other randomized controlled trials for bipolar disorder

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(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) Bhugra D, Ayonrinde O, Butler G, Leese M, Thornicroft G
A randomised controlled trial of assertive outreach vs. treatment as usual for black people with severe mental illness.
Epidemiol Psychiatr Sci. 2011 Mar;20(1):83-9.
[PubMed Citation] [Order full text from Infotrieve]

2) Nieto RG, Castellanos FX
A meta-analysis of neuropsychological functioning in patients with early onset schizophrenia and pediatric bipolar disorder.
J Clin Child Adolesc Psychol. 2011;40(2):266-80.
Despite the nosological distinction between bipolar disorder and schizophrenia, there is increasing evidence that these conditions share phenomenological characteristics. To examine the similarities in their patterns of cognitive impairment, we conducted a meta-analysis from 12 studies of Early Onset Schizophrenia (EOS) and 12 studies of Pediatric Bipolar Disorder (PBD). We found that individuals with PBD suffer from cognitive deficits (e.g., verbal learning and memory, processing speed, or executive control) that are milder but similar in nature to those of patients with EOS. Qualitative similarities between the neuropsychological profiles produced by these groups of patients might represent a "continuum of psychosis" or reflect some degree of genetic biological overlap. [PubMed Citation] [Order full text from Infotrieve]

3) McDonald LJ, Griffin ML, Kolodziej ME, Fitzmaurice GM, Weiss RD
The impact of drug use in social networks of patients with substance use and bipolar disorders.
Am J Addict. 2011 Mar-Apr;20(2):100-5.
In this exploratory analysis, we assessed the effect of drug use among social-network members on recovery from drug dependence in patients with co-occurring bipolar disorder. Patients (n = 57) enrolled in a group therapy study completed assessments over 15 months. Patients with zero to one drug users in their social networks at intake had few days of drug use during treatment and follow-up, whereas those with ? 2 drug users had significantly more days of drug use. Multivariate analysis showed that patients who consistently named multiple drug users in their social networks had a marked increase in drug use over 15 months, while those who never or occasionally named multiple drug users had a small decline in drug use over time. Multiple drug users in social networks of treatment-seeking drug-dependent patients with co-occurring bipolar disorder may indicate poor drug use outcomes; efforts to reduce the association with drug users may be useful. This clinical trial has been registered in a public trials registry at clinicaltrials.gov (identifier is NCT00227838).? [PubMed Citation] [Order full text from Infotrieve]

4) Kessing LV, Hansen HV, Christensen EM, Dam H, Gluud C, Wetterslev J
The effects of centralised and specialised combined pharmacological and psychological intervention compared with decentralised and non-specialised treatment in the early course of severe unipolar and bipolar affective disorders--design of two randomised clinical trials.
Trials. 2011;12(1):32.
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5) Praharaj SK, Jana AK, Goyal N, Sinha VK
Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis.
Br J Clin Pharmacol. 2011 Mar;71(3):377-82.
Olanzapine is an atypical antipsychotic that is useful in schizophrenia and bipolar affective disorder, but its use is associated with troublesome weight gain and metabolic syndrome. A variety of pharmacological agents has been studied in the efforts to reverse weight gain induced by olanzapine, but current evidence is insufficient to support any particular pharmacological approach. We conducted a systematic review and meta-analysis of randomized controlled trials of metformin for the treatment of olanzapine-induced weight gain. Systematic review of the literature revealed 12 studies that had assessed metformin for antipsychotic-induced weight gain. Of these, four studies (n= 105) met the review inclusion criteria and were included in the final analysis. Meta-analysis was performed to see the effect size of the treatment on body weight, waist circumference and body-mass index (BMI). Weighted mean difference (WMD) for body weight was 5.02 (95% CI 3.93, 6.10) kg lower with metformin as compared with placebo at 12 weeks. For waist circumference, the test for heterogeneity was significant (P= 0.00002, I(2) = 85.1%). Therefore, a random effects model was used to calculate WMD, which was 1.42 (95% CI 0.29, 3.13) cm lower with metformin as compared with placebo at 12 weeks. For BMI, WMD was 1.82 (95% CI 1.44, 2.19) kg?m(-2) lower with metformin as compared with placebo at 12 weeks. Existing data suggest that short term modest weight loss is possible with metformin in patients with olanzapine-induced weight gain. [PubMed Citation] [Order full text from Infotrieve]

6) Baker A, Kay-Lambkin FJ, Richmond R, Filia S, Castle D, Williams J, Lewin TJ
Study protocol: a randomised controlled trial investigating the effect of a healthy lifestyle intervention for people with severe mental disorders.
BMC Public Health. 2011;11(1):10.
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7) Nicholas J, Proudfoot J, Parker G, Gillis I, Burckhardt R, Manicavasagar V, Smith M
The ins and outs of an online bipolar education program: a study of program attrition.
J Med Internet Res. 2010;12(5):e57.
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8) Perlis RH, Uher R, Ostacher M, Goldberg JF, Trivedi MH, Rush AJ, Fava M
Association between bipolar spectrum features and treatment outcomes in outpatients with major depressive disorder.
Arch Gen Psychiatry. 2011 Apr;68(4):351-60.
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9) Bora E, Yücel M, Pantelis C, Berk M
Meta-analytic review of neurocognition in bipolar II disorder.
Acta Psychiatr Scand. 2011 Mar;123(3):165-74.
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10) Daray FM, Thommi SB, Ghaemi SN
The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis.
Bipolar Disord. 2010 Nov;12(7):702-6.
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11) Sidor MM, Macqueen GM
Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis.
J Clin Psychiatry. 2011 Feb;72(2):156-67.
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12) Vázquez G, Tondo L, Baldessarini RJ
Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: a meta-analytic review.
Pharmacopsychiatry. 2011 Jan;44(1):21-6.
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13) Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE, Kieseppä T, Altshuler LL, Fornito A, Malhi GS, McIntosh AM, Yurgelun-Todd DA, Labar KS, Sharma V, MacQueen GM, Murray RM, McDonald C
Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data.
Biol Psychiatry. 2011 Feb 15;69(4):326-35.
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14) Berwaerts J, Lane R, Nuamah IF, Lim P, Remmerie B, Hough DW
Paliperidone extended-release as adjunctive therapy to lithium or valproate in the treatment of acute mania: a randomized, placebo-controlled study.
J Affect Disord. 2011 Mar;129(1-3):252-60.
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15) Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J, Hansen AR, Paulson OB, Siebner HR, Kessing LV
Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder.
Trials. 2010;11:97.
BACKGROUND: Depression and bipolar disorder are associated with reduced neural plasticity and deficits in memory, attention and executive function. Drug treatments for these affective disorders have insufficient clinical effects in a large group and fail to reverse cognitive deficits. There is thus a need for more effective treatments which aid cognitive function. Erythropoietin (Epo) is involved in neuroplasticity and is a candidate for future treatment of affective disorders. The investigators have demonstrated that a single dose of Epo improves cognitive function and reduces neurocognitive processing of negative emotional information in healthy and depressed individuals similar to effects seen with conventional antidepressants. The current study adds to the previous findings by investigating whether repeated Epo administration has antidepressant effects in patients with treatment resistant depression and reverses cognitive impairments in these patients and in patients with bipolar disorder in remission. METHODS/DESIGN: The trial has a double-blind, placebo-controlled, parallel-group design. 40 patients with treatment-resistant major depression and 40 patients with bipolar disorder in remission are recruited and randomised to receive weekly infusions of Epo (Eprex; 40,000 IU) or saline (NaCl 0.9%) for 8 weeks. Randomisation is stratified for age and gender. The primary outcome parameters for the two studies are: depression severity measured with the Hamilton Depression Rating Scale 17 items (HDRS-17) 1 in study 1 and, in study 2, verbal memory measured with the Rey Auditory Verbal Learning Test (RAVLT) 23. With inclusion of 40 patients in each study we obtain 86% power to detect clinically relevant differences between intervention and placebo groups on these primary outcomes. TRIAL REGISTRATION: The trial is approved by the Local Ethics Committee: H-C-2008-092, Danish Medicines Agency: 2612-4020, EudraCT: 2008-04857-14, Danish Data Agency: 2008-41-2711 and ClinicalTrials.gov: NCT 00916552. [PubMed Citation] [Order full text from Infotrieve]

16) Wang KS, Liu XF, Aragam N
A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.
Schizophr Res. 2010 Dec;124(1-3):192-9.
Schizophrenia and bipolar disorder both have strong inherited components. Recent studies have indicated that schizophrenia and bipolar disorder may share more than half of their genetic determinants. In this study, we performed a meta-analysis (combined analysis) for genome-wide association data of the Affymetrix Genome-Wide Human SNP array 6.0 to detect genetic variants influencing both schizophrenia and bipolar disorder using European-American samples (653 bipolar cases and 1034 controls, 1172 schizophrenia cases and 1379 controls). The best associated SNP rs11789399 was located at 9q33.1 (p=2.38 × 10(-6), 5.74 × 10(-4), and 5.56 × 10(-9), for schizophrenia, bipolar disorder and meta-analysis of schizophrenia and bipolar disorder, respectively), where one flanking gene, ASTN2 (220kb away) has been associated with attention deficit/hyperactivity disorder and schizophrenia. The next best SNP was rs12201676 located at 6q15 (p=2.67 × 10(-4), 2.12 × 10(-5), 3.88 × 10(-8) for schizophrenia, bipolar disorder and meta-analysis, respectively), near two flanking genes, GABRR1 and GABRR2 (15 and 17kb away, respectively). The third interesting SNP rs802568 was at 7q35 within CNTNAP2 (p=8.92 × 10(-4), 1.38 × 10(-5), and 1.62 × 10(-7) for schizophrenia, bipolar disorder and meta-analysis, respectively). Through meta-analysis, we found two additional associated genes NALCN (the top SNP is rs2044117, p=4.57 × 10(-7)) and NAP5 (the top SNP is rs10496702, p=7.15 × 10(-7)). Haplotype analyses of above five loci further supported the associations with schizophrenia and bipolar disorder. These results provide evidence of common genetic variants influencing schizophrenia and bipolar disorder. These findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in schizophrenia and bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

17) Tesli M, Athanasiu L, Mattingsdal M, Kähler AK, Gustafsson O, Andreassen BK, Werge T, Hansen T, Mors O, Mellerup E, Koefoed P, Jönsson EG, Agartz I, Melle I, Morken G, Djurovic S, Andreassen OA
Association analysis of PALB2 and BRCA2 in bipolar disorder and schizophrenia in a scandinavian case-control sample.
Am J Med Genet B Neuropsychiatr Genet. 2010 Oct 5;153B(7):1276-82.
A recent genome-wide association study (GWAS) found significant association between the PALB2 SNP rs420259 and bipolar disorder (BD). The intracellular functions of the expressed proteins from the breast cancer risk genes PALB2 and BRCA2 are closely related. Therefore, we investigated the relation between genetic variants in PALB2 and BRCA2 and BD. Due to increasing evidence of genetic overlap between BD and schizophrenia (SCZ), we also investigated association with SCZ. In a Scandinavian case-control sample (n?=?686/2,538) we found the BRCA2 SNP rs9567552 to be significantly associated with BD (Nominal P?=?0.00043). Additionally, we replicated the association between PALB2 SNP rs420259 and BD (Nominal P?=?0.025). We then combined our sample with another Nordic case-control sample (n?=?435/11,491) from Iceland, and added results from the Wellcome Trust Case Control Consortium (WTCCC) (n?=?1,868/2,938) and the STEP-UCL/ED-DUB-STEP2 study (n?=?2,558/3,274) in a meta-analysis which revealed a P-value of 1.2?×?10(-5) for association between PALB2 SNP rs420259 and BD (n?=?5,547/20,241). Neither the PALB2 SNP rs420259 nor the BRCA2 SNP rs9567552 were nominally significantly associated with the SCZ phenotype in our Scandinavian sample (n?=?781/2,839). Our findings support PALB2 and BRCA2 as risk genes specifically for BD, and suggest that altered DNA repair related to neurogenesis may be involved in BD pathophysiology. © 2010 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]

18) Perlick DA, Miklowitz DJ, Lopez N, Chou J, Kalvin C, Adzhiashvili V, Aronson A
Family-focused treatment for caregivers of patients with bipolar disorder.
Bipolar Disord. 2010 Sep;12(6):627-37.
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19) Pavuluri MN, Henry DB, Findling RL, Parnes S, Carbray JA, Mohammed T, Janicak PG, Sweeney JA
Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder.
Bipolar Disord. 2010 Sep;12(6):593-605.
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20) Nilsson KK, Jørgensen CR, Craig TK, Straarup KN, Licht RW
Self-esteem in remitted bipolar disorder patients: a meta-analysis.
Bipolar Disord. 2010 Sep;12(6):585-92.
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