randomized controlled trials of carbamazepine (Tegretol) for bipolar disorder

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

Hartong EG, Moleman P, Hoogduin CA, Broekman TG, Nolen WA; LitCar Group.
Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients.
J Clin Psychiatry. 2003 Feb;64(2):144-51.
"BACKGROUND: Alternatives to lithium for prophylactic treatment of patients with bipolar affective disorders are increasingly being advocated. However, trials comparing lithium with alternatives are scarce and often biased. METHOD: We studied 94 patients with at least 2 episodes of bipolar disorder (DSM-III-R) during the previous 3 years who were in remission at entry into the study. Treatment with lithium or carbamazepine had not exceeded a total of 6 months during their lifetime. Patients were randomly assigned to carbamazepine or lithium at entry into the 2-year double-blind study or during the acute index episode previous to entry into the study. No concurrent antipsychotics or antidepressants were allowed. RESULTS: On lithium treatment, 12/44 patients developed an episode, compared with 21/50 on carbamazepine treatment. Episodes on lithium treatment occurred almost exclusively during the first 3 months of the trial. Carbamazepine carried a constant risk of an episode of about 40% per year. Efficacy of lithium was superior to that of carbamazepine in patients with a (hypo)manic index episode that had not been treated with study drug during the index episode (p <.01) and also in patients with prior hypomanic but no manic episodes (p <.05). The proportion of patients who dropped out was slightly higher among those taking lithium (16/44) compared with those taking carbamazepine (13/50), resulting in 16/44 patients (36%) on lithium treatment completing the 2 years with no episode, compared with 16/50 (32%) on carbamazepine treatment. CONCLUSION: Lithium appears to be superior in prophylactic efficacy to carbamazepine in bipolar patients not previously treated with mood stabilizers. Our results should reinforce efforts to put and maintain such patients on treatment with lithium." [Abstract]

Kleindienst N, Greil W.
Psychiatric Hospital of the University of Munich, Germany. niko@psy.med.uni-muenchen.de
Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study.
Neuropsychobiology. 2000;42 Suppl 1:2-10.
"In a randomized clinical trial with an observation period of 2.5 years, the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients (DSM-IV). In order to investigate the efficacy of the two drugs in clearly defined subsamples, a series of subgroup analyses was carried out. First, patients with a bipolar I disorder (n = 114) were analyzed separately. In these patients, lithium was superior to carbamazepine. In contrast, carbamazepine was at least equally as efficacious as lithium in the subsample of patients with bipolar II disorder or bipolar disorder not otherwise specified (n = 57). In a second analysis on differential efficacy, the whole sample was subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity; n = 67) and a nonclassical subgroup including all other patients (n = 104). Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis (26 vs. 62%, p = 0.012). For the nonclassical group, a tendency in favor of carbamazepine was found. In a third step, we analyzed the impact of episode sequence on differential efficacy. In a global view, the episode sequence prior to the index episode was not correlated to differential efficacy. Our results might, however, indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium. Besides differential efficacy, suicidal behavior and patients' satisfaction with treatment were investigated. Regarding suicidal behavior, a trend in favor of lithium was found. The data on patients' satisfaction were significantly in favor of carbamazepine. In conclusion, lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide. The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients. Hence, treatment alternatives to lithium are desirable for the majority of bipolar patients." [Abstract]

Kleindienst N, Greil W.
Department of Psychiatry. University of Munich, Germany.
Inter-episodic morbidity and drop-out under carbamazepine and lithium in the maintenance treatment of bipolar disorder.
Psychol Med. 2002 Apr;32(3):493-501.
"BACKGROUND: Evaluation of mood-stabilizing treatment strategies usually focuses on their efficacy in preventing recurrences. The aim of this study is to supplement evaluation by two important aspects: inter-episodic morbidity and drop-out. METHODS: Using a global outcome measure, response to prophylactic lithium and carbamazepine was evaluated in N = 171 bipolar patients (DSM-IV) participating in a randomized controlled trial with an observation period of 2 1/2 years (MAP study). RESULTS: The rates of re-hospitalization were similar for both treatments. However, the percentage of good clinical response (i.e. patients with a low score of inter-episodic morbidity and without both re-hospitalization and drop-out during the observation period) was significantly higher in patients randomized to lithium (40% v. 24%). This superiority of lithium resulted essentially from a lower drop-out rate in patients without re-hospitalization (17% v. 42%). Regarding severity of inter-episodic morbidity, no clear difference between the drugs was found. For both medications the predominant symptomatology was minor depressive (but not manic, mixed or schizoaffective) symptoms. In the lithium group, inter-episodic morbidity in patients without re-hospitalization significantly decreased during the first 10 months and remained on the lower level for the rest of the observation period. For carbamazepine, reduction of inter-episodic morbidity over time did not reach statistical significance. Inter-episodic morbidity was significantly related to drop-out and to re-hospitalization for both medications. CONCLUSION: Taking inter-episodic morbidity, drop-out and re-hospitalization into consideration, the response rate in bipolar patients (DSM-IV) was higher for prophylactic lithium than for carbamazepine. The global outcome parameter used appears to be a valuable measure of clinical response to mood stabilizing drugs." [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]

Greil W, Kleindienst N.
Psychiatric Hospital, University of Munich, Germany. wgreil@psy.med.uni-muenchen.de
Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified.
Int Clin Psychopharmacol. 1999 Sep;14(5):283-5.
"In a randomized clinical trial (MAP study), the prophylactic efficacy of lithium and carbamazepine was compared in a subgroup of patients (n = 57) who presented either a bipolar II disorder or a bipolar disorder not otherwise specified (DSM-IV). During the observation period of 2.5 years, no significant differences between the drugs were found considering hospitalization, recurrences, subclinical recurrences, concomitant medication and severe side-effects." [Abstract]

Greil W, Kleindienst N.
Psychiatric Hospital, University of Munich, Germany. wgreil@psy.med.uni-muenchen.de
The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder.
Int Clin Psychopharmacol. 1999 Sep;14(5):277-81.
"In a randomized prospective clinical trial with an observation period of 2.5 years, a subgroup analysis was carried out for the 114 patients with bipolar I disorder (DSM-IV) regarding the prophylactic efficacy of lithium and carbamazepine. Treatment outcome was evaluated taking rehospitalization, recurrence, subclinical recurrence, concomitant medication and severe adverse effects into consideration. Special interest was paid to the enzyme-inducing properties of carbamazepine, which might lessen the efficacy of psychotropic comedication. Lithium was superior to carbamazepine in bipolar I patients for various outcome criteria. Analyses in patients without psychotropic comedication indicate that the superiority of lithium is not the result of carbamazepine reducing plasma levels of concomitant drugs." [Abstract]

Greil W, Kleindienst N, Erazo N, Muller-Oerlinghausen B.
Psychiatric Hospital of the University of Munich, Germany. wgreil@psy.med.uni-muenchen.de
Differential response to lithium and carbamazepine in the prophylaxis of bipolar disorder.
J Clin Psychopharmacol. 1998 Dec;18(6):455-60.
"In a randomized, prospective, multicenter study with an observation period of 2.5 years, the differential prophylactic efficacy of lithium versus carbamazepine was compared in 171 patients fulfilling DSM-IV criteria for bipolar disorder. Serum drug levels were 0.6+/-0.1 mmol/L for lithium and 6.1+/-1.3 microg/mL for carbamazepine. Patients were subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity, N = 67) and a nonclassical subgroup including all other patients (N = 104). Classical bipolar patients had a lower rehospitalization rate with lithium than with carbamazepine prophylaxis (p = 0.005). For the nonclassical group, a trend in favor of carbamazepine was found. In the lithium group, there was a positive association between hospitalization rate and number of nonclassical features (bipolar II/not otherwise specified, mood-incongruent delusions, comorbidity; p = 0.035). For carbamazepine, this association was negative (p = 0.033). Analyses including mixed states as an additional nonclassical feature confirmed the results. In conclusion, lithium seems to be superior to carbamazepine in treating classical bipolar cases. Patients with nonclassical features might profit more from prophylaxis with carbamazepine, which seems to have a broader spectrum of activity." [Abstract]

Denicoff KD, Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM.
Section on Psychobiology, National Institute of Mental Health, Bethesda, Md. 20892, USA.
Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder.
J Clin Psychiatry. 1997 Nov;58(11):470-8.
"BACKGROUND: We compared the prophylactic efficacy of lithium, carbamazepine, and the combination and identified possible clinical markers of response. METHOD: Fifty-two outpatients who met DSM-III-R criteria for bipolar illness were randomly assigned in a double-blind design for an intended 1 year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and then a third year on the combination. Patients received monthly detailed evaluations, and daily life chart ratings of the degree of functional incapacity associated with mania or depression were completed. RESULTS: For evaluable patients: 13 (31.0%) of 42 failed to complete a full year of lithium therapy owing to lack of efficacy, and 2 dropped out because of side effects; 13 (37.1%) of 35 withdrew from carbamazepine within the first year owing to lack of efficacy, and 10 dropped out because of side effects (9 of the 10 had a rash); 7 (24.1%) of 29 withdrew from the combination therapy owing to lack of efficacy. The percentage of the evaluable patients who had marked or moderate improvement on the Clinical Global Impressions scale was 33.3% on lithium. 31.4% on carbamazepine, and 55.2% on the combination treatment, which was not significantly different. By a variety of measures, lithium was more effective than carbamazepine in the prophylaxis of mania. Patients with a past history of rapid cycling did poorly on monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine), but significantly better on the combination (56.3%, p < .05). CONCLUSION: These prospective, randomized data suggest a high incidence of inadequate response to either mood stabilizer or their combination despite use of adjunctive agents as needed. Additional novel treatment regimens are needed to better decrease affective morbidity in large numbers of bipolar outpatients." [Abstract]

Greil W, Ludwig-Mayerhofer W, Erazo N, Schochlin C, Schmidt S, Engel RR, Czernik A, Giedke H, Muller-Oerlinghausen B, Osterheider M, Rudolf GA, Sauer H, Tegeler J, Wetterling T.
Psychiatric Hospital, University of Munich, Germany.
Lithium versus carbamazepine in the maintenance treatment of bipolar disorders--a randomised study.
J Affect Disord. 1997 Apr;43(2):151-61.
"In a randomised multicentre study, the prophylactic efficacy of lithium and carbamazepine was compared in 144 patients with bipolar disorder (74 vs. 70 patients; observation period: 2.5 years; lithium serum level: 0.63 +/- 0.12 mmol/l, carbamazepine dose: 621 +/- 186 mg/day). Hospitalisations, recurrences, need of psychotropic comedication and adverse effects prompting discontinuation were defined as treatment failures. Survival analyses regarding hospitalisations and recurrences showed no statistically significant differences between both drugs. Results were distinctly in favour of lithium, considering recurrences combined with comedication (P = 0.041) and/or adverse effects (P = 0.007). Whereas adverse effects prompting discontinuation were more frequent under carbamazepine (9 vs. 4, ns), lithium patients reported more often slight/moderate side effects (61% vs. 21% after 2.5 years; P = 0.0006). In completers, recurrences occurred in 28% (lithium) vs. 47% (carbamazepine) of the patients (P = 0.06). Lithium seems to be superior to carbamazepine in maintenance treatment of bipolar disorder, in particular when applying broader outcome criteria including psychotropic comedication and severe side effects." [Abstract]

Small JG, Klapper MH, Milstein V, Kellams JJ, Miller MJ, Marhenke JD, Small IF.
Department of Psychiatry, Indiana University School of Medicine.
Carbamazepine compared with lithium in the treatment of mania.
Arch Gen Psychiatry. 1991 Oct;48(10):915-21.
"Fifty-two hospitalized manic patients were randomized to treatment with either carbamazepine or lithium carbonate after a 2-week drug withdrawal period. All of the probands were tertiary referrals with a high proportion of failures of previous lithium and other treatment. Weekly ratings of manic, depressive, and psychotic symptoms were obtained for 8 weeks, and responders were followed up for up to 2 years. One third of patients responded favorably. Double-blind assessments revealed no statistically reliable differences between the two treatment groups. Patients receiving carbamazepine were somewhat more manageable than patients treated with lithium early in the study, whereas lithium-treated patients remained longer in the follow-up phase. However, numbers of long-term survivors were too small to be conclusive. This study adds to the growing body of evidence that acutely manic patients respond as well to carbamazepine as to lithium. However, monotherapy with either drug is not sufficient for the majority of manic patients who are referred for tertiary care." [Abstract]

Okuma T, Yamashita I, Takahashi R, Itoh H, Otsuki S, Watanabe S, Sarai K, Hazama H, Inanaga K.
National Center Hospital for Mental, Nervous and Muscular Disorders, Tokyo, Japan.
Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study.
Pharmacopsychiatry. 1990 May;23(3):143-50.
"A multi-institutional study comparing the antimanic effect of carbamazepine (CBZ) and lithium carbonate (Li) was performed using a double-blind group comparison design in a series of 105 patients with bipolar disorders. CBZ and Li were given for four weeks using a fixed-flexible method at an equipotent dose ratio of 1:1, starting from an initial dosage of 400 mg with a maximum dosage of 1200 mg. The final global improvement rate, based on the number of cases showing moderate to marked amelioration of manic symptoms, was 62% in the CBZ group and 59% in the Li group, with no significant difference being found between the two groups. Incidence of cutaneous side-effects was significantly higher in the CBZ group. The mean daily dosage and serum level of CBZ in the fourth week were 674 +/- 239 mg and 7.3 +/- 2.4 micrograms/ml respectively; these were within the therapeutic range. The daily dose and serum level of Li, however, were 710 +/- 239 mg and 0.46 +/- 0.22 mEq/l, and the Li level seemed to be too low to compare its therapeutic effect with that of CBZ. Prior to the present study, approximately 80% of the patients in both groups had been receiving antipsychotic medication, equivalent to 8.0 mg of haloperidol on average, without favorable response. This medication was maintained unchanged during treatment. While the shortcomings of the present study limit the interpretation of the data, it may be suggested that the usefulness of CBZ as a drug for the treatment of manic states is comparable to that of Li." [Abstract]

Small JG, Klapper MH, Marhenke JD, Milstein V, Woodham GC, Kellams JJ.
Indiana University School of Medicine, Department of Psychiatry, Larue D. Carter Memorial Hospital, Indianapolis, IN 46202, USA.
Lithium combined with carbamazepine or haloperidol in the treatment of mania.
Psychopharmacol Bull. 1995;31(2):265-72.
"Hospitalized manic patients were withdrawn from psychoactive medications for 2 weeks after which they were randomized to double-blind treatment with carbamazepine plus lithium [CBZ-Li] or haloperidol plus lithium [HAL-Li] with benztropine. Unit dosages of Li 300 mg, CBZ 200 mg and HAL 2 mg were titrated to therapeutic plasma levels and maintained for 8 weeks. No rescue medications were permitted after 3 weeks. Standard ratings of psychopathology and side effects were accomplished weekly. Sixty patients entered the study but only 33 remained for randomization after drug washout. By 8 weeks both groups were improved from baseline without statistically reliable differences between them. However HAL-Li patients had more extrapyramidal side effects that were major reasons for dropout, whereas CBZ-Li patients were more often noncompliant and initially required more rescue medications. We conclude that either combination treatment can be beneficial but CBZ-Li has the advantage because of fewer neurologic side effects." [Abstract]

Weisler RH, Keck PE, Swann AC, Cutler AJ, Ketter TA, Kalali AH
Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial.
J Clin Psychiatry. 2005 Mar;66(3):323-30.
BACKGROUND: Although carbamazepine has long been used for the treatment of acute mania, only recently was its efficacy confirmed in a large, multicenter, parallel-group, placebo-controlled, randomized trial. In the present study, we further evaluated the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ) in patients with bipolar I disorder experiencing manic or mixed episodes. METHOD: Hospitalized bipolar I disorder (DSM-IV criteria) patients (N = 239) with manic or mixed episodes were randomly assigned on a double-blind basis to receive ERC-CBZ or placebo for 3 weeks, following a single-blind placebo lead-in. Treatment with ERC-CBZ was initiated at 200 mg twice daily, and investigators were encouraged to increase doses, as necessary and tolerated, by 200 mg/day up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression. The study was conducted from July 23, 2002, to April 1, 2003. RESULTS: 144 patients (60.3%) completed the study, with a significant number of placebo patients discontinuing due to lack of efficacy (p < .001). Extended-release carbamazepine treatment was associated with significant improvements in mean YMRS total and CGI total scores, using last-observation-carried-forward analyses, beginning at day 7 (p < .05). Adverse events occurring more frequently in the ERC-CBZ-treated group included dizziness (41.8%), somnolence (27.9%), and nausea (23.0%). Patients taking ERC-CBZ experienced a significant increase in total cholesterol, composed of increases in both high-density and low-density lipoproteins. CONCLUSION: Extended-release carbamazepine monotherapy had significantly greater efficacy compared with placebo in the treatment of acute mania in this large, randomized, double-blind, placebo-controlled trial. [Abstract]

Weisler RH, Kalali AH, Ketter TA; SPD417 Study Group.
A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes.
J Clin Psychiatry. 2004 Apr;65(4):478-84.
BACKGROUND: Carbamazepine has been used to treat mania for over 2 decades. Most evaluations of carbamazepine have had important limitations, such as absence of a parallel placebo group, small sample size, or the confounding influence of concomitant treatment. All studies have used conventional, immediate-release carbamazepine formulations. We assessed the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ; SPD417) in bipolar disorder patients with manic or mixed episodes. METHOD: Following a single-blind placebo lead-in, DSM-IV-defined bipolar disorder patients with manic or mixed episodes were randomly assigned to receive ERC-CBZ (N = 101) or placebo (N = 103) for 3 weeks. Patients were hospitalized through the first 7 days of the double-blind period. ERC-CBZ was initiated at 400 mg/day and increased, as necessary and tolerated, up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D). Data were gathered from December 1999 to June 2001. RESULTS: Ninety-six (47.1%) of 204 patients completed the study. The mean +/- SD final ERC-CBZ dose was 756.44 +/- 413.38 mg/day with a mean plasma drug level of 8.9 microg/mL. Starting at week 2, ERC-CBZ was associated with significantly greater improvements in YMRS (p =.032) using last-observation-carried-forward analyses. At end point, the responder rate (patients with at least a 50% decrease in YMRS score) also favored ERC-CBZ (41.5% vs. 22.4%; p =.0074). In a post hoc analysis of mixed patients, HAM-D score was significantly improved in patients remaining on ERC-CBZ treatment on day 21 (p =.01). Adverse events occurring more frequently in the ERC-CBZ group than in the placebo group included dizziness, nausea, and somnolence. CONCLUSION: We found ERC-CBZ to be effective in the first large, randomized, double-blind, placebo-controlled parallel trial of carbamazepine monotherapy in acute mania. This trial provides important additional evidence supporting the use of carbamazepine in acute mania. [Abstract]

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Recent Carbamazepine RCT Results

1) 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]

2) 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]

3) 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]

4) 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]

5) Campos RN, Costa LF, Bio DS, de Souza MG, Garcia CR, Demétrio FN, Moreno DH, Moreno RA
LICAVAL: combination therapy in acute and maintenance treatment of bipolar disorder.
Trials. 2010;11:72.
[PubMed Citation] [Order full text from Infotrieve]

6) El-Mallakh RS, Salem MR, Chopra A, Mickus GJ, Penagaluri P, Movva R
A blinded, randomized comparison of immediate-release and extended-release carbamazepine capsules in manic and depressed bipolar subjects.
Ann Clin Psychiatry. 2010 Feb;22(1):3-8.
[PubMed Citation] [Order full text from Infotrieve]

7) Mosolov SN, Kostiukova EG, Ladyzhenskiĭ MIa
[Comparative efficacy and tolerability of carbamazepine and oxcarbazepine during long therapy of patients with bipolar and schizoaffective disorders].
Zh Nevrol Psikhiatr Im S S Korsakova. 2009;109(10):36-41.
An aim of the study was to adjust the technique of using oxcarbazepine (OCB) and to study its preventive action and tolerability compared to carbamazepine (CBM) in patients with bipolar and schizoaffective disorders. The study included 48 patients (7 male and 41 female), aged from 18 to 70 years, with phasic psychoses (bipolar disorder, type I - 29 patients and schizoaffective disorder - 19 patients). Patients were randomized into 2 treatment groups: 1 - 28 patients who received CBM in doses 300-1600 mg/day (mean 700+/-120 mg/day) during 25,43+/-2,34 months; 2 - 20 patients who received OCB in doses 600-1800 mg/day (mean 900+/-145 mg/day) during 12+/-0,65 months. Duration of affective symptoms during the preventive therapy with CBM was reduced by 50,1% and that for OCB - by 49,1%; a number of episodes decreased by 34,6 and 35,1%, respectively. A significant effect, i.e. complete stopping of phases, was found in 35,7% of patients of the CBM group and in 40% of patients of the OCB group. The drugs had approximately equal preventive efficacy in regard to depressive and mania phases and episodes of schizoaffective disorders as well. Moreover, both drugs were clearly able to stop the rapid cyclic course of bipolar affective disorder. Side-effects were seen in 67,86% of patients treated with CBM and 55% of patients treated with OCB. Preventive features of OCB were comparable to those of CBM for intensity and spectrum of action. The adjustment of doses for OCB therapy does not need any significant correction, the drug causes less side-effects and subjectively is better tolerated by patients. [PubMed Citation] [Order full text from Infotrieve]

8) Rosa AR, Fountoulakis K, Siamouli M, Gonda X, Vieta E
Is anticonvulsant treatment of mania a class effect? Data from randomized clinical trials.
CNS Neurosci Ther. 2011 Jun;17(3):167-77.
Our aim was to evaluate the efficacy and tolerability of anticonvulsant agents for the treatment of acute bipolar mania and ascertain if their effects on mania are a "class" effect. We conducted a systematic review of randomized controlled trials (RCTs) with placebo or active comparator, in acute bipolar mania in order to summarize available data on anticonvulsant treatment of mania/mixed episodes. We searched (PubMed/MEDLINE) with the combination of the words "acute mania" and "clinical trials" with each one of the following words: "anticonvulsants/antiepileptics,"valproic/valproate/divalproex,"carbamazepine,"oxcarbazepine,"lamotrigine,"gabapentin,"topiramate,"phenytoin,"zonisamide,"retigabine,"pregabalin,"tiagabine,"levetiracetam,"licarbazepine,"felbamate," and "vigabatrin." Original articles were found until November 1, 2008. Data from 35 randomized clinical trials suggested that not all anticonvulsants are efficacious for the treatment of acute mania. Valproate showed greater efficacy in reducing manic symptoms, with response rates around 50% compared to a placebo effect of 20-30%. It appears to have a more robust antimanic effect than lithium in rapid cycling and mixed episodes. As valproate, the antimanic effects of carbamazepine have been demonstrated. Evidences did not support the efficacy of the gabapentin, topiramate as well as lamotrigine as monotherapy in acute mania and mixed episodes. Oxcarbazepine data are inconclusive and data regarding other anticonvulsants are not available. Anticonvulsants are not a class when treating mania. While valproate and carbamazepine are significantly more effective than placebo, gabapentin, topiramate, and lamotrigine are not. However, some anticonvulsants may be efficacious in treating some psychiatric comorbidities that are commonly associated to bipolar illness. [PubMed Citation] [Order full text from Infotrieve]

9) El-Mallakh RS, Salem MR, Chopra AS, Mickus GJ, Penagaluri P
Adverse event load in bipolar participants receiving either carbamazepine immediate-release or extended-release capsules: a blinded, randomized study.
Int Clin Psychopharmacol. 2009 May;24(3):145-9.
In epilepsy, slow-release formulations of carbamazepine (CBZ) have fewer adverse events (AEs) compared with immediate-release (IR) formulations. As CBZ is used for mania, it is important to determine whether a similar pattern exists for bipolar patients. This was a 3-month, blinded, random-assignment study to an IR formulation or extended-release carbamazepine capsules (ERCC, Equetro) in type I or type II bipolar patients already on CBZ or clinically determined to benefit from it. Dosages were titrated to patients' clinical needs. Mood and AE ratings were performed at baseline and monthly for 3 months. There was no difference in mood ratings or in the total level of AEs in patients receiving IR or ERCC. However, autonomic AEs (5.0+/-1.1 vs. 2.0+/-0.7, P = 0.02) and gastrointestinal AEs (1.6+/-0.4 vs. 0.6+/-0.3, P = 0.05) were significantly less in participants receiving ERCC. CBZ level in patients receiving ERCC were higher (9.2+/-1.7 vs. IR 7.2+/-1.3 microg/ml, P = 0.005). Total AE load was directly related to CBZ level only in participants receiving the IR formulation. In conclusion, ERCC is better tolerated than IR CBZ in bipolar patients. [PubMed Citation] [Order full text from Infotrieve]

10) Kakkar AK, Rehan HS, Unni KE, Gupta NK, Chopra D, Kataria D
Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study.
Eur Psychiatry. 2009 Apr;24(3):178-82.
[PubMed Citation] [Order full text from Infotrieve]

11) Juruena MF, Ottoni GL, Machado-Vieira R, Carneiro RM, Weingarthner N, Marquardt AR, Fleig SS, Broilo L, Busnello EA
Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double-blind, randomized trial.
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Feb 1;33(1):94-9.
Bipolar affective disorders often require adjunctive therapy to treat persistent symptoms. In order to evaluate bipolar symptoms inadequately responsive to lithium, we have compared the effects of two structurally related compounds carbamazepine (CBZ) and oxcarbazepine (OXC). We evaluated the efficacy and safety of CBZ and OXC administration in residual symptoms as an adjunctive therapy in Bipolar I (BP I) and Bipolar II (BP II) patients while on lithium maintenance treatment. We selected from 153 bipolar patients in treatment those fulfilling Research Diagnostic Criteria for mania or hypomania, according to the SADS-L and conducted in 52 bipolar patients (27 BP I, 25 BP II) a double-blind, randomized, parallel-group, single centre, clinical trial. Bipolar I and II outpatients, were randomly assigned on a 1:1 ratio to OXC (n=26) or CBZ (n=26) for an 8-week period as add-on treatment to the existing lithium regimen. Outcome measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale 21 items (HDRS-21) and Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression severity (CGI-S) and improvement illness (CGI-I). These scales were administered at baseline and at the end of weeks 2, 4 and 8. All the fifty-two patients completed the trial. Overall, females were 35 (65%) and mean (S.D.) age was 39.4 (11.9) years; final doses at the end of week 8 in OXC group was 637.7 (210) mg/day and in the CBZ group 673.5 (179) mg/day; lithium plasma levels were 0.73 (0.25) meq/l and 0.71 (0.28) meq/l, respectively. Both OXC and CBZ were effective in reducing bipolar scores from baseline to endpoint (p<0.01). OXC was more effective than CBZ at weeks 4 and 8 on all 5 outcome measures. OXC resulted in greater significant mean reductions in YMRS, HDRS-21, MADRS, CGI-S and CGI-I scores from baseline to week 4 (p<0.05) and from baseline to week 8 (p<0.001), except YMRS (p<0.01). OXC appeared to be significantly more effective and with better tolerability than CBZ as add-on strategy treatment in BP I and BP II patients. This pilot, randomized clinical trial, suggests the potential usefulness of OXC as adjunctive therapy to lithium both in acute and long-term treatment of bipolar disorder. However, further adequately placebo-controlled trials are needed to expand these findings. [PubMed Citation] [Order full text from Infotrieve]

12) El-Mallakh RS, Ketter TA, Weisler RH, Hirschfeld R, Cutler AJ, Gazda T, Keck P, Swann AC, Kalali AH
Switching from other agents to extended-release carbamazepine in acute mania.
Psychopharmacol Bull. 2008;41(1):52-8.
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13) Vieta E, Cruz N, García-Campayo J, de Arce R, Manuel Crespo J, Vallès V, Pérez-Blanco J, Roca E, Manuel Olivares J, Moríñigo A, Fernández-Villamor R, Comes M
A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder.
Int J Neuropsychopharmacol. 2008 Jun;11(4):445-52.
We evaluated the prophylactic efficacy and the long-term tolerability of oxcarbazepine administration in the treatment of bipolar I and II disorder as an adjunctive therapy to lithium. We conducted a 52-wk, double-blind, randomized, placebo-controlled, parallel-group, multicentre, clinical trial. Bipolar I and II DSM-IV outpatients, having had two or more episodes in the last year, but currently being in remission, were randomly assigned on a 1:1 ratio to oxcarbazepine (n=26) or placebo (n=29) as adjuncts to ongoing treatment with lithium. The primary efficacy variable was the length of the remission period assessed by means of the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS). Other assessments were the Clinical Global Impression (CGI-BP-M), functional activity (GAF), anxiety (HAMA) and impulsiveness (BIS-11). The average time until first recurrence of any type was 19.2+/-13.9 wk and 18.6+/-17.0 wk for oxcarbazepine and placebo respectively (p=0.315). Ten (38.46%) patients had a recurrence of any kind in the oxcarbazepine group vs. 17 (58.62%) in the placebo group (p=0.1354). There was a trend for depressive episodes being less likely in the oxcarbazepine group compared to the placebo group (11.54% and 31.03% respectively, p=0.085), and for better functionality with the GAF (p=0.074). Impulsivity was significantly better prevented by oxcarbazepine (p=0.0443). Overall, oxcarbazepine was well tolerated. This pilot, randomized clinical trial, suggests that oxcarbazepine might have some prophylactic efficacy with regards to impulsivity and perhaps mood episodes in patients taking lithium, although further, adequately powered controlled trials are needed to confirm these findings. [PubMed Citation] [Order full text from Infotrieve]

14) Tohen M, Bowden CL, Smulevich AB, Bergstrom R, Quinlan T, Osuntokun O, Wang WV, Oliff HS, Martenyi F, Kryzhanovskaya LA, Greil W
Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes.
Br J Psychiatry. 2008 Feb;192(2):135-43.
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15) Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D
Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials.
Bipolar Disord. 2007 Sep;9(6):551-60.
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16) Amann B, Grunze H, Vieta E, Trimble M
Antiepileptic drugs and mood stability.
Clin EEG Neurosci. 2007 Apr;38(2):116-23.
This paper will discuss different definitions of the term "mood stabilizer" and highlight in detail the antiepileptic drugs carbamazepine, valproate and lamotrigine with respect to their relative strengths in stabilizing mood in bipolar patients. These drugs are heterogeneous in their mechanisms of action and in their efficacy to stabilize patients with epilepsy and the various mood states in bipolar disorder. Lamotrigine has obtained approval in several countries for the indication of preventing bipolar depressive episodes, which raises the question of differential efficacy of other antiepileptic drugs as mood stabilizers in the prevention of either depressive or hypo-/manic episodes. A Medline Search to 2006 was conducted for controlled acute and maintenance studies of the three scientifically and clinically most established antiepileptic drugs carbamazepine, valproate and lamotrigine. The medications discussed in this review only partly fulfill definitions of a mood stabilizer, and we suggest that future research should focus on combined treatment strategies. [PubMed Citation] [Order full text from Infotrieve]

17) Suppes T, Kelly DI, Hynan LS, Snow DE, Sureddi S, Foster B, Curley E
Comparison of two anticonvulsants in a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder.
Aust N Z J Psychiatry. 2007 May;41(5):397-402.
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18) Kleindienst N, Severus WE, Greil W
Are serum lithium levels related to the polarity of recurrence in bipolar disorders? Evidence from a multicenter trial.
Int Clin Psychopharmacol. 2007 May;22(3):125-31.
The primary objective is to test whether the polarity of recurrence (depressive vs manic or mixed), is related to lithium levels. A total of 86 euthymic bipolar patients (DSM-IV) on lithium monotherapy were prospectively followed up for 2.5 years with regular monitoring of both lithium levels and psychopathology. The last lithium level during the free interval that preceded worsening of affective symptoms was related to polarity of symptoms. To account for effects of major confounders, results were corroborated by multivariate analysis. An intervention for manic or mixed symptomatology was required in 27 patients, whereas 22 patients were treated for depressive symptoms. Average lithium levels preceding reappearance of manic or mixed symptomatology were lower than levels preceding reappearance of depressive symptoms (0.53+/-0.13 vs 0.66+/-0.21 mmol/l, P=0.01). This result was confirmed using logistic regression analyses with type of index episode, diagnostic subtype and residual manic and depressive symptoms as covariates. The results indicate that manic or mixed recurrences might rather occur at lower lithium levels, whereas the depressive pole prevails in the higher range. If substantiated by further studies, this finding might indicate that higher lithium levels are needed to prevent manic episodes than to prevent depressive episodes. [PubMed Citation] [Order full text from Infotrieve]

19) Brown ES
Management of comorbid bipolar disorder and substance abuse.
J Clin Psychiatry. 2006 Aug;67(8):e05.
Rates of alcohol and other substance abuse or dependence disorders are substantially higher in persons with bipolar disorders than in the general population, reaching approximately 61% in patients with bipolar I disorder. As a result, clinicians must be prepared to treat substance use disorders and bipolar disorder simultaneously. This presentation reviews data from the 4 published randomized, controlled trials of pharmacotherapy (lithium, carbamazepine, valproate, and quetiapine) in this population. Also reviewed are data from promising open-label, uncontrolled trials. While the results of published research have been generally positive and support the efficacy and tolerability of several agents from different classes in patients with a dual diagnosis of bipolar disorder and substance abuse or dependence, more randomized, controlled research is needed. [PubMed Citation] [Order full text from Infotrieve]

20) Zhang ZJ, Kang WH, Li Q, Tan QR
The beneficial effects of the herbal medicine Free and Easy Wanderer Plus (FEWP) for mood disorders: double-blind, placebo-controlled studies.
J Psychiatr Res. 2007 Nov;41(10):828-36.
Our previous study has shown the beneficial effects of the herbal medicine called Free and Easy Wanderer Plus (FEWP) as adjunctive therapy with carbamazepine (CBZ) in the 12-week treatment of bipolar disorders (Zhang ZJ, Kang WH, Tan QR, Li Q, Gao CG, Zhang FG, et al., Adjunctive herbal medicine with carbamazepine for bipolar disorders: a double-blind, randomized, placebo-controlled study. J Psychiatr Res; 2005). Here, we present follow-up data obtained from a continuation of the previously reported study. Treatment and clinical evaluation of bipolar patients (n=188) who had randomly received 12-week CBZ plus placebo (n=92) or CBZ plus FEWP (n=96) were extended to 26 weeks under double-blind condition. Patients in adjunctive FEWP showed a significantly lower overall discontinuation rate (31%) at endpoint compared to placebo (51%, p=0.009), and of 15% in adjunctive FEWP discontinued due to intolerable side effects, markedly lower than those in placebo (28%, p=0.019). No difference in discontinuation for lack of efficacy and exacerbation was observed in the two groups. Patients receiving adjunctive FEWP had significantly fewer adverse side effects and lower serum levels of CBZ than those in placebo. A separate study was further conducted to evaluate the effectiveness of FEWP as monotherapy in depressed patients. A total of 87 unipolar and 62 bipolar depressed patients were randomly assigned to treatment with 36 g/day FEWP (n=86) or placebo (n=63) for 12 weeks under double-blind condition. Efficacy was measured using the Hamilton Rating Scale for Depression (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression-Severity (CGI-S). Both unipolar and bipolar patients assigned to FEWP displayed significantly greater improvement on the three efficacy indices and significantly higher clinical response rate (74%) than those treated with placebo (42%, p<0.001) at endpoint. These results suggest that adjunctive FEWP improves tolerability of CBZ in the long-term use, which may be associated with the suppression of blood CBZ concentrations via herb-drug interactions. FEWP monotherapy may be also an effective alternative treatment for depressed conditions. [PubMed Citation] [Order full text from Infotrieve]