Carbamazepine Compared With Lithium
in the Treatment of Mania
Joyce G. Small, MD; Marietta H. Klapper, MS; Victor Milstein, PhD; Jeffrey J. Kellams, MD;
Marvin J. Miller, MD; Jon D. Marhenke, MD; Iver F. Small, MD
\s=b\ Fifty-two hospitalized
manic patients were randomized
to treatment with either carbamazepine or lithium carbon-
ate 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 re-
ceiving 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 ma-
jority of manic patients who are referred for tertiary care.
(Arch Gen Psychiatry. 1991;48:915-921)
has
Carbamazepi
tance
of
treatment
n eas an
already gained widespread accep¬
alternative
mania.
The evidence for
to lithium
carbonate for the
its efficacy is based
on both open and controlled trials. The latter have estab¬
lished that carbamazepine is superior to placebo1"6 for the
management of mania. Moreover, comparisons of car¬
bamazepine with neuroleptics4-7'10 have shown that the
former has equivalent therapeutic efficacy and less neu¬
rotoxicity. Lithium or carbamazepine, combined with
neuroleptics, have been shown to be therapeutically
equivalent in the treatment of mania,1112 but the separate
effects of lithium or carbamazepine cannot be ascertained
from drug combinations. To our knowledge, only two in¬
vestigations have compared the antimanic efficacy of
lithium and carbamazepine individually. Post et al13
reported that carbamazepine appeared to be equivalent to
lithium in nonconcurrent, double-blind, placebo-
controlled trials. Furthermore, they indicated that car¬
bamazepine was more effective in treating patients who
Accepted for publication March 26, 1991.
From the Department of Psychiatry, Indiana University School of
Medicine and Larue D. Carter Memorial Hospital, Indianapolis.
Reprints not available.
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were poorly responsive to lithium and in patients in the
later stages of bipolar illness. However, a recent report
suggested that tolerance may develop with long-term
use.14 In contrast, Lerer et al15 found more consistent im¬
provement with lithium than with carbamazepine, al¬
though a few patients did respond dramatically to car¬
bamazepine. However, the two double-blind studies
involved small numbers of patients (fewer than 20 per
cell) and therapeutic trials of only 3 or 4 weeks in duration.
Clearly, further research is needed to expand the database
on the antimanic efficacy of carbamazepine and to resolve
some of the inconsistencies. Accordingly, a prospective
study of lithium and carbamazepine in the treatment of
mania was undertaken, the outcome of which is described
in this report.
PATIENTS AND METHODS
This study was conducted during a 5-year period at an
academic tertiary care facility at the Indiana University School of
Medicine, Indianapolis. Patients were referred from community
mental health centers, private psychiatrists, and family physi¬
cians throughout the state, usually after inadequate response to
ambulatory treatment or brief hospitalization.
Patients were newly hospitalized adults with diagnoses of bi¬
polar disorder presenting in manic or mixed phases. Diagnosis
was established by examination of the patient and independent
interviews with relatives using the Schedule for Affective Disor¬
ders and Schizophrenia-Lifetime version.16 Patients met DSM-
III-R" criteria for a manic episode with or without coexisting
symptoms of depression. They were required to have a history
of at least one affective episode within the previous 2.5 years.
They were not otherwise selected for treatment resistance or
failure of lithium or carbamazepine treatment. All patients had
bipolar I disorders as defined by Research Diagnostic Criteria.18
Furthermore, a score of 7 or more on the manic subsection of the
Depression and Mania Scale19 (SDMS-D&M: score range, 3 to 15)
and scores of 60 or less on the Global Assessment Scale20 (GAS:
score range, 1 to 100) were inclusion requirements. Patients with
other Axis I DSM-III-R diagnoses, significant medical problems,
affective episodes associated with physical illness, current sub¬
stance abuse, any contraindication to either lithium or
or
carbamazepine wereexcluded. Other DSM-III-R Axis II or III
disorders were not reasons for exclusion. Patients gave written
informed consent after all procedures had been fully explained.
Admission workup included physical examination, electroen¬
cephalogram, electrocardiogram, and laboratory studies, includ¬
ing measures of electrolytes and thyroid, renal, hepatic, and hé¬
matologie status and urinalysis. Ongoing treatment with lithium
 or carbamazepine was discontinued for 2 weeks, and neurolep¬
tics were tapered and entirely discontinued for 1 week. During
this period, the only adjuvant medications that were permitted
were chloral hydrate for treatment of insomnia and amobarbital
sodium (Amytal) orally or intramuscularly for treatment of dis¬
turbed behavior, with the latter not to exceed 3 consecutive days
at a maximum dose of 750 mg/24 hr. After drug washout, baseline
evaluations for the study were completed. The clinical ratings of
psychopathology were done by blinded clinicians who were not
informed of the randomized treatment that was assigned nor
were these clinicians involved in patient management. Before the
study, clinical raters achieved interrater agreements of greater
than 80% that were rechecked at intervals during the study.
Ratings were done weekly, usually in the morning, consisting
of the SDMS-D&M, the GAS, the Manic Rating Scale (MRS) of
Young et al,21 the 24-item Hamilton Depression Rating Scale,22
the Brief Psychiatric Rating Scale (BPRS)2*3 (which was expanded
to include an additional rating of elevated mood), and the Clin¬
ical Global Impression Scale (CGI).24 The Shopsin-Gershon So¬
cial Behavior Checklist25 was done daily (5 d/wk) by an activity
therapist who was also unaware of the assigned treatment.
After completion of baseline evaluations, patients who con¬
tinued to display significant psychopathology (SDMS-M score,
s 7; GAS score, =s60) were randomly assigned to treatment with
lithium carbonate (300 mg) plus carbamazepine placebo tablets
or to carbamazepine (200-mg tablets) and lithium placebo
capsules. Patients were randomized so that equal numbers were
assigned to each treatment group for each block of 12 patients.
Medications were prescribed in initial dosages of one or two
capsules and tablets daily, with dosage increments every 3 to 4
days until trough plasma lithium ion levels (10 to 12 hours after
the last dose) were between 0.6 and 1.5 mmol/L and plasma car¬
bamazepine levels were between 25 and 50 µ /L. The latter
was primarily a measure of the parent compound without sep¬
aration of the epoxide metabolite.26 Dosages were increased to
ceiling levels or dosage-limiting side effects. The "blind" of the
attending clinicians was preserved by providing dummy plasma
levels of lithium or carbamazepine, as was done in the study by
Lerer et al.15
For the first 8 weeks of treatment, the clinical ratings and
evaluations were done weekly along with the determinations of
serum levels, blood chemistry values, and complete blood cell
counts. Side effects were monitored with the General Inquiry
part of the Systematic Assessment for Treatment Emergent
Events (SAFTEE).27 As during the washout phase, the only ad¬
juvant medications that were allowed were chloral hydrate and
amobarbital with repeated efforts to withdraw them after the
first 3 weeks with double-blind medications. Patients who
became unmanageable or who refused to continue were termi¬
nated after final ratings and evaluations were obtained.
At the end of 8 weeks, patients who were unimproved and/or
still met inclusion criteria for the study were discontinued from
the study after completion of all ratings and assessments.
Patients who were improved or in remission continued to receive
double-blind medications for up to 2 years, with the same clin¬
ical ratings and laboratory studies performed every 4 to 6 weeks.
Patients who relapsed or were rehospitalized for another affec¬
tive episode were dropped from the study after completion of
ratings and laboratory assessments.
Statistical procedures consisted of two-way analysis of vari¬
ance for repeated measures of all the clinical ratings. Where the
main effects of group (lithium vs carbamazepine) and time
(prestudy and the eight weekly ratings) were significant (P<. 05),
r tests of comparisons of the two treatment groups were under¬
taken for each time of assessment.
RESULTS
Demographic, Historical, and Baseline Data
Ninety-four patients were accepted and hospitalized for the
study on the basis of the available clinical information that
included presumptive diagnosis of a manic episode, as well as
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expressed willingness by referring physicians, relatives, and
patients for research participation. Patients were generally
referred after failure of short-term trials of lithium combined
with neuroleptics and/or carbamazepine. After preliminary
workup, 11 patients (12%) were excluded. Six patients were as¬
signed other DSM-III-R Axis I diagnoses (schizoaffective, three;
borderline personality disorder, two; and adjustment reaction,
one), and three other patients were eliminated because of med¬
ical contraindications to the study. One patient was excluded
because of no verified history of a previous affective episode, and
there was one administrative dropout (insurance carrier required
transfer to another facility). During the 2-week run-in phase, an
additional 31 patients were eliminated (37% of the reduced sam¬
ple) because of cycling to depression (n ll), sustained remis¬
=
sion (n 10), or patient refusal (n 7). Another patient decom-
= =
pensated so rapidly that emergency electroconvulsive treatment
was instituted. There were two other administrative dropouts.
Fifty-two patients, 48 of whom remained in the study for 3 or
more weeks, initially received double-blind medications, with 24
in each treatment group. Four were dropped before that time, ie,
three patients who were being treated with lithium for unman¬
ageable behavior and one patient who was receiving carba¬
mazepine who developed a rash.
Demographic and historical data are summarized in Table 1.
The patients who received lithium were, on average, almost 8
years older than the patients who were randomized to carbam¬
azepine (P .02). Otherwise, the groups were similar in terms of
=
sex distribution, education, and marital status. There were no
significant differences between the clinical characteristics of the
older (age, >50 years) patients (n 7) and younger individuals
=
who were treated with lithium (n 17). All patients had experi¬
=
enced previous manic episodes, but four and nine patients who
were assigned to lithium and carbamazepine treatments, respec¬
tively, had no confirmed history of depression (Fisher's Exact
Probability Test, =
.114). Three patients in each treatment
group had mixed episodes of mania and depression that were
defined as scores of 7 or more on the baseline SDMS-D. Three
patients, ie, one assigned to carbamazepine treatment and two
assigned to lithium treatment, had baseline Hamilton Depres¬
sion Rating Scale scores of 41 or greater (no psychopathology
equals a total score of 24). One patient had a rapid-cycling illness
with four or more episodes per year. There were no significant
group differences in age at onset, number of previous episodes,
manic proneness, or length of index episode before study entry.
Scores on the items from the Schedule for Affective Disorders
and Schizophrenia-Lifetime version that rated social relation¬
ships, healthiest and sickest levels of functioning, and outcome
of the last episode were similar in the two groups. Comorbidity,
namely, personality disorders (n 3), physical and neurologic
=
problems (n 15), and/or history of significant substance abuse
=
(n 6), was judged to be present in seven carbamazepine-treated
=
and 12 lithium-treated patients (Fisher's Exact Test, P= .238).
Lithium treatment of the current episode before hospitaliza¬
tion was evaluated by utilizing the definitions of adequate and
inadequate lithium therapy according to Black et al.28 To be de¬
fined as adequate, patients had to receive lithium treatment for
a minimum of 2 weeks with a blood level of least 0.9 mmol/L.
Patients who received lithium but did not meet these require¬
ments were rated as inadequately treated. This information was
available from outside records in all patients. In these respects,
the two groups were very similar. In addition, every one of the
patients had been treated with neuroleptics. Six patients who
were assigned to lithium treatment and five who were assigned
to carbamazepine treatment had also received carbamazepine for
the current episode with plasma levels at or below 33 µ /L.
Total scores on each of the clinical ratings at baseline were
compared for patients who were assigned to lithium and
carbamazepine therapy; f test comparisons did not yield any
significant differences at or beyond the .05 level. Likewise, the
mean baseline scores on CGI item 1 (lithium score, 5.3; carbam¬
azepine score, 5.0) and GAS (lithium score, 36; carbamazepine
score, 39) were similar in the two groups.
 "blind" of the clinicians and patients, 46% of patients were
within the specified therapeutic range within 1 week and 83%
within 2 weeks. Fifty-eight percent of the lithium-treated pa¬
Treatment Group tients achieved plasma levels of 0.9 mmol/L within the first 3
Lithium weeks. The remainder did not because of dosage-limiting side
effects or erratic compliance.
Carbonate Carbamazepine No significant toxicity was encountered (except for the one
( = 24) ( =
24)
Sex carbamazepine-treated patient who was dropped because of a
M 11 10
rash). Restricting attention to the first 8 weeks, patients in the
carbamazepine-treated group stayed in the study for an average
13 14 of 7.4 weeks compared with 6.5 weeks for the lithium-treated
Age, y group (P=.05). Attrition for unmanageability, dangerous be¬
Mean 42.6 34.3* havior, or refusal became progressively more of a problem in the
later weeks of the study, particularly with lithium. This could
Range 26-73 22-56 have been related to the limitations on as-needed (pm) medica¬
Mean education, y 12.0 13.5 tions, as well as lithium's lack of sedating effects as compared
Marital status, No. of with carbamazepine.
Table 3 shows mean total scores on the major clinical ratings
patients at baseline and at the end of 8 weeks of treatment for the 48 pa¬
Married 5 5
tients who completed at least 3 weeks of treatment, with differ¬
Ever married 11 8 ences between the two times of treatment indicated. Scores from
Single 8 11 the last available ratings on patients who were dropped were in¬
Mean age at onset, y 26.0 23.3 cluded in all subsequent analyses. End-point analyses showed
that patients in both groups were significantly improved on the
No. of previous episodes SDMS-M, CGI (item 1), and Shopsin-Gershon Social Behavior
Mania
1-4 11 12
Checklist, whereas the lithium-treated patients were also rated
as better on the MRS and GAS. The groups were not different
5-9 11 10 in the number of rating scales that showed improvement (Fish¬
alO 2 2 er's Exact Probability Test, P>,25). The lithium-treated group
showed minor nonsignificant worsening of depressive manifes¬
Depression tations as measured by the SDMS-D and Hamilton Depression
1-4 14 17
Rating Scale that was not observed with carbamazepine, which
5-9 7 6 may exert antidepressant effects.29 On the other ratings, patients
aio 3 1
who were treated with lithium did a little better than those who
were treated with carbamazepine, although none of the differ¬
Ratio, manic:depressed 1.2:1 1.4:1 ences were significant. Analysis of covariance for the effects of

Length of index episode age did not change the significance of any of the rating scale data.
before admission to Likewise, end-point analysis of all 52 patients who entered the
study, wk study, as well as analysis that was limited to the first 4 weeks of
Mean 9.2 8.9 the study, revealed no significant group differences. Similarly,
SD 7.2 6.6 analysis of all patients who finished 6 weeks of treatment
showed no differences between lithium and carbamazepine.
Lithium treatment of index Comparisons of the GAS ratings throughout the first 8 weeks
episode before of the study (end-point analysis) are displayed in Fig 1. Although
admission to study, No. there were no statistically significant group differences, the pro¬
of patients file graphs indicate that the carbamazepine-treated patients were
Adequate 8 9
better between weeks 2 and 5 with convergence of the curves
Inadequate 10 12 during weeks 6, 7, and 8.
None 6 3 Profiles of the total MRS data showed that the groups were very
similar for the first 2 weeks and again during weeks 6, 7, and 8 (Fig
SADS-L itemst
Best level of social
2). The carbamazepine-treated patients had fewer manic symptoms
relations in past 5 y 3.3 3.0 during weeks 3, 4, and 5. The CGI data showed very similar rela¬
tionships. The Shopsin-Gershon Social Behavior Checklist, which
Healthiest overall was done by an independent, blind-activity therapist, judged the
functioning in past 5 y 2.3 2.9 carbamazepine-treated patients as better functioning during weeks
Outcome of last episode 1.92 2.14 3 to 5 with similar profiles before and afterward.
Other analyses examined the demographic of the treatment
'Age difference, P= .02.
groups, including family history, comorbidity (Axis II and III
tSADS-L indicates Schedule for Affective Disorders and Schizophre¬
nia-Lifetime version. Scores are given for items.
diagnoses), electroencephalographic ratings of abnormality,
and total scores and factors on each of the baseline ratings.
None of these pretreatment ratings was associated with a
Comparison of Lithium and Carbamazepine Therapies favorable response to lithium, defined as a CGI rating of
Table 2 provides an overview of the first 8 weeks of treatment. moderately or greatly improved. Patients who were mini¬
Doses of sedatives and numbers of patients who received them mally improved, unchanged, or worse were classified as non¬
were similar in the two groups, except in weeks 2 and 3, when responders. On the other hand, there were several assess¬
the lithium-treated patients received more chloral hydrate or ments, listed in Table 4, that distinguished carbamazepine-
amobarbital. Numbers of patients who were receiving lithium treated responders from nonresponders. In each instance, a
and carbamazepine are indicated with the mean serum levels favorable response was associated with lower baseline ratings
and dosages and the weekly mean total SAFTEE General Inquiry (less psychopathology) and fewer electroencephalographic ab¬
scores. Some of the former are spuriously low since poorly com¬ normalities before treatment. Ages of responders (mean, 37.8
pliant patients were included until dropout. Despite the rela¬ years) and nonresponders (mean, 38.7 years) were not signif¬
tively slow titration of lithium that was necessary to preserve the icantly different (P = .82).

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 Week of Study

1 8
Carbamazepine Treatment Group
No. of patients 24 24 24 23 23 23 20 17
Mean dose, mg/d 700 850 932 980 1016 1052 1040 1036
Serum level, µ /L 30 32 37 32 35 35 33 37
SAFTEE-GI 1.6 1.6 1.6 1.5 1.6 1.7 1.6 1.5
Use of prn medications
Chloral hydrate
Mean weekly dose, g 2.0 1.0 1.2 1.9 1.4 0.8 1.4 0.8
No. of patients 11 9 6 4 4 10 4 4
Amobarbital sodium
(Amytal)
Mean weekly dose, mg 1320 525 317 400 800 908 350 367
No. of patients 12 8 9 9 4 6 5 4
Lithium Carbonate Treatment Group
No. of patients 24 24 24 21 20 19 14 11
Mean dose, mg/d 1035 1260 1275 1272 1260 1278 1125 1155
Mean serum level
(median), mmol/L 0.58 (0.58) 0.79 (0.75) 0.80 (0.75) 0.82 (0.83) 0.92 (0.89) 0.64 (0.66) 0.79 (0.75) 0.73 (0.74)
SAFTEE-GI 1.7 1.5 1.6 1.6 1.6 1.5 1.6 1.7
Use of as-needed medications
Chloral hydrate
Mean weekly dose, g 2.1 2.4t 1.6 1.4 1.6 1.6 1.9 0.5
No. of patients 14 13 11 9 5 7 4 3
Amobarbital
Mean dose, mg 1206 946 990t 500 490 562 850 400
No. of patients 16 12 10 5 4 2 1
*SAFTEE-GI indicates Systematic Assessment of Treatment Emergent Events, and prn, as needed,
ti test: o7 46, P= .01 (lithium treatment group compared with carbamazepine treatment group),
=

tttest: df=46, P= .0001 (lithium treatment group compared with carbamazepine treatment group).

Treatment Group
Lithium Carbonate Carbamazepine
%
Baseline 8 wk % Improvement Baseline 8 wk % Improvement Differencet
MRS 30.3 20.6 32 30.9 22.4 28 4
SDMS-M 11.3 8.0 29§ 11.3 7.9 30§ -1
SDMS-D 3.4 4.0 -18 3.4 3.4 0 -18
HAM-D 29.9 30.4 -2 29.4 26.9 8 10
BPRS 49.1 43.2 12 47.0 42.2 10 2
CGI-1 5.3 4.3 19 5.0 4.1 18 1
GAS 35.7 47.5 33 38.8 50.5 30 3
BCL 32.5 20.9 36 34.8 24.9 28 8
*MRS indicates Young Manic Rating Scale; SDMS-M, manic subsection of symptoms of Depression and Mania Scale; SDMS-D, depression
subsection of Depression and Mania Scale; HAM-D, Hamilton Depression Rating Scale; BPRS, Brief Psychiatric Rating Scale; CGI-1, Clinical Global
Impression Scale item 1; GAS, Global Assessment Scale; and BCL, Shopsin-Gershon Social Behavior Checklist. Differences between lithium
treatment group and carbamazepine treatment group were not significant at baseline or week 8.
tPercent difference between lithium treatment group and carbamazepine treatment group.
between baseline and 8 weeks: t test (df= 23), P<.05.
§Difference between baseline and 8 weeks: t test (df= 23), P<.01.

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Weeks
Fig 1.—Global Assessment Scales. Triangles indicate scores from
carbamazepine-treated patients; squares, scores from lithium
carbonate-treated group; and vertical lines, 1 SD. Week 0 (baseline)
preceded active drug therapy.
Weeks
Fig 2. —Manic Rating Scale.Triangles are scores from
carbamazepine-treated patients; squares, scores from lithium
carbonate-treated group; and vertical lines, 1 SD. Week 0 (baseline)
preceded active drug therapy.
Discriminant function analysis that utilized individual items
from the MRS and BPRS was also performed in an attempt to
separate responders and nonresponders to each of the drugs.
For lithium, MRS items in descending order of potency were in¬
sight, sleep, aggression, appearance, energy, irritability, and sex
that identified 88% of responders and 88% of nonresponders.
For carbamazepine, corresponding MRS items were energy, ap¬
pearance, sleep, aggression, insight, and sex that together cor-
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Score
Treatment ·-"-*
Group Variable Responder Nonresponder
Lithium carbonate None
Carbamazepine GAS 49.1 34.2 .001
MRS 21.6 35.6 .001
BPRS total 38.0 51.6 .001
CGI-1 4.1 5.4 .001
BPRSH-S 7.3 12.3 .005
SDMS-M 9.8 12.1 .006
BPRST-D 5.6 9.3 .02
EEG 1.1 1.6 .05
*For the lithium treatment group, there were eight responders and 16
nonresponders; for the carbamazepine treatment group, there were eight
responders and 16 nonresponders. GAS indicates Global Assessment
Scale; MRS, Young Manic Rating Scale; BPRS, Brief Psychiatric Rating
Scale; CGI-1, Clinical Global Impression Scale item 1; H-S, Hostile-
Suspicious; SDMS-M, manic subsection of Depression and Mania Scale;
T-D, Thinking Disturbance; and EEG, electroencephalogram.
rectly predicted 100% of responders and 88% of nonresponders,
with an overall accuracy of 92%. In addition, BPRS items of con¬
ceptual disorganization and suspiciousness separated 88% of
carbamazepine-treated responders and 94% of nonresponders,
with an overall accuracy of 92%. Individual items that recorded
the presence or absence of hallucinations and noncongruent de¬
lusions were not significantly associated with outcome. Neither
was adequacy of previous lithium treatment nor outcome of the
previous episode significantly related to response to either med¬
ication. Similarly, blood levels of lithium or carbamazepine were
not predictive of therapeutic outcome. These analyses supported
the conclusion that severity of mania was the strongest predic¬
tor of response to either drug and that more manifestations of
psychosis predicted poorer response to carbamazepine but not
to lithium.
Longitudinal Course—Outcome Measures
At the end of 8 weeks, two thirds of the 48 patients were
dropped for lack of efficacy or refusal to continue. Eight patients
remained in each group to continue with double-blind medica¬
tions for up to 2 years. The pattern of dropouts from the study
after 8 weeks appeared to be different for lithium and carbam¬
azepine. All of the carbamazepine-treated patients were
dropped by 24 weeks, whereas all but one of the lithium-treated
patients gradually left the study throughout the first year. One
patient treated with lithium continued to receive double-blind
medications for 2 years. Average stay after 8 weeks was 9.1 ad¬
ditional weeks for carbamazepine and 14.9 weeks for lithium
(Fisher's Exact Probability Test, =.20). Analyses of survival
curves after 8 weeks revealed no statistically significant group
differences (Mantel-Cox test,30 =.14). However, numbers of
patients were too small to rule out potential type II errors.
Adequacy of maintenance of the clinicians' blind was assessed
by asking attending physicians and nurses to guess the assigned
treatment. Their responses were more often correct than incor¬
rect, but accuracy did not reach statistical significance (P>.05).
Three lithium-treated patients were dropped because of recur¬
rences (manic, two patients; depressed, one patient), and four
were dropped because of noncompliance. Five carbamazepine-
treated patients were dropped because of recurrence (manic, two
patients; depressed, three patients), one patient was dropped
because of low granulocyte count, and two patients were
dropped because of noncompliance. At the time of recurrence,
most patients did not continue double-blind treatment. They
 were either rehospitalized or unavailable for follow-up (sought
treatment at other facilities, left the city, etc).
After discontinuation of blinded medications, 12 patients (half
originally assigned to lithium treatment and half to carbam¬
azepine treatment) were treated by physician's choice with
lithium-carbamazepine combined without knowledge of the
study assigned treatment. Three patients in each group re¬
sponded favorably without need for other medications. The re¬
mainder of the study dropouts were treated with neuroleptics
and/or electroconvulsive therapy according to best medical
judgment. The latter was prescribed after withdrawal of blinded
medications for at least a week without breaking the study codes
for nine patients who were assigned to lithium treatment and for
eight patients who were assigned to carbamazepine treatment.
The majority of the patients (87%) ultimately responded well
enough for hospital discharge, except for three patients (13%)
from each treatment group who were transferred to long-stay
institutions. The mean duration of hospitalization was 169 days
for lithium-treated patients and 146 days for carbamazepine-
treated patients (difference not significant), excluding one pa¬
tient who was assigned to lithium treatment and who is still
awaiting placement.
COMMENT
The results of this study indicate that either lithium
or carbamazepine alone was a modestly effective inter¬
vention in the short-term treatment of acute mania.
One third of patients who were on either therapeutic
regimen demonstrated moderate to marked improve¬
ment during the first 8 weeks of treatment without
significant toxic effects or morbidity. The treatment
groups were equivalent in terms of the identifying and
demographic data, except that the carbamazepine-
treated group was younger than the lithium-treated
patients. Otherwise, the historical data and baseline
ratings of psychopathology were similar in the two
groups. Clinical ratings during the first 8 weeks re¬
vealed no statistically significant differences that fa¬
vored either treatment. Most scores on the major study
assessments were significantly improved by the end of
8 weeks.
Analysis of baseline data revealed no predictors of re¬
sponse to lithium. However, patients who responded to
carbamazepine had lower (better) ratings on the GAS,
MRS, BPRS, CGI, and SDMS-M and more normal elec¬
troencephalographic findings than those who did not.
Although the differences between the groups were not
significant, profiles of response indicated that the
carbamazepine-treated patients were functioning some¬
what better than the lithium-treated group during weeks
2 to 5 as indicated by the GAS, CGI, MRS and Shopsin-
Gershon Social Behavior Checklist. After 8 weeks, lithium
appeared to have some advantage with more prolonged
survival times, but group differences were not statistically
significant. However, numbers of patients were too small
to avoid possible type II errors. Discriminant function
analysis indicated that the strongest predictor of clinical
outcome during the first 8 weeks of treatment with either
drug was the severity of mania, with sicker patients
achieving poorer therapeutic results. Lower BPRS scores
of severity of psychosis predicted better response to car¬
bamazepine but not to lithium.
The study selection criteria may have prejudiced
against either drug to some degree since the patients were
required to be in a manic episode at the time of the study
and also have a relatively high risk of recurrence with a
previous episode within the past 2Vi years. The bias was
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more against lithium than carbamazepine since most pa¬
tients had failed lithium trials before study entry, and es¬
pecially since the patients who were assigned to lithium
treatment were older.13 Moreover, they became some¬
what more depressed during the study, suggesting mixed
features that are known to be associated with a poor lith¬
ium response.29 However, neither adequacy of previous
lithium treatment nor history of carbamazepine exposure
predicted outcome with either lithium or carbamazepine.
One third of patients did respond to monotherapy with
either drug, and 87% of the patients were ultimately dis¬
charged to the community, indicating that these patients
were not particularly treatment resistant. In these re¬
spects, this sample was typical of admissions to tertiary
care facilities. Moreover, there are some advantages to
studying such patients since they are at a high enough risk
for relapse and recurrence to demonstrate differences be¬
tween treatment groups within a reasonable period. The
major bias introduced was toward poor compliance with
treatment that proved to be a problem throughout the
study. There was a particularly high dropout rate between
entry to the study and initiation of treatment during the
preliminary drug washout. This was even more pro¬
nounced than in our previous study that compared lith¬
ium and electroconvulsive therapy in which low doses of
neuroleptics were permitted.31 Dropouts after 8 weeks of
treatment were similarly high and occurred mainly for
noncompliance. These problems limit the amount and
value of follow-up data but were largely unavoidable
given the manic patient's characteristic denial of illness
and need for treatment.
The results of this study are largely in agreement with
findings from the literature. We are in accord with Post et
al13 who found that the short-term effects of two drugs
were equivalent, but that carbamazepine appeared to lose
efficacy on long-term follow-up.14*29 Our findings also
concur with those reported Lenzi et al,11 who observed
somewhat better symptomatic control with carba¬
mazepine than lithium during the first 3 weeks of treat¬
ment, and with those of Luznat et al,12 who found that the
two drugs were equivalent. The only discrepancy was
with the study of Lerer et al,15 in which they found early
advantages for lithium. However, we did observe that
lithium response was not limited by severity of illness,
whereas carbamazepine was less effective in the sicker
patients. Comorbidity was not predictive of treatment
outcome; this finding is at variance with retrospective and
case-control findings by Black et al.28-32
The strengths of this study are that an exceptionally
difficult cohort of patients was collected, withdrawn from
lithium, carbamazepine, and neuroleptic medications,
and randomized to treatment with lithium or carbam¬
azepine alone for 8 weeks. Under these circumstances, we
found that comparable, albeit limited, benefits were
achieved with either lithium or carbamazepine, with
some advantages for carbamazepine during the early
part
of the study and for lithium later on. These observations
suggest that a combination of the two drugs might be a
useful therapeutic approach. This possibility should be
investigated in future studies that compare the two agents
together with a standard treatment, such as lithium,
combined with neuroleptics. We are presently in the
midst of conducting such an investigation. Trials of other
anticonvulsants and alternative drug therapies are also
important avenues for future research, given the growing
 body of patients with bipolar illness who do not respond
well to conventional management.29
This study was supported in part by grant MH40930 from the Na¬
tional Institute of Mental Health, Bethesda, Md.
lames Norton, PhD, of the Department of Psychiatry, Indiana
University School of Medicine, Indianapolis, was a statistical con¬
sultant for this study.
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