Hypersomnia With Narcolepsy
in BipOlar Depression: Using the Multiple
Eric A. Nofzinger, M.D., Jonathan M. Himmeihoch,
Michael M.D., and
Objective: pressed phase disorders, hypothesis
This study ofbipolar
it has
was
been tested
characterized objectively the hypersomnia affective disorder. On the basis ofprevious
hypothesized by using
that the hypersomnia a multiple sleep latency primary bipolar underwent
multiple sleep latency test. Data on with similar data on 23 nondepressed
their nocturnal narcoleptic
Despite in the
their results
complaints from the
REM sleep was notably contrast to the findings
during narcoleptic
naps in the Conclusions:
than
an increase
1991;
in true
sleep
7, 1990; revisions received Jan. 25 and March 13, 27, 1991. From the Department of Psychiatry, University of Pittsburgh School of Medicine, and the Sleep Evaluation Center, Western Psychiatric Institute and Clinic. Address reprint requests to Dr. Nofzinger, Western Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213. Supported in part by NIMH grants MH-37266, MH-37869, MH00295, and MH-3091S and by a grant from theJohn D. and Catherinc T. MacArthur Foundation. Copyright U 1991 American Psychiatric Association.
Psychiatry
March
1 48:9,
September
were compared evaluation. &
or REM
to the lack in the anergic sleep
in marked of sleepiness of interest, depressed
propensity.
148:1177-1181)
June
accepted
naps sleep
known REM on the basis followed by a
depressed patients, The complaint
propensity
rather Psychiatry
with selected
This dis-
were noted for the bipolar to the working hypothesis,
condition,
lthough hypemsomnia is considered an atypical symptom of affective disorders, it is relatively common in younger depressed patients, particularly those with bipolar affective disorder ( 1-3). Little information is available to assist the clinician in evaluating this complaint. Can measurable correlates of a complaint of hypersomnia be determined with traditional methods of assessing sleepiness? What is the biological nature of the complaint? Is it similar to any other well-documented disorders involving sleepiness? The answers to these questions may provide a window on the pathophysiology of the anergia that can characterize the depressed phase of bipolar affective disorder and, eventually, may aid in developing specific treatment approaches. In a previous report (4), we noted an unusually high
]
and daytime referred for
appears to be related retardation inherent
A
Am
sleep patients
the hypersomnic bipolar depressed patient withdrawal, decreased energy, or psychomotor (AmJ
Received
is related to greater REM sleep. test to compare bipolar affective
sleep disorder associated depressed patients were 2 nights ofpolysomnography
daytime group.
in
1991;
frequently seen in the dework in sleep and affective
of hypersomnia, no abnormalities multiple sleep latency test. Contrary
absent for the
Test
E. Thase, M.D., Charles F. Reynolds ifi, M.D., Alan Malinger, M.D., Patricia Houck, M.S.H., David J. Kupfer, M.D.
order with narcolepsy, a well-defined sleep dysfunction. Method: Twenty-five ofcomplaints ofhypersomnia. They
yjj group
A Comparison Sleep Latency
1991
percentage of REM sleep in patients with anengic bipolar depression. Some evidence (5, 6) also suggests that the anergic phase of bipolar depression may mespond preferentially to treatment with more alerting REM-suppressing antidepressants, such as the monoamine oxidase inhibitor (MAOI) tranylcypromine. The constellation of hypersomnia, high REM sleep indices, and responsiveness to alerting REM-suppressing antidepressants led us to hypothesize that objective measures of hypersomnia in depressed bipolar patients are similar to those in patients with narcolepsy, a clinical sleep disorder characterized by hypersomnia and pathological manifestations of REM sleep (7). Although psychostimulants are the mainstay of narcolepsy treatment, some patients also benefit from MAOIs (8). We therefore prospectively used the multiple sleep latency test to evaluate a group of bipolar outpatients who were experiencing a current episode of hypersomnic depression. The usefulness of this instrument in assessing states of pathological sleepiness is well established (9). On the basis of our hypothesis that the hypersomnia in bipolar depressed patients has biological similarities to narcolepsy, we compared the profile of the bipolar depressed group with that of a group of
1177
HYPERSOMNIA
nondepressed in our sleep
IN
BIPOLAR
narcoleptic evaluation
DEPRESSION
patients center.
concurrently
studied
METhOD Our selection of patients with bipolar disorder has been described in a previous report (4). The diagnosis of primary bipolar depression was confirmed with the Research Diagnostic Criteria (RDC) (10) and was based on a semistructured interview conducted by an experienced clinical psychologist and supervised by one of us (M.E.T., J.M.H.). Of the more than 70 eligible bipolar patients who were screened, 56 met the following operational definition ofanergic depression: 1) definite anergia (score of 2 on item 1 3 of the Hamilton Rating Scale for Depression [ill), 2) psychomotor retardation (score of 2 or more on Hamilton item 8), and 3) at least one of two associated reversed neurovegetative features: a) weight gain of 2.2 kg or more or b) hypersomnia, i.e., 1 or more hours of sleep pen day more than usual. Among the 56 anergic bipolar depressed patients accepted for treatment in our mesearch clinic, we identified 25 patients with definite hypemsomnia, as defined as spending 1 or more hours more in bed each day than usual and napping more than 30 minutes most days. Their mean±SD level of severity on the first 17 items of the Hamilton scale after a 14day evaluation period was 19.7±5.7. The mean±SD age of these 25 hypersomnic bipolar patients (10 men and 15 women) was 36.6±1 1.9 years, and the mean±SD length of their current episodes of depression was 148±9.2 weeks. The mean±SD number of prior depressive episodes was 7.7±6.7, and the mean± SD number of prior hypomanic/manic episodes was 5.4±5.8. According to the RDC, 13 patients met the cmitenia for bipolar I disorder and 12 were classified as having bipolar II disorder; no patient was experiencing four or more episodes per year at the time of intake into the trial. The comparison group consisted of 23 narcoleptic patients (nine men and 14 women). The narcoleptic patients had been referred to our sleep evaluation centen over 2 years for evaluation of excessive daytime somnolence. The referred patients were screened to exclude patients with concurrent RDC diagnoses of alcoholism or drug abuse, borderline or antisocial personality disorder, mental retardation, schizophmenia, schizoaffective disorder, seizure disorder, episode of psychotic major depression, or unipolam or bipolar affective disorder; the final diagnoses were made by one of us (C.F.R.) in accordance with the Association of Sleep Disorders Centers’ classification of sleep and arousal disorders (12). The mean±SD age of the 23 narcoleptic patients was 42.2±1 1 .4 years. The age difference between our narcoleptic and bipolar groups did not reach statistical significance (t=-l.66, df=46, p=O.1O). Cataplexy, sleep paralysis, and hypnagogic hallucinations were reported in 14, 12, and 14 narcoleptic patients, respectively.
1178
The bipolar patients and narcoleptic patients received similar evaluations with all-night EEG and the multiple sleep latency test A 2-week drugand alcohol-free washout period was observed. The EEG sleep studies were completed over 2 consecutive nights in our outpatient sleep evaluation center. Our methods for conducting and scoring EEG sleep studies have been published elsewhere (13). Since our pnimary interest in this study was characterizing the daytime hypersomnia of our bipolar group, sleep vanables were selected with the intent of documenting an adequate duration and quality of nocturnal sleep and of identifying any higher REM sleep indices in the depressed group. These variables included mean±SD sleep latency, time spent asleep, sleep efficiency, REM latency, REM percent, and REM density (13). All subjects normally retired to their rooms and the lights were turned off by 1 1 :30 p.m. They were allowed to sleep until 7:00 a.m. the next morning. Naps were recorded at 10:00 a.m., 12:00 noon, 2:00 p.m., 4:00 p.m., and 6:00 p.m. on the day after the second night of polysomnography. The daytime nap studies consisted of EEG (C3/A2), referential electro-oculogram, and submental bipolar electromyogram. Our procedures for conducting multiple sleep latency test studies have been reported elsewhere (14). The sleepiness index was defined as 100 - (sum of sleep latencies for five naps). Sleep-onset REM periods were defined as REM periods within 10 minutes of sleep onset. Nap studies for patients who fell asleep during the nap penod were scored in accordance with standard criteria (15). When a subject did not fall asleep during the daytime nap, the sleep latency was recorded as 20 minutes. EEG sleep variables were analyzed by a series of twotailed t tests to assess differences between the bipolar and narcoleptic groups in 2-night averaged data. A Fisher’s exact probability was calculated to compare the prevalences of sleep-onset REM periods in the two groups. Nap data were analyzed by repeated measures analyses of variance (ANOVAs), with diagnosis as the group effect and nap period as the repeated measure. On variables showing significant Group by Nap interactions, a profile contrast within each group was performed on the nap data to identify the nap period in which the change occurred.
RESULTS All-Night
Sleep
Studies
The bipolar patients appeared to have an adequate duration (385.5±66.7 minutes) and quality (sleep efficiency=86.l %±8.6%) of nocturnal sleep. They did not fall asleep as quickly as the narcoleptic patients (sleep latency=26.0±21.3 minutes and 10.5±15.0 minutes, mespectively; t=2.87, df=46, p
in BipOlar Depression: Using the Multiple
Eric A. Nofzinger, M.D., Jonathan M. Himmeihoch,
Michael M.D., and
Objective: pressed phase disorders, hypothesis
This study ofbipolar
it has
was
been tested
characterized objectively the hypersomnia affective disorder. On the basis ofprevious
hypothesized by using
that the hypersomnia a multiple sleep latency primary bipolar underwent
multiple sleep latency test. Data on with similar data on 23 nondepressed
their nocturnal narcoleptic
Despite in the
their results
complaints from the
REM sleep was notably contrast to the findings
during narcoleptic
naps in the Conclusions:
than
an increase
1991;
in true
sleep
7, 1990; revisions received Jan. 25 and March 13, 27, 1991. From the Department of Psychiatry, University of Pittsburgh School of Medicine, and the Sleep Evaluation Center, Western Psychiatric Institute and Clinic. Address reprint requests to Dr. Nofzinger, Western Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213. Supported in part by NIMH grants MH-37266, MH-37869, MH00295, and MH-3091S and by a grant from theJohn D. and Catherinc T. MacArthur Foundation. Copyright U 1991 American Psychiatric Association.
Psychiatry
March
1 48:9,
September
were compared evaluation. &
or REM
to the lack in the anergic sleep
in marked of sleepiness of interest, depressed
propensity.
148:1177-1181)
June
accepted
naps sleep
known REM on the basis followed by a
depressed patients, The complaint
propensity
rather Psychiatry
with selected
This dis-
were noted for the bipolar to the working hypothesis,
condition,
lthough hypemsomnia is considered an atypical symptom of affective disorders, it is relatively common in younger depressed patients, particularly those with bipolar affective disorder ( 1-3). Little information is available to assist the clinician in evaluating this complaint. Can measurable correlates of a complaint of hypersomnia be determined with traditional methods of assessing sleepiness? What is the biological nature of the complaint? Is it similar to any other well-documented disorders involving sleepiness? The answers to these questions may provide a window on the pathophysiology of the anergia that can characterize the depressed phase of bipolar affective disorder and, eventually, may aid in developing specific treatment approaches. In a previous report (4), we noted an unusually high
]
and daytime referred for
appears to be related retardation inherent
A
Am
sleep patients
the hypersomnic bipolar depressed patient withdrawal, decreased energy, or psychomotor (AmJ
Received
is related to greater REM sleep. test to compare bipolar affective
sleep disorder associated depressed patients were 2 nights ofpolysomnography
daytime group.
in
1991;
frequently seen in the dework in sleep and affective
of hypersomnia, no abnormalities multiple sleep latency test. Contrary
absent for the
Test
E. Thase, M.D., Charles F. Reynolds ifi, M.D., Alan Malinger, M.D., Patricia Houck, M.S.H., David J. Kupfer, M.D.
order with narcolepsy, a well-defined sleep dysfunction. Method: Twenty-five ofcomplaints ofhypersomnia. They
yjj group
A Comparison Sleep Latency
1991
percentage of REM sleep in patients with anengic bipolar depression. Some evidence (5, 6) also suggests that the anergic phase of bipolar depression may mespond preferentially to treatment with more alerting REM-suppressing antidepressants, such as the monoamine oxidase inhibitor (MAOI) tranylcypromine. The constellation of hypersomnia, high REM sleep indices, and responsiveness to alerting REM-suppressing antidepressants led us to hypothesize that objective measures of hypersomnia in depressed bipolar patients are similar to those in patients with narcolepsy, a clinical sleep disorder characterized by hypersomnia and pathological manifestations of REM sleep (7). Although psychostimulants are the mainstay of narcolepsy treatment, some patients also benefit from MAOIs (8). We therefore prospectively used the multiple sleep latency test to evaluate a group of bipolar outpatients who were experiencing a current episode of hypersomnic depression. The usefulness of this instrument in assessing states of pathological sleepiness is well established (9). On the basis of our hypothesis that the hypersomnia in bipolar depressed patients has biological similarities to narcolepsy, we compared the profile of the bipolar depressed group with that of a group of
1177
HYPERSOMNIA
nondepressed in our sleep
IN
BIPOLAR
narcoleptic evaluation
DEPRESSION
patients center.
concurrently
studied
METhOD Our selection of patients with bipolar disorder has been described in a previous report (4). The diagnosis of primary bipolar depression was confirmed with the Research Diagnostic Criteria (RDC) (10) and was based on a semistructured interview conducted by an experienced clinical psychologist and supervised by one of us (M.E.T., J.M.H.). Of the more than 70 eligible bipolar patients who were screened, 56 met the following operational definition ofanergic depression: 1) definite anergia (score of 2 on item 1 3 of the Hamilton Rating Scale for Depression [ill), 2) psychomotor retardation (score of 2 or more on Hamilton item 8), and 3) at least one of two associated reversed neurovegetative features: a) weight gain of 2.2 kg or more or b) hypersomnia, i.e., 1 or more hours of sleep pen day more than usual. Among the 56 anergic bipolar depressed patients accepted for treatment in our mesearch clinic, we identified 25 patients with definite hypemsomnia, as defined as spending 1 or more hours more in bed each day than usual and napping more than 30 minutes most days. Their mean±SD level of severity on the first 17 items of the Hamilton scale after a 14day evaluation period was 19.7±5.7. The mean±SD age of these 25 hypersomnic bipolar patients (10 men and 15 women) was 36.6±1 1.9 years, and the mean±SD length of their current episodes of depression was 148±9.2 weeks. The mean±SD number of prior depressive episodes was 7.7±6.7, and the mean± SD number of prior hypomanic/manic episodes was 5.4±5.8. According to the RDC, 13 patients met the cmitenia for bipolar I disorder and 12 were classified as having bipolar II disorder; no patient was experiencing four or more episodes per year at the time of intake into the trial. The comparison group consisted of 23 narcoleptic patients (nine men and 14 women). The narcoleptic patients had been referred to our sleep evaluation centen over 2 years for evaluation of excessive daytime somnolence. The referred patients were screened to exclude patients with concurrent RDC diagnoses of alcoholism or drug abuse, borderline or antisocial personality disorder, mental retardation, schizophmenia, schizoaffective disorder, seizure disorder, episode of psychotic major depression, or unipolam or bipolar affective disorder; the final diagnoses were made by one of us (C.F.R.) in accordance with the Association of Sleep Disorders Centers’ classification of sleep and arousal disorders (12). The mean±SD age of the 23 narcoleptic patients was 42.2±1 1 .4 years. The age difference between our narcoleptic and bipolar groups did not reach statistical significance (t=-l.66, df=46, p=O.1O). Cataplexy, sleep paralysis, and hypnagogic hallucinations were reported in 14, 12, and 14 narcoleptic patients, respectively.
1178
The bipolar patients and narcoleptic patients received similar evaluations with all-night EEG and the multiple sleep latency test A 2-week drugand alcohol-free washout period was observed. The EEG sleep studies were completed over 2 consecutive nights in our outpatient sleep evaluation center. Our methods for conducting and scoring EEG sleep studies have been published elsewhere (13). Since our pnimary interest in this study was characterizing the daytime hypersomnia of our bipolar group, sleep vanables were selected with the intent of documenting an adequate duration and quality of nocturnal sleep and of identifying any higher REM sleep indices in the depressed group. These variables included mean±SD sleep latency, time spent asleep, sleep efficiency, REM latency, REM percent, and REM density (13). All subjects normally retired to their rooms and the lights were turned off by 1 1 :30 p.m. They were allowed to sleep until 7:00 a.m. the next morning. Naps were recorded at 10:00 a.m., 12:00 noon, 2:00 p.m., 4:00 p.m., and 6:00 p.m. on the day after the second night of polysomnography. The daytime nap studies consisted of EEG (C3/A2), referential electro-oculogram, and submental bipolar electromyogram. Our procedures for conducting multiple sleep latency test studies have been reported elsewhere (14). The sleepiness index was defined as 100 - (sum of sleep latencies for five naps). Sleep-onset REM periods were defined as REM periods within 10 minutes of sleep onset. Nap studies for patients who fell asleep during the nap penod were scored in accordance with standard criteria (15). When a subject did not fall asleep during the daytime nap, the sleep latency was recorded as 20 minutes. EEG sleep variables were analyzed by a series of twotailed t tests to assess differences between the bipolar and narcoleptic groups in 2-night averaged data. A Fisher’s exact probability was calculated to compare the prevalences of sleep-onset REM periods in the two groups. Nap data were analyzed by repeated measures analyses of variance (ANOVAs), with diagnosis as the group effect and nap period as the repeated measure. On variables showing significant Group by Nap interactions, a profile contrast within each group was performed on the nap data to identify the nap period in which the change occurred.
RESULTS All-Night
Sleep
Studies
The bipolar patients appeared to have an adequate duration (385.5±66.7 minutes) and quality (sleep efficiency=86.l %±8.6%) of nocturnal sleep. They did not fall asleep as quickly as the narcoleptic patients (sleep latency=26.0±21.3 minutes and 10.5±15.0 minutes, mespectively; t=2.87, df=46, p
