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) 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.
BACKGROUND: Combinations of olanzapine and carbamazepine are often used in clinical practice in the management of mania. AIMS: To assess the efficacy and safety of olanzapine plus carbamazepine in mixed and manic bipolar episodes. METHOD: Randomised, double-blind, 6-week trial of olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day; n=58) v. placebo plus carbamazepine (n=60) followed by open-label, 20-week olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day, n=86), with change in manic symptoms as main outcome measure. Safety and pharmacokinetics were also evaluated. RESULTS: There were no significant differences (baseline to endpoint) in efficacy measures between treatment groups, but at 6 weeks triglyceride levels were significantly higher (P=0.008) and potentially clinically significant weight gain (>or=7%) occurred more frequently (24.6% v. 3.4%, P=0.002) in the combined olanzapine and carbamazepine group. Carbamazepine reduced olanzapine concentrations but olanzapine had no effect on carbamazepine concentrations. CONCLUSIONS: The combination of olanzapine and carbamazepine did not have superior efficacy to carbamazepine alone. The increases in weight and triglycerides observed during combination treatment are a matter of concern. [PubMed Citation] [Order full text from Infotrieve]

2) 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.
OBJECTIVES: We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials in acute bipolar mania to summarize available data on drug treatment of mania. METHODS: We included trials of medications licensed in the USA or UK for the treatment of any phase of bipolar disorder. Outcomes investigated were changes in mania scores, attrition, extrapyramidal effects and weight change. Data were combined through meta-analyses. RESULTS: We included 13 studies (involving 3,089 subjects) and identified 2 studies for each of the following medications: carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate semisodium and aripiprazole. All drugs showed significant benefit compared with placebo for reduction in mania scores. Compared with placebo, for all antipsychotics pooled, response to treatment (> or =50% reduction in Young Mania Rating Scale scores) was increased more than 1.7 times [relative risk (RR) = 1.74, 95% confidence interval (CI) = 1.54, 1.96]; for all mood stabilizers pooled, response to treatment was doubled (RR 2.01, 95% CI = 1.66, 2.43). Overall withdrawals were 34% fewer (24-43%) with antipsychotics, and 26% fewer (10-39%) with mood stabilizers. However, for carbamazepine, aripiprazole and lithium an increase in risk of withdrawal could not be excluded. Small but significant increases in extrapyramidal side effects occurred with risperidone and aripiprazole. CONCLUSIONS: Antipsychotics and mood stabilizers are significantly more effective than placebo for the treatment of acute mania. Their effect sizes are similar. Small differences between effect sizes may be due to differences in the patients included in the studies or to chance. Carbamazepine and lithium may be more poorly tolerated, and antipsychotics cause more extrapyramidal side effects. [PubMed Citation] [Order full text from Infotrieve]

3) 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]

4) 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.
OBJECTIVE: Oxcarbazepine was compared to divalproex to assess clinical effectiveness of a proven agent, divalproex, against a newer, less studied agent, oxcarbazepine, in the treatment of hypomania. METHOD: Thirty patients with bipolar disorder, currently hypomanic, were randomized to receive oxcarbazepine or divalproex as add-on or monotherapy for 8 weeks. A rater blind to treatment assignment performed all symptom ratings. Hypomania and depression were rated using the Young Mania Rating Scale (YMRS) and the Inventory of Depressive Symptoms-Clinician Version (IDS-C). Random regression models were used to assess clinical symptom scores. RESULTS: There were no significant differences of YMRS or IDS-C scores between groups. Mean YMRS scores at baseline were 22.07+/-5.86 and 20.53+/-6.02 for the oxcarbazepine and the divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the YMRS was 63.8% and 79.0% for oxcarbazepine and divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the IDS-C was 48.7% versus 19.7% for oxcarbazepine and divalproex groups, respectively. Significant antimanic efficacy was noted for each medication. Both medications were generally well tolerated. CONCLUSION: In this pilot study, oxcarbazepine was as effective as divalproex in the treatment of hypomania. Further controlled trials are warranted. [PubMed Citation] [Order full text from Infotrieve]

5) 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]

6) 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]

7) 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]

8) Cipriani A, Rendell JM, Geddes JR
Haloperidol alone or in combination for acute mania.
Cochrane Database Syst Rev. 2006;3:CD004362.
BACKGROUND: The main objectives in treating mania are to control dangerous behaviour, reduce suicide, produce appropriate acute sedation and shorten the episode of mood disturbance. Among different drugs, haloperidol has for many years been used in treating psychotic patients, but it has a troublesome side effect profile. OBJECTIVES: To assess the effects of haloperidol for the treatment of mania in comparison with placebo or other active drugs, either as monotherapy or add-on treatment. SEARCH STRATEGY: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (11 October 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (1966-2003), EMBASE (1980-2003), CINAHL (1982-2003), PsycINFO (1872-2003) and reference lists. We also contacted experts, triallists and pharmaceutical companies in the field. SELECTION CRITERIA: Randomised trials comparing haloperidol with placebo or other active treatment in the treatment of acute manic or mixed episodes in patients with bipolar disorder or schizoaffective disorder. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects information from the trials. MAIN RESULTS: Fifteen trials involving 2022 people were included. Compared to placebo, haloperidol was more effective at reducing manic symptoms, both as monotherapy (Weighted Mean Difference (WMD) -5.85, 95% Confidence Interval (CI) -7.69 to -4.00) and as adjunctive treatment to lithium or valproate (WMD -5.20, 95% CI -9.26 to -1.14). There was a statistically significant difference, with haloperidol being less effective than aripiprazole (Relative Risk (RR) 1.45, 95% CI 1.22 to 1.73). No significant differences between haloperidol and risperidone, olanzapine, carbamazepine or valproate were found. Compared with placebo, a statistically significant difference in favour of haloperidol in failure to complete treatment (RR 0.74, 95% Cl 0.57 to 0.96) was reported. Haloperidol was associated with less weight gain than olanzapine (RR: 0.28, 95% CI 0.12 to 0.67), but with a higher incidence of tremor (RR: 3.01, 95% CI 1.55 to 5.84) and other movement disorders. AUTHORS' CONCLUSIONS: There is some evidence that haloperidol is an effective treatment for acute mania. From the limited data available, there was no difference in overall efficacy of treatment between haloperidol and olanzapine or risperidone. Some evidence suggests that haloperidol could be less effective than aripiprazole. Referring to tolerability, when considering the poor evidence comparing drugs, clinicians and patients should consider different side effect profiles as an important issue to inform their choice. [PubMed Citation] [Order full text from Infotrieve]

9) Wagner KD, Kowatch RA, Emslie GJ, Findling RL, Wilens TE, McCague K, D'Souza J, Wamil A, Lehman RB, Berv D, Linden D
A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents.
Am J Psychiatry. 2006 Jul;163(7):1179-86.
OBJECTIVE: This multicenter trial examined the efficacy and safety of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. METHOD: A total of 116 outpatients 7 to 18 years of age with bipolar I disorder, manic or mixed, were recruited at 20 centers in the United States and randomly assigned to receive 7 weeks of double-blinded, flexibly dosed treatment with oxcarbazepine (maximum dose 900-2400 mg/day) or placebo. The primary efficacy measure was the mean change from baseline to endpoint in the Young Mania Rating Scale (YMRS), using the last-observation-carried-forward method. RESULTS: Oxcarbazepine (mean dose=1515 mg/day) did not significantly improve YMRS scores at endpoint compared with placebo [adjusted mean change: oxcarbazepine, -10.90 (N=55); placebo, -9.79 (N=55)]. Dizziness, nausea, somnolence, diplopia, fatigue, and rash were each reported in at least 5% of the patients in the oxcarbazepine group with an incidence at least twice that of the placebo group. The majority of adverse events were mild to moderate and occurred during the titration period. Eleven patients (19%) in the oxcarbazepine group discontinued the study because of adverse events, compared with two (4%) in the placebo group. CONCLUSIONS: Oxcarbazepine is not significantly superior to placebo in the treatment of bipolar disorder in youths. While the overall adverse event profile was similar to that reported for patients with epilepsy, the incidence of psychiatric adverse events for both the oxcarbazepine and placebo groups was higher than that reported for the epilepsy population. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

10) Ghaemi SN, Hsu DJ, Thase ME, Wisniewski SR, Nierenberg AA, Miyahara S, Sachs G
Pharmacological Treatment Patterns at Study Entry for the First 500 STEP-BD Participants.
Psychiatr Serv. 2006 May;57(5):660-5.
OBJECTIVE: This study assessed patterns of psychopharmacological treatment for bipolar disorder. METHOD: Intake treatment data were examined for the first 500 patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1998 to 1999). Diagnoses were assessed by using the Structured Clinical Interview for DSM-IV mood modules. Data on treatments were obtained by interviewing patients during the initial psychiatric examination. RESULTS: Of the 500 participants, 73.6 percent had bipolar I disorder, 23.0 percent had bipolar II disorder, and 3.4 percent had bipolar disorder not otherwise specified. Upon examination, 63.4 percent were euthymic, 24.6 percent were depressed, and 12.0 percent were experiencing manic, hypomanic, or mixed states. Standard mood stabilizers (lithium, valproate, or carbamazepine) were the most commonly prescribed class of drugs that participants were taking at intake (71.9 percent). The next most common class of agents was antidepressants (40.6 percent), followed by novel anticonvulsants (31.8 percent), second-generation neuroleptics (27.2 percent), and benzodiazepines (25.0 percent). Eleven percent of patients were treated with standard mood stabilizer monotherapy. These prescribing patterns were further analyzed by subtype of illness and compared with patterns in other clinical and community settings. CONCLUSION: In a large, well-characterized cross-sectional analysis of prescription patterns in the U.S. psychiatric academic setting, patients with bipolar disorder were primarily treated with standard mood stabilizers, followed by moderate use of antidepressants, novel anticonvulsants, and second-generation neuroleptics. Results can be useful in understanding the current clinical standard of care, as well as in guiding research studies toward areas in which there is a relative absence of evidence to inform clinical practice. Studies of longitudinal prescribing patterns in bipolar disorder are also needed. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

11) Vieta E, Manuel Goikolea J, Martínez-Arán A, Comes M, Verger K, Masramon X, Sanchez-Moreno J, Colom F
A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder.
J Clin Psychiatry. 2006 Mar;67(3):473-7.
OBJECTIVE: To conduct the first randomized, controlled trial assessing the prophylactic efficacy of gabapentin in bipolar disorder. METHOD: We conducted a 1-year, double-blind, randomized, comparative, placebo-controlled, parallel-group, multicenter study. As this was a pure prophylactic trial, only euthymic bipolar I and II patients (DSM-IV) were randomly assigned in a 1:1 ratio to gabapentin (N = 13) or placebo (N = 12) added to the current treatment (lithium, valproate, carbamazepine, or any combination but not antipsychotics or antidepressants). Subjects participated in the study for 12 months. The primary efficacy parameter was the Clinical Global Impressions scale for Bipolar Illness, Modified (CGI-BP-M), which was assessed at all visits. Other assessments were the Young Mania Rating Scale (YMRS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), Pittsburgh Sleep Quality Index (PSQI), and the systematic collection of reported adverse events. Data were collected from May 1999 to February 2004. RESULTS: The change from baseline to month 12 in mean CGI-BP-M scores between groups was statistically significant (p = .0046). Mean score change from baseline to endpoint in the gabapentin group was -2.1, and the mean score change in the placebo group was -0.6. No emerging manic or depressive symptoms were seen in either group as measured with the YMRS, HAM-D, HAM-A, and PSQI. In the PSQI-6 subscale (use of sleeping medication), the mean score change at month 12 in the gabapentin group was 0.9, and the mean score change in the placebo group was 0.05 (p = .0267). Overall, gabapentin was well tolerated. CONCLUSION: This small, randomized clinical trial comparing the prophylactic efficacy of adjunctive gabapentin to placebo suggests that, despite lack of acute efficacy, treatment with gabapentin might provide some benefit on the long-term outcome of bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

12) Weisler RH, Hirschfeld R, Cutler AJ, Gazda T, Ketter TA, Keck PE, Swann A, Kalali A
Extended-release carbamazepine capsules as monotherapy in bipolar disorder : pooled results from two randomised, double-blind, placebo-controlled trials.
CNS Drugs. 2006;20(3):219-31.
OBJECTIVES: Recently, two large, 3-week, randomised, double-blind, placebo-controlled trials using nearly identical protocols demonstrated that monotherapy with carbamazepine extended-release capsules (CBZ-ERC) was effective for the treatment of acute mania in patients with bipolar I disorder. By pooling data from these two trials, a more highly powered analysis of the efficacy and safety of CBZ-ERC in bipolar I disorder could be conducted. METHODS: Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Clinical Global Impression (CGI)-Severity (CGI-S) scale, the CGI-Improvement (CGI-I) scale and the Hamilton Depression Rating Scale (HDRS). A sub-analysis of the data based on manic versus mixed presentation was performed, as well as sub-analyses by age, sex and ethnicity. RESULTS: Of the 443 randomised patients in the pooled population, 240 completed the studies. Forty-two percent of CBZ-ERC-treated patients did not complete the studies, compared with 50% of placebo-treated patients (p=0.087). Ten percent of patients given CBZ-ERC withdrew because of lack of efficacy, compared with 22% of patients given placebo (p<0.001). At endpoint, CBZ-ERC compared with placebo was associated with significant improvements in mean YMRS total scores in patients experiencing both manic (p<0.0001) and mixed (p<0.01) episodes, using last-observation-carried-forward analyses. CGI-I and CGI-S scores also showed significant improvements from baseline for both manic and mixed patients at endpoint. In patients with mixed episodes, at endpoint there was a mean improvement in HDRS total score of 4.8 points with CBZ-ERC, compared with 2.3 points with placebo (p<0.05). Ninety percent of patients given CBZ-ERC experienced an adverse event, compared with 64% of those patients given placebo. Discontinuation because of adverse events occurred in 10.8% of patients taking CBZ-ERC, compared with 5.5% of patients taking placebo. CONCLUSIONS: These results confirm previous findings that CBZ-ERC is effective in the treatment of bipolar I disorder patients with either acute manic or mixed episodes. These data suggest that further randomised controlled studies are warranted to delineate the effect of CBZ-ERC on depressive symptoms in patients with bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

13) Zhang ZJ, Kang WH, Tan QR, Li Q, Gao CG, Zhang FG, Wang HH, Ma XC, Chen C, Wang W, Guo L, Zhang YH, Yang XB, Yang GD
Adjunctive herbal medicine with carbamazepine for bipolar disorders: A double-blind, randomized, placebo-controlled study.
J Psychiatr Res. 2007 Apr-Jun;41(3-4):360-9.
Chinese herbal medicines possess the therapeutic potential for mood disorders. This double-blind, randomized, placebo-controlled study was designed to evaluate the efficacy and side effects of the herbal medicine called Free and Easy Wanderer Plus (FEWP) as an adjunct to carbamazepine (CBZ) in patients with bipolar disorders. One hundred and twenty-four bipolar depressed and 111 manic patients were randomized to treatment with CBZ alone, CBZ plus FEWP, or equivalent placebo for 12 weeks. CBZ was initiated at 300mg/day and FEWP was given at a fixed dose of 36g/day. Efficacy measures included the Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale , Young Mania Rating Scale, Bech-Rafaelsen Mania Scale, and Clinical Global Impression-Severity (CGI-S). CBZ monotherapy produced significantly greater improvement on manic measures at week 2 through endpoint and CGI-S of depression at endpoint compared to placebo. CBZ monotherapy also yielded significantly higher clinical response rates than placebo on bipolar depression (63.8% vs. 34.8%, p=0.044) and mania (87.8% vs. 57.1%, p=0.012). Compared to CBZ monotherapy, adjunctive FEWP with CBZ resulted in significantly better outcomes on the three measures of depression at week 4 and week 8 and significantly greater clinical response rate in depressed subjects (84.8% vs. 63.8%, p=0.032), but failed to produce significantly greater improvement on manic measures and the response rate in manic subjects. There was a lesser incidence of dizziness and fatigue in the combination therapy compared to CBZ monotherapy. These results suggest that adjunctive FEWP has additive beneficial effects in bipolar patients, particularly for those in depressive phase. [PubMed Citation] [Order full text from Infotrieve]