Lithium alone or in combination with carbamazepine for the treatment of rapid-cycling bipolar affective disorder Di Costanzo E, Schifdno F. Lithium alone or in combination with carbamazepine for the treatment of rapid-cycling bipolar affective disorder. Acta Psychiatr Scand 1991: 83: 456-459.
The authors retrospectively examined the clinical outcome (after 1, 2 and 5 years of beginning the therapeutic protocols) for 16 rapid-cycling bipolar affective disorder patients given either lithium alone or lithium plus carbamazepine. The results suggest that both therapeutic protocols have been safe and clinically effective. However, improvement was observed earlier in the patients given lithium and carbarnazepine.
Since Dunner & Fieve’s (1) studies, there has been a growing interest in clinical research on patients affected by rapid-cycling affective disorder (defined as the occurrence of 4 or more episodes of affective illness per year, regardless of polarity). Tricyclic antidepressant therapy withdrawal (2,3), treatments with lithium salts (4-7), carbamazepine (8-lo), sodium valproate (1 l), thyroid hormones (12-14), monoamine oxidase (MAO) inhibitors ( 1 9 , neuroleptics (16), verapamil (17-20) and clonidine (21) have all been proposed for rapid circularity therapy but, to date, there is no universally accepted clinical protocol of adequate efficacy and tolerability (22). Bearing in mind this lack of precise prescription guidelines, this study compared the efficacy of treatment with lithium alone or in combination with carbamazepine. Material and methods Patients
The group consisted of 16 subjects all suffering from major affective disorders with rapid circularity who consecutively attended the psychiatric units in the towns of Udine and Gorizia (a catchment area of about 450,000 inhabitants in the north-east of Italy) and underwent pharmacological treatment in the period from January l , 1978 to September 30, 1985. All patients were diagnosed by their attending physicians, based on DSM-I1 (1978-1980) and DSMI11 (thereafter). Patients included in the sample met the following criteria (the suggestions made by Wolpert et al. (23) to increase diagnostic homogeneity
456
E. Di Costanzo’, F. Schifano’
’
Department of Psychiatry, Conegliano General Hospital, Conegliano, Treviso, Department of Pharmacology, University of Padova, Italy
Key words: lithium: carbamazepine; rapid cycling; bipolar affective disorder
Fabrizio Schifano, MD, Sew. di Medicina delle Dipendenze, Ospedale Psichiatrico Provinciale, via dei Colli, 1-35100 Padova, Italy Accepted for publication January 26, 1991
were taken into account): a) they were diagnosed as having a major affective disorder; b) their clinical charts provided evidence that they had manifested a major affective syndrome with a clinical course of rapid circularity (this was assessed according to the DSM-I11 criteria and operational definitions based on Research Diagnostic Criteria to categorize the frequency of affective cycling patterns); and c) they did not have mood-incongruent psychotic symptoms (we focused only on the patients whose primary illness was a major affective disorder without concurrent schizophrenia-like or schizoaffective features). All 16 patients were prescribed either lithium salts or a combination of lithium and carbamazepine; allocation to treatments was made on a pseudorandomization basis (lithium was prescribed every second consecutive patient). Seven were males and 9 females. The mean age was 42 years (range: 2759). The mean age of occurrence of the first affective episode was 28 years (range: 18-45). The presence of affective disorders in first- and/or second-degree relathes was ascertained in 50% of the cases. The mean number of affective episodes in the 12 months prior to beginning administration of the drug protocols under study (regardless ofpolarity) was 7 (range: 4-1 5). Possible precipitating factors for rapid cycling were thought to be: administration of tricyclic antidepressants, 3 cases; administration of an association of tricyclics and M A 0 inhibitors, 2; formal psychotherapy, 2; and administration of M A 0 inhibitors, 1. The groups did not differ significantly in sociodemographic and clinical characteristics.
Lithium in combination with carbamazepine Clinical assessment
Data for in- and outpatients were collected and analysed on the basis of a retrospective review of their clinical charts. Detailed diagnostic intake summaries written by resident physicians were available, along with complete psychiatric nursing notes and clinical histories for each patient. This material was carefully rated using an inventory of manic, depressive and psychotic symptoms based on DSM-I11 criteria to determine the profile of daily and weekly affective symptoms. For each patient (and for each of the 2 groups of patients administered with the same therapeutic protocol), the time spent with the prevalent mood of depression or mania and the time spent with euthymia were calculated as a percentage (no mixed episodes were found in this sample). Assessments were made at the baseline (beginning administration of the therapeutic protocol administration), and after 1, 2 and 5years. Each assessment refers to the 12 months prior to the cut-off time. Drugs
The daily dosage of lithium salts was enough to attain a serum level of 0.6-1.0 mEq/l. The range of serum levels for carbamazepine was 4.6-8.8 pg/ml. The side effects of the treatments were not severe enough to interrupt the prescription for any patient, but in 2 cases (patients 11 and 14) it was necessary to reduce the daily dosage to eliminate ataxia. Compliance was checked by evaluating serum levels of the drugs. None of the patients had taken lithium or carbamazepine prior to the study. None of the patients was prescribed antidepressants during the trial. Neuroleptics and benzodiazepines were used only when essential for manic episodes. Statistical analysis
The data were statistically analysed using Student’s t-test, paired t-test and chi-square test (with Yates’ correction when necessary). Results
The data on clinical essessment of the 16 patients were analysed longitudinally (to assess improvement in each group) and cross-sectionally (to assess differences between the two treatments). Patients given lithium alone showed a global improvement: the (regardless of polarity) 27 affective episodes were observed during the first year of administration and 22 during the second (50 affective episodes were counted in the whole group in the year prior to beginning treatment). Probably because compliance was not satisfactory, in the time-span
between 2 and 5 years after the treatment began 4 patients showed a worsening clinical picture. The amount of time spent with depressive mood in this group was greater at baseline (44%) than at 1 year (29%; P
The authors retrospectively examined the clinical outcome (after 1, 2 and 5 years of beginning the therapeutic protocols) for 16 rapid-cycling bipolar affective disorder patients given either lithium alone or lithium plus carbamazepine. The results suggest that both therapeutic protocols have been safe and clinically effective. However, improvement was observed earlier in the patients given lithium and carbarnazepine.
Since Dunner & Fieve’s (1) studies, there has been a growing interest in clinical research on patients affected by rapid-cycling affective disorder (defined as the occurrence of 4 or more episodes of affective illness per year, regardless of polarity). Tricyclic antidepressant therapy withdrawal (2,3), treatments with lithium salts (4-7), carbamazepine (8-lo), sodium valproate (1 l), thyroid hormones (12-14), monoamine oxidase (MAO) inhibitors ( 1 9 , neuroleptics (16), verapamil (17-20) and clonidine (21) have all been proposed for rapid circularity therapy but, to date, there is no universally accepted clinical protocol of adequate efficacy and tolerability (22). Bearing in mind this lack of precise prescription guidelines, this study compared the efficacy of treatment with lithium alone or in combination with carbamazepine. Material and methods Patients
The group consisted of 16 subjects all suffering from major affective disorders with rapid circularity who consecutively attended the psychiatric units in the towns of Udine and Gorizia (a catchment area of about 450,000 inhabitants in the north-east of Italy) and underwent pharmacological treatment in the period from January l , 1978 to September 30, 1985. All patients were diagnosed by their attending physicians, based on DSM-I1 (1978-1980) and DSMI11 (thereafter). Patients included in the sample met the following criteria (the suggestions made by Wolpert et al. (23) to increase diagnostic homogeneity
456
E. Di Costanzo’, F. Schifano’
’
Department of Psychiatry, Conegliano General Hospital, Conegliano, Treviso, Department of Pharmacology, University of Padova, Italy
Key words: lithium: carbamazepine; rapid cycling; bipolar affective disorder
Fabrizio Schifano, MD, Sew. di Medicina delle Dipendenze, Ospedale Psichiatrico Provinciale, via dei Colli, 1-35100 Padova, Italy Accepted for publication January 26, 1991
were taken into account): a) they were diagnosed as having a major affective disorder; b) their clinical charts provided evidence that they had manifested a major affective syndrome with a clinical course of rapid circularity (this was assessed according to the DSM-I11 criteria and operational definitions based on Research Diagnostic Criteria to categorize the frequency of affective cycling patterns); and c) they did not have mood-incongruent psychotic symptoms (we focused only on the patients whose primary illness was a major affective disorder without concurrent schizophrenia-like or schizoaffective features). All 16 patients were prescribed either lithium salts or a combination of lithium and carbamazepine; allocation to treatments was made on a pseudorandomization basis (lithium was prescribed every second consecutive patient). Seven were males and 9 females. The mean age was 42 years (range: 2759). The mean age of occurrence of the first affective episode was 28 years (range: 18-45). The presence of affective disorders in first- and/or second-degree relathes was ascertained in 50% of the cases. The mean number of affective episodes in the 12 months prior to beginning administration of the drug protocols under study (regardless ofpolarity) was 7 (range: 4-1 5). Possible precipitating factors for rapid cycling were thought to be: administration of tricyclic antidepressants, 3 cases; administration of an association of tricyclics and M A 0 inhibitors, 2; formal psychotherapy, 2; and administration of M A 0 inhibitors, 1. The groups did not differ significantly in sociodemographic and clinical characteristics.
Lithium in combination with carbamazepine Clinical assessment
Data for in- and outpatients were collected and analysed on the basis of a retrospective review of their clinical charts. Detailed diagnostic intake summaries written by resident physicians were available, along with complete psychiatric nursing notes and clinical histories for each patient. This material was carefully rated using an inventory of manic, depressive and psychotic symptoms based on DSM-I11 criteria to determine the profile of daily and weekly affective symptoms. For each patient (and for each of the 2 groups of patients administered with the same therapeutic protocol), the time spent with the prevalent mood of depression or mania and the time spent with euthymia were calculated as a percentage (no mixed episodes were found in this sample). Assessments were made at the baseline (beginning administration of the therapeutic protocol administration), and after 1, 2 and 5years. Each assessment refers to the 12 months prior to the cut-off time. Drugs
The daily dosage of lithium salts was enough to attain a serum level of 0.6-1.0 mEq/l. The range of serum levels for carbamazepine was 4.6-8.8 pg/ml. The side effects of the treatments were not severe enough to interrupt the prescription for any patient, but in 2 cases (patients 11 and 14) it was necessary to reduce the daily dosage to eliminate ataxia. Compliance was checked by evaluating serum levels of the drugs. None of the patients had taken lithium or carbamazepine prior to the study. None of the patients was prescribed antidepressants during the trial. Neuroleptics and benzodiazepines were used only when essential for manic episodes. Statistical analysis
The data were statistically analysed using Student’s t-test, paired t-test and chi-square test (with Yates’ correction when necessary). Results
The data on clinical essessment of the 16 patients were analysed longitudinally (to assess improvement in each group) and cross-sectionally (to assess differences between the two treatments). Patients given lithium alone showed a global improvement: the (regardless of polarity) 27 affective episodes were observed during the first year of administration and 22 during the second (50 affective episodes were counted in the whole group in the year prior to beginning treatment). Probably because compliance was not satisfactory, in the time-span
between 2 and 5 years after the treatment began 4 patients showed a worsening clinical picture. The amount of time spent with depressive mood in this group was greater at baseline (44%) than at 1 year (29%; P
