Lithium treatment: a comparison of onceand twice-daily dosing Abraham G, Delva N, Waldron J, Lawson JS, Owen J . Lithium treatment: a comparison of once- and twice-daily dosing. Acta Psychiatr Scand 1992: 85: 65-69. The effects of once- and twice-daily dosing with lithium carbonate were compared in a non-blind, cross-over study on 20 consecutive patients with mood disorders. Mental status, side effects and target organ function were examined after a minimum of a l-month treatment with each regimen. Eighteen patients completed the study and 2 withdrew because of side effects. There were no significant differences between the 2 groups on the Hamilton Rating Scale for Depression, the Bech-Rafaelsen Mania Scale, the UKU Side Effects Scale or in serum lithium, electrocardiogram and urine volumes. Most blood tests showed no significant difference between the 2 treatment schedules except for white blood cells, ionized calcium and phosphate concentration. The once-daily regimen was associated with a higher white cell count, increased serum phosphate and elevated serum ionized calcium. We conclude that patients are able to tolerate once-daily dosing with lithium carbonate as well as twice-daily dosing.
The efficacy of lithium in managing the major mood disorders is now firmly established. Adequate evidence supports its use in the treatment of the acutely manic state, in the acute treatment of depression in combination with antidepressant medication, and in the prophylaxis of both mania and depression in bipolar and unipolar illness. As a result, the number of patients receiving lithium therapy is very large. However, long-term lithium treatment can be associated with several adverse effects involving the gastrointestinal and nervous systems and renal manifestations (1-3). The latter includes impaired urinary acidification (4), polyuria and impaired concentrating ability (5, 6) and chronic tubulointerstitial nephropathy (7,8). Since lithium is often administered to patients for years, it is important that it be given in a way that leads to the best psychotropic effects with a minimum of side effects. Today many patients receive their lithium in several divided doses, and to reduce side effects, the dosage level in the individual is adjusted to the lowest possible level consistent with therapeutic effectiveness. However, several recent studies (9-12) indicate that kidney functioning may be better preserved by giving the same total dose once daily, or even once every second day (1, 13). Since the benefits and disadvantages of administering lithium either way are not agreed upon by all investigators, we thought it appropriate to examine the effects of single and divided dosage regimens on
G.Abraham, N. Delva, J. Waldron, J. S. Lawson, J. Owen Kingston Psychiatric Hospital and Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada
Key words: lithium: prophylaxis; dosing Dr. G. Abraham, Kingston Psychiatric Hospital, 752 King Street West, Postal Bag 603, Kingston, Ontario K7L 4x3, Canada Accepted for publication August 16, 1991
the occurrence of side effects, target organ function, and mental stability. Material and methods
The sample consisted of 20 consecutive outpatients with a diagnosis of mood disorder (16 bipolar disorder and 4 unipolar depression according to the DSM-III-R criteria) treated with lithium at either the Community Mental Health Clinic of Kingston General Hospital or the Outpatient Clinic of Kingston Psychiatric Hospital for 6 months or more. Written informed consent to the study was obtained from all patients. Patients were required to have been clinically stable and on a constant dose of lithium for a minimum of 1 month. There were 16 men and 4 women in the study; their ages ranged from 18 to 64 years, with a mean of 44 years for men and 43 years for women. Ten patients on a single daily dose and 10 on a divided dose were recruited, and those who were receiving lithium 3-4 times per day were switched to a twice-daily regimen on entry into the study. The average duration of lithium treatment was 4.4 years (range: 6 months to 15 years). The patients received conventional lithium tablets with a mean dose of 1008 3 16 mg per day (range 600-1800 mg per 24 h). In the twice-daily dosing, lithium was taken around 0800 and 2000, and at bedtime (about 2000) in the once-daily schedule. Additional psychotropic treatment given to the patients included neuroleptics to
65
Abraham et al. 4 patients with one also on a benztropine, and antidepressants to 4 with one also on tryptophan. These treatments were kept unchanged during both treatment schedules. After at least 1 month without any change in regimen, the followinginvestigations were performed: the UKU Side Effects Scale (14), the Structured Interview Guide for the 21-item Hamilton Rating Scale for Depression (HRSD) (15), the BechRafaelsen Mania Scale (BRMAS) (16), an electrocardiogram, hematology, blood chemistry and urine collection. The blood sample for lithium level and blood chemistry was taken in the morning, about 12 h after the last dose of lithium. After these studies were completed, the patients were switched over to the alternate dosing regimen: those taking lithium once daily were switched to twice daily and vice versa. They were then maintained on this regimen for 1 month; at the end of this the studies were repeated. A preliminary analysis showed no evidence that the order in which the regimens were administered (single dose first or divided dose first) affected the difference between the 2 dosing methods for any of the dependent variables. The order effect was therefore ignored in subsequent analysis. The method of paired t-tests was used to evaluate the effects of‘regimen on the dependent variables. It would be usual to apply the Bonferroni correction to control the true probability of a type I error (spurious significance) when multiple t-tests are to be performed on a set of independent variables. This was not done here for 2 reasons. First, the Bonferroni procedure greatly reduces the power of statistical tests (i.e. increases the probability of the type I1 error, in which a veridical difference is missed) when, as in the present case, the size of the sample is small. Second, for the present purposes, a type I1 error is the more serious one, as it would mean missing a possibly adverse effect of the proposed once-daily regimen. Thus, the procedure we used might be considered the more conservative one in regard to demonstrating the acceptability of a novel treatment regimen. Results
Of the 20 patients who entered the study, 2 were unable to complete it. One became very drowsy and was unable to carry out his usual daily activities 1 week after he was switched from twice to once daily. He lost confidence in himself, his mouth became dry and he developed a distressing tremor in the morning. His urine also smelled “strong”. The second patient developed severe polyuria after he changed from 4 times to twice-daily dosing and experienced nocturnal frequency of 7-8 times that completely 66
prevented him from sleeping. He thus became totally exhausted and unable to do anything in the daytime and, in addition, became frightened that this severe insomnia would lead to deep depression, as his previous episodes of depression started with insomnia. As a result, he switched back to his original regimen on the advice of his family physician. These 2 patients were excluded from the final analysis of the study. One woman complained of tremors and developed restless sleep after she switched from onceto twice-daily dosing, and these symptoms persisted throughout the study period. However, she completed the study and the symptoms subsided when she reverted to the once-daily regimen. There was no statistically significant difference between the 2 treatment regimens on any of the rating scales. The mean scores on the rating scales were as follows (oncedaily/twice-daily schedules): the 21-item HRSD 3.l/ 2.5, the 11-item BRMAS O.Oj0.2. These scores indicate low mental disorder. The mean serum lithium concentration was 0.64 mmol/l on a twice-daily regimen and 0.69 mmol/l on a once-daily regimen (NS). The mean 24-h urine volumes, 2177ml on the twice-daily regimen and 2443 on the once-daily regimen, were not significantly different (Table 1). The absence of difference between the 2 regimens was reconfirmed by reanalyzing volume-to-creatinine ratios, which remained unchanged (175.8 in the once-daily regimen and 168.8 in the twice-daily regimen). We reviewed the urine volume in regard to the gender of the patients: in the 4 women, once-daily dosing caused an increase in urine volume in 1 subject and a decrease in 2. Urine volume on once-daily dosing decreased in 2 and increased in 10 of the men. All other renal function tests also failed to show any difference between the 2 treatment conditions. Table 2 shows the result of blood tests and electrocardiography; most tests did not change significantly with a change in treatment schedules. In comparison to twice-daily dosing, the once-daily regimen was associated with a higher white cell count (P< 0.05), increased serum phosphate levels Table 1. Kidney functioning tests in patients treated with lithium once (OD)or twice (BID) daily
Blood urea nitrogen (mmol/l) (normal range 3.5-7.0) Creatinine ( pnol/l) (normal range < 130) 24-h urine volume (ml) Creatinine clearance (mtis) 24-h urinary protein excretion (g) 24-h urinary creatinine excretion (mmol) Results shown are meanfsD
OD regimen
BID regimen
4.7f0.7
5.0k1.0
86t.10.6 2443f 1552 1.8k0.6 0.2f0.1 13.9k4.5
86.6f9.5 21 77 f 1343 1.7k0.5 0.3k0.1 12.9f3.9
Lithium dosing Table 2. Hematology, blood chemistry and electrocardiogram results
OD regimen Hemoglobin (g/l) (normal range, men: 140-180) (normal range, women: 120-160) WBC (cellsX 109/1) (normal range 4-1 1) Thyroid-stimulatinghormone (mU/I) (normal range 0.5-5.0) Ionized calcium (mmol/l) (normal range 1.19-1.31) Phosphate (mmol/l) (normal range 0.8-1.50) Heart rate (BPM) ~
BID regimen
149f12
148f13
8.3f2.2*
7.1k2.5
0.24kO.l
0.22kO.l
1.28$0.05**
1.23fO.04
1.02f0.15* 66210
0.95f0.14 65f10
______
Results shown are meanfsD.
P
The efficacy of lithium in managing the major mood disorders is now firmly established. Adequate evidence supports its use in the treatment of the acutely manic state, in the acute treatment of depression in combination with antidepressant medication, and in the prophylaxis of both mania and depression in bipolar and unipolar illness. As a result, the number of patients receiving lithium therapy is very large. However, long-term lithium treatment can be associated with several adverse effects involving the gastrointestinal and nervous systems and renal manifestations (1-3). The latter includes impaired urinary acidification (4), polyuria and impaired concentrating ability (5, 6) and chronic tubulointerstitial nephropathy (7,8). Since lithium is often administered to patients for years, it is important that it be given in a way that leads to the best psychotropic effects with a minimum of side effects. Today many patients receive their lithium in several divided doses, and to reduce side effects, the dosage level in the individual is adjusted to the lowest possible level consistent with therapeutic effectiveness. However, several recent studies (9-12) indicate that kidney functioning may be better preserved by giving the same total dose once daily, or even once every second day (1, 13). Since the benefits and disadvantages of administering lithium either way are not agreed upon by all investigators, we thought it appropriate to examine the effects of single and divided dosage regimens on
G.Abraham, N. Delva, J. Waldron, J. S. Lawson, J. Owen Kingston Psychiatric Hospital and Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada
Key words: lithium: prophylaxis; dosing Dr. G. Abraham, Kingston Psychiatric Hospital, 752 King Street West, Postal Bag 603, Kingston, Ontario K7L 4x3, Canada Accepted for publication August 16, 1991
the occurrence of side effects, target organ function, and mental stability. Material and methods
The sample consisted of 20 consecutive outpatients with a diagnosis of mood disorder (16 bipolar disorder and 4 unipolar depression according to the DSM-III-R criteria) treated with lithium at either the Community Mental Health Clinic of Kingston General Hospital or the Outpatient Clinic of Kingston Psychiatric Hospital for 6 months or more. Written informed consent to the study was obtained from all patients. Patients were required to have been clinically stable and on a constant dose of lithium for a minimum of 1 month. There were 16 men and 4 women in the study; their ages ranged from 18 to 64 years, with a mean of 44 years for men and 43 years for women. Ten patients on a single daily dose and 10 on a divided dose were recruited, and those who were receiving lithium 3-4 times per day were switched to a twice-daily regimen on entry into the study. The average duration of lithium treatment was 4.4 years (range: 6 months to 15 years). The patients received conventional lithium tablets with a mean dose of 1008 3 16 mg per day (range 600-1800 mg per 24 h). In the twice-daily dosing, lithium was taken around 0800 and 2000, and at bedtime (about 2000) in the once-daily schedule. Additional psychotropic treatment given to the patients included neuroleptics to
65
Abraham et al. 4 patients with one also on a benztropine, and antidepressants to 4 with one also on tryptophan. These treatments were kept unchanged during both treatment schedules. After at least 1 month without any change in regimen, the followinginvestigations were performed: the UKU Side Effects Scale (14), the Structured Interview Guide for the 21-item Hamilton Rating Scale for Depression (HRSD) (15), the BechRafaelsen Mania Scale (BRMAS) (16), an electrocardiogram, hematology, blood chemistry and urine collection. The blood sample for lithium level and blood chemistry was taken in the morning, about 12 h after the last dose of lithium. After these studies were completed, the patients were switched over to the alternate dosing regimen: those taking lithium once daily were switched to twice daily and vice versa. They were then maintained on this regimen for 1 month; at the end of this the studies were repeated. A preliminary analysis showed no evidence that the order in which the regimens were administered (single dose first or divided dose first) affected the difference between the 2 dosing methods for any of the dependent variables. The order effect was therefore ignored in subsequent analysis. The method of paired t-tests was used to evaluate the effects of‘regimen on the dependent variables. It would be usual to apply the Bonferroni correction to control the true probability of a type I error (spurious significance) when multiple t-tests are to be performed on a set of independent variables. This was not done here for 2 reasons. First, the Bonferroni procedure greatly reduces the power of statistical tests (i.e. increases the probability of the type I1 error, in which a veridical difference is missed) when, as in the present case, the size of the sample is small. Second, for the present purposes, a type I1 error is the more serious one, as it would mean missing a possibly adverse effect of the proposed once-daily regimen. Thus, the procedure we used might be considered the more conservative one in regard to demonstrating the acceptability of a novel treatment regimen. Results
Of the 20 patients who entered the study, 2 were unable to complete it. One became very drowsy and was unable to carry out his usual daily activities 1 week after he was switched from twice to once daily. He lost confidence in himself, his mouth became dry and he developed a distressing tremor in the morning. His urine also smelled “strong”. The second patient developed severe polyuria after he changed from 4 times to twice-daily dosing and experienced nocturnal frequency of 7-8 times that completely 66
prevented him from sleeping. He thus became totally exhausted and unable to do anything in the daytime and, in addition, became frightened that this severe insomnia would lead to deep depression, as his previous episodes of depression started with insomnia. As a result, he switched back to his original regimen on the advice of his family physician. These 2 patients were excluded from the final analysis of the study. One woman complained of tremors and developed restless sleep after she switched from onceto twice-daily dosing, and these symptoms persisted throughout the study period. However, she completed the study and the symptoms subsided when she reverted to the once-daily regimen. There was no statistically significant difference between the 2 treatment regimens on any of the rating scales. The mean scores on the rating scales were as follows (oncedaily/twice-daily schedules): the 21-item HRSD 3.l/ 2.5, the 11-item BRMAS O.Oj0.2. These scores indicate low mental disorder. The mean serum lithium concentration was 0.64 mmol/l on a twice-daily regimen and 0.69 mmol/l on a once-daily regimen (NS). The mean 24-h urine volumes, 2177ml on the twice-daily regimen and 2443 on the once-daily regimen, were not significantly different (Table 1). The absence of difference between the 2 regimens was reconfirmed by reanalyzing volume-to-creatinine ratios, which remained unchanged (175.8 in the once-daily regimen and 168.8 in the twice-daily regimen). We reviewed the urine volume in regard to the gender of the patients: in the 4 women, once-daily dosing caused an increase in urine volume in 1 subject and a decrease in 2. Urine volume on once-daily dosing decreased in 2 and increased in 10 of the men. All other renal function tests also failed to show any difference between the 2 treatment conditions. Table 2 shows the result of blood tests and electrocardiography; most tests did not change significantly with a change in treatment schedules. In comparison to twice-daily dosing, the once-daily regimen was associated with a higher white cell count (P< 0.05), increased serum phosphate levels Table 1. Kidney functioning tests in patients treated with lithium once (OD)or twice (BID) daily
Blood urea nitrogen (mmol/l) (normal range 3.5-7.0) Creatinine ( pnol/l) (normal range < 130) 24-h urine volume (ml) Creatinine clearance (mtis) 24-h urinary protein excretion (g) 24-h urinary creatinine excretion (mmol) Results shown are meanfsD
OD regimen
BID regimen
4.7f0.7
5.0k1.0
86t.10.6 2443f 1552 1.8k0.6 0.2f0.1 13.9k4.5
86.6f9.5 21 77 f 1343 1.7k0.5 0.3k0.1 12.9f3.9
Lithium dosing Table 2. Hematology, blood chemistry and electrocardiogram results
OD regimen Hemoglobin (g/l) (normal range, men: 140-180) (normal range, women: 120-160) WBC (cellsX 109/1) (normal range 4-1 1) Thyroid-stimulatinghormone (mU/I) (normal range 0.5-5.0) Ionized calcium (mmol/l) (normal range 1.19-1.31) Phosphate (mmol/l) (normal range 0.8-1.50) Heart rate (BPM) ~
BID regimen
149f12
148f13
8.3f2.2*
7.1k2.5
0.24kO.l
0.22kO.l
1.28$0.05**
1.23fO.04
1.02f0.15* 66210
0.95f0.14 65f10
______
Results shown are meanfsD.
P
