Sleep EEG recordings in generalized anxiety disorder with significant depression

Journal of Affective Disorders. 15 (1988) 113-118 Elsevier

113

J A D 00556

Sleep EEG recordings in generalized anxiety disorder with significant depression G.N. Papadimitriou

~, P. L i n k o w s k i 2, M . K e r k h o f s 2, C. K e m p e n a e r s a n d J. M e n d l e w i c z 2

/ Department of Psychiatry, Athens University, Athens, Greece and 2 Department of Psvchiat(v, Universi(v Clinics of Brussels', Erasme Hospital, Brussels, Belgium (Received 5 August 1987) (Revision received 15 February 1988) (Accepted 1 March 1988)

Summary After one accommodation night, sleep EEG recordings were performed during three consecutive nights in ten drug-free inpatients presenting generalized anxiety disorder (GAD) with significant depression, compared with a age- and sex-matched group of patients with G A D and a group of primary major depressive disorder (MDD) patients. GAD patients with depression did not differ from G A D patients in any sleep variable. Patients with MDD showed more stage shifts and a greater number of awakenings than patients with GAD. REM latency was significantly shorter in M D D patients than in the other groups, and may thus help to differentiate anxious from depressed patients.

Key words: Generalized anxiety; Major depression; Sleep EEG measures; REM sleep

Introduction Sleep studies in patients with various anxiety disorders have shown disturbances in sleep continuity, sleep architecture and REM sleep. Panic disorder patients present a shorter REM latency, less REM density, increased movement time and longer sleep latency compared to normals (Uhde

Address for correspondence: J. Mendlewicz, M.D., Ph.D.. Professor and Head, Department of Psychiatry, Free University of Brussels, Erasme Hospital, 808 route de Lennik, 1070 Brussels, Belgium.

et al., 1984; Dub6 et al., 1986). Compared to patients with major depressive disorder (MDD), panic disorder patients demonstrate a longer REM latency and lower REM percentage (Dub6 et al., 1986). Reynolds et al. (1983) have found a higher stage 2 and lower REM percentage, longer REM latency and less REM activity in patients with generalized anxiety disorder (GAD) compared to MDD. In comparison with normal subjects, patients with primary obsessive-compulsive disorder have less total sleep time, with more awakenings and a shorter REM latency, but they have similar REM latency values compared to M D D patients (Insel

0165-0327/88/$03.50 '~' 1988 Elsevier Science Publishers B.V. (Biomedical Division)

114 et al., 1982). Anxious patients have difficulties in initiating and maintaining sleep (Roffwarg, 1979). Shorter REM latency in M D D patients has received a lot of attention (Kupfer, 1976) and may be related to the pathophysiology of depression, although the specificity of this marker has recently been debated (for instance: Insel et al., 1982; Uhde et al., 1984; Zarcone et al., 1987). Furthermore, some anxious patients may present with significant depressive symptoms and should be investigated separately from major depressives as well as 'pure' anxiety syndromes. The aim of the present study was thus to compare sleep EEG recordings in G A D patients with significant depression to the patterns observed in G A D (without significant depression or other anxiety disorder) and those of primary M D D patients, in order to investigate possible biological indices in this separate group of patients in the Research Diagnostic Criteria (RDC, Spitzer et al., 1978). Methods

Ten patients (six males and four females, mean age 33.0 _+ 10.5 years) presenting G A D with significant depression according to RDC were compared with an age- and sex-matched group of patients with G A D and a group of primary unipolar M D D patients, endogenous type. The Schedule for Affective Disorders and Schizophrenia (SADS, Endicott and Spitzer, 1978) was administered; severity of depression was assessed by the Hamilton ( N I M H 24-item form) (Hamilton, 1960) and Montgomery A,sberg (Montgomery and Asberg, 1979) depression scales. None of the patients with G A D met R D C for major or minor depressive disorder. All patients were drug-free for at least 2 weeks before the sleep recordings. Obese patients, or patients with somatic disorders, were excluded from the study, as well as patients who had used neuroleptics, monoamine oxidase inhibitors or lithium salts in the last 3 months. The clinical characteristics of our sample are presented in Table 1. Sleep EEG was recorded during one night in three patients with G A D + depression and three GAD, during two nights in two MDD, during

TABLE 1 CLINICAL CHARACTERISTICSOF SAMPLES Diagnosis (RDC) Number of patients Males Females Age range(years) mean+SD Hamilton range mean_+SD Montgomery-,&sbergrange mean± SD

GAD+ depression 10 6 4 19 53 33.0+10.5 7 20 15+3 6 23 13+_5

GAD

MDD

10 6 4 20 55 33.1+7.8 7 16 10+_2 2 19 8+5

10 6 4 22 54 34.7+8.4 21 49 28+8 22 49 30+9

three nights in seven G A D + depression, seven G A D and eight MDD. The routine procedure in our sleep laboratory has been described elsewhere (Kerkhofs et al., 1985). Sleep analysis was done according to the criteria of Rechtschaffen and Kales (1968) by a experience scorer, blind to the diagnostic category of the patients. The sleep variables studied were grouped into sleep continuity, sleep architecture and REM sleep. Sleep continuity includes time (min) in bed (TIB): sleep onset latency (SOL): time from lights out until the first 20 s of stage 1; sleep period time (SPT): T 1 B - ( S O L + time spent awake from last epoch of sleep until end of recording); total sleep time (TST): SPT awake time during the night; number of awakenings (NA); length (rain) of awakening (LA); number of stage shifts (NSS); sleep efficiency index (SEI): ratio of TST to TIB × 100; early morning awakening (EMA): time spent awake between least epoch of sleep and end of recording. Sleep architecture includes minutes of each stage of sleep and percentages of each stage of sleep and awakening expressed as a ratio of TST. REM sleep includes REM latency 1 (RL 1): minutes from the first stage 1 until the first REM epoch; REM latency 2 (RL 2): minutes from the first stage 2 until the first REM epoch; REM activity (RA): each 40-s period of REM sleep is scored on a 0 - 8 point scale for REM patterns, RA value is determined by the sum of scores for the whole night; REM density (RD): ratio of RA to the total duration of REM sleep; REM intensity (RI): ratio of RA to TST. The variables of all successive nights were analyzed by

115

(longer in the first night in comparison to the second and third night, P = 0.02) and for the percentage of stage 1 (greater in the second than in the third night, P = 0.008). For G A D patients, there was also a night effect for TIB (longer in the second night than in the third night, P = 0.05) and for the duration of REM latency 1 and 2 (longer in the first vs. the third night, P = 0.01). In primary M D D the number of stage shifts was found to be greater in the second and third nights in comparison to the first night ( P = 0.04). Two patient in each group showed a 'paradoxical' evolution of REM latency (increase of REM latency from first to second night; Ansseau et al., 1985).

Friedman non-parametric analysis of variance to explore a possible night effect. The comparison of the three groups was performed with the Kruskal-Wallis non-parametric test at a level of 0.05 and pairwise comparison according to Hollander and Wolfe (1973). The correlation between REM latency values and Hamilton scores was assessed with the Spearman non-parametric test. All sleep variables in the first night, as well as in the mean of the three consecutive nights, are presented as means _+ SD. Results In G A D patients with depression, a significant night effect was found for the duration of stage 1 TABLE 2 SLEEP EEG VARIABLES ON THE FIRST N I G H T Sleep variable

G A D + depression (n =10)

G A D ( n = 10)

M D D ( n = 10)

Sleep continuity TIB (min) SOL (min) SPT (min) TST (min) NA LA (min) NSS SEI (%) EMA (min)

496.3 _+78.8 38.2 _+28.6 444.5 _+72.9 379.0__+ 78.0 33.0 -+ 26.1 72.3 + 45.5 212.0-+ 87.7 75.0-+ 12.1 13.5 -+ 17.6

434.3_+ 81.6 39.8_+ 23.6 384.1_+ 89.0 324.4-+ 103.1 25.0-+ 25.9 b 59.7+ 64.1 188.0+ 62.8 74.3_+ 16.1 10.4_+ 13.8

474.8 + 24.6+ 443.7+ 354.8-+ 42.0 ± 92.8-+ 241.0_+ 73.8_+ 6.5_+

50.6 14.6 48.9 67.3 27.0 60.2 55.2 13.5 6.4

Sleep architecture Stage 1 (min) 2 (min) 3 (min) 4 (min) REM (rain) Awake (%) Stage 1 (%) 2 (%) 3 (%) 4(%) REM (%)

51.0 -+ 25.1 197.4_+ 53.4 28.8 _+19.2 19.6 _+24.3 74.4_+ 29.1 16.5_+ 9.9 11.4_+ 5.2 44.3_+ 9.3 6.6_+ 4.3 4.2_+ 4.8 16.6_+ 5.6

41.6_+ 165.7_+ 25.4+ 23.6_+ 60.4_+ 15.6_+ 11.1+ 43.5_+ 6.9_+ 5.8_+ 16.6_+

45.6+ 152.8_+ 39.7_+ 23.5_+ 89.2_+ 20.8+ 10.1_+ 34.5_+ 7.9+ 5.2_+ 20.2_+

25.6 57.1 23.9 28.2 28.8 13.2 4.9 12.7 2.8 6.2 7.0

REM sleep RL I (min) RL 2 (min) RA RD RI

124.4_+ 77.6 109.1 _+80.5 161.0 _+87.0 2.6_+ 1.4 0.4 _+ 0.3

114.6+ 52.4 101.9_+ 47.6 h 106.0 _+105.7 1.7+ 1.1 0.3_+ 0.2

* P values > 0.05 (NS), except when otherwise stated. Pairwise contrasts ( P < 0.05): a: G A D + D vs. MDD. b: G A D vs. MDD.

17.8 53.8 19.1 22.4 32.0 15.9 5.1 11.3 4.6 4.9 8.3

68.7_+ 46.0 56.3_+ 48.2 175.0 _+133.1 1.9_+ 1.4 0.4_+ 0.3

Kruskal-Wallis P values *

0.05

ab

0.05

ll6 n u m b e r o f a w a k e n i n g s ( P < 0.01) a n d s t a g e s h i f t s ( P < 0.05) a n d for R E M s l e e p m e a s u r e s in R L 1 (P<0.01) and RL 2 (P<0.01). REM latency values distinguished GAD patients with signific a n t d e p r e s s i o n f r o m M D D ( R L 1 : 1 0 6 . 0 _+ 47.3 r a i n vs. 5 7 . 8 _ 2 2 . 6 rain, P<0.05, a n d R L 2: 94.1 ± 50.2 m i n vs. 43.6_+ 24.1 m i n , P < 0.05). G A D d i f f e r e d f r o m M D D f o r s l e e p c o n t i n u i t y in t h e n u m b e r o f a w a k e n i n g s (16.0 _+ 6.1 vs. 39.0 +_ 20.2, P < 0.05) a n d t h e n u m b e r o f s t a g e s h i f t s ( 1 7 1 . 0 ± 61.1 vs. 2 5 1 . 0 +_ 56.9, P < 0.05) a n d for R E M sleep in R L 2 (82.4 _+ 29.4 r a i n vs. 43.6 _+ 24.1 rain, P < 0.05). N o s i g n i f i c a n t d i f f e r e n c e s w e r e o b s e r v e d in GAD patients with depression compared with pa-

O n t h e first r e c o r d i n g n i g h t ( T a b l e 2), t h e c o m parison of the sleep measures between the three g r o u p s s h o w e d d i f f e r e n c e s for s l e e p c o n t i n u i t y in t h e n u m b e r o f a w a k e n i n g s ( P < 0.05) a n d for R E M s l e e p v a r i a b l e s in R L 2 ( P < 0.05). C o m p a r e d t o MDD patients, GAD patients with depression w e r e c h a r a c t e r i z e d b y a l o n g e r R L 2 (56.3 _+ 48.2 r a i n vs. 109.1 _+ 80.5 r a i n , P < 0.05). Patients with GAD had a smaller number of a w a k e n i n g s (25.0 _+ 25.9 vs. 42.0 + 27.0, P < 0.05) b u t a l o n g e r R E 2 (101.9 _+ 47,6 m i n vs. 56.3 _+ 48.2 m i n , P < 0.05) t h a n M D D p a t i e n t s . For the mean of the three consecutive nights ( T a b l e 3), t h e c o m p a r i s o n b e t w e e n t h e g r o u p s s h o w e d d i f f e r e n c e s for sleep c o n t i n u i t y in t h e

TABLE 3 SLEEP EEG VARIABLES ON THE MEAN OF THE THREE NIGHTS Sleep variable

GAD + depression (24 nights)

GAD (24 nights)

MDD (28 nights)

Kruskai Wallis P values *

Sleep continuity T1B (rain) SOL(rain) SPT(min) TST(min) NA LA(min) NSS SEI (%) EMA (rain)

494.8 ± 24.4 27.6+ 17.8 457.0_+43.3 394.1_+61.6 31.0_+20.6 68.2_+22.7 222.0_+74.4 79.4+ 9.9 10.5+10.2

445.8 + 35.9_+ 398.6_+ 358.7+ 16.0+ 44.2_+ 171.0_+ 80.4_+ 11.2_+

78.7 24.7 81.8 76.2 6.1b 55.6 61.1b 8.9 12.4

482.9 + 23.6_+ 452.6+ 387.7+ 39.0+ 66.1± 251.0-+ 79.9+ 6.6_+

43.4 11.9 48.2 60.0 20.2h 30.7 56.9 h 8.2 6.3

0.01

Sleep architecture Stage 1 (min) 2(rain) 3(min) 4(rain) REM(min) Awake(%) Stage 1 (%) 2(%) 3(%) 4(%) REM (%)

47.2+16.4 216.5_+44.4 28.3_+ 18.1 16.8-+22.1 80.9+26.5 15.1_+ 6.1 10.3_+ 3.7 47.2+ 6.4 6.3+ 3.8 3.5+ 4.5 17.5_+ 5.0

37.5_+ 184.2+ 20.2_+ 29.3_+ 77.3+ 14.5+ 9.4-+ 46.7+ 6.1+ 7.3+ 19.6+

13.0 42.4 14.6 23.7 20.6 10.9 3.0 10.2 3.3 5.7 3.6

48.7+ 170.1+ 38.8_+ 26.9+ 98.5+ 14.6+ 10.9+ 37.2-+ 8.1+ 6.4_+ 21.8+

17.5 51.9 14.7 24.4 26.3 7.2 3.8 8.4 2.5 5.0 5.9

REM sleep RE1 (rain) RL 2 (rain) RA RD RI

106.0_+47.3 ~' 94.1 +50.2 ~' 179.0 _+64.8 2.6 -+ 1.4 0.4+ 0.2

89.4+ 32.9 82.4_+ 29.4 b 142.0 _+125.9 1.6 + 1.3 0.3± 0.2

* P values > 0.05 (NS), except when otherwise stated. Pairwise contrasts ( P < 0.05): a: GAD + D vs. MDD. b: GAD vs. MDD.

57.8+ 22.6 ' 43.6+ 24.1 ,,b 187.0 ± 128.1 1.8 ± 1.0 0.5+ 0.3

0.05

0.01 0.01

117

Discussion 6

GAD with

depression

z, 2~

ol

4 2 0 8 6

MOB

o

~2

D

c

9

:9

4O

60

80

100

REM latency

120

%0

160

180)

(m~n)

Fig. 1. Distribution of REM latency 2 values in ten GAD patients with depression (24 nights), ten GAD (24 nights) and ten M D D patients (28 nights).

tients suffering from G A D only. There was no correlation between RL 2 values and total Hamilton scores or with the sum scores of items 10 and 11 (psychic and somatic anxiety) in either group of patients. The distribution of RL 2 values in the three groups (Fig. 1) showed a similar pattern in G A D with depression and GAD, with a peak frequency at 60 70 min, while in M D D there was a first peak at 0 10 min and a second one at 40-50 min. Using the criterion of 50 min or less for short RL 2 (Mendlewicz et al., 1984), 17 out of 28 nights showed a REM latency < 50 min in MDD, while G A D patients with depression had only two out of 24 nights with a short REM latency (X: 14.37, P < 0.001) and G A D patients only one out of 24 nights (X: 15.84, P < 0.001).

A significant night effect was observed in G A D patients with depression for stage 1 and in G A D for time in bed and REM latency, while in MDD, sleep was more fragmented in the successive nights. This may indicate that G A D patients with or without depression show a better accommodation to the sleep laboratory than patients with MDD. Our data show that there are no significant differences between G A D patients with depression and M D D for sleep continuity and sleep architecture. Also of some interest is the observation that, in the majority of the night parameters tested, intraindividual variability was greater in G A D than in major depressive patients. While M D D patients had a higher total sleep time than the G A D patients the differences were not significant; furthermore sleep efficiency was low ( _+75%) and similar in the three groups of patients. In contrast, short REM latency values in the first night, as well as in the mean of the three nights, distinguished M D D from G A D with depression and GAD. G A D patients also differed from M D D in sleep continuity, having fewer awakenings and stage shifts. G A D with depression could not be differentiated from G A D in any sleep variable• Dub~ et al. (1986) have also been unable to find any difference in sleep between panic disorder patients with depression and panic patients without concomitant depression. On the other hand, Grunhaus et al. (1986) have found longer sleep latency and less sleep efficiency in panic disorder patients with depression than in M D D patients but REM latency was not different between the two groups. Finally, we did not observe any difference in the amount of slow wave and REM sleep between the groups of patients. Ansseau et al. (1985) have reported a paradoxical evolution of REM latency in 52.2% of M D D patients. We have found this to be true in only two out of ten patients (20%) in each group, an observation which could be expected by chance alone. The results of the present study indicate that G A D patients with depression have a similar sleep EEG continuity pattern to M D D patients and a

118 s i m i l a r R E M l a t e n c y to G A D p a t i e n t s . O n t h e other hand, sleep architecture and R E M sleep p h a s i c a c t i v i t y w e r e s i m i l a r in t h e t h r e e g r o u p s . A m a i n f i n d i n g o f o u r s t u d y is also t h a t R E M l a t e n c y w a s s i g n i f i c a n t l y s h o r t e r in M D D p a t i e n t s in c o m p a r i s o n w i t h a g e - m a t c h e d G A D and GAD patients with depression.

patients

D e s p i t e t h e use o f age- a n d s e x - m a t c h e d g r o u p s , o u r s a m p l e s are n e v e r t h e l e s s r e l a t i v e l y small. Therefore, the results of the present study should b e e x t e n d e d in l a r g e r s a m p l e s a n d f u r t h e r s t u d i e s w i t h o t h e r b i o l o g i c a l m a r k e r s a r e n e e d e d to s u p port, on a biological basis, the s y n d r o m e of G A D w i t h d e p r e s s i o n as a s e p a r a t e e n t i t y a c c o r d i n g to the Research Diagnostic Criteria.

Acknowledgement W e w a n t to t h a n k secretarial assistance.

Miss Antonia

Alvaro for

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