Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder Coxhead N, Silverstone T, Cookson J. Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder. Acta Psychiatr Scand 1992: 85: 114-118.


A 12-month double-blind trial of carbamazepine vs lithium, given as sole treatment for the prophylaxis of bipolar affective disorder, was carried out in 3 1 patients. All were previously stable on lithium; 15 were switched over to carbamazepine and 16 remained on lithium. Although the overall relapse rate was similar in the 2 groups (6 on carbamazepine, 8 on lithium), nearly all the relapses in carbamazepine occurred in the first month, probably precipitated by lithium withdrawal. Two patients on carbamazepine developed a rash and were withdrawn. More side effects were noted during the early stages on carbamazepine. Patients on lithium tended to gain weight ( + 4 kg) compared with carbamazepine ( - 3.1 kg). It is concluded that carbamazepine is as effective as lithium in the prophylaxis of bipolar affective disorder; changeover from lithium to carbamazepine should be done slowly.

Carbamazepine is being used increasingly as a prophylactic agent in bipolar disorder (1, 2) but there are few double-blind trials of its efficacy in this condition. Takezaki & Hanaoka first suggested some prophylactic benefit in manic depression. Later reports (3) of open and preliminary double-blind trials, and open trials in lithium nonresponders have described some benefit (4-6). Only small numbers of bipolar patients were included in these studies. In a larger series of 55 bipolar patients, the addition of carbamazepine to their existing regimen produced substantial benefit in a majority (7). Subsequent open trials comparing carbamazepine with lithium have generally suggested equal efficacy of the 2 treatments (8). Three double-blind studies have compared carbamazepine with lithium. In the first, carbamazepine and lithium were stated to have comparable prophylactic efficacy, but the patients were diagnostically heterogeneous (9). In another group containing 20 bipolar and 17 unipolar patients, carbamazepine was reported to be almost as effective as lithium (10). A further comparative controlled trial in 40 bipolar patients suggested that carbamazepine might be slightly more effective than lithium (1 1). This article reports a randomized double-blind comparative prophylactic trial of lithium and carbamazepine in a diagnostically homogeneous group of outpatients suffering from bipolar disorder, in whom no other psychotropic medication was allowed apart from occasional night sedation. 114

N. Coxhead, T. Silverstone, J. Cookson Academic Unit of Human Psychopharmacology, Medical Colleges of St. Bartholomew’s and the Royal London Hospitals, London, United Kingdom

Key words: carbamazepine; lithium; prophylaxis; affective disorder; weight gain Professor Trevor Silverstone, Academic Unit of Human Psychopharmacology, St. John’s Wing, Homerton Hospital, London E9 6SR, UK Accepted for publication August 16, 199 1

Material and methods Patient selection

Patients currently on lithium as prophylaxis for bipolar disorder were assessed. They were considered suitable for entry into the trial if: (a) a case-note analysis and interview confirmed the diagnosis of bipolar disorder according to DSM-111 criteria; (b) the patient had no medical condition considered to contraindicate continuing lithium therapy or starting carbamazepine; (c) the patient was on no other psychotropic medication; (d) it was considered clinically and ethically appropriate to change the patient’s medication; (e) the responsible clinician agreed; and (f) the patient, and when appropriate, a relative, gave written consent after details of the study were explained to them. Of 145 patients assessed, only 32 were entered. Common reasons for nonparticipation included reluctance by the patient to take part and the use of concomitant additional psychotropic medication that it was thought inadvisable to withdraw. Assessment

Patients fulfilling the above criteria were assessed prior to entry by a standard psychiatric history, physical examination and side effect checklist, and investigations including electrocardiogram, full blood count (including platelets), serum urea and electrolytes, liver function tests and thyroid function tests and serum lithium measurement.

Carbamazepine vs lithium Patients were then assessed at the start of trial, after 2 and 4 weeks on the trial medication and at 4-weekly intervals thereafter for 1 year. All the assessments were carried out by the same investigator (N.C.) who was blind to the trial medication. Each assessment consisted of a clinical and social inquiry, a structured assessment of side effects, the BechRafaelsen Mania Rating Scale (12), the Hamilton Rating Scale for Depression (HRSD) (13), a global rating of affective state and a rating of the duration and severity of mood changes since the previous visit. The affective morbidity index (14) was calculated using the global ratings of the duration and severity of mood changes since the previous assessment. This had the advantage of summarizing in one number the overall affective morbidity for each patient during their time in the study. Patients were weighed and a blood sample taken for serum drug level at each visit. A full blood count and liver function tests were carried out every 12 weeks, and thyroid function tests, blood urea and electrolyte measurements every 24 weeks. Medication

Patients were observed for 4 weeks on their previous dose of lithium. If their mania rating score remained zero, their HRSD score stayed below 4 at -4, - 2 and 0 weeks and no other psychotropic drug was taken during this period, they were started on the trial medication. This was given according to a double-dummy design with patients randomly assigned to receive either carbamazepine 200 mg plus placebo-lithium carbonate tablets or active lithium carbonate 400 mg plus placebo-carbamazepine tablets. The starting dosage was carbamazepine 200 mg twice daily or lithium carbonate 400 mg twice daily. Serum drug level results were sent to 1 of the 2 investigators uninvolved in the clinical ratings (T.S. or J.C.), who advised on changes in dosage on the basis of these levels combined with reports of the patients’ clinical state. Lithium carbonate dosage was adjusted to achieve a serum level of 0.6-1.0mmol/l and carbamazepine was adjusted towards levels of 38-51 mmol/l. . No other psychotropic medication apart from temazepam up to 20 mg at night was allowed. If it was necessary to prescribe any other medication, the patient was withdrawn from the trial. Statistics

The chi-square test was used to compare numbers of patients remaining in the study at 3 months and 1 year. The two-sample t-test was used to compare means. Statistically significant was defined as P < 0.05.


Thirty-one patients entered the study; 16 were allocated to receive lithium carbonate and 15 carbamazepine. The 2 groups did not differ significantly in age, sex, number of previous admissions, duration of illness, family history or nature of last episode (Table 1). The study group as a whole contained twice as many women as men. None of the participants had had less than 2 previous admissions and 3 had had 4 or more episodes during the previous 2 years; all 3 were allocated to receive carbamazepine. Overall, the group had a prolonged duration of illness with several previous admission, but there was wide variation. The clinical course of the patients who participated in the year-long trial is summarized in Table 2. There were no withdrawals caused by side effects of lithium, but 2 early withdrawals in the carbamazepine group were caused by erythematous rash. Although approximately equal numbers of patients in each group relapsed during the course of the year (8 on lithium and 6 on carbamazepine), with 7 patients completing in each group, the timing of relapse was different in the 2 groups. All but one of the relapsers in the carbamazepine group became ill within the first 4 weeks, whereas relapses while on lithium were more evenly distributed over the first seven months (Fig. 1). The 2 groups were compared in terms of numbers of patients surviving at 3 months and 1 year: no significant differences were found (chi-square: P > 0.2 at 3 months; P> 0.5 at 1 year). If survival from week 4 onwards is considered, there was a trend for patients on carbamazepine to survive longer but the numbers are too small for any firm statistical conclusion. The maximum degree of psychopathology present in each group during the year was determined by counting the number of patients with no or few manic

Table 1. Demographic and clinical comparison

Age (years) Sex

No. of previous admissions Duration of illness (years) Nature of last inpatient episode (mania:depression) Family history of major affective disorder in first-degree relatives

Mean (SDI Median (range) M:F Mean (SD) Median (range) Mean (SD) Median (range)

Lithium n= 16

Carbamazepine n= 15

49 1101 48 (35-66) 5:11 7.1 (4.6) 6.5 (2-18) 17 (14) 14.5 (1-47)

47 (14) 52 (23-65) 5:lO 6.1 (3.7) 5 (2-17) 17 ( 1 1 ) 13 (1-38)






Coxhead et al. Table 3. Maximum mania and depression scores during the year

Table 2. Course of illness during the trial Lithium n= 16 Withdawn because of noncompliance Withdrawn because of side effects Relapsed (admitted) Completed 1 year

Numbers of patients in each group

Carbamazepine n=15



0 8 (5) 7

2 6 (51 7

Bech-Rafaelsen Mania Rating Scale Maximum score: 0-3

4-7 28

symptoms (Bech-Rafaelsen score 0-3), moderate symptoms (score 4-7) or severe symptoms (score 18). The same exercise was done for depressive symptoms using HRSD scores as follows: mild (05), moderate (6-11) and severe ( 2 12). The maximum severity of affective symptoms was similar in the 2 groups, taking into account relapsers and those completing the study (Table 3). The variability of the affective morbidity index was too large for any formal statistical differentiation between the 2 treatment groups. Nevertheless, it is clear that some patients completing the trial continued to suffer significant degrees of affective morbidity, although this was generally less than that experienced by the patients who relapsed (Table 4).

Hamilton Rating Scale for Depression Maximum score: 0-5 6-1 1 2 12





1 6

1 4


12 2 1

3 1

The most frequently reported side effects of carbamazepine were drowsiness, dizziness, giddiness, nausea and indigestion, with 12 of the 15 patients starting on carbamazepine complaining of at least 1 of these symptoms during the first 4 weeks. In some patients this necessitated a reduction in dosage, which could be reversed after 1-2 weeks. The only side effect of carbamazepine leading to immediate withdrawal from the study was an itchy and erythematous rash occurring in 2 patients on day 13 and day 14. Abnormal laboratory results, apparently caused by carbamazepine, were seen in 1 patient


14 Number of patients remaining

12 10




- Lithium



* * * * * * * Carbamazepine











Months Fig. 1. Number of patients remaining relapse-free each month during the 12 months of the trial




Carbamazepine vs lithium

was withdrawn 2 weeks later because of a manic relapse. No other psychotropic medication was given to patients remaining in the study.

Table 4. Affective morbidity index Mean (SD) Lithium

Carbamazepine Completing (n= 7 )






0.41 (0.26)

0.22 (0.20)

0.86 (0.50)

0.12 (0.12)


who developed hyponatraemia and in another who had an isolated mildly elevated alkaline phosphatase. Neither abnormality led to withdrawal from the study and both patients completed the year. Nine of 16 patients on lithium complained of thirst and/or polyuria at some stage and in 3 patients these were reported as severe; 5 patients noted weight gain. Patients in the lithium group tended to gain weight (mean gain 4 kg) and those on carbamazepine lost weight (mean loss 3.1 kg). Although the difference at one year was not statistically significant, the trend towards a continuing divergence in mean weights was still apparent at the termination of the study. Four patients on lithium complained of weight gain - in 1 this amounted to 15.5 kg. Eighteen patients entering the study had been on lithium carbonate for more than 1 year beforehand: 6 had a body mass index >25 and 5 >30. Serum levels and response

There were no statistically significant differences between the mean serum levels of either drug in the patients completing 1 year in the study vs those who had relapsed. However, the percentage of serum drug levels below the target levels were higher in the relapsing groups (50% vs 10% for lithium; 37% vs 14% for carbamazepine). In patients starting to relapse, an attempt was made to treat them with increased dosages of medication, but no relapses were curtailed by this strategy. Acute symptoms often developed very rapidly, and this approach was not continued for more than a few days. Dosage

There was no difference between the mean dosages of lithium carbonate in patients relapsing and those completing the study. However, patients relapsing on carbamazepine received lower dosages of medication (mean 480 mg/d) than those completing 1 year (mean 604 mg/d) (P

Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder.

A 12-month double-blind trial of carbamazepine vs lithium, given as sole treatment for the prophylaxis of bipolar affective disorder, was carried out ...
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