Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM.
of Psychiatry, University of Oxford, Warneford Hospital, UK. firstname.lastname@example.org
lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized
Am J Psychiatry. 2004 Feb;161(2):217-22.
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."
S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G.
Department of Psychiatry,
University of Oxford, Oxford, UK, OX3 7JX. email@example.com
for maintenance treatment of mood disorders.
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.
Department of Psychiatry and Neuroscience Program, Harvard Medical School, Boston,
Lower suicide risk with long-term lithium treatment
in major affective illness: a meta-analysis.
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]
RW, Luckenbaugh DA, Post RM, Leverich GS, Nolen WA.
Altrecht Institute for
Mental Health Care and University Medical Center Utrecht, Utrecht, The Netherlands.
Rapid and non-rapid cycling bipolar disorder: a
meta-analysis of clinical studies.
J Clin Psychiatry. 2003
"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]
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.
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."
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.
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]
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."
M, Ichim L, Brook S.
Department of Psychiatry, University of the Witwatersrand
Medical School, Parktown, South Africa. email@example.com
compared to lithium in mania: a double-blind randomized controlled trial.
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."
J, Berk M, Brook S.
Department of Psychiatry, University of the Witwatersrand
Medical School, Johannesburg, South Africa.
with both lithium and haloperidol in mania: a double-blind randomized controlled
Clin Neuropharmacol. 1998 May-Jun;21(3):176-80.
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]
A, Diaz E, Baker CB, Pearsall HR, Woods SW.
Department of Psychiatry, Yale
University School of Medicine, New Haven, CT 06508, USA.
of divalproex versus lithium on length of hospital stay among patients with bipolar
Psychiatr Serv. 2000 Sep;51(9):1184-6.
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."
EG, Moleman P, Hoogduin CA, Broekman TG, Nolen WA; LitCar Group.
for Clinical Psychiatric Research (IPPO), The Hague, Nijmegen, the Netherlands.
Prophylactic efficacy of lithium versus carbamazepine
in treatment-naive bipolar patients.
J Clin Psychiatry.
"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. firstname.lastname@example.org
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]
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]
Ebert D, Jaspert A, Murata H, Kaschka WP.
Klinik, Universitat Erlangen, Germany.
Initial lithium augmentation
improves the antidepressant effects of standard TCA treatment in non-resistant
Psychopharmacology (Berl). 1995 Mar;118(2):223-5.
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
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.
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
JG, Klapper MH, Kellams JJ, Miller MJ, Milstein V, Sharpley PH, Small IF.
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.
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."
Swann AC, Bowden CL, Calabrese JR, Dilsaver SC,
University of Texas-Houston Medical School and Harris County Psychiatric
Mania: differential effects of previous depressive and
manic episodes on response to treatment.
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."
AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD.
Department of Psychiatry
and Behavioral Sciences, University of Texas Health Science Center, Houston 77030,
Differential effect of number of previous episodes of affective
disorder on response to lithium or divalproex in acute mania.
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]
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. firstname.lastname@example.org
randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment
of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.
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
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.
of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. email@example.com
efficacy of divalproex in the prevention of bipolar depression.
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]
AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, Dilsaver SC, Davis JM.
of Psychiatry, University of Texas Medical School at Houston, USA.
during mania. Treatment response to lithium or divalproex.
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]
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.
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.
size of efficacy measures comparing divalproex, lithium and placebo in acute mania.
"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
University of Texas, Houston Medical
[Prediction of treatment response in acute mania: controlled
clinical trials with divalproex]
Encephale. 2001 May-Jun;27(3):277-9.
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]
AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD.
University of Texas-Houston
Health Science Center, P.O. Box 20708, Houston, TX 77225, USA.
of response to divalproex, lithium, or placebo in four naturalistic subtypes of
Neuropsychopharmacology. 2002 Apr;26(4):530-6.
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]
AC, Daniel DG, Kochan LD, Wozniak PJ, Calabrese JR.
mania: specificity of its role in severity and treatment response.
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
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.
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.
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
Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA,
Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study
Department of Psychiatry, University of Texas Health Science Center
at San Antonio, 78229, USA. firstname.lastname@example.org
18-month trial of lamotrigine and lithium maintenance treatment in recently manic
or hypomanic patients with bipolar I disorder.
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."
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.
Research Laboratories, Eli Lilly & Co, Indianapolis, IN 46285, USA.
of olanzapine in combination with valproate or lithium in the treatment of mania
in patients partially nonresponsive to valproate or lithium monotherapy.
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."
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.
prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood
stabiliser v. mood stabiliser alone.
Br J Psychiatry. 2004
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]
RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Voss CB, Johnson WE.
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.
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]
B, Cooper TB, Sun K, Zimerman B, Frazier J, Williams M, Heath J.
University School of Medicine, St. Louis, MO 63110, USA.
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]
JC, Czobor P, Charles O, Tuma I, Winsberg B, Allen MH, Trujillo M, Volavka J.
Kline Institute, Orangeburg, New York 10962, USA. email@example.com
mania: haloperidol dose and augmentation with lithium or lorazepam.
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
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]