randomized controlled trials of valproate (Depakote) for bipolar disorder


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

Macritchie K, Geddes JR, Scott J, Haslam D, de Lima M, Goodwin G.
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OXON, UK, OX3 7JX. john.geddes@psych.ox.ac.uk
Valproate for acute mood episodes in bipolar disorder.
Cochrane Database Syst Rev. 2003;(1):CD004052.
"BACKGROUND: Bipolar disorder is a common debilitating illness, characterised by acute affective episodes with full or partial inter-episode remission. Effective and acceptable treatment of acute episodes is required. Valproate has become a leading adjunctive and alternative mood stabilising treatment to lithium in bipolar disorder. OBJECTIVES: To determine the efficacy and acceptability of valproate in the treatment of acute episodes of bipolar disorder. SEARCH STRATEGY: The search included the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registrar (CCDANCTR), the Cochrane Controlled Clinical Trials Register (CCTR), reference lists of relevant papers and books, and contact with authors of trials, experts and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing valproate with placebo, other mood stabilisers and antipsychotic medication in the treatment of any bipolar affective episode. Participants were of both sexes, of all ages, with a diagnosis of bipolar affective disorder approximating to ICD 10 Code F31 and DSM IV 296. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed independently by two reviewers blind to the authorship and source of papers. Ten randomised controlled trials were found comparing valproate with other interventions in mania. None was found examining its use in depression or mixed affective episodes. Data were extracted on the main outcome 'failure to respond by the end of the study' assessed by a less than 50% reduction in the Young Mania Rating Scale or the SADS-S mania scale. Three trials (316 participants) compared valproate with placebo. Three trials (158 participants) compared valproate with lithium. Two trials (363 participants) compared valproate with olanzapine. One trial (36 participants) compared valproate with haloperidol. Two trials (59 patients) compared valproate with carbamazepine. Acceptability of treatment was estimated using the outcome measure 'total number of subjects withdrawing from the study'. Three trials (321 patients) contributed to the comparison between valproate and placebo, two studies (144 patients) contributed to the comparison with lithium. One study (30 patients) provided data on this outcome in the comparison between valproate and carbamazepine. Pooled relative risks (with 95% confidence intervals) were calculated using fixed effect approaches. MAIN RESULTS: Valproate was more efficacious than placebo (RRR 38%; RR 0.62; 95% C.I. 0.51 to 0.77) in the treatment of mania. There was no significant difference between valproate and lithium (RRI 5%; RR 1.05; 95% C.I. 0.74-1.50) or between valproate and carbamazepine (RRR 34%; RR 0.66; 95% C.I. 0.38 to 1.16). Valproate was less effective than olanzapine (failure to achieve clinical response; RRI 25%; RR 1.25, 95% C.I. 1.01 to 1.54; average of 2.8 point less change on the Mania Rating Scale (95% CI 0.83 to 4.79). There were no significant differences in acceptability as measured by total number of subjects withdrawing from the study. There were significant differences in the side effect profiles of valproate and olanzapine, with more sedation and weight gain on olanzapine. REVIEWER'S CONCLUSIONS: There is consistent, if limited, evidence to suggest that valproate is an efficacious treatment for acute mania. Valproate may be less effective than olanzapine but may cause less sedation and weight gain. More well designed, randomised controlled trials investigating the relative efficacy and acceptability of valproate in the treatment of the full range of acute affective episodes occurring in bipolar disorder are required." [Abstract]

Hirschfeld RM, Baker JD, Wozniak P, Tracy K, Sommerville KW.
University of Texas Medical Branch at Galveston, Galveston, USA. rohirsch@utmb.edu
The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder.
J Clin Psychiatry. 2003 Jul;64(7):841-6.
"BACKGROUND: Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex. METHOD: In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. RESULTS: The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters. CONCLUSION: These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex." [Abstract]

Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW.
Rush-Presbyterian St. Luke's Medical Center, Chicago, Ill 60612-3824, USA. John_Zajecka@rush.edu
A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder.
J Clin Psychiatry. 2002 Dec;63(12):1148-55.
"BACKGROUND: This study compared the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD: This randomized, 12-week, double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and randomly assigned to treatment with divalproex or olanzapine. After an inpatient period of up to 21 days, subjects were followed as outpatients. Dose adjustment was permitted during the inpatient period. Efficacy was assessed using change from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint was change from baseline in weight. Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs. RESULTS: 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomly assigned to treatment. No significant differences between groups were found for any efficacy variable for change from baseline to day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine (p =.210). A significantly (p <.05) greater proportion of olanzapine-treated subjects experienced somnolence, weight gain, edema, rhinitis, and speech disorder (slurred speech); no adverse events were significantly greater in the divalproex group. A number of laboratory measures also demonstrated significant treatment differences, but the clinical significance of many of these is uncertain. Mean body weight changes were significantly greater in the olanzapine group (+ 8.8 lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050). One death occurred during the study (olanzapine group, diabetic ketoacidosis). CONCLUSION: No significant difference in efficacy was found between treatment groups. Divalproex was associated with a more favorable adverse event profile and significantly less weight gain than olanzapine." [Abstract]

Tohen M, Ketter TA, Zarate CA, Suppes T, Frye M, Altshuler L, Zajecka J, Schuh LM, Risser RC, Brown E, Baker RW.
Lilly Research Laboratories, IN 46285, USA. m.tohen@lilly.com
Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study.
Am J Psychiatry. 2003 Jul;160(7):1263-71.
"OBJECTIVE: Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex. METHOD: This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest. RESULTS: Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness. CONCLUSIONS: In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ." [Abstract]

Revicki DA, Paramore LC, Sommerville KW, Swann AC, Zajecka JM; Depakote Comparator Study Group.
Center for Outcomes Research, MEDTAP International, Bethesda, MD 20814, USA. revicki@medtap.com
Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes.
J Clin Psychiatry. 2003 Mar;64(3):288-94.
"BACKGROUND: Divalproex sodium is a mood stabilizer used in the United States for the treatment of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical antipsychotic, was approved for the treatment of acute mania. This study compares the clinical, health-related quality of life (HRQL), and economic outcomes of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD: This 12-week, double-blind, double-dummy, randomized clinical trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for an acute manic episode recruited from 21 U.S. clinical centers. Subjects were randomly assigned to treatment with either divalproex or olanzapine and were followed in hospital for up to 21 days. If after 21 days clinical improvements (based on the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects showing clinical improvement were treated for up to 12 weeks. HRQL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and costs were collected over the 12-week study. RESULTS: A total of 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed beyond 21 days. No statistically significant differences between the treatment groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week outpatient medical costs were significantly lower for the divalproex-treated group (541 US dollars) compared with the olanzapine-treated group (1080 US dollars) (p =.004). There was no significant difference in total medical costs between the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars; p =.88). CONCLUSION: Divalproex is associated with lower 12-week outpatient costs compared with olanzapine. Divalproex and olanzapine have similar short-term effects on clinical or HRQL outcomes in bipolar disorder subjects." [Abstract]

Tohen M, Baker RW, Altshuler LL, Zarate CA, Suppes T, Ketter TA, Milton DR, Risser R, Gilmore JA, Breier A, Tollefson GA.
Lilly Research Laboratories, Indianapolis, IN 46285, USA. m.tohen@lilly.com
Olanzapine versus divalproex in the treatment of acute mania.
Am J Psychiatry. 2002 Jun;159(6):1011-7.
"OBJECTIVE: The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. METHOD: A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures. RESULTS: The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment. CONCLUSIONS: The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex." [Abstract]

Dalkilic A, Diaz E, Baker CB, Pearsall HR, Woods SW.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
Effects of divalproex versus lithium on length of hospital stay among patients with bipolar disorder.
Psychiatr Serv. 2000 Sep;51(9):1184-6.
"The medical records of all inpatients with bipolar disorder at the Connecticut Mental Health Center in 1997 were examined to compare length of stay for patients who began monotherapy with divalproex (27 treatment starts) and lithium (20 treatment starts). No statistically significant difference was found in length of stay (11. 5+/-6.9 and 10.3+/-5.2 days for patients on divalproex and lithium, respectively) or other length-of-stay variables. Demographic variables, diagnostic variables, and dosages of neuroleptics and benzodiazepines used adjunctively were similar as well. Dosages and blood levels for divalproex and lithium were consistent with practice guidelines. Prospective randomized studies are needed to compare the cost-effectiveness of divalproex and of lithium in the treatment of bipolar disorder." [Full Text]

McElroy SL, Keck PE, Stanton SP, Tugrul KC, Bennett JA, Strakowski SM.
Department of Psychiatry, University of Cincinnati College of Medicine, Ohio, 45267, USA.
A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania.
J Clin Psychiatry. 1996 Apr;57(4):142-6.
"BACKGROUND: Uncontrolled evidence suggests that divalproex administered via the oral loading strategy of 20 mg/kg/day may produce clinically significant antimanic response within 3 days of treatment in some patients. We conducted a prospective study to compare the antimanic response of divalproex oral loading with that of haloperidol in the initial treatment of acute psychotic mania. METHOD: After a < or = 1-day screening period, 36 consecutive hospitalized patients with bipolar disorder, manic or mixed phase and with psychotic features, were randomly assigned to receive either divalproex 20 mg/kg/day or haloperidol 0.2 mg/kg/day for 6 full days, without other psychotropic agents except lorazepam up to 4 mg/day for management of agitation. Serum valproate concentrations were measured after 1 day of treatment. Response was measured daily by a blind rater using the Young Mania Rating Scale and the Scale for Assessment of Positive Symptoms. RESULTS: Divalproex oral loading and haloperidol were equally effective in acutely reducing manic and psychotic symptoms. The greatest rate of improvement for both drug regimens occurred over the first 3 full days of treatment. Side effects were infrequent and minor for both treatments, except for extrapyramidal side effects which were significantly more common with haloperidol. CONCLUSION: Divalproex oral loading may produce rapid onset of antimanic and antipsychotic response comparable to that of haloperidol and with minimal side effects in the initial treatment of acute psychotic mania in a subset of bipolar patients." [Abstract]

Kowatch RA, Suppes T, Carmody TJ, Bucci JP, Hume JH, Kromelis M, Emslie GJ, Weinberg WA, Rush AJ.
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas 75235-9070, USA. kowatch@utsw.swmed.edu
Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder.
J Am Acad Child Adolesc Psychiatry. 2000 Jun;39(6):713-20.
"OBJECTIVE: To develop effect sizes for 3 mood stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase treatment of bipolar I or II disorder, mixed or manic episode, in children and adolescents aged 8 to 18 years. METHOD: Forty-two outpatients with a mean age of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were randomly assigned to 6 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS). RESULTS: Using a > or = 50% change from baseline to exit in the Y-MRS scores to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%; and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were well tolerated, and no serious adverse effects were seen. CONCLUSIONS: Divalproex sodium, lithium, and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode." [Abstract]

Bahk WM, Shin YC, Woo JM, Yoon BH, Lee JS, Jon DI, Chung SK, Choi SK, Paik IH, Pae CU
Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study.
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jan;29(1):115-21.
Mood stabilizers and atypical antipsychotics are commonly combined for the treatment of bipolar mania. The aim of this study was to compare the effectiveness and tolerability of topiramate and divalproex in combination with risperidone for treating acute mania patients in a naturalistic treatment setting. Seventy-four patients who met the DSM-IV criteria for bipolar mania were enrolled in this study. In order to assess the efficacy and the extrapyramidal symptoms (EPS), the Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI) and Simpson-Angus Rating Scale (SARS) were measured at the baseline and at weeks 1, 3 and 6. From the baseline to the endpoint, the YMRS and CGI scores were reduced by 67.9% and 56.6% in the topiramate plus risperidone group (TPMG). The YMRS and CGI scores were also reduced by 63.7% and 58.2% in the divalproex plus risperidone group (DVPG). The weight and body mass index (BMI) increased significantly by 3.6% and 3.3% from the baseline to the endpoint in the DVPG, while they decreased by 0.5% and 0.4%, respectively, with no significant difference in the TPMG. There were no serious adverse events in either group. Despite the methodological limitations, topiramate was effective and tolerable for treating acute mania and may also be a promising alternative to a weight-gain liable mood stabilizer (MS) such as divalproex. [Abstract]

Baker RW, Brown E, Akiskal HS, Calabrese JR, Ketter TA, Schuh LM, Trzepacz PT, Watkin JG, Tohen M
Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania.
Br J Psychiatry. 2004 Dec;185472-8.
BACKGROUND: Few controlled studies examine the treatment of depressive features in mania. AIMS: To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania. METHOD: Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5-20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients. RESULTS: In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy. CONCLUSIONS: In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings. [Abstract]

Yatham LN, Paulsson B, Mullen J, Vågerö AM
Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania.
J Clin Psychopharmacol. 2004 Dec;24(6):599-606.
Quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) for the treatment of mania was evaluated in 2 double-blind, placebo-controlled studies. Patients were randomized to 3 or 6 weeks of treatment with QTP plus Li/DVP or placebo (PBO) plus Li/DVP. Quetiapine was dosed up to 800 mg/d; Li was dosed to achieve serum concentrations of 0.7-1.0 mEq/L and DVP to 50-100 microg/mL. A total of 402 patients were randomized: 197 to QTP + Li/DVP and 205 to PBO + Li/DVP. The mean quetiapine dose in responders was 492 (+/-204) mg/d. Improvement in the Young Mania Rating Scale (YMRS) at day 21 in the QTP + Li/DVP group (-15.29) was statistically superior to the PBO + Li/DVP group (-12.19) (P < 0.05). A statistically significant difference in favor of quetiapine was observed within the first week (P < 0.05). Significantly more QTP + Li/DVP patients achieved a response (> or =50% decrease in the YMRS) at day 21 (QTP + Li/DVP, 55.7%; PBO + Li/DVP, 41.6%;P < 0.01). Improvements in Clinical Global Impression-Bipolar Severity of Illness scores by day 21 were also significantly greater in QTP + Li/DVP-treated patients (-1.59) versus PBO + Li/DVP (-1.19) (P < 0.01). Common adverse events (> or =5% and twice that in the PBO + Li/DVP group) in the QTP + Li/DVP group were somnolence, dry mouth, and asthenia. Quetiapine combined with Li/DVP was not associated with extrapyramidal symptoms (including akathisia) or emergent depression. More QTP + Li/DVP-treated patients completed the trial, and there was no difference in discontinuation rates due to adverse events between the two groups. Quetiapine, in combination with lithium or divalproex, is well tolerated and has superior efficacy to lithium or divalproex alone in the treatment of bipolar mania. [Abstract]

Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD.
Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston 77030, USA.
Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania.
Am J Psychiatry. 1999 Aug;156(8):1264-6.
"OBJECTIVE: The authors investigated the relationship between number of lifetime episodes of affective disorder and the antimanic response to lithium, divalproex, or placebo. METHOD: The subjects were 154 of the 179 inpatients with acute mania who entered a 3-week parallel group, double-blind study. The primary efficacy measure was the manic syndrome score from the Schedule for Affective Disorders and Schizophrenia. The relationship between improvement and number of previous episodes was investigated by using nonlinear regression analysis. RESULTS: An apparent transition in the relationship between number of previous episodes and response to antimanic medication occurred at about 10 previous episodes. For patients who had experienced more episodes, response to lithium resembled the response to placebo but was worse than response to divalproex. For patients who had experienced fewer episodes, however, the responses to lithium and divalproex did not differ and were better than the response to placebo. This differential response pattern was not related to rapid cycling or mixed states. CONCLUSIONS: A history of many previous episodes was associated with poor response to lithium or placebo but not to divalproex." [Abstract]

Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD.
University of Texas-Houston Medical School and Harris County Psychiatric Center, USA.
Mania: differential effects of previous depressive and manic episodes on response to treatment.
Acta Psychiatr Scand. 2000 Jun;101(6):444-51.
"OBJECTIVE: We compared effects of previous depressive or manic episodes on antimanic response. METHOD: In-patients in a parallel-groups, double-blind comparison of lithium, divalproex or placebo for manic episodes had comprehensive evaluations of illness history. We used non-linear curve fitting of change in Manic Syndrome Score (MSS) of the Schedule for Affective Disorders and Schizophrenia (SADS) versus previous depressive or manic episodes to investigate their relationships to MSS improvement. RESULTS: Response to lithium, but not to divalproex or placebo, worsened with increased depressive or manic episodes. More than 11 manic, or four depressive, episodes was associated with response to lithium that did not differ from placebo. Effects of previous depressive and manic episodes appeared independent, and could not be accounted for by increased rapid cycling or mixed states. CONCLUSION: At least four previous depressive or 12 previous manic episodes are associated with reduced antimanic response to lithium." [Abstract]

Gyulai L, Bowden CL, McElroy SL, Calabrese JR, Petty F, Swann AC, Chou JC, Wassef A, Risch CS, Hirschfeld RM, Nemeroff CB, Keck PE Jr, Evans DL, Wozniak PJ.
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. gyulai@mail.med.upenn.edu
Maintenance efficacy of divalproex in the prevention of bipolar depression.
Neuropsychopharmacology. 2003 Jul;28(7):1374-82. Epub 2003 May 28.
"Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness." [Abstract]

Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou JC, Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ.
Department of Psychiatry, University of Texas Health Science Center at San Antonio, 78284-7792, USA. bowdenc@uthscsa.edu
A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.
Arch Gen Psychiatry. 2000 May;57(5):481-9.
"BACKGROUND: Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS: A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. RESULTS: The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS: The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures." [Abstract]

Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, Dilsaver SC, Davis JM.
Department of Psychiatry, University of Texas Medical School at Houston, USA.
Depression during mania. Treatment response to lithium or divalproex.
Arch Gen Psychiatry. 1997 Jan;54(1):37-42.
"BACKGROUND: Little information exists from controlled studies about clinical characteristics that predict treatment response in mania. The presence of depressive symptoms during manic episodes may be associated with poor response to psychopharmacological treatments. This is an investigation of the relation between depressive symptoms and treatment response in acute manic episodes. METHODS AND DESIGN: In a parallel-group, double-blind study, 179 patients hospitalized for acute manic episodes were randomized to receive divalproex sodium, lithium carbonate, or placebo (ratio, 2:1:2). The study was carried out at 9 academic medical centers. Patients had comprehensive evaluations of behavior and symptoms before and during 3 weeks of treatment. The primary outcome measure, change in mania factor scores derived from the Schedule for Affective Disorders and Schizophrenia: Change Version, was compared in patients with and without depressive symptoms at baseline according to nurse- or physician-rated scales. RESULTS: Depressive symptoms were associated with poor antimanic response to lithium and with better response to divalproex. This was not due to differences in overall severity of illness, substance abuse, gender, age, or history. CONCLUSIONS: These data suggest that even a modest level of pretreatment depression-related symptoms is a robust predictor of lithium nonresponse, and is associated with better response to divalproex. Although their overall efficacy in acute mania is similar, lithium and divalproex may be most effective in clinically and biologically distinct groups of patients." [Abstract]

Swann AC.
University of Texas, Houston Medical Scholl, USA.
[Prediction of treatment response in acute mania: controlled clinical trials with divalproex]
Encephale. 2001 May-Jun;27(3):277-9.
"OBJECTIVE: To determine predictive factors for response to mood stabilising treatment in manic episodes and to determine the mood stabilising properties of divalproex. METHODS: For predictive factors, 179 subjects in 3 parallel groups (divalproex, lithium, placebo) were evaluated over a period of 21 days by using structured interviews conducted by the clinician (SADS-C) and by nursing staff (ADRS). For the follow-on study, 372 stabilised patients were randomised to three groups: divalproex, lithium or placebo. RESULTS: The presence of depressive symptoms was associated with poor response to lithium, and patients with manic episodes with depressive symptoms or with rapid cycling exhibited good response to divalproex, while classical manic episodes showed good response to lithium and divalproex, and dysphoric or irritable manic episodes responded well to divalproex but not to lithium. A high number of both manic and depressive prior episodes is predictive of poor response to lithium and favourable response to divalproex. The effects of depressive and manic episodes appear to be independent and do not correlate with the duration of the illness or age at onset. Divalproex was superior to placebo in preventing all types of episodes, whether or not relapse was depressive or manic, and it was also superior to lithium in preventing depressive episodes. CONCLUSION: Specific features of the disease history and of the semiology of individual episodes help predict therapeutic response to mood stabilisers." [Abstract]

Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD.
University of Texas-Houston Health Science Center, P.O. Box 20708, Houston, TX 77225, USA.
Pattern of response to divalproex, lithium, or placebo in four naturalistic subtypes of mania.
Neuropsychopharmacology. 2002 Apr;26(4):530-6.
"We investigated effects of antimanic treatments on specific aspects of mania, prediction of response, and the existence of naturalistic subgroups of patients with different treatment response in 179 inpatients randomized to antimanic treatment with lithium, divalproex, or placebo. Psychiatric symptom ratings were conducted by clinicians and nurses before and during treatment. Factor analysis using physician and nurse rating scales, followed by a cluster analysis, yielded anxious-depressive, psychotic, classic, and irritable subtypes. We compared: (1) treatment effects on factor scores; (2) responses to treatment across subtypes; and (3) pattern of symptom change with each treatment. The anxious-depressed subtype did not respond to any treatment; the psychotic and classic subtypes responded similarly to lithium and to divalproex; and the irritable-dysphoric subtype responded better to divalproex than to lithium. Overall, divalproex improved impulsivity and hostility significantly more than placebo, and lithium or divalproex improved hyperactivity more than placebo. These data suggest that there are naturalistic subtypes of manic episodes with different responses to treatment." [Abstract]

Swann AC, Daniel DG, Kochan LD, Wozniak PJ, Calabrese JR.
Psychosis in mania: specificity of its role in severity and treatment response.
J Clin Psychiatry. 2004 Jun;65(6):825-9.
BACKGROUND: Psychosis is a prominent characteristic of manic episodes. We investigated relationships between the presence of psychotic features, the severity of the manic syndrome, and syndrome severity's response to treatment. METHOD: 179 subjects meeting Research Diagnostic Criteria for a manic episode of bipolar I disorder were hospitalized for acute manic episodes and treated in a randomized trial of lithium, divalproex sodium, or placebo. Factor and cluster analyses were carried out using the clinician-rated Schedule for Affective Disorders and Schizophrenia, Change version (SADS-C) and the nurse-rated Affective Disorder Rating Scale (ADRS). RESULTS: Subjects with psychotic features had significantly (p < .005) greater overall impairment (lower Global Assessment Scale [GAS] scores) but did not differ in severity of mania scores compared with those without psychotic features. Psychosis factor scores correlated significantly (p < .000001) with GAS scores but not with mania scores. Baseline psychosis factor scores did not correlate with subsequent treatment-associated change in mania scores, but change in mania scores during treatment correlated significantly (p < .000001) with change in the psychosis factor. Changes in psychosis factor scores correlated significantly with changes in mania rating scale scores regardless of treatment. CONCLUSIONS: Psychotic features as a component of manic episodes contribute substantially to overall impairment. Treatments that successfully treat mania also reduce psychosis scores. [Abstract]

Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME
Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study.
Arch Gen Psychiatry. 2005 Jan;62(1):37-45.
BACKGROUND: More than half of all individuals with bipolar disorder have a substance abuse problem at some point in their lifetime. Patients with comorbid substance abuse disorders often are excluded from clinical trials. Thus, treatments targeting this high-risk clinical population are lacking. OBJECTIVE: To evaluate the efficacy of divalproex sodium (hereafter referred to as valproate) in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism. DESIGN: A 24-week, double-blind, placebo-controlled, randomized parallel-group trial. SETTING: A university hospital serving as a primary catchment-area hospital and tertiary-care facility. PARTICIPANTS: Fifty-nine subjects with diagnoses of bipolar I disorder and alcohol dependence.Intervention All study subjects received treatment as usual, including lithium carbonate and psychosocial interventions, and were randomized to receive valproate or placebo. MAIN OUTCOME MEASURES: Primary alcohol use outcomes included changes in alcohol use as indicated by changes in proportion of heavy drinking days and number of drinks per heavy drinking day. Other alcohol use outcomes included proportion of any drinking days, number of drinks per drinking day, and relapse to sustained heavy drinking. Mood outcomes included changes in depressive and manic symptoms. We used the mixed model to analyze longitudinal data. The first model used time of assessment, bipolar subtype (mixed, manic, or depressed), and treatment group (placebo or valproate) as covariates. The second nested model included the additional covariate of medication adherence. RESULTS: The valproate group had a significantly lower proportion of heavy drinking days (P = .02) and a trend toward fewer drinks per heavy drinking day (P = .055) than the placebo group. When medication adherence was added as covariate, the valproate group had significantly fewer drinks per heavy drinking day (P = .02) and fewer drinks per drinking day (P = .02). Higher valproate serum concentration significantly correlated with improved alcohol use outcomes. Manic and depressive symptoms improved equally in both groups. Level of gamma-glutamyl transpeptidase was significantly higher in the placebo group compared with the valproate group. CONCLUSIONS: Valproate therapy decreases heavy drinking in patients with comorbid bipolar disorder and alcohol dependence. The results of this study indicate the potential clinical utility of the anticonvulsant mood stabilizer, valproate, in bipolar disorder with co-occurring alcohol dependence. [Abstract]

Tohen M, Chengappa KN, Suppes T, Zarate CA Jr, Calabrese JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD, Tollefson GD, Breier A.
Lilly Research Laboratories, Eli Lilly & Co, Indianapolis, IN 46285, USA.
Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy.
Arch Gen Psychiatry. 2002 Jan;59(1):62-9.
"BACKGROUND: A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes. METHODS: The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer). RESULTS: Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. CONCLUSION: Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes." [Abstract]

Tohen M, Chengappa KN, Suppes T, Baker RW, Zarate CA, Bowden CL, Sachs GS, Kupfer DJ, Ghaemi SN, Feldman PD, Risser RC, Evans AR, Calabrese JR.
Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone.
Br J Psychiatry. 2004 Apr;184:337-45.
BACKGROUND: Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone. METHOD: Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months. RESULTS: The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023). CONCLUSIONS: Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy. [Abstract]

Muller-Oerlinghausen B, Retzow A, Henn FA, Giedke H, Walden J.
Department of Psychiatry, University Clinic Benjamin Franklin, Berlin, Germany. bmoe@zedat.fu-berlin.de
Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. European Valproate Mania Study Group.
J Clin Psychopharmacol. 2000 Apr;20(2):195-203.
"To compare the efficacy of sodium valproate administered as adjunct to neuroleptic medication for patients with acute mania with the efficacy of neuroleptics alone, the authors conducted a 21-day, randomized, double-blind, parallel-group, placebo-controlled trial. The study design closely reflected a clinical psychiatric setting in Europe where patients with acute mania commonly receive neuroleptic medication. In this trial, 136 hospitalized patients met the ICD-10 criteria for acute manic episodes; these patients received a fixed dose of 20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel GmbH, Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably haloperidol and/or perazine. The primary outcome measure was the mean dose of neuroleptic medication (after conversion into haloperidol-equivalents) for the 21-day study period. Severity of symptoms was measured using the Young Mania Rating Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression Scale. Intent-to-treat analysis was based on 69 patients treated with valproate and 67 patients who received placebo. Groups were comparable with regard to demographic and clinical baseline data. Premature discontinuations occurred in only 13% of the patients. The mean neuroleptic dose declined continuously in the valproate group, whereas only slight variations were observed in the placebo group; the difference was statistically significant (p = 0.0007) for study weeks 2 and 3. The combination of neuroleptic and valproate proved superior to neuroleptics in attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement rate shown on the YMRS) was higher for the combination with valproate than for the group receiving only neuroleptics (70% vs. 46%; p = 0.005). Adverse events consisted of those known for valproate or neuroleptics; the only adverse event was asthenia, which occurred more frequently with the combination therapy. Valproate represents a useful adjunct medication for the treatment of acute manic symptoms. Valproate is beneficial because it allows the administration of fewer neuroleptic medications and produces improved and quicker remission of manic symptoms." [Abstract]

Pope HG Jr, McElroy SL, Keck PE Jr, Hudson JI.
Biological Psychiatry Laboratory, McLean Hospital, Belmont, Mass 02178.
Valproate in the treatment of acute mania. A placebo-controlled study.
Arch Gen Psychiatry. 1991 Jan;48(1):62-8.
"We conducted a placebo-controlled, double-blind study of valproate, a drug originally developed as an antiepileptic, in 36 patients with acute manic episodes who had previously failed to respond to or to tolerate lithium carbonate. Treatment duration was 7 to 21 days, with no other psychotropic medications permitted except lorazepam up to 4 mg/d during the first 10 days of treatment. Serum valproate concentrations were measured three times weekly; an unblinded investigator then adjusted dosage to produce serum concentrations between 50 and 100 mg/L. Valproate proved superior to placebo in alleviating manic symptoms. The 17 patients randomized to active drug demonstrated a median 54% decrease in scores on the Young Mania Rating Scale as compared with a median 5.0% decrease among the 19 patients receiving placebo. On the 100-point Global Assessment Scale of overall psychiatric functioning, patients receiving valproate improved by a median of 20 points as compared with a zero-point change with placebo. Significant differences also emerged on the Brief Psychiatric Rating Scale and in the number of supplemental doses of lorazepam required by the patients in each group. Substantial antimanic effects appeared within 1 to 4 days of achieving therapeutic serum valproate concentrations. Adverse effects were infrequent, with no adverse effect appearing significantly more frequently with valproate than with placebo. We conclude that valproate represents a useful new drug for the treatment of manic patients." [Abstract]

Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM, Rush AJ, Small JG, et al.
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group.
JAMA. 1994 Mar 23-30;271(12):918-24.
"OBJECTIVE--To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. DESIGN--Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness. PATIENTS--A total of 179 hospitalized, acutely manic patients meeting the Research Diagnostic Criteria for manic disorder, approximately half of whom had been nonresponsive to lithium previously, were studied at nine university-affiliated hospitals. INTERVENTIONS--After a minimum 3-day washout period, random assignment for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated to a target concentration of 1041 mumol/L (150 micrograms/mL) or 1.5 mmol/L (conventionally expressed as milliequivalents per liter), respectively. MAIN OUTCOME MEASURES--Primary outcome measures were changes in the Mania Rating scale derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS--Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P = .017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P = .004) and 49% for lithium (P = .025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients. CONCLUSIONS--Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium." [Abstract]

Bowden CL, Davis J, Morris D, Swann A, Calabrese J, Lambert M, Goodnick P.
Psychiatric Institute, Chicago, Illinois, USA.
Effect size of efficacy measures comparing divalproex, lithium and placebo in acute mania.
Depress Anxiety. 1997;6(1):26-30.
"Effect size (ES) is a statistical concept that can be used to improve the interpretation of results from psychopharmacological studies. ES may aid interpretation of results when sample size is unbalanced or small or when units or levels of baseline measures differ across items. Usually, an investigator can define a threshold value for a clinically meaningful ES based on published data and clinical judgment or by resorting to conventions, e.g., a medium ES = 0.5 S.D., which can usually be discerned by the trained clinician. In the present study, we apply ES analysis to results from a study comparing the effectiveness of divalproex (DIVAL), lithium (LI), and placebo (PLA) in hospitalized, acutely manic patients. One hundred seventy-six patients were randomly assigned to DIVAL, LI, or PLA in a 2:1:2 ratio, with drug administered in a double-blind, parallel group design for 21 days. The primary efficacy measure was the Mania Rating Scale from the Schedule for Affective Disorders and Schizophrenia, composed of the Manic Syndrome Score (MSS) from items that are relatively specific to the manic state, and the Behavior and Ideation Score (BIS), which reflects severe but nonspecific psychopathology. Improvement of the MSS after 5 days of treatment was difficult to interpret based on percentage change (DIVAL = 19%, LI = 13.5%, PLA = 8.5%). However, the corresponding effect sizes of 0.79, 0.55, and 0.35 indicated a medium to marked ES for DIVAL, a medium ES for LI, and a small ES for PLA at this early point in treatment. Similarly, the ES for change on the MSS at the end of treatment indicated a large, readily observable improvement with both DIVAL (ES = 1.01) and LI (ES = 0.79) vs. an ES of 0.37 for PLA. ES analysis also indicated that the BIS is a less robust indicator of change to either drug. The ES at the end of treatment for the BIS was 0.67 for DIVAL-, 0.62 for LI-, and 0.25 for PLA-treated patients." [Abstract]

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Recent Valproate RCT Results

1) 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]

2) 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.
[PubMed Citation] [Order full text from Infotrieve]

3) 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.
[PubMed Citation] [Order full text from Infotrieve]

4) 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]

5) Vasudev A, Macritchie K, Vasudev K, Watson S, Geddes J, Young AH
Oxcarbazepine for acute affective episodes in bipolar disorder.
Cochrane Database Syst Rev. 2011;(12):CD004857.
[PubMed Citation] [Order full text from Infotrieve]

6) West AE, Weinstein SM, Celio CI, Henry D, Pavuluri MN
Co-morbid disruptive behavior disorder and aggression predict functional outcomes and differential response to risperidone versus divalproex in pharmacotherapy for pediatric bipolar disorder.
J Child Adolesc Psychopharmacol. 2011 Dec;21(6):545-53.
[PubMed Citation] [Order full text from Infotrieve]

7) Pavuluri MN, Ellis JA, Wegbreit E, Passarotti AM, Stevens MC
Pharmacotherapy impacts functional connectivity among affective circuits during response inhibition in pediatric mania.
Behav Brain Res. 2012 Jan 15;226(2):493-503.
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8) Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR
Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis.
Lancet. 2011 Oct 8;378(9799):1306-15.
[PubMed Citation] [Order full text from Infotrieve]

9) Meltzer HY, Bonaccorso S, Bobo WV, Chen Y, Jayathilake K
A 12-month randomized, open-label study of the metabolic effects of olanzapine and risperidone in psychotic patients: influence of valproic acid augmentation.
J Clin Psychiatry. 2011 Dec;72(12):1602-10.
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10) Kemp DE, Karayal ON, Calabrese JR, Sachs GS, Pappadopulos E, Ice KS, Siu CO, Vieta E
Ziprasidone with adjunctive mood stabilizer in the maintenance treatment of bipolar I disorder: long-term changes in weight and metabolic profiles.
Eur Neuropsychopharmacol. 2012 Feb;22(2):123-31.
This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (n=127) vs. placebo+MS (n=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes. [PubMed Citation] [Order full text from Infotrieve]

11) Liu HY, Potter MP, Woodworth KY, Yorks DM, Petty CR, Wozniak JR, Faraone SV, Biederman J
Pharmacologic treatments for pediatric bipolar disorder: a review and meta-analysis.
J Am Acad Child Adolesc Psychiatry. 2011 Aug;50(8):749-62.e39.
[PubMed Citation] [Order full text from Infotrieve]

12) Oquendo MA, Galfalvy HC, Currier D, Grunebaum MF, Sher L, Sullivan GM, Burke AK, Harkavy-Friedman J, Sublette ME, Parsey RV, Mann JJ
Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior.
Am J Psychiatry. 2011 Oct;168(10):1050-6.
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13) Vieta E, Günther O, Locklear J, Ekman M, Miltenburger C, Chatterton ML, Åström M, Paulsson B
Effectiveness of psychotropic medications in the maintenance phase of bipolar disorder: a meta-analysis of randomized controlled trials.
Int J Neuropsychopharmacol. 2011 Sep;14(8):1029-49.
The purpose of this meta-analysis was to examine the efficacy of maintenance treatments for bipolar disorder. Placebo-controlled or active comparator bipolar maintenance clinical trials of ?6 months' duration with at least 15 patients/treatment group were identified using Medline, EMBASE, clinicaltrials.gov, and Cochrane databases (1993 to July 2010). The main outcome measure was relative risk for relapse for patients in remission. Twenty trials (5,364 patients) were identified. Overall, lithium and quetiapine were the most studied agents (eight and five trials, respectively). The majority of studies included patients who had previously responded to treatment for an acute episode. All interventions, with the exception of perphenazine+mood stabilizer, showed a relative risk for manic/mixed or depressive relapse below 1.0, although there was variation in the statistical significance of the findings vs. placebo. No monotherapy was associated with a significantly reduced risk for both manic/mixed and depressed relapse. Of the combination treatments, only quetiapine+lithium/divalproex, was associated with a significantly reduced risk vs. comparator (placebo+lithium/valproate) for relapse at both the manic/mixed and depressed poles of bipolar illness. Limitations for the analysis include differences in study durations and definitions of relapse. In conclusion, available maintenance therapies show considerable variation in efficacy. The efficacy of lithium and divalproex has been confirmed, but newer therapies, such as a number of atypical antipsychotics were also shown to be effective in bipolar disorder. Efficacy of all maintenance interventions needs to be balanced against the safety and tolerability profiles of individual agents. [PubMed Citation] [Order full text from Infotrieve]

14) Sachs GS, Ice KS, Chappell PB, Schwartz JH, Gurtovaya O, Vanderburg DG, Kasuba B
Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial.
J Clin Psychiatry. 2011 Oct;72(10):1413-22.
[PubMed Citation] [Order full text from Infotrieve]

15) Pavuluri MN, Passarotti AM, Lu LH, Carbray JA, Sweeney JA
Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder: fMRI outcomes.
Psychiatry Res. 2011 Jul 30;193(1):28-37.
The aim of this research was to determine the relative effects of risperidone and divalproex on brain function in pediatric mania. This is a double-blind 6-week functional magnetic resonance imaging trial with 24 unmedicated manic patients randomized to risperidone or divalproex, and 14 healthy controls (HCs) matched for IQ and demographic factors (mean age: 13.1±3.3years). A pediatric affective color matching task, in which subjects matched the color of a positive, negative or neutral word with one of two colored circles, was administered. The primary clinical measure was the Young Mania Rating Scale (YMRS). The risperidone group, relative to HC, showed an increase in activation from pre- to post-treatment in right pregenual and subgenual anterior cingulate cortex and decreased activation in bilateral middle frontal gyrus during the negative condition; and decreased activation in left inferior and medial, and right middle frontal gyri, left inferior parietal lobe, and right striatum with positive condition. In the divalproex group, relative to HC, there was an increased activation in right superior temporal gyrus in the negative condition; and in left medial frontal gyrus and right precuneus with the positive condition. Greater pre-treatment right amygdala activity with negative and positive condition in the risperidone group, and left amygdala activity with positive condition in divalproex group, predicted poor response on YMRS. Risperidone and divalproex yield differential patterns of prefrontal activity during an emotion processing task in pediatric mania. Increased amygdala activity at baseline is a potential biomarker predicting poor treatment response to both the risperidone and divalproex. [PubMed Citation] [Order full text from Infotrieve]

16) Li SC, Aggarwal SK
Estimation of resource utilisation difference between lithium and valproate treatment groups from the VALID study.
J Med Econ. 2011;14(3):350-6.
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17) Marcus R, Khan A, Rollin L, Morris B, Timko K, Carson W, Sanchez R
Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study.
Bipolar Disord. 2011 Mar;13(2):133-44.
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18) Wang Z, Gao K, Kemp DE, Chan PK, Serrano MB, Conroy C, Fang Y, Ganocy SJ, Findling RL, Calabrese JR
Lamotrigine adjunctive therapy to lithium and divalproex in depressed patients with rapid cycling bipolar disorder and a recent substance use disorder: a 12-week, double-blind, placebo-controlled pilot study.
Psychopharmacol Bull. 2010;43(4):5-21.
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19) Tarr GP, Glue P, Herbison P
Comparative efficacy and acceptability of mood stabilizer and second generation antipsychotic monotherapy for acute mania--a systematic review and meta-analysis.
J Affect Disord. 2011 Nov;134(1-3):14-9.
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20) Yildiz A, Vieta E, Leucht S, Baldessarini RJ
Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials.
Neuropsychopharmacology. 2011 Jan;36(2):375-89.
We conducted meta-analyses of findings from randomized, placebo-controlled, short-term trials for acute mania in manic or mixed states of DSM (III-IV) bipolar I disorder in 56 drug-placebo comparisons of 17 agents from 38 studies involving 10,800 patients. Of drugs tested, 13 (76%) were more effective than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperdone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone. Their pooled effect size for mania improvement (Hedges' g in 48 trials) was 0.42 (confidence interval (CI): 0.36-0.48); pooled responder risk ratio (46 trials) was 1.52 (CI: 1.42-1.62); responder rate difference (RD) was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat of 6 (all p<0.0001). In several direct comparisons, responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate, or carbamazepine; lithium did not differ from valproate, nor did second generation antipsychotics differ from haloperidol. Meta-regression associated higher study site counts, as well as subject number with greater placebo (not drug) response; and higher baseline mania score with greater drug (not placebo) response. Most effective agents had moderate effect-sizes (Hedges' g=0.26-0.46); limited data indicated large effect sizes (Hedges' g=0.51-2.32) for: carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen. The findings support the efficacy of most clinically used antimanic treatments, but encourage more head-to-head studies and development of agents with even greater efficacy. [PubMed Citation] [Order full text from Infotrieve]