schizophrenia initiating treatment with olanzapine but was associated with cognitive impairment as an adverse event. [PubMed Citation] [Order full text from Infotrieve]

10) Rabheru K
Maintenance electroconvulsive therapy (M-ECT) after acute response: examining the evidence for who, what, when, and how?
J ECT. 2012 Mar;28(1):39-47.
[PubMed Citation] [Order full text from Infotrieve]

11) Anand A, Gunn AD, Barkay G, Karne HS, Nurnberger JI, Mathew SJ, Ghosh S
Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial.
Bipolar Disord. 2012 Feb;14(1):64-70.
[PubMed Citation] [Order full text from Infotrieve]

12) Tolliver BK, Desantis SM, Brown DG, Prisciandaro JJ, Brady KT
A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with bipolar disorder: a preliminary report.
Bipolar Disord. 2012 Feb;14(1):54-63.
[PubMed Citation] [Order full text from Infotrieve]

13) Carlson BX, Ketter TA, Sun W, Timko K, McQuade RD, Sanchez R, Vester-Blokland E, Marcus R
Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392).
Bipolar Disord. 2012 Feb;14(1):41-53.
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14) Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV
Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.
Bipolar Disord. 2012 Feb;14(1):31-40.
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15) Thase ME, Bowden CL, Nashat M, Eudicone JM, Marcus R, McQuade RD, Carlson BX
Aripiprazole in bipolar depression: a pooled, post-hoc analysis by severity of core depressive symptoms.
Int J Psychiatry Clin Pract. 2012 Jun;16(2):121-31.
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16) Pavuluri MN, Passarotti AM, Fitzgerald JM, Wegbreit E, Sweeney JA
Risperidone and divalproex differentially engage the fronto-striato-temporal circuitry in pediatric mania: a pharmacological functional magnetic resonance imaging study.
J Am Acad Child Adolesc Psychiatry. 2012 Feb;51(2):157-170.e5.
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17) Citrome L
Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder.
Int J Clin Pract. 2012 Mar;66(3):318-25.
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18) 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
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.
Arch Gen Psychiatry. 2012 May;69(5):515-28.
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19) Samamé C, Martino DJ, Strejilevich SA
Social cognition in euthymic bipolar disorder: systematic review and meta-analytic approach.
Acta Psychiatr Scand. 2012 Apr;125(4):266-80.
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20) Szegedi A, Calabrese JR, Stet L, Mackle M, Zhao J, Panagides J
Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension.
J Clin Psychopharmacol. 2012 Feb;32(1):46-55.
In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks. [PubMed Citation] [Order full text from Infotrieve]