Carbamazepine Compared With Lithium in the Treatment of Mania
Joyce
G.
Marietta H. Klapper, MS; Victor Milstein, PhD; Jeffrey J. Kellams, MD; Marvin J. Miller, MD; Jon D. Marhenke, MD; Iver F. Small, MD
Small, MD;
hospitalized
\s=b\ Fifty-two to treatment with either ate after a 2-week
manic patients were randomized carbamazepine or lithium carbondrug 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.
(Arch Gen Psychiatry. 1991;48:915-921) has
already gained widespread accep¬ Carbamazepi n e alternative carbonate for the of The evidence for
tance treatment
as an
to lithium
mania. its efficacy is based 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, placebocontrolled trials. Furthermore, they indicated that car¬ bamazepine was more effective in treating patients who on
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.
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 was conducted during a 5-year
This study 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 DSMIII-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¬
any contraindication to either lithium or excluded. 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 stance
abuse,
carbamazepine
or
were
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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¬ or
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 (P50 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 .114). Three patients in each treatment Probability Test, 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. =
=
=
=
=
=
=
=
=
=
Downloaded From: http://archpsyc.jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/12511/ by a University of New England Library User on 05/08
Treatment
Lithium Carbonate ( = 24)
Group
Carbamazepine (
=
24)
Sex M
11
10
13
14
42.6
34.3*
26-73
22-56
12.0
13.5
Age, y
Mean
Range Mean education, y Marital status, No. of
patients
Married Ever married
Single
5
5
11
8
8
11
26.0
23.3
11
12
11
10
2
2
1-4
14
17
5-9
7
6
Mean age at onset, y No. of previous episodes Mania 1-4 5-9 alO
Depression
aio
Ratio, manic:depressed
3
1
1.2:1
1.4:1
Mean
9.2
8.9
SD
7.2
6.6
8
9
10
12
6
3
3.3
3.0
2.3
2.9
1.92
2.14
Length of index episode before admission to
study, wk Lithium treatment of index episode before admission to study, No. of patients
Adequate Inadequate None
SADS-L itemst Best level of social relations in past 5 y Healthiest overall functioning in past 5 y Outcome of last episode
'Age difference,
P= .02. tSADS-L indicates Schedule for Affective Disorders and nia-Lifetime version. Scores are given for items.
Schizophre¬
Comparison of Lithium and Carbamazepine Therapies Table 2 provides an overview of the first 8 weeks of treatment. Doses of sedatives and numbers of patients who received them were similar in the two groups, except in weeks 2 and 3, when the lithium-treated patients received more chloral hydrate or amobarbital. Numbers of patients who were receiving lithium and carbamazepine are indicated with the mean serum levels and dosages and the weekly mean total SAFTEE General Inquiry scores. Some of the former are spuriously low since poorly com¬ pliant patients were included until dropout. Despite the rela¬ tively slow titration of lithium that was necessary to preserve the
"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¬ tients achieved plasma levels of 0.9 mmol/L within the first 3 weeks. The remainder did not because of dosage-limiting side effects or erratic compliance. No significant toxicity was encountered (except for the one carbamazepine-treated patient who was dropped because of a rash). Restricting attention to the first 8 weeks, patients in the carbamazepine-treated group stayed in the study for an average of 7.4 weeks compared with 6.5 weeks for the lithium-treated group (P=.05). Attrition for unmanageability, dangerous be¬ havior, or refusal became progressively more of a problem in the later weeks of the study, particularly with lithium. This could have been related to the limitations on as-needed (pm) medica¬ tions, as well as lithium's lack of sedating effects as compared with carbamazepine. Table 3 shows mean total scores on the major clinical ratings at baseline and at the end of 8 weeks of treatment for the 48 pa¬ tients who completed at least 3 weeks of treatment, with differ¬ ences between the two times of treatment indicated. Scores from the last available ratings on patients who were dropped were in¬ cluded in all subsequent analyses. End-point analyses showed that patients in both groups were significantly improved on the SDMS-M, CGI (item 1), and Shopsin-Gershon Social Behavior Checklist, whereas the lithium-treated patients were also rated as better on the MRS and GAS. The groups were not different in the number of rating scales that showed improvement (Fish¬ er's Exact Probability Test, P>,25). The lithium-treated group showed minor nonsignificant worsening of depressive manifes¬ tations as measured by the SDMS-D and Hamilton Depression Rating Scale that was not observed with carbamazepine, which may exert antidepressant effects.29 On the other ratings, patients who were treated with lithium did a little better than those who were treated with carbamazepine, although none of the differ¬ ences were significant. Analysis of covariance for the effects of age did not change the significance of any of the rating scale data. Likewise, end-point analysis of all 52 patients who entered the study, as well as analysis that was limited to the first 4 weeks of the study, revealed no significant group differences. Similarly, analysis of all patients who finished 6 weeks of treatment showed no differences between lithium and carbamazepine. Comparisons of the GAS ratings throughout the first 8 weeks of the study (end-point analysis) are displayed in Fig 1. Although there were no statistically significant group differences, the pro¬ file graphs indicate that the carbamazepine-treated patients were better between weeks 2 and 5 with convergence of the curves during weeks 6, 7, and 8. 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 2). The carbamazepine-treated patients had fewer manic symptoms during weeks 3, 4, and 5. The CGI data showed very similar rela¬ tionships. The Shopsin-Gershon Social Behavior Checklist, which was done by an independent, blind-activity therapist, judged the carbamazepine-treated patients as better functioning during weeks 3 to 5 with similar profiles before and afterward. Other analyses examined the demographic of the treatment groups, including family history, comorbidity (Axis II and III 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 favorable response to lithium, defined as a CGI rating of moderately or greatly improved. Patients who were mini¬ mally improved, unchanged, or worse were classified as non¬ responders. On the other hand, there were several assess¬ ments, listed in Table 4, that distinguished carbamazepinetreated responders from nonresponders. In each instance, a favorable response was associated with lower baseline ratings (less psychopathology) and fewer electroencephalographic ab¬ normalities before treatment. Ages of responders (mean, 37.8 (mean, 38.7 years) were not signif¬ years) and nonresponders icantly different (P = .82).
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Week of Study 8
1
No. of patients
Carbamazepine Treatment Group 24 24 23
23
23
20
17
700
850
932
980
1016
1052
1040
1036
30
32
37
32
35
35
33
37
24
dose, mg/d Serum level, µ /L Mean
1.6
SAFTEE-GI Use of prn medications Chloral hydrate Mean weekly dose, g No. of patients
1.6
1.6
2.0
1.5
1.6
1.7
1.6
1.5
1.0
1.2
1.9
1.4
1.4
0.8
11
9
6
4
4
10
4
4
1320
525
317
400
800
908
350
367
12
8
9
9
4
6
5
4
0.8
Amobarbital sodium
(Amytal) Mean
weekly dose, mg
No. of patients
Lithium Carbonate Treatment No. of patients Mean
dose, mg/d
Mean
serum
(median),
level mmol/L
Group
24
24
24
21
20
19
14
11
1035
1260
1275
1272
1260
1278
1125
1155
0.58 (0.58) 0.79 (0.75) 0.80 (0.75) 0.82 (0.83) 0.92 (0.89) 1.7
SAFTEE-GI
1.5
1.6
1.6
0.64 (0.66) 0.79 (0.75) 0.73 (0.74)
1.6
1.5
1.6
1.7
Use of as-needed medications
Chloral Mean
hydrate weekly dose, g
2.1
No. of patients
2.4t
14
13
1206
946
16
12
1.6
1.4
1.6
1.6
1.9
0.5
9
5
7
4
3
500
490
562
850
400
5
4
2
1
11
Amobarbital
dose, mg No. of patients
Mean
990t 10
*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
MRS
30.3
20.6
SDMS-M
11.3
8.0
SDMS-D
3.4
4.0
-18
HAM-D
29.9
30.4
-2
29.4
BPRS
49.1
43.2
12
47.0
CGI-1
5.3
4.3
19
5.0
4.1
GAS
35.7
47.5
33
38.8
50.5
30
3
BCL
32.5
20.9
36
34.8
24.9
28
8
%
8 wk
32
Baseline 30.9
22.4
28
29§
11.3
7.9
30§
-1
3.4
3.4
0
-18
26.9
8
10
42.2
10
2
18
1
Improvement
%
Improvement
Differencet 4
*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
Joyce
G.
Marietta H. Klapper, MS; Victor Milstein, PhD; Jeffrey J. Kellams, MD; Marvin J. Miller, MD; Jon D. Marhenke, MD; Iver F. Small, MD
Small, MD;
hospitalized
\s=b\ Fifty-two to treatment with either ate after a 2-week
manic patients were randomized carbamazepine or lithium carbondrug 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.
(Arch Gen Psychiatry. 1991;48:915-921) has
already gained widespread accep¬ Carbamazepi n e alternative carbonate for the of The evidence for
tance treatment
as an
to lithium
mania. its efficacy is based 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, placebocontrolled trials. Furthermore, they indicated that car¬ bamazepine was more effective in treating patients who on
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.
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 was conducted during a 5-year
This study 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 DSMIII-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¬
any contraindication to either lithium or excluded. 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 stance
abuse,
carbamazepine
or
were
Downloaded From: http://archpsyc.jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/12511/ by a University of New England Library User on 05/08
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¬ or
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 (P50 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 .114). Three patients in each treatment Probability Test, 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. =
=
=
=
=
=
=
=
=
=
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Treatment
Lithium Carbonate ( = 24)
Group
Carbamazepine (
=
24)
Sex M
11
10
13
14
42.6
34.3*
26-73
22-56
12.0
13.5
Age, y
Mean
Range Mean education, y Marital status, No. of
patients
Married Ever married
Single
5
5
11
8
8
11
26.0
23.3
11
12
11
10
2
2
1-4
14
17
5-9
7
6
Mean age at onset, y No. of previous episodes Mania 1-4 5-9 alO
Depression
aio
Ratio, manic:depressed
3
1
1.2:1
1.4:1
Mean
9.2
8.9
SD
7.2
6.6
8
9
10
12
6
3
3.3
3.0
2.3
2.9
1.92
2.14
Length of index episode before admission to
study, wk Lithium treatment of index episode before admission to study, No. of patients
Adequate Inadequate None
SADS-L itemst Best level of social relations in past 5 y Healthiest overall functioning in past 5 y Outcome of last episode
'Age difference,
P= .02. tSADS-L indicates Schedule for Affective Disorders and nia-Lifetime version. Scores are given for items.
Schizophre¬
Comparison of Lithium and Carbamazepine Therapies Table 2 provides an overview of the first 8 weeks of treatment. Doses of sedatives and numbers of patients who received them were similar in the two groups, except in weeks 2 and 3, when the lithium-treated patients received more chloral hydrate or amobarbital. Numbers of patients who were receiving lithium and carbamazepine are indicated with the mean serum levels and dosages and the weekly mean total SAFTEE General Inquiry scores. Some of the former are spuriously low since poorly com¬ pliant patients were included until dropout. Despite the rela¬ tively slow titration of lithium that was necessary to preserve the
"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¬ tients achieved plasma levels of 0.9 mmol/L within the first 3 weeks. The remainder did not because of dosage-limiting side effects or erratic compliance. No significant toxicity was encountered (except for the one carbamazepine-treated patient who was dropped because of a rash). Restricting attention to the first 8 weeks, patients in the carbamazepine-treated group stayed in the study for an average of 7.4 weeks compared with 6.5 weeks for the lithium-treated group (P=.05). Attrition for unmanageability, dangerous be¬ havior, or refusal became progressively more of a problem in the later weeks of the study, particularly with lithium. This could have been related to the limitations on as-needed (pm) medica¬ tions, as well as lithium's lack of sedating effects as compared with carbamazepine. Table 3 shows mean total scores on the major clinical ratings at baseline and at the end of 8 weeks of treatment for the 48 pa¬ tients who completed at least 3 weeks of treatment, with differ¬ ences between the two times of treatment indicated. Scores from the last available ratings on patients who were dropped were in¬ cluded in all subsequent analyses. End-point analyses showed that patients in both groups were significantly improved on the SDMS-M, CGI (item 1), and Shopsin-Gershon Social Behavior Checklist, whereas the lithium-treated patients were also rated as better on the MRS and GAS. The groups were not different in the number of rating scales that showed improvement (Fish¬ er's Exact Probability Test, P>,25). The lithium-treated group showed minor nonsignificant worsening of depressive manifes¬ tations as measured by the SDMS-D and Hamilton Depression Rating Scale that was not observed with carbamazepine, which may exert antidepressant effects.29 On the other ratings, patients who were treated with lithium did a little better than those who were treated with carbamazepine, although none of the differ¬ ences were significant. Analysis of covariance for the effects of age did not change the significance of any of the rating scale data. Likewise, end-point analysis of all 52 patients who entered the study, as well as analysis that was limited to the first 4 weeks of the study, revealed no significant group differences. Similarly, analysis of all patients who finished 6 weeks of treatment showed no differences between lithium and carbamazepine. Comparisons of the GAS ratings throughout the first 8 weeks of the study (end-point analysis) are displayed in Fig 1. Although there were no statistically significant group differences, the pro¬ file graphs indicate that the carbamazepine-treated patients were better between weeks 2 and 5 with convergence of the curves during weeks 6, 7, and 8. 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 2). The carbamazepine-treated patients had fewer manic symptoms during weeks 3, 4, and 5. The CGI data showed very similar rela¬ tionships. The Shopsin-Gershon Social Behavior Checklist, which was done by an independent, blind-activity therapist, judged the carbamazepine-treated patients as better functioning during weeks 3 to 5 with similar profiles before and afterward. Other analyses examined the demographic of the treatment groups, including family history, comorbidity (Axis II and III 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 favorable response to lithium, defined as a CGI rating of moderately or greatly improved. Patients who were mini¬ mally improved, unchanged, or worse were classified as non¬ responders. On the other hand, there were several assess¬ ments, listed in Table 4, that distinguished carbamazepinetreated responders from nonresponders. In each instance, a favorable response was associated with lower baseline ratings (less psychopathology) and fewer electroencephalographic ab¬ normalities before treatment. Ages of responders (mean, 37.8 (mean, 38.7 years) were not signif¬ years) and nonresponders icantly different (P = .82).
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Week of Study 8
1
No. of patients
Carbamazepine Treatment Group 24 24 23
23
23
20
17
700
850
932
980
1016
1052
1040
1036
30
32
37
32
35
35
33
37
24
dose, mg/d Serum level, µ /L Mean
1.6
SAFTEE-GI Use of prn medications Chloral hydrate Mean weekly dose, g No. of patients
1.6
1.6
2.0
1.5
1.6
1.7
1.6
1.5
1.0
1.2
1.9
1.4
1.4
0.8
11
9
6
4
4
10
4
4
1320
525
317
400
800
908
350
367
12
8
9
9
4
6
5
4
0.8
Amobarbital sodium
(Amytal) Mean
weekly dose, mg
No. of patients
Lithium Carbonate Treatment No. of patients Mean
dose, mg/d
Mean
serum
(median),
level mmol/L
Group
24
24
24
21
20
19
14
11
1035
1260
1275
1272
1260
1278
1125
1155
0.58 (0.58) 0.79 (0.75) 0.80 (0.75) 0.82 (0.83) 0.92 (0.89) 1.7
SAFTEE-GI
1.5
1.6
1.6
0.64 (0.66) 0.79 (0.75) 0.73 (0.74)
1.6
1.5
1.6
1.7
Use of as-needed medications
Chloral Mean
hydrate weekly dose, g
2.1
No. of patients
2.4t
14
13
1206
946
16
12
1.6
1.4
1.6
1.6
1.9
0.5
9
5
7
4
3
500
490
562
850
400
5
4
2
1
11
Amobarbital
dose, mg No. of patients
Mean
990t 10
*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
MRS
30.3
20.6
SDMS-M
11.3
8.0
SDMS-D
3.4
4.0
-18
HAM-D
29.9
30.4
-2
29.4
BPRS
49.1
43.2
12
47.0
CGI-1
5.3
4.3
19
5.0
4.1
GAS
35.7
47.5
33
38.8
50.5
30
3
BCL
32.5
20.9
36
34.8
24.9
28
8
%
8 wk
32
Baseline 30.9
22.4
28
29§
11.3
7.9
30§
-1
3.4
3.4
0
-18
26.9
8
10
42.2
10
2
18
1
Improvement
%
Improvement
Differencet 4
*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
