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Effects of lithium on sleep in mania
BIOL PSYCHIATRY 1989:25:665-668
665
Effects of Lithium on Sleep in Mania James I. Hudson, Joseph F. Lipinski, Frances R. Frankenburg, Mauricio Tohen, and David J. Kupfer
Introduction Lithium has effects on the electroencephalographic (EEG) sleep of normal individuals (Itoh et al. 1987) and patients with depression (Kupfer et al. 1970; Mendels and Chemik 1973; Chemik and Mendels 1974), including increased delta (Stages 3 and 4) sleep and REM latency and decreased REM sleep and REM activity. To test whether or not lithium would have similar effects in mania, we studied the EEG sleep of five manic patients before and after treatment with lithium.
Methods A cohort of nine unmedicated patients with a current diagnosis of bipolar disorder, manic, by DSM-El-R criteria, underwent EEG sleep study, as described in detail elsewhere (Hudson et al. 1988). We report on five patients from that co-
From the Clinical Research Section, Laboratories for Psychiatric Research, McLean Hospital, Belmont, and the Department of Psychiatry, Harvard Medical School, Boston, MA (J.I.H., J.F.L., F.R.F., M.T.), and the Western Psychiatric Institute and Chic, and the Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA (D.J.K.). Supported in part by a grant from the John D. and Catherine T. MacArthur Research Network on the Psychobiology of Depression and Other Affective Disorders, a MacArthur Foundation Network I Scholarship (J.I.H.), NIMH Mental Health Clinical Research Center Grant MH36224, and NIMH Grants MHZ%18 and MH24652. Address reprint requests to Dr. J.I. Hudson, Laboratories for Psychiatric Research, McLean Hospital, 115 Mill Street, Belmont, MA 02178. Received and revised April 29, 1988.
Q 1989 Society of Biological Psychiatry
hort (nos. 3,4,6,8, and 9) who agreed to EEG sleep evaluation after lithium treatment. There were four women and one man (mean age +SD 33 + 11.8 years, range 18-49). Patients were initially unmedicated and were studied for 2 or 3 consecutive nights (mean 2.6) before treatment with lithium. After the initial studies, the patients were treated with lithium and again underwent EEG sleep evaluation. The duration of lithium treatment prior to study ranged from 9 to 23 days (mean 15.2 & 5.8); the dose of lithium carbonate administered ranged from 900 mg to 1800 mg daily (mean 1260 + 330), resulting in stable lithium levels of 0.5-0.9 mEq/liter (mean 0.72 2 0.16). Other medications given during this interval included dicloxacillin (n = 1) and occasional doses of acetaminophen (n = 4). Patients were studied in hospital beds connected by cable to a monitoring room. Fourchannel all-night EEG sleep recordings were performed, and summary variables were derived from visual scoring, as previously described (Hudson et al. 1988). Severity of illness was assessed by the Brief Psychiatric Rating Scale (BPRS) (Overall et al. 1962), augmented to include nine items covering symptoms of mania (BPRS-A). In addition, global severity of illness was assessed on a 7-point scale (GSS) devised at our center (1 = not ill; 2 = very mild; 3 = mild; 4 = moderate; 5 = moderately severe; 6 = severe; 7 = extremely severe). Although all patients met criteria for manic episodes within the 2 weeks prior to study, two patients were
0006-3223l89lSO3.50
666
BIOL PSYCHIATRY 1989;25:665-668
improving, so that they were only mildly ill at the time of study. The other three patients were rated as moderately ill at the time of study. As there were no significant internight differences (by Analysis of Variance, ANOVA) on any variable either pre- or posttreatment, the mean value of all nights for each subject was used for analysis. Pre- versus posttreatment values were compared by the Wilcoxon test for paired data. One-tailed tests on the following variables were used, as we had hypothesized that they would change in the direction indicated: increased time spent asleep, increased sleep efficiency, increased percentage of delta sleep, decreased REM time and percentage of REM sleep, increased REM latency, decreased REM activity, decreased REM density, decreased REM intensity, and decreased BPRS-A scores. Other tests were two-tailed. Correlations were assessed by the Spearman rank correlation test.
Results Values for EEG sleep variables before and after treatment with lithium are presented in Table 1. On indices of sleep continuity and sleep architecture, the only significant change after lithium was decreased percentage of REM sleep (p < 0.05). By contrast, there were changes in several REM measures after lithium treatment: all patients exhibited increased REM latency and decreased REM intensity (p < 0.05), and there was a trend toward decreased REM density (p < 0.1). All patients experienced a reduction of BPRSA scores (mean 65 ? SD 11 pretreatment versus 41 2 4.2 posttreatment, p < 0.05) and GSS scores (4.1 ? 0.8 versus 2.6 t 0.7,~ < 0.05). There were no significant correlations among EEG sleep variables, nor between BPRS-A scores and EEG sleep variables.
Discussion The major finding of this investigation is that lithium affected several aspects of REM sleep in manic patients. Percentage of REM sleep
Brief
Report-
decreased, REM latency increased, REM intensity decreased, and there was a trend toward decreased REM density. Sleep continuity and sleep architecture indices (other than percentage of REM sleep) were not significantly changed. The changes in REM measures in the manic patients are similar to those seen after lithium administration to normal individuals (Itoh et al. 1987) and depressed patients (Kupfer et al. 1970; Mendels and Chemik 1973; Chemik and Mendels 1974). However, we did not observe the increase in delta sleep reported in depressed patients and observed as a nonsignificant trend in normal individuals. Our results suggest that with the possible exception of not increasing delta sleep, the effects of lithium on EEG sleep in manic patients are similar to those produced in depressed patients and normal subjects. Two other studies (Chemik et al. 1974; Kupfer et al. 1974) have assessed the effects of lithium on EEG sleep in patients with various types of affective disorder. Chemik and colleagues (1974) studied four unipolar depressed, five bipolar depressed, one bipolar mixed, one manic, one hypomanic, and three euthymic patients; Kupfer and associates (1974) studied two bipolar depressed, two hypomanic, one manic, and one schizoaffective. Both studies found effects similar to those observed in depressed patients and normal individuals. These observations alone do not permit firm conclusions regarding the possible differential effects of lithium on separate types of affective disorder. However, considering the results of these studies along with those of the present study and previous studies of depression and normal individuals, it is likely that the major effects of lithium on EEG sleep are independent of clinical diagnosis. The effects of lithium on REM sleep in mania are of interest in that decreasing REM sleep time, increasing REM latency, and decreasing REM density are also effects of treatment with antidepressant medications (Gillin et al. 1984). Furthermore, it appears that unmedicated manic patients often exhibit REM
BIOL PSYCHIATRY
Brief Reports
1989;25:665Xi68
667
Table 1. EEG Sleep Characteristics of Five Manic Patients before and after Treatment with Lithium On lithium
Unmedicated SD
EEG sleep variables
Mean
Sleep continuity Total recording period (TRF’) (min) Time spent asleep (TSA) @in) Time awake (min) Sleep efficiency (TSAflRP) (%) Sleep latency (min)
384 326 48 85 9.8
29 90 76 21 4.4
Sleep architecture Stage 1 (8) Stage 2 (%) Stage 3 + 4 (%) Stage REM (%)
4.6 59 14 22
1.9 10 8.5 4.1
REM measures REM latency (min) REM time (RT) (min) REM activity (RA) (units) REM density (RAIRT) REM intensity (RA/TSA) No. of REM periods
50 74 90 1.3 0.28 3.5
12 28 36 0.27 0.08 0.95
Mean 391 359 25 91 13
SD
P”
26 29 24 6.5 10
NV NS NS NS NS
3.8 67 11 18
2.0 6.5 9.2 1.7
NS NS NS co.05
87 64 12 1.1 0.20 3.5
43 3.9 19 0.22 0.06 0.50
co.05 NS NS
“Wilcoxon test for paireddata.
bNotsignificant.
sleep disturbances similar to those seen in depression: we found significantly shortened REM latency and increased REM density in the cohort of nine manic patients from whom the subjects in the present study were drawn when compared to normal individuals (Hudson et al. 1988). The findings of the present study suggest that lithium and antidepressant medications may act in a similar way to correct these REM abnormalities. As patients improved during treatment with lithium, it is unclear whether or not the effects on REM sleep were due to direct effects of lithium or to clinical improvement. Although this issue cannot be resolved with certainty, it seems likely that a direct drug effect is largely responsible, as similar changes occur in normal individuals treated with lithium. Furthermore, Chemik et al. (1974) found that the characteristic effects of lithium on EEG sleep appeared within the first 24 hr of lithium treatment and that on longitudinal stud-
ies, the magnitude of these effects was highly correlated with the plasma and intraerythrocyte (RISC) lithium levels. We are grateful for the assistance of Marcia German, Wendy Miller, Rim Zierk, and the nursing staff of the McLean Hospital Clinical Evaluation Units.
References Chernik DA, Mendels J (1974): Longitudinal study of the effects of lithium carbonate on the sleep of hospitalized depressed patients. Biol Psychiatry 9:117-123. Chemik DA, Cochrane C, Mendels J (1974): Effects of lithium on sleep. .I Psychiatr Res l&133146. Gillin JC, Sitaram N, Wehr T, Duncan W, Post RM, Murphy DL, Me&Bon WB, Wyatt RJ, Burmey WE (1984): Sleep and affective illness. In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders. Frontiers of Clinical Neuroscience, vol
1. Baltimore: Williams & Wilkins, pp 157-189.
668
BIOL PSYCHIATRY 1989:25:665-668
Hrief
Report\
Hudson JI, Lipinski JF, Frankenburg FR, Grochocinski VJ, Kupfer DJ (1988): Electroencephalographic sleep in mania. Arch Gen Psychiarq 451267-273.
Kupfer DJ, Reynolds CF, Weiss BL, Foster FG (1974): Lithium carbonate and sleep in affective disorders. Further considerations. Arch Gen P~chiar~ 30:7984.
Itoh H, Kabashima T, Tamura M, Onda M, Takahashi T, Higuchi H, Sasaki M, Atsuyoshi M (1987): Lithium influence on nocturnal sleep and daytime Sleep Res sleepiness of normal subjects. 16:617.
Mendels J. Chemik DA (1973): The effect of lithium carbonate on the sleep of depressed patients. lrtr Pharmacopsychiatry 8: 184- 192.
Kupfer DJ, Wyatt RJ, Greenspan K, Snyder F ( 1970): Lithium carbonate and sleep in affective illness. Arch Gen Psychiatry 23:35-40.
Overall JE, Gorham DR ( 1962): The Brief Psychiatric Rating Scale. Psycho/ Rep 10:799-S 12.
665
Effects of Lithium on Sleep in Mania James I. Hudson, Joseph F. Lipinski, Frances R. Frankenburg, Mauricio Tohen, and David J. Kupfer
Introduction Lithium has effects on the electroencephalographic (EEG) sleep of normal individuals (Itoh et al. 1987) and patients with depression (Kupfer et al. 1970; Mendels and Chemik 1973; Chemik and Mendels 1974), including increased delta (Stages 3 and 4) sleep and REM latency and decreased REM sleep and REM activity. To test whether or not lithium would have similar effects in mania, we studied the EEG sleep of five manic patients before and after treatment with lithium.
Methods A cohort of nine unmedicated patients with a current diagnosis of bipolar disorder, manic, by DSM-El-R criteria, underwent EEG sleep study, as described in detail elsewhere (Hudson et al. 1988). We report on five patients from that co-
From the Clinical Research Section, Laboratories for Psychiatric Research, McLean Hospital, Belmont, and the Department of Psychiatry, Harvard Medical School, Boston, MA (J.I.H., J.F.L., F.R.F., M.T.), and the Western Psychiatric Institute and Chic, and the Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA (D.J.K.). Supported in part by a grant from the John D. and Catherine T. MacArthur Research Network on the Psychobiology of Depression and Other Affective Disorders, a MacArthur Foundation Network I Scholarship (J.I.H.), NIMH Mental Health Clinical Research Center Grant MH36224, and NIMH Grants MHZ%18 and MH24652. Address reprint requests to Dr. J.I. Hudson, Laboratories for Psychiatric Research, McLean Hospital, 115 Mill Street, Belmont, MA 02178. Received and revised April 29, 1988.
Q 1989 Society of Biological Psychiatry
hort (nos. 3,4,6,8, and 9) who agreed to EEG sleep evaluation after lithium treatment. There were four women and one man (mean age +SD 33 + 11.8 years, range 18-49). Patients were initially unmedicated and were studied for 2 or 3 consecutive nights (mean 2.6) before treatment with lithium. After the initial studies, the patients were treated with lithium and again underwent EEG sleep evaluation. The duration of lithium treatment prior to study ranged from 9 to 23 days (mean 15.2 & 5.8); the dose of lithium carbonate administered ranged from 900 mg to 1800 mg daily (mean 1260 + 330), resulting in stable lithium levels of 0.5-0.9 mEq/liter (mean 0.72 2 0.16). Other medications given during this interval included dicloxacillin (n = 1) and occasional doses of acetaminophen (n = 4). Patients were studied in hospital beds connected by cable to a monitoring room. Fourchannel all-night EEG sleep recordings were performed, and summary variables were derived from visual scoring, as previously described (Hudson et al. 1988). Severity of illness was assessed by the Brief Psychiatric Rating Scale (BPRS) (Overall et al. 1962), augmented to include nine items covering symptoms of mania (BPRS-A). In addition, global severity of illness was assessed on a 7-point scale (GSS) devised at our center (1 = not ill; 2 = very mild; 3 = mild; 4 = moderate; 5 = moderately severe; 6 = severe; 7 = extremely severe). Although all patients met criteria for manic episodes within the 2 weeks prior to study, two patients were
0006-3223l89lSO3.50
666
BIOL PSYCHIATRY 1989;25:665-668
improving, so that they were only mildly ill at the time of study. The other three patients were rated as moderately ill at the time of study. As there were no significant internight differences (by Analysis of Variance, ANOVA) on any variable either pre- or posttreatment, the mean value of all nights for each subject was used for analysis. Pre- versus posttreatment values were compared by the Wilcoxon test for paired data. One-tailed tests on the following variables were used, as we had hypothesized that they would change in the direction indicated: increased time spent asleep, increased sleep efficiency, increased percentage of delta sleep, decreased REM time and percentage of REM sleep, increased REM latency, decreased REM activity, decreased REM density, decreased REM intensity, and decreased BPRS-A scores. Other tests were two-tailed. Correlations were assessed by the Spearman rank correlation test.
Results Values for EEG sleep variables before and after treatment with lithium are presented in Table 1. On indices of sleep continuity and sleep architecture, the only significant change after lithium was decreased percentage of REM sleep (p < 0.05). By contrast, there were changes in several REM measures after lithium treatment: all patients exhibited increased REM latency and decreased REM intensity (p < 0.05), and there was a trend toward decreased REM density (p < 0.1). All patients experienced a reduction of BPRSA scores (mean 65 ? SD 11 pretreatment versus 41 2 4.2 posttreatment, p < 0.05) and GSS scores (4.1 ? 0.8 versus 2.6 t 0.7,~ < 0.05). There were no significant correlations among EEG sleep variables, nor between BPRS-A scores and EEG sleep variables.
Discussion The major finding of this investigation is that lithium affected several aspects of REM sleep in manic patients. Percentage of REM sleep
Brief
Report-
decreased, REM latency increased, REM intensity decreased, and there was a trend toward decreased REM density. Sleep continuity and sleep architecture indices (other than percentage of REM sleep) were not significantly changed. The changes in REM measures in the manic patients are similar to those seen after lithium administration to normal individuals (Itoh et al. 1987) and depressed patients (Kupfer et al. 1970; Mendels and Chemik 1973; Chemik and Mendels 1974). However, we did not observe the increase in delta sleep reported in depressed patients and observed as a nonsignificant trend in normal individuals. Our results suggest that with the possible exception of not increasing delta sleep, the effects of lithium on EEG sleep in manic patients are similar to those produced in depressed patients and normal subjects. Two other studies (Chemik et al. 1974; Kupfer et al. 1974) have assessed the effects of lithium on EEG sleep in patients with various types of affective disorder. Chemik and colleagues (1974) studied four unipolar depressed, five bipolar depressed, one bipolar mixed, one manic, one hypomanic, and three euthymic patients; Kupfer and associates (1974) studied two bipolar depressed, two hypomanic, one manic, and one schizoaffective. Both studies found effects similar to those observed in depressed patients and normal individuals. These observations alone do not permit firm conclusions regarding the possible differential effects of lithium on separate types of affective disorder. However, considering the results of these studies along with those of the present study and previous studies of depression and normal individuals, it is likely that the major effects of lithium on EEG sleep are independent of clinical diagnosis. The effects of lithium on REM sleep in mania are of interest in that decreasing REM sleep time, increasing REM latency, and decreasing REM density are also effects of treatment with antidepressant medications (Gillin et al. 1984). Furthermore, it appears that unmedicated manic patients often exhibit REM
BIOL PSYCHIATRY
Brief Reports
1989;25:665Xi68
667
Table 1. EEG Sleep Characteristics of Five Manic Patients before and after Treatment with Lithium On lithium
Unmedicated SD
EEG sleep variables
Mean
Sleep continuity Total recording period (TRF’) (min) Time spent asleep (TSA) @in) Time awake (min) Sleep efficiency (TSAflRP) (%) Sleep latency (min)
384 326 48 85 9.8
29 90 76 21 4.4
Sleep architecture Stage 1 (8) Stage 2 (%) Stage 3 + 4 (%) Stage REM (%)
4.6 59 14 22
1.9 10 8.5 4.1
REM measures REM latency (min) REM time (RT) (min) REM activity (RA) (units) REM density (RAIRT) REM intensity (RA/TSA) No. of REM periods
50 74 90 1.3 0.28 3.5
12 28 36 0.27 0.08 0.95
Mean 391 359 25 91 13
SD
P”
26 29 24 6.5 10
NV NS NS NS NS
3.8 67 11 18
2.0 6.5 9.2 1.7
NS NS NS co.05
87 64 12 1.1 0.20 3.5
43 3.9 19 0.22 0.06 0.50
co.05 NS NS
“Wilcoxon test for paireddata.
bNotsignificant.
sleep disturbances similar to those seen in depression: we found significantly shortened REM latency and increased REM density in the cohort of nine manic patients from whom the subjects in the present study were drawn when compared to normal individuals (Hudson et al. 1988). The findings of the present study suggest that lithium and antidepressant medications may act in a similar way to correct these REM abnormalities. As patients improved during treatment with lithium, it is unclear whether or not the effects on REM sleep were due to direct effects of lithium or to clinical improvement. Although this issue cannot be resolved with certainty, it seems likely that a direct drug effect is largely responsible, as similar changes occur in normal individuals treated with lithium. Furthermore, Chemik et al. (1974) found that the characteristic effects of lithium on EEG sleep appeared within the first 24 hr of lithium treatment and that on longitudinal stud-
ies, the magnitude of these effects was highly correlated with the plasma and intraerythrocyte (RISC) lithium levels. We are grateful for the assistance of Marcia German, Wendy Miller, Rim Zierk, and the nursing staff of the McLean Hospital Clinical Evaluation Units.
References Chernik DA, Mendels J (1974): Longitudinal study of the effects of lithium carbonate on the sleep of hospitalized depressed patients. Biol Psychiatry 9:117-123. Chemik DA, Cochrane C, Mendels J (1974): Effects of lithium on sleep. .I Psychiatr Res l&133146. Gillin JC, Sitaram N, Wehr T, Duncan W, Post RM, Murphy DL, Me&Bon WB, Wyatt RJ, Burmey WE (1984): Sleep and affective illness. In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders. Frontiers of Clinical Neuroscience, vol
1. Baltimore: Williams & Wilkins, pp 157-189.
668
BIOL PSYCHIATRY 1989:25:665-668
Hrief
Report\
Hudson JI, Lipinski JF, Frankenburg FR, Grochocinski VJ, Kupfer DJ (1988): Electroencephalographic sleep in mania. Arch Gen Psychiarq 451267-273.
Kupfer DJ, Reynolds CF, Weiss BL, Foster FG (1974): Lithium carbonate and sleep in affective disorders. Further considerations. Arch Gen P~chiar~ 30:7984.
Itoh H, Kabashima T, Tamura M, Onda M, Takahashi T, Higuchi H, Sasaki M, Atsuyoshi M (1987): Lithium influence on nocturnal sleep and daytime Sleep Res sleepiness of normal subjects. 16:617.
Mendels J. Chemik DA (1973): The effect of lithium carbonate on the sleep of depressed patients. lrtr Pharmacopsychiatry 8: 184- 192.
Kupfer DJ, Wyatt RJ, Greenspan K, Snyder F ( 1970): Lithium carbonate and sleep in affective illness. Arch Gen Psychiatry 23:35-40.
Overall JE, Gorham DR ( 1962): The Brief Psychiatric Rating Scale. Psycho/ Rep 10:799-S 12.