Hartong EG, Moleman P, Hoogduin
CA, Broekman TG, Nolen WA; LitCar Group.
efficacy of lithium versus carbamazepine in treatment-naive bipolar patients.
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. email@example.com
efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder:
results of the MAP study.
Neuropsychobiology. 2000;42 Suppl
"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."
N, Greil W.
Department of Psychiatry. University of Munich, Germany.
morbidity and drop-out under carbamazepine and lithium in the maintenance treatment
of bipolar disorder.
Psychol Med. 2002 Apr;32(3):493-501.
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]
RA, Suppes T, Carmody TJ, Bucci JP, Hume JH, Kromelis M, Emslie GJ, Weinberg WA,
Department of Psychiatry, University of Texas Southwestern Medical
Center at Dallas 75235-9070, USA. firstname.lastname@example.org
of lithium, divalproex sodium, and carbamazepine in children and adolescents with
J Am Acad Child Adolesc Psychiatry. 2000
"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."
W, Kleindienst N.
Psychiatric Hospital, University of Munich, Germany. email@example.com
versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar
disorder not otherwise specified.
Int Clin Psychopharmacol.
"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."
Greil W, Kleindienst N.
University of Munich, Germany. firstname.lastname@example.org
comparative prophylactic efficacy of lithium and carbamazepine in patients with
bipolar I disorder.
Int Clin Psychopharmacol. 1999 Sep;14(5):277-81.
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]
W, Kleindienst N, Erazo N, Muller-Oerlinghausen B.
Psychiatric Hospital of
the University of Munich, Germany. email@example.com
response to lithium and carbamazepine in the prophylaxis of bipolar disorder.
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."
KD, Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM.
Section on Psychobiology,
National Institute of Mental Health, Bethesda, Md. 20892, USA.
prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar
J Clin Psychiatry. 1997 Nov;58(11):470-8.
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]
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,
Psychiatric Hospital, University of Munich, Germany.
versus carbamazepine in the maintenance treatment of bipolar disorders--a randomised
J Affect Disord. 1997 Apr;43(2):151-61.
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]
JG, Klapper MH, Milstein V, Kellams JJ, Miller MJ, Marhenke JD, Small IF.
of Psychiatry, Indiana University School of Medicine.
compared with lithium in the treatment of mania.
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.
"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.
combined with carbamazepine or haloperidol in the treatment of mania.
"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
randomized, double-blind, placebo-controlled trial of extended-release carbamazepine
capsules as monotherapy for bipolar disorder patients with manic or mixed episodes.
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]