Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM.
Department of Psychiatry, University of Oxford, Warneford Hospital, UK. john.geddes@psych.ox.ac.uk
Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials.
Am J Psychiatry. 2004 Feb;161(2):217-22.
"OBJECTIVE: The authors sought to determine the efficacy and acceptability of lithium for relapse prevention in bipolar disorder. METHOD: A systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo in the long-term treatment of bipolar disorders was conducted. Data were obtained from searching the registers of the Cochrane Collaboration; reviewing reference lists, journals, and conference abstracts; and contacting authors, experts, and pharmaceutical companies. Outcomes investigated included risk of relapse (manic, depressive, and total) as well as risk of specific adverse effects and total withdrawal rates. RESULTS: Five randomized controlled trials (770 participants) were included. Lithium was more effective than placebo in preventing all relapses (random effects relative risk=0.65, 95% CI=0.50 to 0.84) and manic relapses (relative risk=0.62, 95% CI=0.40 to 0.95). The protective effect of lithium on depressive relapses was smaller and was less robust (relative risk=0.72, 95% CI=0.49 to 1.07). CONCLUSIONS: Lithium treatment reduces the risk of relapse in bipolar disorder. The preventive effect is clear for manic episodes, although it is equivocal for depressive episodes." [Abstract]

Burgess S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G.
Department of Psychiatry, University of Oxford, Oxford, UK, OX3 7JX. john.geddes@psychiatry.oxford.ac.uk
Lithium for maintenance treatment of mood disorders.
Cochrane Database Syst Rev. 2001;(3):CD003013.
"BACKGROUND: Mood disorders are common, disabling and tend to be recurrent. They carry a high risk of suicide. Maintenance treatment, aimed at the prevention of relapse, is therefore of vital importance. Lithium has been used for some years as the mainstay of maintenance treatment in bipolar affective disorder, and to a lesser extent in unipolar disorder. However, the efficacy and effectiveness of prophylactic lithium therapy has been disputed. Low suicide rates in lithium-treated patients have led to claims that lithium has a specific anti-suicidal effect. If so, this is of considerable importance as treatments for mental disorders in general have not been shown convincingly to be effective in suicide prevention. OBJECTIVES: 1. To investigate the efficacy of lithium treatment in the prevention of relapse in recurrent mood disorders. 2. To examine the effect of lithium treatment on consumers' general health and social functioning, its acceptability to consumers, and the side-effects of treatment. 3. To investigate the hypothesis that lithium has a specific effect in reducing the incidence of suicide and deliberate self-harm in persons with mood disorders. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and The Cochrane Controlled Clinical Trials Register (CCTR) were searched. Reference lists of relevant papers and major text books of mood disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Specialist journals concerning lithium were hand searched. SELECTION CRITERIA: Randomised controlled trials comparing lithium with placebo, where the stated intent of treatment was maintenance or prophylaxis. Participants were males and females of all ages with diagnoses of mood disorder. Discontinuation studies (in which all participants had been stable on lithium for some time before being randomised to either continued lithium treatment or placebo substitution) were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted from the original reports independently by two reviewers. The main outcomes studied were related to the objectives stated above. Data were analysed for all diagnoses of mood disorder and for bipolar and unipolar disorder separately. Data were analysed using Review Manager version 4.0. MAIN RESULTS: Nine studies were included in the review, reporting on 825 participants randomly allocated to lithium or placebo. Lithium was found to be more effective than placebo in preventing relapse in mood disorder overall, and in bipolar disorder. The most consistent effect was found in bipolar disorder (random effects OR 0.29; 95% CI 0.09 to 0.93 ). In unipolar disorder, the direction of effect was in favour of lithium, but the result (when heterogeneity between studies was allowed for) did not reach statistical significance. Considerable heterogeneity was found between studies in all groups of patients. The direction of effect was the same in all studies; no study found a negative effect for lithium. Heterogeneity may have been due to differences in selection of participants, and to differing exposures to lithium in the pre-study phase resulting in variable influence of a discontinuation effect. There was little reported data on overall health and social functioning of participants under the different treatment conditions, or on the participants' own views of their treatment. Descriptive analysis showed that assessments of general health and social functioning generally favoured lithium. Small absolute numbers of deaths and suicides, and the absence of data on non-fatal suicidal behaviours, made it impossible to draw meaningful conclusions about the place of lithium therapy in suicide prevention. REVIEWER'S CONCLUSIONS: This systematic review indicates that lithium is an efficacious maintenance treatment for bipolar disorder. In unipolar disorder the evidence of efficacy is less robust. This review does not cover the relative efficacy of lithium compared with other maintenance treatments, which is at present unclear. There is no definitive evidence from this review as to whether or not lithium has an anti-suicidal effect. Systematic reviews and large scale randomised studies comparing lithium with other maintenance treatments (e.g. anti-convulsants, antidepressants) are necessary. Outcomes relating to death and suicidal behaviour should be included in all future maintenance studies of mood disorder." [Abstract]

Tondo L, Hennen J, Baldessarini RJ.
Consolidated Department of Psychiatry and Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA.
Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis.
Acta Psychiatr Scand. 2001 Sep;104(3):163-72.
"OBJECTIVE: To compare suicide rates with vs. without long-term lithium treatment in major affective disorders. METHOD: Broad searching yielded 22 studies providing suicide rates during lithium maintenance; 13 also provide rates without such treatment. Study quality was scored, between-study variance tested, and suicide rates on vs. off lithium examined by meta-analyses using random-effects regression methods to model risk ratios. RESULTS: Among 5647 patients (33 473 patient-years of risk) in 22 studies, suicide was 82% less frequent during lithium-treatment (0.159 vs. 0.875 deaths/100 patient-years). The computed risk-ratio in studies with rates on/off lithium was 8.85 (95% CI, 4.12-19.1; P<0.0001). Higher rates off-lithium were not accounted for by treatment-discontinuation. CONCLUSION: Suicide risk was consistently lower during long-term treatment of major affective illnesses with lithium in all studies in the meta-analysis, including the few involving treatment-randomization." [Abstract]

Kupka RW, Luckenbaugh DA, Post RM, Leverich GS, Nolen WA.
Altrecht Institute for Mental Health Care and University Medical Center Utrecht, Utrecht, The Netherlands. r.kupka@planet.nl
Rapid and non-rapid cycling bipolar disorder: a meta-analysis of clinical studies.
J Clin Psychiatry. 2003 Dec;64(12):1483-94.
"BACKGROUND: Rapid cycling, defined as 4 or more mood episodes per year, is a course specifier of bipolar disorder associated with relative treatment resistance. Several risk factors have been suggested to be associated with rapid cycling. The purpose of this meta-analysis was to compare clinical studies for the evidence of discriminating factors between rapid and non-rapid cycling. DATA SOURCES AND SELECTION: We searched MEDLINE and reference lists of articles and book chapters and selected all of the clinical studies published from 1974 to 2002 comparing subjects with rapid and non-rapid cycling bipolar disorder. Prevalence rates and mean random effect sizes for 18 potential risk factors that were reported by at least 3 studies were calculated. In addition, we differentiated between current and lifetime diagnoses of rapid cycling. DATA SYNTHESIS: Twenty studies were identified. Rapid cycling was present in 16.3% of 2054 bipolar patients in 8 studies that included patients who were consecutively admitted to an inpatient or outpatient facility, without a priori selection of rapid cyclers and without matching the numbers of rapid cyclers to non-rapid cycling controls. Female gender and bipolar II subtype both had a small, but statistically significant, effect (p <.000 for female gender, p <.001 for bipolar II subtype). The further absence of recurrences with lithium prophylaxis was reported in 34% of rapid cyclers compared with 47% of non-rapid cyclers, a nearly significant difference, and a partial response was present in 59% and 65% of patients, respectively. The effect of hypothyroidism was significant (p <.01) in studies using current, but not lifetime, definitions of rapid cycling. In 46% of cases, a rapid cycling course was preceded by treatment with antidepressants, but systematic data on their causal role are lacking. CONCLUSION: Rapid cycling is slightly more prevalent in women and in patients with bipolar II subtype. In contrast to common opinion, lithium prophylaxis has at least partial efficacy in a considerable number of rapid cyclers, especially when antidepressants are avoided. Hypothyroidism may be associated with mood destabilization in vulnerable patients." [Abstract]

Poolsup N, Li Wan Po A, de Oliveira IR.
Centre for Evidence-Based Pharmacotherapy, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
Systematic overview of lithium treatment in acute mania.
J Clin Pharm Ther. 2000 Apr;25(2):139-56.
"OBJECTIVE: To evaluate the efficacy of lithium in the treatment of acute mania. METHOD: Systematic overview of the literature and meta-analysis of randomised controlled trials. Estimation of (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates. RESULTS: A total of 658 patients from 12 trials were included. Treatment periods ranged from 3 to 4 weeks. The response rate ratio for lithium against placebo was 1.95 (95%CI 1.17-3.23). The mean number needed to treat was five (95%CI 3-20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1.96, 95%CI 1.02-3.77). The mean number needed to treat was four (95%CI 3-9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1.01 (95%CI 0.54-1.88) for lithium compared to carbamazepine and 1.22 (95%CI 0.91-1.64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were -2.79 (95%CI -4.22 to -1.36) in favour of risperidone with respect to symptom severity improvement and -0.76 (95%CI -1.11 to -0.41) on the basis of reduction in global severity of disease. Symptom and global severity was as well controlled with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate. CONCLUSION: The clinical trial evidence suggests that lithium should remain the first line treatment for acute mania." [Abstract]

Ichim L, Berk M, Brook S.
Department of Psychiatry, University of the Witwatersrand Medical School, Parktown, South Africa.
Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial.
Ann Clin Psychiatry. 2000 Mar;12(1):5-10.
"BACKGROUND: Preliminary data from case reports and small open trials suggest a role for lamotrigine in the treatment of bipolar disorder, although controlled data for the manic phase are lacking. METHOD: Thirty inpatients with a DSM-IV diagnosis of bipolar I disorder, currently manic, were randomly allocated to receive either lamotrigine (25 mg once daily for 1 week, 50 mg once daily for the second week, and 100 mg once daily for the last 2 weeks) or lithium (400 mg twice daily) in a 4-week randomized, double-blind, clinical trial. RESULTS: Both treatments improved symptoms of mania, as assessed by the Mania Rating Scale, Brief Psychiatric Rating Scale, Clinical Global Impression severity and improvement scales, and the Global Assessment of Functioning scale. There were no significant differences between groups at any time point, suggesting that the dose escalation required for lamotrigine did not adversely affect its onset of action. Secondary outcome measures, including the use of lorazepam as rescue medication, did not differ between the groups. No significant adverse events were noted in either group. CONCLUSION: In this pilot study, lamotrigine was as effective as lithium in the treatment of patients with bipolar disorder hospitalised for acute mania." [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]

Berk M, Ichim L, Brook S.
Department of Psychiatry, University of the Witwatersrand Medical School, Parktown, South Africa. 039berk@chiron.wits.ac.za
Olanzapine compared to lithium in mania: a double-blind randomized controlled trial.
Int Clin Psychopharmacol. 1999 Nov;14(6):339-43.
"Neuroleptics are of established efficacy in mania. Controlled data on the use of olanzapine in mania is however, absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly allocated to receive either olanzapine or lithium in a 4 week double-blind randomized controlled design. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2, olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P = 0.025). Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine appears to be at least as effective as lithium in the treatment of mania." [Abstract]

Segal J, Berk M, Brook S.
Department of Psychiatry, University of the Witwatersrand Medical School, Johannesburg, South Africa.
Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.
Clin Neuropharmacol. 1998 May-Jun;21(3):176-80.
"Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania. Forty-five inpatients with DSM-IV mania were studied in a 28-day randomized, controlled, double-blind trial of either 6 mg daily of risperidone, 10 mg daily of haloperidol, or 800 to 1200 mg daily of lithium. The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 (Brief Psychiatric rating scale; lithium 9.1, haloperidol 4.9, risperidone 6.5, F = 1.01, df = 2, p = 0.37; Mania rating scale; lithium 15.7, haloperidol 10.2, risperidone 12.4, F = 1.07, df = 2, p = 0.35 [analysis of variance]). The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement. This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania. The extrapyramidal side effects of risperidone and haloperidol were not significantly different." [Abstract]

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

Hartong EG, Moleman P, Hoogduin CA, Broekman TG, Nolen WA; LitCar Group.
Institute for Clinical Psychiatric Research (IPPO), The Hague, Nijmegen, the Netherlands. e.hartong@xs4all.nl
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]

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]

Ebert D, Jaspert A, Murata H, Kaschka WP.
Psychiatrische Klinik, Universitat Erlangen, Germany.
Initial lithium augmentation improves the antidepressant effects of standard TCA treatment in non-resistant depressed patients.
Psychopharmacology (Berl). 1995 Mar;118(2):223-5.
"The hypothesis was tested that an initial lithium-tricyclic antidepressant (TCA) combination has a better antidepressant effect than standard TCA treatment in non-refractory depression at the beginning of an episode. Twenty bipolar melancholic type depressed inpatients under lithium-TCA treatment were compared with 20 patients with the same diagnosis and TCA-placebo treatment for 5 weeks under double-blind conditions. All patients were male. Initial lithium-TCA treatment reduced depressive symptoms significantly more than antidepressant treatment with TCA and placebo after 5 weeks, but not in weeks 1 or 2. It can be concluded that lithium augmentation of TCA treatment should be started even at the beginning of antidepressant TCA treatment to provide a better treatment response in those patients who will profit from long-term lithium prophylaxis, e.g. bipolar patients with melancholic type depression." [Abstract]

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

Small JG, Klapper MH, Kellams JJ, Miller MJ, Milstein V, Sharpley PH, Small IF.
Department of Psychiatry, Larue D. Carter Memorial Hospital, Indiana University School of Medicine, Indianapolis 46202.
Electroconvulsive treatment compared with lithium in the management of manic states.
Arch Gen Psychiatry. 1988 Aug;45(8):727-32.
"Thirty-four hospitalized manic patients were randomized to treatment with either lithium carbonate or an average series of nine bilateral electroconvulsive treatments (ECTs), followed by maintenance with lithium carbonate. Weekly ratings of manic, depressive, and psychotic symptoms were obtained for eight weeks, and patients were followed up monthly for up to two years. Ratings by nonblind and blind observers indicated that the patients who underwent ECT improved more during the first eight weeks than did patients who were treated with lithium carbonate. This was especially true of patients with mixed symptoms of mania and depression and/or extreme manic behavior. Clinical ratings after eight weeks showed no significant differences between the lithium carbonate- and ECT-treated patients. Likewise, the two groups had comparable rates of relapse, recurrence, and rehospitalization during the follow-up period." [Abstract]

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

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

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

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

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

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

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

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

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

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

Bowden CL, Grunze H, Mullen J, Brecher M, Paulsson B, Jones M, Vågerö M, Svensson K
A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder.
J Clin Psychiatry. 2005 Jan;66(1):111-21.
OBJECTIVE: To evaluate the efficacy and tolerability of quetiapine monotherapy versus placebo for the treatment of mania associated with bipolar disorder. METHOD: In an international, multicenter, double-blind, parallel-group, 12-week study, patients with a DSM-IV diagnosis of bipolar I disorder (manic episode) were randomly assigned to treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or lithium. The primary efficacy measure was change from baseline in Young Mania Rating Scale (YMRS) score at day 21. Data were gathered from April 2001 to May 2002. RESULTS: More patients in the quetiapine (72/107) and lithium (67/98) groups completed the study compared with the placebo group (35/97). Improvement (reduction) in YMRS score was significantly greater for quetiapine than placebo at day 7 (-8.03 vs. -4.89; p < .01), and the difference between groups continued to increase over time to day 21 (-14.6 vs. -6.7; p < .001) and to endpoint at day 84 (-20.3 vs. -9.0; p < .001). Significantly more quetiapine patients compared with placebo patients fulfilled YMRS response criteria at day 21 (53.3% vs. 27.4%; p < .001) and at day 84 (72.0% vs. 41.1%; p < .001). Quetiapine was also superior to placebo in efficacy at day 21 and day 84 by all secondary measures. Lithium-treated patients improved significantly compared with placebo patients and similarly to quetiapine-treated patients on the primary efficacy measure. The most common adverse events for quetiapine were dry mouth, somnolence, and weight gain, while lithium was associated with tremor and insomnia. The quetiapine and placebo groups had similar, low levels of extrapyramidal symptom-related adverse events. CONCLUSIONS: Quetiapine demonstrated superior efficacy to placebo in patients with bipolar mania and was well tolerated. [Abstract]

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

Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R, Greene P, Leadbetter R.
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, England, UK.
A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder.
J Clin Psychiatry. 2004 Mar;65(3):432-41.
BACKGROUND: Two clinical trials, prospectively designed for combined analysis, compared placebo, lithium, and lamotrigine for treatment of bipolar I disorder in recently depressed or manic patients. METHOD: 1315 bipolar I patients (DSM-IV) enrolled in the initial open-label phase, and 638 were stabilized and randomly assigned to 18 months of double-blind monotherapy with lamotrigine (N = 280; 50-400 mg/day fixed dose or 100-400 mg/day flexible dose), lithium (N = 167; serum level of 0.8-1.1 mEq/L), or placebo (N = 191). The primary endpoint was time from randomization to intervention for a mood episode. Data were gathered from August 1997 to August 2001. RESULTS: Lamotrigine and lithium were superior to placebo for time to intervention for any mood episode (median survival: placebo, 86 days [95% CI = 58 to 121]; lithium, 184 days [95% CI = 119 to not calculable]; lamotrigine, 197 days [95% CI = 144 to 388]). Lamotrigine was superior to placebo for time to intervention for depression (median survival: placebo, 270 days [95% CI = 138 to not calculable]; lithium, median not calculable; lamotrigine, median not calculable). Lithium and lamotrigine were superior to placebo for time to intervention for mania (median survival not calculable for any group). Results of additional analyses adjusted for index mood were similar; however, only lithium was superior to placebo for intervention for mania. There was no evidence that either active treatment caused affective switch. Adverse event analysis indicated more diarrhea (19% vs. 7%, p <.05) and tremor (15% vs. 4%, p <.05) in lithium-treated patients compared with lamotrigine-treated patients. CONCLUSIONS: Lamotrigine and lithium stabilized mood by delaying the time to treatment for a mood episode. Lamotrigine was effective against depression and mania, with more robust activity against depression. Lithium was effective against mania.
[Abstract]

Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group.
Department of Psychiatry, University of Texas Health Science Center at San Antonio, 78229, USA. bowdenc@uthscsa.edu
A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.
Arch Gen Psychiatry. 2003 Apr;60(4):392-400.
"BACKGROUND: Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. METHODS: After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. RESULTS: Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (lamotrigine vs placebo, P =.02; lithium vs placebo, P =.006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode (P =.02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode (P =.006). The most common adverse event reported for lamotrigine was headache. CONCLUSIONS: Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression." [Abstract]

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

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

Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Voss CB, Johnson WE.
Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination.
Arch Gen Psychiatry. 1984 Nov;41(11):1096-104.
"In a double-blind, long-term follow-up study, 117 bipolar patients received lithium carbonate, imipramine hydrochloride, or both and 150 unipolar patients received lithium carbonate, imipramine, both lithium carbonate and imipramine, or placebo. With bipolar patients, lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes. The combination treatment provided no advantage over lithium carbonate alone. With unipolar patients, imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences. The combination treatment provided no advantage over imipramine alone. The lithium carbonate-treated group had fewer manic episodes than the other groups. Treatment outcome, which was evaluated primarily in terms of the occurrence of major depression or manic episodes, was significantly related to characteristics of the index episode, ie, the episode that brought the patient into the study." [Abstract]

Geller B, Cooper TB, Sun K, Zimerman B, Frazier J, Williams M, Heath J.
Washington University School of Medicine, St. Louis, MO 63110, USA.
Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency.
J Am Acad Child Adolesc Psychiatry. 1998 Feb;37(2):171-8.
"OBJECTIVE: To perform a double-blind, placebo-controlled, random assignment, parallel group, pharmacokinetically dosed study of lithium for adolescents with bipolar disorders (BP) and temporally secondary substance dependency disorders (SDD). METHOD: Subjects were 16.3 +/- 1.2 years old and were comprehensively assessed during a 6-week outpatient protocol that included random weekly urine collection for drug assays and random and weekly serum collection for lithium levels. RESULTS: Using both intent-to-treat (N = 25) and completer (n = 21) analyses, there were significant differences on continuous and categorical measures between the active and placebo groups for both psychopathology measures and weekly random urine drug assays. The mean scheduled weekly serum lithium level of active responders was 0.9 mEq/L. Addiction to both alcohol and marijuana was the most frequent category of SDD. Mean age at onset of BP was 9.6 +/- 3.9 years and of SDD was 15.3 +/- 1.3 years. There were multigenerational mood disorders in 96% and multigenerational SDD in 56% of families. CONCLUSIONS: Lithium treatment of BP with secondary SDD in adolescents was an efficacious treatment for both disorders. These results warrant replication with a long-term maintenance phase. The mean 6-year interval between the onset of BP and onset of SDD strongly argues for earliest recognition of BP." [Abstract]

Chou JC, Czobor P, Charles O, Tuma I, Winsberg B, Allen MH, Trujillo M, Volavka J.
Nathan Kline Institute, Orangeburg, New York 10962, USA. chou@nki.rfmh.org
Acute mania: haloperidol dose and augmentation with lithium or lorazepam.
J Clin Psychopharmacol. 1999 Dec;19(6):500-5.
"Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol." [Abstract]

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