27
Psychiatry Research, 40~2740 Elsevier
Electroencepkalographic Sleep Studies in Depressed Outpatients Treated With Interpersonal Psychotherapy: II. Longitudinal Studies at Baseline and Recovery Daniel J. Buysse, David J. Kupfer, Ellen Frank, Timothy Angela Ritenour Received September February 9, 1992.
30, 1991; revised
version
received
H. Monk, and
January
29, 1992; accepted
Abstract. Electroencephalographic (EEG) sleep studies may help to identify persistent versus episodic biological characteristics of major depressive disorder. This report examines longitudinal EEG sleep studies in depressed patients treated with psychotherapy alone. Nineteen patients were studied during a symptomatic baseline period and again during early remission after treatment with interpersonal psychotherapy (IPT). EEG sleep findings at baseline were not markedly abnormal, but they were similar to those in other published studies of young adult outpatients. No changes were found in visually scored EEG sleep measures between depression and early remission. Automated measures of delta sleep and rapid eye movement (REM) activity showed small state-related changes, with delta activity increasing from baseline to remission, and automated REM measures decreasing. Strong baseline-remission correlations were noted for most sleep measures, including slow wave sleep, phasic REM activity, and automated delta EEG counts; measures of sleep continuity and tonic REM sleep were not strongly correlated. Consistent adaptation effects across nights were observed for sleep continuity and REM measures during each clinical phase. These findings support the hypothesis that most visually scored EEG sleep measures, as well as the sleep adaptation process, are stable through the acute episode of depression, at least into early symptomatic remission. They also suggest that finer-grained automated analyses of delta and REM activity may provide more sensitive tools for examining state-related changes. Key Words.
Affective
disorders,
polysomnography,
psychotherapy,
remission.
Electroencephalographic (EEG) sleep studies have been used to examine several aspects of the neurobiology of depression, including questions of episodic (state-like) versus persistent (trait-like) physiological characteristics and the prediction of treatment response. To date, very few studies have addressed these issues in depressed patients treated with psychotherapy alone. Such studies are desirable because they examine sleep physiology in the absence of the confounding effects of antidepressant medications. In the accompanying article, we compared the baseline
Daniel J. Buysse, M.D., is Assistant Professor of Psychiatry; David J. Kupfer, M.D., is Professor and Chairman; Ellen Frank, Ph.D., is Associate Professor of Psychology and Psychiatry; Timothy H. Monk, Ph.D., is Associate Professor of Psychiatry; and Angela Ritenour, B.A., is Research Associate, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA. (Reprint requests to Dr. D.J. Buysse, WPIC, 3811 O’Hara St., Pittsburgh, PA 15213, USA.) 0165-1781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd
28
EEG sleep findings of depressed patients who responded to psychotherapy with those of a comparable group of depressed patients who did not respond to psychotherapy. In this report, we address the question of whether EEG sleep patterns during an episode of depression are stable into early symptomatic remission in psychotherapeutically treated patients. Previous EEG sleep studies have examined the issue of episodic versus persistent EEG sleep characteristics. Some of these studies (Hauri et al., 1974; Knowles et al., 1986) were cross-sectional, comparing the sleep of recovered depressives to that of healthy control subjects. Several longitudinal within-subject studies have also been reported, but they have used both psychotherapeutic and psychopharmacological treatments, with studies during recovery being preceded by medication discontinuation (Schulz et al., 1979; Rush et al., 1986; Giles et al., 1987). In general, both cross-sectional and longitudinal studies have demonstrated that most EEG sleep measures are relatively stable between the depressive episode and drug-free remission. There is some evidence that rapid eye movement (REM) sleep measures may show a greater degree of “normalization” during recovery (Kupfer et al., 1988; Riemann and Berger, 1989). However, it remains possible that medication withdrawal effects or medication effects on neurotransmission may have affected EEG sleep patterns in the recovery phase of these investigations. One recent study has examined EEG sleep measures at baseline and recovery in depressed patients treated with cognitive-behavioral psychotherapy (Thase and Simons, 1992). There were no significant changes in visually scored EEG sleep measures between depression and recovery in this study. Other types of EEG sleep analysis, such as automated period analysis or power spectral analysis, were not reported. Kupfer and Ehlers (1989) have conceptualized the EEG sleep patterns of depressed patients as including both episodic, state-related features (primarily in REM sleep) and persistent features that may be present during recovery as well (primarily in slow wave sleep [SWS]). In the current study, we hypothesized that tonic and phasic REM sleep measures would be elevated during the acute episode compared with recovery, while sleep continuity and SWS measures would not change between the two clinical phases in depressed patients treated with psychotherapy. On the basis of previous work with younger depressed outpatients (Kupfer et al., 19896) we also hypothesized that we would observe adaptation effects during two consecutive nights in the sleep laboratory.
Methods Patients (Table 1). Patients were 16 women and 3 men between the ages of 18 and 50 (mean = 32.3, SD = 7.2 years) who were evaluated and treated as outpatients. Details of patient selection are presented in Part I of this report and are summarized briefly here. This group of psychotherapy responders is identical to one of the groups described in Part 1. Inclusion criteria included the presence of a definite current episode of major depressive disorder, definite or probable endogenous subtype, according to the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer, 1978) and Research Diagnostic Criteria (RDC; Spitzer et al., 1978); at least two previous lifetime episodes, with the most recent prior episode occurring within the previous 2% years; and a period of symptomatic remission lasting at least
29
Table 1. Demographic and clinical data Descriptor Sex (males/females)
3116
Age (yrl Mean
32.3 7.2
SD Age at first episode (yr)
23.3
Mean
7.6
SD No. of previous episodes
3.7
Mean SD
1.2
Median
4
Duration of index episode (wk) 22.9
Mean
16.2
SD Duration of acute treatment phase (wk) Mean
15.9
SD
10.4
Median
14
Ranae
2-41’
Baseline
Remission
Mean
SD
19.6 8.9
GAS BDI
HRSD (17 item) score Raskin depression
rating
Mean
SD
4.0
4.1
2.4
1.8
4.5
1 .l
56.7
5.2
80.8
7.0
21 .o
6.3
6.0
4.3
Note. HRSD = Hamilton Rating Scale for Depression. GAS = Global Assessment Inventory. 1. Sleep studies dunng remission were conducted regardless of symptom severity.
Scale. BDI = Beck Depression
after a mlmmum of 12 weeks in the acute treatment
phase,
10 weeks between the index episode and the preceding episode. Patients with other RDC diagnoses in the previous 2% years, with the exception of hypomania, were excluded. Three patients were diagnosed as having definite, and one as having probable, bipolar II disorder. All patients met the minimum severity criterion of a score 3 15 on the 17-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). Patients with serious or progressive medical illness were excluded on the basis of medical history, physical examination, and laboratory studies. Patients habitually taking medications with known effects on EEG sleep were also excluded. Patients were also instructed not to use any alcohol or prescription or nonprescription medications before sleep studies. A review of actual histories indicates that six patients used some alcohol in the 2 weeks before sleep studies at baseline, with the maximum consumption being four drinks in the past 2 weeks. Nine patients used alcohol during the 2 weeks before sleep studies in the period of remission, with a maximum of five drinks in one patient. One patient was taking fluoxetine when recruited into the study; the last dose was taken 14 days before baseline sleep studies. Treatment successfully
Procedures and Definition treated with psychotherapy
of Response. alone and did
All patients not receive
in this report were any antidepressant
30 medication. The specific form of therapy was interpersonal psychotherapy (IPT; Klerman et al., 1984). Therapists were all master’s or doctoral level clinicians, who were trained and supervised by a certified IPT trainer (Cleon L. Cornes, M.D.). Sessions were initially scheduled twice weekly, then weekly for the remainder of the 12- to 20-week acute treatment period. Once a patient met criteria for remission (see below), IPT sessions were discontinued, although patients continued to meet on a monthly basis with their therapist in a supportive context. In the event of partial response, patients were allowed to continue in weekly IPT sessions for longer than 20 weeks. During acute treatment, clinical status was monitored weekly with the HRSD, Beck Depression Inventory (Beck et al., 1961), Raskin Severity of Depression Scale (Raskin et al., 1969), and Global Assessment Scale (Endicott et al., 1976). Remission was defined as 4 consecutive weeks with an HRSD score < 7, Raskin depression rating < 5, and not meeting RDC for current depressive episode. The patients described here were not part of a treatment study per se, but rather, part of a study designed to examine biological and social/activity rhythms in remitted depressives. Since our goal was to achieve symptomatic remission, the duration of acute treatment with IPT was not rigidly defined. Mean duration of IPT treatment until symptomatic remission was 15.9 (SD = 10.4) weeks (Table 1). Repeat biological studies were scheduled to occur as soon as possible after patients met criteria for remission, but with a minimum acute treatment duration of 12 weeks. EEG Sleep Studies. Two consecutive nights of EEG sleep studies were conducted during the acute episode (baseline), and again following remission. Sleep studies included one channel of EEG recording (C3 or C4, referenced to Al-A2), bilateral electro-oculograms (EOG; referenced to Al-A2), and bipolar submental electromyogram (EMG). High and low frequency filter settings were 30 Hz and 0.3 Hz, respectively, for EEG and EOG, and 90 Hz and 10 Hz for EMG. Paper speed was 10 mm/set, and sensitivity on the EEG channel was 5 flV/mm. EEG sleep records were scored in 60-second epochs using standard criteria (Rechtschaffen and Kales, 1968) by polysomnographic technologists without knowledge of the patient’s clinical state. Sleep onset was defined as the first of 10 consecutive minutes of Stage 2 or deeper non-REM sleep, interrupted by no more than 2 minutes of Stage 1 or wakefulness. REM latency was defined as the interval between sleep onset and REM period 1 with > 3 consecutive minutes of REM sleep. In addition, technicians scored phasic REM activity by estimating the amount of eye movement activity on a I- to 8-point scale for each minute of sleep. Sleep stage scoring reliability is maintained at > 85% for major sleep variables through the use of monthly reliability checks. Each night of sleep studies was also subjected to automated delta and REM sleep analysis, as described in previous publications (Kupfer et al., 1984). These techniques provide another measure of the number of slow frequency EEG waves and phasic eye movements. Sleep times were determined by each patient’s current sleep-wake schedule. During the baseline phase, patients estimated their habitual sleep-wake times, and followed these times in the laboratory. Before studies in the remission phase, patients kept a 2-week sleep-wake diary, from which habitual sleep-wake times were again calculated. At the time of EEG sleep studies, patients also had lo-minute blood samples for determination of melatonin values and core body temperature measurements via flexible rectal thermistor. Findings from these studies will be presented in subsequent reports. Blood sampling started at 5 p.m. and ended 30 minutes before patients’ bedtimes; the intravenous catheter was removed before sleep studies. Core body temperature measurements continued through the night of EEG sleep recordings. Statistical Analyses. Differences in clinical rating scale data from the acute episode to remission were assessed with paired t tests. Major domains of EEG sleep measures at baseline and remission were compared with a repeated-measures multivariate analysis of variance (MANOVA), using individual sleep study nights (night 1 and night 2) and clinical phase (baseline acute episode vs. remission) as repeated-measure factors. Sleep domains were sleep
31 continuity, sleep architecture, REM sleep, automated delta measures, and automated REM sleep measures. MANOVA was used as the major statistical technique to reduce the number of statistical comparisons between correlated sleep measures. Table 2 also reports individual values from analysis of variance (ANOVA) to facilitate comparisons of specific sleep measures. If one were to consider only ANOVA results, a Bonferroni-corrected p value of 0.002 would be considered statistically significant. As an additional measure of baselineremission stability in sleep measures, we performed Pearson correlations on baseline and remission sleep values, using the mean of nights 1 and 2 at each time point.
Results As would be predicted from the selection and remission criteria, patients demonstrated clinically significant differences on all depression rating scales between the baseline and remission (Table 1). The mean duration of acute treatment was 15.9 weeks (median = 14, range = 2-41), and the mean HRSD score was reduced from 19.6 at baseline to 4.1 at recovery. Baseline EEG sleep measures during the depressive episode were not markedly abnormal, especially compared with values seen in inpatient or older depressive samples (cf. Kupfer et al., 1989~1; Reynolds et al., 1991). However, values for most variables, including REM latency, sleep efficiency, and REM %, were very similar to those reported in recent studies of younger depressed outpatients (cf. Kupfer et al., 19896; Rush et al., 1989; Jarrett et al., 1990). There were no statistically significant effects of clinical phase (baseline depressed vs. remission) on any visually scored EEG sleep measure, including sleep continuity factors, sleep architecture, or REM variables (Fig. 1; Table 2). Automated delta analyses showed a significant clinical phase effect (MANOVA: F= 2.54; df = 7,26; p = 0.04), representing small increases in delta activity between baseline and remission. None of the individual univariate ANOVAs for automated delta measures showed significant clinical phase effects. Automated REM measures also showed significant clinical phase effects (MANOVA: F = 2.33; df = 7, 27; p = 0.05), indicating reductions in REM activity from baseline to remission. Again, these findings were small in magnitude, with none of the univariate ANOVAs for REM measures showing significant changes as a function of clinical phase. Significant night I-night 2 differences were observed within all sleep domains except automated delta sleep measures (Table 2). Within the domain of sleep continuity, night 2 sleep was characterized by longer sleep duration (ANOVA: F= 10.31; df = 1,36;p = 0.003) and improved sleep efficiency (ANOVA: F= 13.68; df = 1, 36; p = 0.0007). Night 2 sleep was also characterized by lower Stage 1 % (ANOVA: F = 4.72; df = 1,36; p = 0.04) and increased REM sleep, both in absolute minutes (Fig. 2) (ANOVA: F = 20.67; df = 1, 36; p = 0.0001) and % REM sleep (ANOVA F = 10.92; df = 1, 36; p = 0.002). Visually scored phasic REM activity and REM density were higher on night 2 than on night 1 (Fig. 3) (ANOVA: F = 25.69; df = 1, 36; p = 0.0001, and F = 6.22; df = 1, 36; p = 0.02). These changes were mirrored by automated REM analyses, which showed higher total REM counts for the entire night (ANOVA: F = 20.51; df = 1, 34; p = O.OOOl), and for the first (ANOVA: F = 11.02; df = 1,33; p = 0.002) and second (ANOVA: F = 7.06; df = 1, 33; p = 0.01) REM periods of the night.
32
Table 2. Baseline and remission sleep measures (n = 19)
Baseline
Remission Night 2
Night 1 Variable
Night 1
Night 2
Mean
SD
Mean
SD
Mean
SD
Mean
SD
405.1
59.3
422.0
38.2
392.1
63.1
428.5
60.8
90.7
6.7
94.1
3.7
89.2
7.1
93.0
6.1
20.7
18.1
13.7
7.1
25.2
25.2
19.9
18.9
Sleep continuity Time spent asleep (min) Sleep efficiency Sleep latency
(min)2
Sleep architecture % Stage 1’
4.1
3.6
2.8
2.3
3.7
3.0
3.1
2.1
% Stage 3 + 4’
13.3
8.6
11.4
7.6
10.6
8.4
10.5
7.1 29.2
Stage 3 + 4 (min)
54.1
33.3
47.8
31.6
41.4
31.1
45.1
% REM
24.3
6.4
28.0
3.9
23.8
6.3
26.4
3.5
REM (min)’
99.0
29.4
118.1
19.7
93.6
27.5
112.8
20.3
61.3
20.01
68.6
21.4
68.3
21.4
61.3
13.4
145.6
75.7
173.6
70.7
125.4
69.9
173.9
84.7
REM measures REM latency
(min)’
REM activity’
1.01
REM density
0.38
1.21
0.51
0.84
1.07
0.34
0.49
Automated Delta 7814
3688
7163
2927
7696
3812
8117
4966
Total-NREM
11
2648
1603
2626
1531
2824
1672
2600
1344
Total-NREM
2’
2270
1011
2100
1225
2253
1258
2483
1837
Total-whole
night2
Average-whole
night’
25.3
10.8
23.9
10.0
26.8
13.8
25.8
14.5
Average-NREM
1’
40.5
19.8
37.2
13.8
42.5
20.4
41.2
18.6
Average-NREM
2’
31.7
13.3
29.6
15.5
30.0
16.5
31 .o
20.7
1.38
Delta ratio3 Automated
0.76
1.49
0.80
1.72
1.12
1.63
0.79
REM
Total-whole
night2
552
385
721
401
551
403
690
547
Total-REM
1i
54.2
48.7
117.9
95.3
48.1
43.4
97.4
148.5
Total-REM
2’
84.4
82.8
154.6
117.3
158.3
156.4
172.5
157.5
5.5
2.9
6.2
3.3
5.5
3.3
5.9
3.9
Average-REM
1’
3.4
2.4
5.4
3.7
2.9
2.3
4.0
3.9
Average-REM
2’
4.6
3.0
6.2
4.9
5.7
4.9
6.0
5.3
0.91
0.61
1.11
0.73
0.88
1.04
0.75
0.53
Average-whole
REM ratio3 Note. MANOVA
night’
= multivariate analysis of variance. ANOVA = analysis of variance. REM = rapid eye movement
1. Square root transformation performed on data before analysis. Mean values presented in original units. 2. Log transformation (LN [var + I]) performed on data before analysis. Mean values presented in original units. 3. Log transformation (LN [var + 0.11) performed on data before analysis. Mean values presented in original units.
33
MANOVA and ANOVA Clinical phase X night interaction effect
Night effect
Clinical phase effect F
df
P
F
df
P
0.87
4.80
0.84
10.31
3.34
0.01
0.82
3,34
0.49
1,36
0.003
1.40
1,36
1,36
0.45
0.24
13.68
1,36
0.0007
0.02
1,36
0.52
1,36
0.88
0.48
2.66
1,36
0.11
0.08
1.36
0.78
0.30 0.04
5, 32
0.91
4.59
5,32
0.003
1.40
5,32
0.25
1,36
0.85
4.72
1,36
0.04
1.13
1,36
0.29
0.63
1,36
0.43
0.22
1,36
0.64
0.81
1,36
0.38
0.65
1,36
0.42
0.13
1,36
0.72
1.89
1,36
0.18
0.53
1,36
0.47
10.92
1,36
0.002
0.28
1,36
0.60
0.56
1,36
0.46
20.67
1,36
0.0001
0.00
1,36
0.94
0.85
3,34
0.48
8.37
3, 34
0.0003
1.32
1,36
0.85
0.06
1,36
0.81
2.70
3, 34 1,36
0.29
0.04 0.28
1.36
0.60
25.69
1,36
0.0001
1.46
1,36
0.23
1.87
1,36
0.18
6.22
1,36
0.02
0.02
1,36
0.90
2.54
7,26
0.04
0.78
7,26
0.82
0.37
7, 26
0.91
0.00
1,33
0.97
0.05
1,33
0.82
0.61
1,33
0.44
0.00
1,32
0.96
0.01
1,32
0.92
0.69
1,32
0.41
0.01
1,33
0.91
0.00
1,33
0.96
1.32
1,33
0.26
0.06
1,33
0.81
1.13
1,33
0.30
0.21
1,33
0.65
0.08
1,32
0.78
0.01
1,32
0.93
0.12
1,32
0.74
0.06
1,33
0.81
0.25
1,33
0.62
1.67
1.33
0.20
0.85
1,32
0.36
0.55
1,32
0.47
0.72
1,32
0.40
2.33
7,27
0.05
8.57
7, 27
0.0001
0.82
7,27
0.74
F
df
P
0.23
3, 34
0.04
1,36
0.58
0.11
0.13
1,34
0.72
20.51
1,34
0.0001
0.01
1,34
0.92
0.57
1,33
0.45
11.02
1,33
0.002
0.20
1,33
0.66
1.49
1.33
0.23
7.06
1,33
0.01
1.24
1,33
0.27
0.01
1.34
0.92
2.47
1,34
0.13
0.04
0.84
1.17
1,33
0.29
6.38
1,33
0.02
0.48
I,34 1,33
0.26
1,33
0.62
2.39
1,33
0.13
0.15
1,33
0.70
3.79
1,33
0.06
0.81
1,33
0.37
0.58
1,33
0.45
sleep. NREM = non-REM sleep
0.49
34
Fig. 1. REM latency measures from 2 consecutive nights in 19 depressed patients
NlGHll
NKnT2
NiGHTl
NIGHT 2
RR(tSSlON Electroencephalographic sleep measures were visually scored. There were no consistent changes as a function of clinical phase (baseline depressed and asymptomatic remission following psychotherapy). Individuals’ values are shown, with lines connecting nights 1 and 2; horizontal lines indicate group means. Analysis of variance latency showed no significant rapid eye movement latency (REM) effects for night 1 vs. night 2, clinical phase (baseline vs. remission), or night X clinical phase interaction.
Night l-night 2 differences appeared stable across clinical phases. This stability is indicated by the absence of significant clinical phase X sleep night interaction effects (Table 2). Although mean values for most sleep measures showed stability from baseline to recovery, it is also important to determine whether values for individual subjects were consistent across clinical phase. Pearson correlations between baseline and remission (with mean values from nights 1 and 2) were statistically significant (p < 0.05) for 15/25 variables (Table 3). Measures that were most strongly correlated included visually scored slow wave sleep, and both visually scored and automated measures of phasic REM activity. Sleep continuity measures, visually scored REM sleep, and REM latency were less strongly correlated across time. Categorical REM latency values often are used to contrast biological subgroups of depressed patients, and such distinctions might be expected to produce differential patterns of change from baseline to recovery. Therefore, we conducted an additional exploratory analysis that compared EEG sleep measures of patients with baseline REM latency < 60 minutes (n = 10) to sleep EEG measures of those with baseline REM latency > 60 minutes (n = 9). For this analysis, we used mean values from nights 1 and 2 at baseline and remission study points, An ANOVA was performed with subgroups (defined by REM latency) and clinical phase as factors. Aside from REM latency, only delta ratio (ratio of average delta counts in non-REM period 1 to
35
Fig. 2. REM sleet times from 2 consecutive nights in 19 depressed patients
NIGHT1
N&r2
NIGHT1
NtGHl2
RDIISSK)N Electroencephalographic sleep measures were visually scored. There were no consistent changes as a function of clinical phase (baseline depressed and asymptomatic remission following psychotherapy). Individuals’ values are shown, with lines connecting nights 1 and 2; horizontal lines indicate group means. Rapid eye movement (REM) sleep time (min) showed a significant effect for night 1 vs. night 2 [analysis of variance: f = 20.67; of= 1,36; p < 0.01) but no significant clinical phase or night X clinical phase interaction effects.
average delta counts in non-REM period 2) differed between the groups; the low REM latency group had a smaller delta ratio than the high REM latency group (mean across clinical phases for the low REM latency group = 1.14; mean across clinical phases for the high REM latency group = 1.98; F = 12.87; df = 1, 17; p < 0.001). Significant group X clinical phase interaction effects were noted for REM latency (F= 16.8; df = I, 17; p < 0.001) and automated delta sleep counts for the whole night (F= 4.89; df= 1, 17;~ x0.04) and for non-REM period 1 (F= 8.16; df = 1, 17; p = 0.01). In each case, mean values for the short and long REM latency subgroups moved toward each other across clinical phases. More specifically, the short REM latency group showed an increase in delta counts between baseline and recovery, and the long REM latency group showed a decrease.
Discussion The EEG sleep patterns of depressed patients successfully treated with interpersonal psychotherapy did not show any significant overall changes between the time of acute depression and clinical remission on the basis of traditional visual scoring methods. Contrary to expectations, stability was noted for REM sleep measures as well as for sleep continuity and non-REM measures. Automated measures of delta sleep and REM activity showed small but consistent changes related to clinical
36
Fig. 3. Phasic REM activity measures from 2 consecutive depressed patients 400‘.
nights in 19
SOSOO-
E =: 4 =Y H
l50-
_-
-_ -_ -_
lOOSOO-
NtaiTl
t&IT2
N&IT1 RWSSiON
NtGill2
Electroencephalographic sleep measures were visually scored. There were no consistent changes as a function of clinical phase (baseline depressed and asymptomatic remission following psychotherapy). Individuals’ values are shown, with lines connecting nights 1 and 2; horizontal lines indicate group means. Phasic rapid eye movement [REM) activity showed a significant effect for night 1 vs. night 2 (analysis of variance: f = 25.7; df = 1, 36; p < 0.01) but no significant clinical phase or night X clinical phase interaction effects.
phase, with increased delta and decreased REM observed at remission as compared with baseline. Consistent night-to-night differences were also observed across the two clinical phases, indicating a significant “first night effect” at each time point that was larger in magnitude than any state-related changes. These results suggest that visually scored EEG sleep patterns in depression are largely persistent or “trait-like” physiological measures, at least into the early recovery phase in patients successfully treated with psychotherapy. In contrast, more sophisticated automated analyses may be more sensitive in detecting state-related changes. Previous studies of EEG sleep across clinical phases in depressed patients have usually pointed toward persistence of sleep patterns, but some controversy exists. Specifically, cross-sectional studies in remitted depressives have yielded conflicting results: Hauri et al. (1974) found prolonged sleep latency, increased Stage 1 sleep, and decreased SWS in remitted depressives compared with controls, but Knowles et al. (1986) in a study of remitted bipolar depressives, did not find significant differences from controls. Longitudinal within-subject studies (Schulz et al., 1979; Rush et al., 1986) have shown stability of most EEG sleep patterns between the depressed state and clinical remission. Although categorical REM latency remains stable, sleep-onset REM periods appear to be much less frequent during remission. One other report showed a greater degree of normalization in EEG sleep measures
37 during remission, particularly REM sleep measures (Riemann and Berger, 1989). Interpretation of these studies has been confounded by methodological problems such as cross-sectional samples, the use of medications to treat the acute episode, or a change from inpatient to outpatient status between clinical phases. Our current protocol addresses many of these methodological concerns, but yields the same general finding with respect to traditional sleep EEG measures: stability across clinical state. The current findings agree with those recently reported by Thase and Simons (1992), who also found strong correlations and no statistically significant changes in visually scored EEG sleep measures between depression and recovery following cognitive behavior therapy. In contrast to these results using traditional sleep stage scoring, automated delta and REM analyses indicated more subtle changes associated with early remission in the current sample. The strong
Table 3. Baseline-remission correlations Pearson r
Sleep variable
P value
Sleep continuity Time spent asleep
0.53
0.02
Sleep efficiency
0.31
0.20
Sleep latency
0.31
0.20
Stage 1 %
0.60
0.007
Stage 3 + 4 %
0.81
0.0001
Stage 3 + 4 min
0.80
0.0001
REM %
0.41
0.08
REM min
0.43
0.07
REM latency
0.42
0.07
REM activity
0.72
0.0005
REM density
0.24
0.32
Sleep architecture
REM measures
Automated delta measures Total counts, whole night
0.55
0.01
Total counts,
NREM 1
0.54
0.02
Total counts,
NREM 2
0.45
0.06
Average
counts/min,
whole night
0.43
0.07
Average
counts/min,
NREM 1
0.59
0.008
Average
counts/min,
NREM 2
0.44
0.06
0.49
0.03
Delta ratio
Automated REM measures Total counts, whole night
0.83
0.0001
Total counts,
REM 1
0.47
0.04
Total counts,
REM 2
0.52
0.02 0.0001
Average
counts/min,
whole night
0.79
Average
countsimin,
REM 1
0.60
0.007
Average
countsimin,
REM 2
0.76
0.0002
Nore. REM = rapid eye movement sleep. NREM = non-REM sleep
38 correlations across clinical phases, especially for automated REM measures, that the changes are consistent even though they are small in magnitude.
suggest
The possibility remains that we would begin to see more obvious state-related changes after a longer period of clinical recovery. Once again, the literature is contradictory on this point. Giles et al. (1987) described stability of categorically defined REM latency over followup periods of up to 26 months. On the other hand, a study of highly recurrent depressives revealed more REM sleep abnormalities within a few weeks of the onset of a recurrence compared with the index episode, during which patients were studied after a longer duration of illness (Kupfer et al., 1988). Ultimately, REM and non-REM sleep characteristics may be more useful in predicting longer-term outcome, such as recurrences of depression, than in providing correlates of clinical state (Kupfer et al., 1990). Longer-term followup of the current cohort will address this possibility. The night-to-night variability found in our current sample also appears to be a consistent finding across clinical phase. In this regard, the current subjects demonstrate a “first night effect” similar in magnitude, and in the same specific sleep variables, as healthy control subjects and chronic insomniacs (Agnew et al., 1966; Mendels and Hawkins, 1967; Hauri and Fisher, 1986). The only difference observed was more stable REM latency in the current patient group. Other authors have remarked on the night-to-night variability of sleep measures in symptomatic or remitted depressed patients (Hauri et al., 1974; Knowles et al., 1986). These data are also consistent with previous findings from our own laboratory, which have revealed greater adaptation effects in outpatient depressives than control subjects or inpatient depressives (Reynolds et al., 1982; Kupfer et al., 1989b). More specifically, the night-to-night variability seen in the current group of depressed outpatients occurs in most of the same sleep variables (measures of tonic and phasic REM sleep) noted by Reynolds et al. in an independent outpatient sample. Furthermore, Ansseau et al. (1985) have shown that internight variability of REM latency is associated with other EEG sleep measures as well as specific clinical characteristics, such as male gender, incapacitating illness, and bipolar II subtype. When categorized by baseline REM latency, patients with short REM latency and low delta ratios showed an increase in automated measures of delta sleep between baseline and recovery. This may merely represent a regression to the mean, which is suggested by the convergence of REM latency values for the two subgroups across clinical phases. It is also possible, however, that subgroups defined by REM latency may be distinct in a biological sense. Data examining longer-term outcome of depressed patients suggest that low REM latency and low delta ratio are associated with an increased likelihood of recurrence (Giles et al., 1987; Kupfer et al., 1990). Several caveats are in order. First, the current study does not include a healthy control group for comparison. The identification of psychiatrically healthy controls for EEG sleep studies-particularly subjects studied longitudinally-is complicated by the need to ensure not only a negative personal psychiatric history, but a negative family history as well. Sleep measures such as REM latency show familial (probably genetic) aggregation, and may be abnormal in family members of depressed patients who have no personal history of depression (Giles et al., 1989). We are currently collecting EEG sleep data on such a control group.
39
Second, the current study included outpatients with only moderately severe depression and relatively mild EEG sleep stigmata. It could be argued that patients with more severe sleep continuity disturbance and diminished SWS measures at baseline would be more likely to show state-related changes. For example, inpatient or older depressed samples might demonstrate these characteristics and show greater state-related changes. Nevertheless, the current sample is consistent with previously reported outpatient samples, both from our group and others (e.g., Rush et al., 1986; Giles et al., 1987), and we expect that our current findings will be replicable in similar future studies. The authors are grateful for the assistance of the therapists and psychiatrists who treated patients in this study: Debra Frankel, L.S.W., Nancy Lavelle, M.Ed., Gay Herrington, Ph.D., Alan G. Mallinger, M.D., and Edward S. Friedman, M.D. We also thank Cleon Cornes, M.D., for his clinical wisdom and supervision, and Sandra O’Donnell, R.N., and Jeff Dettling, M.S.W., for their managerial expertise as project coordinators. The research reported was supported in part by a grant from the John D. and Catherine T. MacArthur Foundation Research Network on the Psychobiology of Depression and by National Institute of Mental Health grant MH-30915 (D.J.K.).
Acknowledgments.
References Agnew, H.W., Jr.; Webb, W.B.; and Williams, R.L. The first night effect: An EEG study of sleep. Psychophysiology, 2:263-266, 1966. Ansseau, M.; Kupfer, D.J.; and Reynolds, C.F. III. Internight variability of REM latency in major depression: Implications for the use of REM latency as a biological correlate. Biological Psychiatry, 20:489-505, 1985. Beck, A.T.; Ward, C.H.; Mendelson, M.; Mock, J.; and Erbaugh, J. An inventory for measuring depression. Archives of General Psychiatry, 453-63, 1961. Endicott, J., and Spitzer, R.L. A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Archives of General Psychiatry, 35:837-844, 1978. Endicott, J.; Spitzer, R.L.; Fleiss, J.L.; and Cohen, J.L. The Global Assessment Scale: A procedure for measuring overall severity of psychiatric disturbance. Archives of General Psychiatry,
33:766-771, 1976.
Giles, D.E.; Kupfer, D.J.; Roffwarg, H.P.; Rush, A.J.; Biggs, M.M.; and Etzel, B.A. Polysomnographic parameters in first-degree relatives of unipolar probands. Psychiatry Research, 27:127-136, 1989.
Giles, D.E.; Rush, A.J.; Jarrett, R.B.; and Roffwarg, H.P. Reduced rapid eye movement latency: A predictor of recurrence in depression. NeuropsychopharmacoZogy, 1:33-39, 1987. Hamilton, M. A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry,
23:56-62, 1960.
Hauri, P.; Chernik, D.; Hawkins, D.; and Mendels, J. Sleep of depressed patients in remission. Archives of General Psychiatry, 31:86-391, 1974. Hauri, P., and Fisher, J. Persistent psychophysiologic (learned) insomnia. Sleep, 9:38-53, 1986. Jarrett, R.B.; Rush, A.J.; Khatami, M.; and Roffwarg, H.P. Does the pretreatment polysomnogram predict response to cognitive therapy in depressed outpatients? A preliminary report. Psychiatry Research, 33:285-299, 1990. Klerman, G.L.; Weissman, M.M.; Rounsaville, B.J.; and Chevron, E.S. Interpersonal Psychotherapy of Depression. New York: Basic Books, Inc., 1984. Knowles, J.B.; Cairns, J.; MacLean, A.W.; Delva, N.; Prowse, A.; Walsron, J.; and Letemendia, F.J. The sleep of remitted bipolar depressives: Comparison with sex- and agematched controls. Canadian Journal of Psychiatry, 3 1:295-298, 1986.
40
Kupfer, D.J., and Ehlers, C.L. Two roads to rapid eye movement latency. Archives of General Psychiatry, 46:945-948, 1989. Kupfer, D.J.; Ehlers, C.L.; Pollock, B.C.; Nathan, R.S.; and Perel, J.M. Clomipramine and EEG sleep in depression. Psychiatry Research, 30:165-180, 1989a. Kupfer, D.J.; Frank, E.; and Ehlers, C.L. EEG sleep in young depressives: First and second night effects. Biological Psychiatry, 25:87-97, 19896. Kupfer, D.J.; Frank, E.; Grochocinski, V.J.; Gregor, M.; and McEachran, A.B. Electroencephalographic sleep profiles in recurrent depression: A longitudinal investigation. Archives of General Psychiatry, 45:678-681, 1988. Kupfer, D.J.; Frank, E.; McEachran, A.B.; and Grochocinski, V.J. Delta sleep ratio: A biological correlate of early recurrence in unipolar affective disorder. Archives of General Psychiatry, 47:1100-l 105, 1990. Kupfer, D.J.; Ulrich, R.F.; Coble, P.A.; Jarrett, D.B.; Grochocinski, V.J.; Doman, J.; Matthews, G.; and BorbCly, A.A. Application of automated REM and slow wave sleep analysis: I. Normal and depressed subjects. Psychiatry Research, 14:325-334, 1984. Mendels, J., and Hawkins, D.R. Sleep laboratory adaptation in normal subjects and depressed patients (“first night effect”). Electroencephalography and Clinical Neurophysiology, 22556-558, 1967. Raskin, A.; Schulterbrandt, J.; Reatig, N.; and McKeon, J.J. Replication of factors of psychopathology in interviewing, ward behavior and self-report ratings of hospitalized depressives. Journal of Nervous and Mental Disease, 148:87-98, 1969. Rechtschaffen, A., and Kales, A. A Manual of Standardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects. (PHS Publication) Washington, DC: Superintendent of Documents, U.S. Government Printing Office, 1968. Reynolds, C.F. III; Hoch, C.C.; Buysse, D.J.; George, C.J.; Houck, P.R.; Mazumdar, S.; Miller, M.; Pollock, B.C.; Rifai, H.; Frank, E.; Cornes, C.; Morycz, R.K.; and Kupfer, D.J. Sleep in late-life recurrent depression: Changes during early continuation therapy with nortriptyline. Neuropsychopharmacology, 5:85-96, 1991. Reynolds, C.F. III; Newton, T.F.; Shaw, D.H.; Coble, P.A.; and Kupfer, D.J. Electroencephalographic sleep findings in depressed outpatients. Psychiatry Research, 6:6575, 1982. Riemann, D., and Berger, M. EEG sleep in depression and in remission and the REM sleep response to the cholinergic agonist RS 86. Neuropsychopharmacoiogy, 2:145-152, 1989. Rush, A.J.; Erman, M.K.; Giles, D.E.; Schlesser, M.A.; Carpenter, G.; Vasavada, N.; and Roffwarg, H.P. Polysomnographic findings in recently drug-free and clinically remitted depressed patients. Archives of General Psychiatry, 43:878-884, 1986. Rush, A.J.; Giles, D.E.; Jarrett, R.B.; Feldman-Koffler, F.; Debus, J.R.; Weissenburger, J.; Orsulak, P.J.; and Roffwarg, H.P. Reduced REM latency predicts response to tricyclic medication in depressed outpatients. Biological Psychiatry, 26161-72, 1989. Schulz, H.; Lund, R.; Cording, C.; and Dirlich, G. Bimodal distribution of REM sleep latencies in depression. Biological Psychiatry, 14:595-600, 1979. Spitzer, R.L.; Endicott, J.; and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 351773-782, 1978. Thase, M.E., and Simons, A.D. The applied use of psychotherapy to study the psychobiology of depression. Journal of Psychotherapy Practice and Research, in press.
Psychiatry Research, 40~2740 Elsevier
Electroencepkalographic Sleep Studies in Depressed Outpatients Treated With Interpersonal Psychotherapy: II. Longitudinal Studies at Baseline and Recovery Daniel J. Buysse, David J. Kupfer, Ellen Frank, Timothy Angela Ritenour Received September February 9, 1992.
30, 1991; revised
version
received
H. Monk, and
January
29, 1992; accepted
Abstract. Electroencephalographic (EEG) sleep studies may help to identify persistent versus episodic biological characteristics of major depressive disorder. This report examines longitudinal EEG sleep studies in depressed patients treated with psychotherapy alone. Nineteen patients were studied during a symptomatic baseline period and again during early remission after treatment with interpersonal psychotherapy (IPT). EEG sleep findings at baseline were not markedly abnormal, but they were similar to those in other published studies of young adult outpatients. No changes were found in visually scored EEG sleep measures between depression and early remission. Automated measures of delta sleep and rapid eye movement (REM) activity showed small state-related changes, with delta activity increasing from baseline to remission, and automated REM measures decreasing. Strong baseline-remission correlations were noted for most sleep measures, including slow wave sleep, phasic REM activity, and automated delta EEG counts; measures of sleep continuity and tonic REM sleep were not strongly correlated. Consistent adaptation effects across nights were observed for sleep continuity and REM measures during each clinical phase. These findings support the hypothesis that most visually scored EEG sleep measures, as well as the sleep adaptation process, are stable through the acute episode of depression, at least into early symptomatic remission. They also suggest that finer-grained automated analyses of delta and REM activity may provide more sensitive tools for examining state-related changes. Key Words.
Affective
disorders,
polysomnography,
psychotherapy,
remission.
Electroencephalographic (EEG) sleep studies have been used to examine several aspects of the neurobiology of depression, including questions of episodic (state-like) versus persistent (trait-like) physiological characteristics and the prediction of treatment response. To date, very few studies have addressed these issues in depressed patients treated with psychotherapy alone. Such studies are desirable because they examine sleep physiology in the absence of the confounding effects of antidepressant medications. In the accompanying article, we compared the baseline
Daniel J. Buysse, M.D., is Assistant Professor of Psychiatry; David J. Kupfer, M.D., is Professor and Chairman; Ellen Frank, Ph.D., is Associate Professor of Psychology and Psychiatry; Timothy H. Monk, Ph.D., is Associate Professor of Psychiatry; and Angela Ritenour, B.A., is Research Associate, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA. (Reprint requests to Dr. D.J. Buysse, WPIC, 3811 O’Hara St., Pittsburgh, PA 15213, USA.) 0165-1781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd
28
EEG sleep findings of depressed patients who responded to psychotherapy with those of a comparable group of depressed patients who did not respond to psychotherapy. In this report, we address the question of whether EEG sleep patterns during an episode of depression are stable into early symptomatic remission in psychotherapeutically treated patients. Previous EEG sleep studies have examined the issue of episodic versus persistent EEG sleep characteristics. Some of these studies (Hauri et al., 1974; Knowles et al., 1986) were cross-sectional, comparing the sleep of recovered depressives to that of healthy control subjects. Several longitudinal within-subject studies have also been reported, but they have used both psychotherapeutic and psychopharmacological treatments, with studies during recovery being preceded by medication discontinuation (Schulz et al., 1979; Rush et al., 1986; Giles et al., 1987). In general, both cross-sectional and longitudinal studies have demonstrated that most EEG sleep measures are relatively stable between the depressive episode and drug-free remission. There is some evidence that rapid eye movement (REM) sleep measures may show a greater degree of “normalization” during recovery (Kupfer et al., 1988; Riemann and Berger, 1989). However, it remains possible that medication withdrawal effects or medication effects on neurotransmission may have affected EEG sleep patterns in the recovery phase of these investigations. One recent study has examined EEG sleep measures at baseline and recovery in depressed patients treated with cognitive-behavioral psychotherapy (Thase and Simons, 1992). There were no significant changes in visually scored EEG sleep measures between depression and recovery in this study. Other types of EEG sleep analysis, such as automated period analysis or power spectral analysis, were not reported. Kupfer and Ehlers (1989) have conceptualized the EEG sleep patterns of depressed patients as including both episodic, state-related features (primarily in REM sleep) and persistent features that may be present during recovery as well (primarily in slow wave sleep [SWS]). In the current study, we hypothesized that tonic and phasic REM sleep measures would be elevated during the acute episode compared with recovery, while sleep continuity and SWS measures would not change between the two clinical phases in depressed patients treated with psychotherapy. On the basis of previous work with younger depressed outpatients (Kupfer et al., 19896) we also hypothesized that we would observe adaptation effects during two consecutive nights in the sleep laboratory.
Methods Patients (Table 1). Patients were 16 women and 3 men between the ages of 18 and 50 (mean = 32.3, SD = 7.2 years) who were evaluated and treated as outpatients. Details of patient selection are presented in Part I of this report and are summarized briefly here. This group of psychotherapy responders is identical to one of the groups described in Part 1. Inclusion criteria included the presence of a definite current episode of major depressive disorder, definite or probable endogenous subtype, according to the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer, 1978) and Research Diagnostic Criteria (RDC; Spitzer et al., 1978); at least two previous lifetime episodes, with the most recent prior episode occurring within the previous 2% years; and a period of symptomatic remission lasting at least
29
Table 1. Demographic and clinical data Descriptor Sex (males/females)
3116
Age (yrl Mean
32.3 7.2
SD Age at first episode (yr)
23.3
Mean
7.6
SD No. of previous episodes
3.7
Mean SD
1.2
Median
4
Duration of index episode (wk) 22.9
Mean
16.2
SD Duration of acute treatment phase (wk) Mean
15.9
SD
10.4
Median
14
Ranae
2-41’
Baseline
Remission
Mean
SD
19.6 8.9
GAS BDI
HRSD (17 item) score Raskin depression
rating
Mean
SD
4.0
4.1
2.4
1.8
4.5
1 .l
56.7
5.2
80.8
7.0
21 .o
6.3
6.0
4.3
Note. HRSD = Hamilton Rating Scale for Depression. GAS = Global Assessment Inventory. 1. Sleep studies dunng remission were conducted regardless of symptom severity.
Scale. BDI = Beck Depression
after a mlmmum of 12 weeks in the acute treatment
phase,
10 weeks between the index episode and the preceding episode. Patients with other RDC diagnoses in the previous 2% years, with the exception of hypomania, were excluded. Three patients were diagnosed as having definite, and one as having probable, bipolar II disorder. All patients met the minimum severity criterion of a score 3 15 on the 17-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). Patients with serious or progressive medical illness were excluded on the basis of medical history, physical examination, and laboratory studies. Patients habitually taking medications with known effects on EEG sleep were also excluded. Patients were also instructed not to use any alcohol or prescription or nonprescription medications before sleep studies. A review of actual histories indicates that six patients used some alcohol in the 2 weeks before sleep studies at baseline, with the maximum consumption being four drinks in the past 2 weeks. Nine patients used alcohol during the 2 weeks before sleep studies in the period of remission, with a maximum of five drinks in one patient. One patient was taking fluoxetine when recruited into the study; the last dose was taken 14 days before baseline sleep studies. Treatment successfully
Procedures and Definition treated with psychotherapy
of Response. alone and did
All patients not receive
in this report were any antidepressant
30 medication. The specific form of therapy was interpersonal psychotherapy (IPT; Klerman et al., 1984). Therapists were all master’s or doctoral level clinicians, who were trained and supervised by a certified IPT trainer (Cleon L. Cornes, M.D.). Sessions were initially scheduled twice weekly, then weekly for the remainder of the 12- to 20-week acute treatment period. Once a patient met criteria for remission (see below), IPT sessions were discontinued, although patients continued to meet on a monthly basis with their therapist in a supportive context. In the event of partial response, patients were allowed to continue in weekly IPT sessions for longer than 20 weeks. During acute treatment, clinical status was monitored weekly with the HRSD, Beck Depression Inventory (Beck et al., 1961), Raskin Severity of Depression Scale (Raskin et al., 1969), and Global Assessment Scale (Endicott et al., 1976). Remission was defined as 4 consecutive weeks with an HRSD score < 7, Raskin depression rating < 5, and not meeting RDC for current depressive episode. The patients described here were not part of a treatment study per se, but rather, part of a study designed to examine biological and social/activity rhythms in remitted depressives. Since our goal was to achieve symptomatic remission, the duration of acute treatment with IPT was not rigidly defined. Mean duration of IPT treatment until symptomatic remission was 15.9 (SD = 10.4) weeks (Table 1). Repeat biological studies were scheduled to occur as soon as possible after patients met criteria for remission, but with a minimum acute treatment duration of 12 weeks. EEG Sleep Studies. Two consecutive nights of EEG sleep studies were conducted during the acute episode (baseline), and again following remission. Sleep studies included one channel of EEG recording (C3 or C4, referenced to Al-A2), bilateral electro-oculograms (EOG; referenced to Al-A2), and bipolar submental electromyogram (EMG). High and low frequency filter settings were 30 Hz and 0.3 Hz, respectively, for EEG and EOG, and 90 Hz and 10 Hz for EMG. Paper speed was 10 mm/set, and sensitivity on the EEG channel was 5 flV/mm. EEG sleep records were scored in 60-second epochs using standard criteria (Rechtschaffen and Kales, 1968) by polysomnographic technologists without knowledge of the patient’s clinical state. Sleep onset was defined as the first of 10 consecutive minutes of Stage 2 or deeper non-REM sleep, interrupted by no more than 2 minutes of Stage 1 or wakefulness. REM latency was defined as the interval between sleep onset and REM period 1 with > 3 consecutive minutes of REM sleep. In addition, technicians scored phasic REM activity by estimating the amount of eye movement activity on a I- to 8-point scale for each minute of sleep. Sleep stage scoring reliability is maintained at > 85% for major sleep variables through the use of monthly reliability checks. Each night of sleep studies was also subjected to automated delta and REM sleep analysis, as described in previous publications (Kupfer et al., 1984). These techniques provide another measure of the number of slow frequency EEG waves and phasic eye movements. Sleep times were determined by each patient’s current sleep-wake schedule. During the baseline phase, patients estimated their habitual sleep-wake times, and followed these times in the laboratory. Before studies in the remission phase, patients kept a 2-week sleep-wake diary, from which habitual sleep-wake times were again calculated. At the time of EEG sleep studies, patients also had lo-minute blood samples for determination of melatonin values and core body temperature measurements via flexible rectal thermistor. Findings from these studies will be presented in subsequent reports. Blood sampling started at 5 p.m. and ended 30 minutes before patients’ bedtimes; the intravenous catheter was removed before sleep studies. Core body temperature measurements continued through the night of EEG sleep recordings. Statistical Analyses. Differences in clinical rating scale data from the acute episode to remission were assessed with paired t tests. Major domains of EEG sleep measures at baseline and remission were compared with a repeated-measures multivariate analysis of variance (MANOVA), using individual sleep study nights (night 1 and night 2) and clinical phase (baseline acute episode vs. remission) as repeated-measure factors. Sleep domains were sleep
31 continuity, sleep architecture, REM sleep, automated delta measures, and automated REM sleep measures. MANOVA was used as the major statistical technique to reduce the number of statistical comparisons between correlated sleep measures. Table 2 also reports individual values from analysis of variance (ANOVA) to facilitate comparisons of specific sleep measures. If one were to consider only ANOVA results, a Bonferroni-corrected p value of 0.002 would be considered statistically significant. As an additional measure of baselineremission stability in sleep measures, we performed Pearson correlations on baseline and remission sleep values, using the mean of nights 1 and 2 at each time point.
Results As would be predicted from the selection and remission criteria, patients demonstrated clinically significant differences on all depression rating scales between the baseline and remission (Table 1). The mean duration of acute treatment was 15.9 weeks (median = 14, range = 2-41), and the mean HRSD score was reduced from 19.6 at baseline to 4.1 at recovery. Baseline EEG sleep measures during the depressive episode were not markedly abnormal, especially compared with values seen in inpatient or older depressive samples (cf. Kupfer et al., 1989~1; Reynolds et al., 1991). However, values for most variables, including REM latency, sleep efficiency, and REM %, were very similar to those reported in recent studies of younger depressed outpatients (cf. Kupfer et al., 19896; Rush et al., 1989; Jarrett et al., 1990). There were no statistically significant effects of clinical phase (baseline depressed vs. remission) on any visually scored EEG sleep measure, including sleep continuity factors, sleep architecture, or REM variables (Fig. 1; Table 2). Automated delta analyses showed a significant clinical phase effect (MANOVA: F= 2.54; df = 7,26; p = 0.04), representing small increases in delta activity between baseline and remission. None of the individual univariate ANOVAs for automated delta measures showed significant clinical phase effects. Automated REM measures also showed significant clinical phase effects (MANOVA: F = 2.33; df = 7, 27; p = 0.05), indicating reductions in REM activity from baseline to remission. Again, these findings were small in magnitude, with none of the univariate ANOVAs for REM measures showing significant changes as a function of clinical phase. Significant night I-night 2 differences were observed within all sleep domains except automated delta sleep measures (Table 2). Within the domain of sleep continuity, night 2 sleep was characterized by longer sleep duration (ANOVA: F= 10.31; df = 1,36;p = 0.003) and improved sleep efficiency (ANOVA: F= 13.68; df = 1, 36; p = 0.0007). Night 2 sleep was also characterized by lower Stage 1 % (ANOVA: F = 4.72; df = 1,36; p = 0.04) and increased REM sleep, both in absolute minutes (Fig. 2) (ANOVA: F = 20.67; df = 1, 36; p = 0.0001) and % REM sleep (ANOVA F = 10.92; df = 1, 36; p = 0.002). Visually scored phasic REM activity and REM density were higher on night 2 than on night 1 (Fig. 3) (ANOVA: F = 25.69; df = 1, 36; p = 0.0001, and F = 6.22; df = 1, 36; p = 0.02). These changes were mirrored by automated REM analyses, which showed higher total REM counts for the entire night (ANOVA: F = 20.51; df = 1, 34; p = O.OOOl), and for the first (ANOVA: F = 11.02; df = 1,33; p = 0.002) and second (ANOVA: F = 7.06; df = 1, 33; p = 0.01) REM periods of the night.
32
Table 2. Baseline and remission sleep measures (n = 19)
Baseline
Remission Night 2
Night 1 Variable
Night 1
Night 2
Mean
SD
Mean
SD
Mean
SD
Mean
SD
405.1
59.3
422.0
38.2
392.1
63.1
428.5
60.8
90.7
6.7
94.1
3.7
89.2
7.1
93.0
6.1
20.7
18.1
13.7
7.1
25.2
25.2
19.9
18.9
Sleep continuity Time spent asleep (min) Sleep efficiency Sleep latency
(min)2
Sleep architecture % Stage 1’
4.1
3.6
2.8
2.3
3.7
3.0
3.1
2.1
% Stage 3 + 4’
13.3
8.6
11.4
7.6
10.6
8.4
10.5
7.1 29.2
Stage 3 + 4 (min)
54.1
33.3
47.8
31.6
41.4
31.1
45.1
% REM
24.3
6.4
28.0
3.9
23.8
6.3
26.4
3.5
REM (min)’
99.0
29.4
118.1
19.7
93.6
27.5
112.8
20.3
61.3
20.01
68.6
21.4
68.3
21.4
61.3
13.4
145.6
75.7
173.6
70.7
125.4
69.9
173.9
84.7
REM measures REM latency
(min)’
REM activity’
1.01
REM density
0.38
1.21
0.51
0.84
1.07
0.34
0.49
Automated Delta 7814
3688
7163
2927
7696
3812
8117
4966
Total-NREM
11
2648
1603
2626
1531
2824
1672
2600
1344
Total-NREM
2’
2270
1011
2100
1225
2253
1258
2483
1837
Total-whole
night2
Average-whole
night’
25.3
10.8
23.9
10.0
26.8
13.8
25.8
14.5
Average-NREM
1’
40.5
19.8
37.2
13.8
42.5
20.4
41.2
18.6
Average-NREM
2’
31.7
13.3
29.6
15.5
30.0
16.5
31 .o
20.7
1.38
Delta ratio3 Automated
0.76
1.49
0.80
1.72
1.12
1.63
0.79
REM
Total-whole
night2
552
385
721
401
551
403
690
547
Total-REM
1i
54.2
48.7
117.9
95.3
48.1
43.4
97.4
148.5
Total-REM
2’
84.4
82.8
154.6
117.3
158.3
156.4
172.5
157.5
5.5
2.9
6.2
3.3
5.5
3.3
5.9
3.9
Average-REM
1’
3.4
2.4
5.4
3.7
2.9
2.3
4.0
3.9
Average-REM
2’
4.6
3.0
6.2
4.9
5.7
4.9
6.0
5.3
0.91
0.61
1.11
0.73
0.88
1.04
0.75
0.53
Average-whole
REM ratio3 Note. MANOVA
night’
= multivariate analysis of variance. ANOVA = analysis of variance. REM = rapid eye movement
1. Square root transformation performed on data before analysis. Mean values presented in original units. 2. Log transformation (LN [var + I]) performed on data before analysis. Mean values presented in original units. 3. Log transformation (LN [var + 0.11) performed on data before analysis. Mean values presented in original units.
33
MANOVA and ANOVA Clinical phase X night interaction effect
Night effect
Clinical phase effect F
df
P
F
df
P
0.87
4.80
0.84
10.31
3.34
0.01
0.82
3,34
0.49
1,36
0.003
1.40
1,36
1,36
0.45
0.24
13.68
1,36
0.0007
0.02
1,36
0.52
1,36
0.88
0.48
2.66
1,36
0.11
0.08
1.36
0.78
0.30 0.04
5, 32
0.91
4.59
5,32
0.003
1.40
5,32
0.25
1,36
0.85
4.72
1,36
0.04
1.13
1,36
0.29
0.63
1,36
0.43
0.22
1,36
0.64
0.81
1,36
0.38
0.65
1,36
0.42
0.13
1,36
0.72
1.89
1,36
0.18
0.53
1,36
0.47
10.92
1,36
0.002
0.28
1,36
0.60
0.56
1,36
0.46
20.67
1,36
0.0001
0.00
1,36
0.94
0.85
3,34
0.48
8.37
3, 34
0.0003
1.32
1,36
0.85
0.06
1,36
0.81
2.70
3, 34 1,36
0.29
0.04 0.28
1.36
0.60
25.69
1,36
0.0001
1.46
1,36
0.23
1.87
1,36
0.18
6.22
1,36
0.02
0.02
1,36
0.90
2.54
7,26
0.04
0.78
7,26
0.82
0.37
7, 26
0.91
0.00
1,33
0.97
0.05
1,33
0.82
0.61
1,33
0.44
0.00
1,32
0.96
0.01
1,32
0.92
0.69
1,32
0.41
0.01
1,33
0.91
0.00
1,33
0.96
1.32
1,33
0.26
0.06
1,33
0.81
1.13
1,33
0.30
0.21
1,33
0.65
0.08
1,32
0.78
0.01
1,32
0.93
0.12
1,32
0.74
0.06
1,33
0.81
0.25
1,33
0.62
1.67
1.33
0.20
0.85
1,32
0.36
0.55
1,32
0.47
0.72
1,32
0.40
2.33
7,27
0.05
8.57
7, 27
0.0001
0.82
7,27
0.74
F
df
P
0.23
3, 34
0.04
1,36
0.58
0.11
0.13
1,34
0.72
20.51
1,34
0.0001
0.01
1,34
0.92
0.57
1,33
0.45
11.02
1,33
0.002
0.20
1,33
0.66
1.49
1.33
0.23
7.06
1,33
0.01
1.24
1,33
0.27
0.01
1.34
0.92
2.47
1,34
0.13
0.04
0.84
1.17
1,33
0.29
6.38
1,33
0.02
0.48
I,34 1,33
0.26
1,33
0.62
2.39
1,33
0.13
0.15
1,33
0.70
3.79
1,33
0.06
0.81
1,33
0.37
0.58
1,33
0.45
sleep. NREM = non-REM sleep
0.49
34
Fig. 1. REM latency measures from 2 consecutive nights in 19 depressed patients
NlGHll
NKnT2
NiGHTl
NIGHT 2
RR(tSSlON Electroencephalographic sleep measures were visually scored. There were no consistent changes as a function of clinical phase (baseline depressed and asymptomatic remission following psychotherapy). Individuals’ values are shown, with lines connecting nights 1 and 2; horizontal lines indicate group means. Analysis of variance latency showed no significant rapid eye movement latency (REM) effects for night 1 vs. night 2, clinical phase (baseline vs. remission), or night X clinical phase interaction.
Night l-night 2 differences appeared stable across clinical phases. This stability is indicated by the absence of significant clinical phase X sleep night interaction effects (Table 2). Although mean values for most sleep measures showed stability from baseline to recovery, it is also important to determine whether values for individual subjects were consistent across clinical phase. Pearson correlations between baseline and remission (with mean values from nights 1 and 2) were statistically significant (p < 0.05) for 15/25 variables (Table 3). Measures that were most strongly correlated included visually scored slow wave sleep, and both visually scored and automated measures of phasic REM activity. Sleep continuity measures, visually scored REM sleep, and REM latency were less strongly correlated across time. Categorical REM latency values often are used to contrast biological subgroups of depressed patients, and such distinctions might be expected to produce differential patterns of change from baseline to recovery. Therefore, we conducted an additional exploratory analysis that compared EEG sleep measures of patients with baseline REM latency < 60 minutes (n = 10) to sleep EEG measures of those with baseline REM latency > 60 minutes (n = 9). For this analysis, we used mean values from nights 1 and 2 at baseline and remission study points, An ANOVA was performed with subgroups (defined by REM latency) and clinical phase as factors. Aside from REM latency, only delta ratio (ratio of average delta counts in non-REM period 1 to
35
Fig. 2. REM sleet times from 2 consecutive nights in 19 depressed patients
NIGHT1
N&r2
NIGHT1
NtGHl2
RDIISSK)N Electroencephalographic sleep measures were visually scored. There were no consistent changes as a function of clinical phase (baseline depressed and asymptomatic remission following psychotherapy). Individuals’ values are shown, with lines connecting nights 1 and 2; horizontal lines indicate group means. Rapid eye movement (REM) sleep time (min) showed a significant effect for night 1 vs. night 2 [analysis of variance: f = 20.67; of= 1,36; p < 0.01) but no significant clinical phase or night X clinical phase interaction effects.
average delta counts in non-REM period 2) differed between the groups; the low REM latency group had a smaller delta ratio than the high REM latency group (mean across clinical phases for the low REM latency group = 1.14; mean across clinical phases for the high REM latency group = 1.98; F = 12.87; df = 1, 17; p < 0.001). Significant group X clinical phase interaction effects were noted for REM latency (F= 16.8; df = I, 17; p < 0.001) and automated delta sleep counts for the whole night (F= 4.89; df= 1, 17;~ x0.04) and for non-REM period 1 (F= 8.16; df = 1, 17; p = 0.01). In each case, mean values for the short and long REM latency subgroups moved toward each other across clinical phases. More specifically, the short REM latency group showed an increase in delta counts between baseline and recovery, and the long REM latency group showed a decrease.
Discussion The EEG sleep patterns of depressed patients successfully treated with interpersonal psychotherapy did not show any significant overall changes between the time of acute depression and clinical remission on the basis of traditional visual scoring methods. Contrary to expectations, stability was noted for REM sleep measures as well as for sleep continuity and non-REM measures. Automated measures of delta sleep and REM activity showed small but consistent changes related to clinical
36
Fig. 3. Phasic REM activity measures from 2 consecutive depressed patients 400‘.
nights in 19
SOSOO-
E =: 4 =Y H
l50-
_-
-_ -_ -_
lOOSOO-
NtaiTl
t&IT2
N&IT1 RWSSiON
NtGill2
Electroencephalographic sleep measures were visually scored. There were no consistent changes as a function of clinical phase (baseline depressed and asymptomatic remission following psychotherapy). Individuals’ values are shown, with lines connecting nights 1 and 2; horizontal lines indicate group means. Phasic rapid eye movement [REM) activity showed a significant effect for night 1 vs. night 2 (analysis of variance: f = 25.7; df = 1, 36; p < 0.01) but no significant clinical phase or night X clinical phase interaction effects.
phase, with increased delta and decreased REM observed at remission as compared with baseline. Consistent night-to-night differences were also observed across the two clinical phases, indicating a significant “first night effect” at each time point that was larger in magnitude than any state-related changes. These results suggest that visually scored EEG sleep patterns in depression are largely persistent or “trait-like” physiological measures, at least into the early recovery phase in patients successfully treated with psychotherapy. In contrast, more sophisticated automated analyses may be more sensitive in detecting state-related changes. Previous studies of EEG sleep across clinical phases in depressed patients have usually pointed toward persistence of sleep patterns, but some controversy exists. Specifically, cross-sectional studies in remitted depressives have yielded conflicting results: Hauri et al. (1974) found prolonged sleep latency, increased Stage 1 sleep, and decreased SWS in remitted depressives compared with controls, but Knowles et al. (1986) in a study of remitted bipolar depressives, did not find significant differences from controls. Longitudinal within-subject studies (Schulz et al., 1979; Rush et al., 1986) have shown stability of most EEG sleep patterns between the depressed state and clinical remission. Although categorical REM latency remains stable, sleep-onset REM periods appear to be much less frequent during remission. One other report showed a greater degree of normalization in EEG sleep measures
37 during remission, particularly REM sleep measures (Riemann and Berger, 1989). Interpretation of these studies has been confounded by methodological problems such as cross-sectional samples, the use of medications to treat the acute episode, or a change from inpatient to outpatient status between clinical phases. Our current protocol addresses many of these methodological concerns, but yields the same general finding with respect to traditional sleep EEG measures: stability across clinical state. The current findings agree with those recently reported by Thase and Simons (1992), who also found strong correlations and no statistically significant changes in visually scored EEG sleep measures between depression and recovery following cognitive behavior therapy. In contrast to these results using traditional sleep stage scoring, automated delta and REM analyses indicated more subtle changes associated with early remission in the current sample. The strong
Table 3. Baseline-remission correlations Pearson r
Sleep variable
P value
Sleep continuity Time spent asleep
0.53
0.02
Sleep efficiency
0.31
0.20
Sleep latency
0.31
0.20
Stage 1 %
0.60
0.007
Stage 3 + 4 %
0.81
0.0001
Stage 3 + 4 min
0.80
0.0001
REM %
0.41
0.08
REM min
0.43
0.07
REM latency
0.42
0.07
REM activity
0.72
0.0005
REM density
0.24
0.32
Sleep architecture
REM measures
Automated delta measures Total counts, whole night
0.55
0.01
Total counts,
NREM 1
0.54
0.02
Total counts,
NREM 2
0.45
0.06
Average
counts/min,
whole night
0.43
0.07
Average
counts/min,
NREM 1
0.59
0.008
Average
counts/min,
NREM 2
0.44
0.06
0.49
0.03
Delta ratio
Automated REM measures Total counts, whole night
0.83
0.0001
Total counts,
REM 1
0.47
0.04
Total counts,
REM 2
0.52
0.02 0.0001
Average
counts/min,
whole night
0.79
Average
countsimin,
REM 1
0.60
0.007
Average
countsimin,
REM 2
0.76
0.0002
Nore. REM = rapid eye movement sleep. NREM = non-REM sleep
38 correlations across clinical phases, especially for automated REM measures, that the changes are consistent even though they are small in magnitude.
suggest
The possibility remains that we would begin to see more obvious state-related changes after a longer period of clinical recovery. Once again, the literature is contradictory on this point. Giles et al. (1987) described stability of categorically defined REM latency over followup periods of up to 26 months. On the other hand, a study of highly recurrent depressives revealed more REM sleep abnormalities within a few weeks of the onset of a recurrence compared with the index episode, during which patients were studied after a longer duration of illness (Kupfer et al., 1988). Ultimately, REM and non-REM sleep characteristics may be more useful in predicting longer-term outcome, such as recurrences of depression, than in providing correlates of clinical state (Kupfer et al., 1990). Longer-term followup of the current cohort will address this possibility. The night-to-night variability found in our current sample also appears to be a consistent finding across clinical phase. In this regard, the current subjects demonstrate a “first night effect” similar in magnitude, and in the same specific sleep variables, as healthy control subjects and chronic insomniacs (Agnew et al., 1966; Mendels and Hawkins, 1967; Hauri and Fisher, 1986). The only difference observed was more stable REM latency in the current patient group. Other authors have remarked on the night-to-night variability of sleep measures in symptomatic or remitted depressed patients (Hauri et al., 1974; Knowles et al., 1986). These data are also consistent with previous findings from our own laboratory, which have revealed greater adaptation effects in outpatient depressives than control subjects or inpatient depressives (Reynolds et al., 1982; Kupfer et al., 1989b). More specifically, the night-to-night variability seen in the current group of depressed outpatients occurs in most of the same sleep variables (measures of tonic and phasic REM sleep) noted by Reynolds et al. in an independent outpatient sample. Furthermore, Ansseau et al. (1985) have shown that internight variability of REM latency is associated with other EEG sleep measures as well as specific clinical characteristics, such as male gender, incapacitating illness, and bipolar II subtype. When categorized by baseline REM latency, patients with short REM latency and low delta ratios showed an increase in automated measures of delta sleep between baseline and recovery. This may merely represent a regression to the mean, which is suggested by the convergence of REM latency values for the two subgroups across clinical phases. It is also possible, however, that subgroups defined by REM latency may be distinct in a biological sense. Data examining longer-term outcome of depressed patients suggest that low REM latency and low delta ratio are associated with an increased likelihood of recurrence (Giles et al., 1987; Kupfer et al., 1990). Several caveats are in order. First, the current study does not include a healthy control group for comparison. The identification of psychiatrically healthy controls for EEG sleep studies-particularly subjects studied longitudinally-is complicated by the need to ensure not only a negative personal psychiatric history, but a negative family history as well. Sleep measures such as REM latency show familial (probably genetic) aggregation, and may be abnormal in family members of depressed patients who have no personal history of depression (Giles et al., 1989). We are currently collecting EEG sleep data on such a control group.
39
Second, the current study included outpatients with only moderately severe depression and relatively mild EEG sleep stigmata. It could be argued that patients with more severe sleep continuity disturbance and diminished SWS measures at baseline would be more likely to show state-related changes. For example, inpatient or older depressed samples might demonstrate these characteristics and show greater state-related changes. Nevertheless, the current sample is consistent with previously reported outpatient samples, both from our group and others (e.g., Rush et al., 1986; Giles et al., 1987), and we expect that our current findings will be replicable in similar future studies. The authors are grateful for the assistance of the therapists and psychiatrists who treated patients in this study: Debra Frankel, L.S.W., Nancy Lavelle, M.Ed., Gay Herrington, Ph.D., Alan G. Mallinger, M.D., and Edward S. Friedman, M.D. We also thank Cleon Cornes, M.D., for his clinical wisdom and supervision, and Sandra O’Donnell, R.N., and Jeff Dettling, M.S.W., for their managerial expertise as project coordinators. The research reported was supported in part by a grant from the John D. and Catherine T. MacArthur Foundation Research Network on the Psychobiology of Depression and by National Institute of Mental Health grant MH-30915 (D.J.K.).
Acknowledgments.
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