REM sleep in depression is influenced by ethnicity

Psychiatry Research 88 Ž1999. 95]105

REM sleep in depression is influenced by ethnicity Russell E. Poland a,b,c,d,U , Uma Rao a,b,c , Preetam Lutchmansingh d, James T. McCracken a,b,c , Ira M. Lesser a,b, Carla Edwardsa , Geoffrey E. Ott d, Keh-Ming Lin a,b a

Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, CA 90509, USA Department of Psychiatry, UCLA School of Medicine, Los Angeles, CA 90024, USA c Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90024, USA d Department of Psychiatry, Cedars-Sinai Medical Center, 8730 Alden Dri¨ e, Room C-202, Los Angeles, CA 90048, USA b

Abstract The influence of ethnicity on the manifestation of EEG sleep changes in depression was studied in 95 patients Ž21 African-Americans wAAx, 17 Asians wASx, 37 Caucasians wCx and 20 Hispanics wHx. with unipolar major depression. Subjects were studied twice for 2 consecutive nights. On the second night of each 2-night session, placebo or scopolamine Ž1.5 mgrkg, IM, at 23.00 h. was administered. On the baseline Žplacebo. night, sleep architecture, sleep continuity and rapid eye movement ŽREM. sleep variables were generally comparable among the groups. However, REM sleep was less in AA and AS subjects than in C and H subjects. Furthermore, the distribution of REM sleep over the course of the night in AA and AS subjects differed significantly from that in the C and H groups. Although scopolamine significantly affected sleep continuity and REM sleep measures, no significant differential effects of scopolamine were observed. Because many antidepressants suppress REM sleep, the differences in baseline REM sleep observed might be related to the greater sensitivity of some ethnic-minority depressed patients to pharmacotherapy. Q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cross-cultural; Polysomnography; Cholinergic; Scopolamine; Major depressive disorder

1. Introduction In many areas of medicine, it has been shown that ethnicity can markedly influence disease U

Corresponding author. Department of Psychiatry, Cedars-Sinai Medical Center, 8730 Alden Drive, Room C-202, Los Angeles, CA 90048, USA. Tel.: q1-310-222-3775; fax: q1-310-987-8397. E-mail address: [email protected] ŽR.E. Poland.

processes ŽCruickshank and Beevers, 1989; Polednak, 1989.. Whereas most psychobiologic data have been collected and interpreted based upon the assumption that ethnicity is not a major determinant of variance, it has become increasingly clear that psychopharmacological and psychobiological processes can be influenced markedly by ethnicity ŽPoland and Lin, 1993; Kalow and Bertilsson, 1994; Lin and Poland, 1995.. Some of these ethnic-related differences might be related

0165-1781r99r$ - see front matter Q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 9 9 . 0 0 0 8 0 - 3

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to socio-cultural factors ŽMyers, 1993; Smith et al., 1993., while others might be due to biological or genetic forces ŽLin and Poland, 1995; Propping and Nothen, 1995.. Despite hundreds of reports ¨ on different aspects of EEG sleep dysregulation associated with major depression, ranging from investigations of pathophysiologic underpinnings to diagnostic implications, very few studies have examined whether ethnicity affects EEG sleep changes and whether EEG sleep changes in depression are ‘universal’ in their appearance. Although there are some data on ethnic differences in sleep complaints and sleep disorders ŽRedline et al., 1994; Ancoli-Israel et al., 1995; Blazer et al., 1995., to our knowledge, only two studies have been undertaken to determine if EEG sleep changes in depression occur consistently across ethnic groups ŽMendlewicz and Kerkhofs, 1991; Giles et al., 1998.. Using a historical case-control design, Giles et al. Ž1998. compared EEG sleep data of Caucasian ŽC. and African-American ŽAA. depressed patients collected in their laboratory. These data revealed that AA subjects did not show the depression-related REM sleep stigmata to the same extent as C subjects despite having a consonant clinical profile. Compared with C subjects, the AA subjects demonstrated increased non-REM sleep, characterized by more stage 2 sleep but diminished slow-wave sleep. Giles et al. Ž1998. suggested that the sleep profile of AA depressed patients more closely resembled sleep changes noted in anxiety disorders. A collaborative cross-cultural study sponsored by the World Health Organization ŽWHO. reported on EEG sleep changes in subjects with major depression studied at eight different sites in Europe, North America and Asia ŽMendlewicz and Kerkhofs, 1991.. As a group, the depressed patients showed sleep continuity disturbances, shortened REM latency, and increased REM density compared with control subjects. However, some sleep measures differed according to site. For example, REM latency was not consistently reduced in subjects from the Tokyo and Mexico City sites. In order to further address the influence of ethnicity on EEG sleep dysregulation in depres-

sion, the present study was undertaken whereby EEG sleep profiles of depressed patients from four major ethnic groups were studied at the same site under identical conditions. In addition, because some data suggest that AA and Asian ŽAS. show differential sensitivity to mydriatics, including anticholinergic agents, as compared to C subjects ŽChen and Poth, 1927; Angenent and Koelle, 1953; Garde et al., 1978; Venter et al., 1984., the effect of scopolamine on EEG sleep was also assessed ŽPoland et al., 1989.. The working hypothesis was that, compared with C and Hispanic ŽH. subjects, AA and AS subjects would demonstrate less REM sleep suppression with scopolamine administration.

2. Methods 2.1. Subjects Twenty-one African-American, 17 Asian Ž15 Chinese, two Japanese., 37 Caucasian and 20 Hispanic ŽMexican-American. patients were studied. Membership in a particular ethnic group required that all four biological grandparents were of the same ethnicity. All subjects were evaluated with the Structured Clinical Interview for DSMIII-R ŽSCID. ŽSpitzer et al., 1986.. Depressed patients met DSM-III-R criteria for unipolar major depression, with Hamilton Depression Rating Scale ŽHAM-D. ŽHamilton, 1960. scores of G 15 Ž 17-item scale . . All subjects had been medication-free for at least 1 month. No subjects had been taking a monoamine oxidase inhibitor or fluoxetine. Patients were excluded for any current or past Žwithin the prior 5 years. history of an alcohol or substance abuserdependence disorder. No patients had a history of, or met criteria for, psychosis. Subjects were medically healthy, as determined by physical examination, electrocardiogram, full chemistry panel, thyroid function tests, urine drug screens, and clinical psychiatric interviews. In order to rule out known sleep disorders, a sleep questionnaire was completed. Subjects with a personal history of a major sleep disorder or a family history of narcolepsy were excluded from the study. None of the subjects

R.E. Poland et al. r Psychiatry Research 88 (1999) 95]105

were aware of the inclusionrexclusion criteria. Subjects also were screened for the presence of sleep disorderŽs. on the first night of the sleep protocol, and were excluded if a sleep disorder was detected. Although most subjects normally retired between 22.00 h and midnight and awoke between 05.30 and 08.00 h, subjects were requested to go to bed between 22.30 and 23.30 h and awaken between 06.30 and 07.30 h for at least 1 week prior to the study. A sleep log was maintained prior to and during the study. All subjects were studied twice for 2 consecutive nights approximately 1 week apart. On all nights, conventional EEG electrodes were attached by 21.00 h, and sleep recordings were made from 23.00 h Žlights out. to 07.00 h. Examination of sleep logs revealed that there were no significant differences between home and laboratory sleeprwake schedules. On night 2 of each 2-night session, subjects were given either saline or a threshold dose of scopolamine Ž1.5 mgrkg, IM. ŽPoland et al., 1989, 1997., in a double-blind, randomized fashion, at 23.00 h immediately prior to lights out. The four ethnic groups were balanced in terms of the order of drug Žplacebo vs. scopolamine. administration.

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2.2. Sleep EEG methodology The International 10]20 System was utilized for EEG electrode placement, electromyogram, electrooculogram and electrocardiogram. In order to rule out the presence of sleep disorders, a full sleep polysomnography was performed on the first night, including respiratory, oximetry and leg movement measurements. Bilateral EEG recordings were obtained from left ŽC3. and right ŽC4. central leads referenced to the opposite mastoid, A2 and A1, as well as to a linked reference ŽA1q A2.. Sleep recordings were coded and scored blindly according to standard criteria ŽRechtschaffen and Kales, 1968.. REM latency was defined as the time between sleep onset Žfirst minute of stage 2 or deeper sleep, followed by at least 9 min of stage 2 or deeper sleep, interrupted by no more than 1 min of waking or stage 1. and the first REM period G 3 min in length. REM latency is reported with and without intervening wake time subtracted. Other REM sleep measures, including REM density and REM activity, and additional sleep variables were scored according to the criteria of Kupfer Ž1976., as was done previously ŽPoland et al., 1989, 1993, 1997..

Table 1 Demographic and clinical characteristics of African-American, Asian, Caucasian and Hispanic subjects a African-American Sex ŽFrM. Age Žyears. Female Male Weight Žkg. Female Male Height Žinches. Female Male HAM-D Female Male a

Asian

Caucasian

Hispanic

Statistic 2

P

16r5

13r4

18r19

15r5

x s 7.39

0.06

36.1" 13.3 42.2" 13.5

33.5" 14.2 45.3" 17.9

45.4" 6.9 43.2" 13.1

38.6" 9.2 40.8" 12.2

F s 3.51 F s 0.09

0.02b 0.97

83.0" 18.3 102.2" 9.7

58.6" 10.4 60.9" 17.7

73.8" 18.8 85.5" 16.6

78.6" 23.4 82.5" 14.0

F s 4.59 F s 5.25

0.006c 0.005d

65.2" 3.9 68.6" 4.9

65.1" 4.8 69.5" 4.8

64.8" 2.5 69.5" 4.3

64.0" 3.6 67.0" 1.6

F s 0.31 F s 0.51

0.81 0.68

20.9" 3.5 20.6" 4.6

21.9" 4.9 20.3" 3.9

23.3" 5.9 21.5" 4.9

20.7" 5.5 24.4" 4.0

F s 0.91 F s 0.80

0.44 0.51

Note: Values are raw numbers or means " S.D.s; HAM-Ds 17-item Hamilton Depression Rating Scale score. Caucasians differed significantly from African-Americans and Asians. c Asians differed significantly from all other ethnic groups. d Asians differed significantly from all other ethnic groups; Caucasians also differed significantly from African-Americans. b

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2.3. Statistics Statistical analyses were performed by repeated measures analysis of variance ŽANOVA., with age and gender used as co-variates. If the ANOVA was significant for group Žethnicity . andror interaction Žscopolamine treatment . effectŽs., further analyses were performed using unpaired and paired t-tests to locate significant differences across- and within-group, respectively. Logarithmic transformations were performed for stage 1 sleep, sleep latency, number of arousals and REM activity measures to normalize variability. Relationships between continuous variables were examined using Pearson product-moment correlation coefficients. Only polysomnography data from the second night of each 2-night session were used in the statistical analyses, the first night being considered as an adaptation night. All tests were two-tailed. A value of PF 0.05 was considered statistically significant.

3. Results 3.1. Demographic and clinical data The demographic and clinical data are shown in Table 1. With the exception of C subjects, more females than males were studied and the females were younger than the males. Among females, C subjects were significantly older than AA and AS subjects. AS subjects weighed significantly less than the other ethnic groups. Also, C subjects weighed significantly less than AA subjects. Height and HAM-D scores were comparable among the groups. All subjects were outpatients.

reduced stage 1 sleep as compared to males at baseline Ž5.9" 3.0 vs. 8.8" 6.4%, F1,92 s 21.01, PF 0.0001.. In contrast, males had less stage 4 sleep than females Ž9.9" 7.4 vs. 12.4" 6.9%, F1,92 s 1.97, NS., but this difference was significant only in the AA group Ž PF 0.005; see Fig. 1.. After co-varying for age and gender, REM sleep was significantly reduced in AA and AS subjects at baseline compared with their C counterparts. H did not differ significantly from any group. Scopolamine significantly increased stages 1 and 2, and reduced REM sleep consistently across ethnic groups. Examination of the sleep architecture data in minutes showed the same pattern of results Ždata not shown.. 3.2.2. Sleep continuity Sleep continuity variables for the four ethnic groups following placebo and scopolamine administration are outlined in Table 2. Age significantly affected total sleep time, sleep efficiency and awake time. Gender did not significantly influence any sleep continuity variables. After controlling for the effects of age and gender, baseline sleep latency was significantly less in AA than in C and H subjects, with AS subjects being intermediate. AS subjects had significantly less total sleep time and sleep efficiency at baseline compared with the other three ethnic groups. Furthermore, there was a non-significant trend for AS subjects to have the most awake time. Scopolamine significantly affected total sleep time, sleep efficiency and awake time. Although there were no significant differential responses to scopolamine, there was a tendency for scopolamine to prolong total sleep time, improve sleep efficiency and reduce awake time in the AS subjects with minimal change of these measures in the other ethnic groups.

3.2. Sleep measures 3.2.1. Sleep architecture The various sleep stages, in percentages, following placebo and scopolamine administration are presented in Table 2. Age significantly affected stages 1, 2 and 3, whereas gender significantly affected stages 1 and 4. After controlling for the effects of age, females had significantly

3.2.3. REM sleep REM sleep variables for the four ethnic groups following placebo and scopolamine administration are given in Table 2. Age significantly affected REM latency when awake time was subtracted. Age also affected total REM activity and REM density. None of the REM sleep measures were influenced by gender. After controlling for

Table 2 Sleep architecture, continuity and REM sleep variables Žmean " S.D.. following placebo and scopolamine ŽSCOP, 1.5 mgrkg, IM. in African-American, Asian, Caucasian and Hispanic patients with major depression, controlling for the effects of age and gender a Asian Ž N s 17 .

Placebo

Placebo

SCOP

Caucasian Ž N s 37 . SCOP

Placebo

Hispanic Ž N s 20 . SCOP

Placebo

Repeated measurement ANCOVA SCOP

6.3 " 3.8 52.5 " 7.2 7.2 " 3.2 11.3 " 6.8 22.5 " 6.2

7.6 " 4.0 58.5 " 6.5 5.1 " 2.6 13.1 " 5.6 15.4 " 4.3

7.8 " 8.3 49.5 " 13.2 7.7 " 2.8 12.0 " 8.8 21.1 " 6.5

7.7 " 7.8 55.8 " 9.3 6.1 " 3.3 16.2 " 10.6 13.9 " 4.7

7.2 " 3.6 49.6 " 8.6 7.2 " 3.4 10.8 " 7.1 25.1 " 4.7

9.1 " 4.2 52.7 " 7.5 7.2 " 3.7 13.7 " 6.0 17.2 " 6.9

6.2 " 2.6 49.6 " 6.8 6.7 " 2.5 12.7 " 6.4 24.5 " 5.0

6.8 " 3.0 57.2 " 5.4 6.1 " 2.7 12.9 " 4.5 16.8 " 3.8

16.8 " 12.2

21.7 " 24.8

31.7 " 29.4

48.6 " 37.6

35.5 " 37.5

41.4 " 51.5

36.7 " 38.1

33.8 " 24.4

409.0 " 36.0 411.7 " 26.3 384.7 " 65.1

397.8 " 42.4

452.2 " 28.3 460.3 " 23.4 458.6 " 16.7

460.5 " 22.7

Age

Gender

Group

SCOP

Drug = group interaction

11.26† 4.36U 9.06UUU 2.03 0.14

14.40‡ 0.12 0.13 4.59U 0.40

0.06 1.30 0.54 0.32 2.93U b

5.01U 1.50 3.48 3.33 15.97 U

1.32 0.41 0.87 1.93 0.29

0.66

Sleep continuity Sleep latency Žmin . Total sleep time Žmin . Total study time Žmin . Efficiency Number of arousals Awake time

2.19

4.54UUU c

1.25

407.1 " 40.5 402.1 " 42.2 411.0 " 32.1 410.7 " 24.3 30.50‡

2.58

3.35UU d

7.61UU 1.81

465.7 " 13.3 469.8 " 12.5 456.6 " 30.0 458.8 " 24.9

0.52

2.59

0.54

1.33

0.52

0.59

0.90 " 0.06 60.6 " 83.0

0.89 " 0.05 31.6 " 20.6

0.83 " 0.14 46.6 " 67.9

0.86 " 0.08 30.4 " 19.9

0.87 " 0.09 51.8 " 86.3

0.85 " 0.09 49.7 " 76.4

0.90 " 0.05 18.8 " 6.8

0.89 " 0.05 25.71‡ 24.1 " 9.1 2.56

1.57 2.52

2.91UUU d 1.44

7.92 UU 2.10 1.84 1.80

40.6 " 24.9

45.7 " 28.9

70.8 " 63.9

59.0 " 39.1

55.7 " 41.6

64.9 " 44.9

45.6 " 23.2

48.1 " 26.1 23.12‡

0.25

2.20

7.02 UU 2.03

REM (1st REM episode ) REM latency 73.0 " 40.3 136.0 " 75.5

67.7 " 38.4

159.3 " 75.5

58.8 " 19.7 131.8 " 69.7

2.83

0.07

0.33

16.52‡

0.58

70.9 " 36.8 129.9 " 65.7

66.4 " 37.8

150.8 " 74.6

53.1 " 21.0 118.8 " 5 4.0 59.0 " 20.1 135.4 " 53.8

4.62U

0.22

0.67

23.00‡

0.67

26.8 " 28.1

12.9 " 12.9

28.8 " 22.9

16.6 " 18.2

39.6 " 36.6

18.8 " 23.1

26.4 " 22.4

21.7 " 28.1

0.35

0.67

1.19

0.36

0.67

1.5 " 0.9

1.0 " 0.7

1.6 " 1.0

1.3 " 0.9

1.7 " 1.0

1.2 " 0.7

1.5 " 0.8

1.1 " 0.7

0.32

0.69

0.42

0.31

0.11

14.5 " 8.0

10.8 " 6.5

16.1 " 8.4

11.8 " 7.8

20.6 " 10.8

13.2 " 9.6

16.5 " 8.1

16.2 " 9.9

0.03

0.01

1.67

0.01

1.70

61.5 " 21.2 141.2 " 57.2

Žmin. REM latency-W Žmin . REM activity Žunits . REM density Žunitsrmin . REM duration Žmin .

R.E. Poland et al. r Psychiatry Research 88 (1999) 95]105

Sleep architecture Stage 1 sleep Ž% . Stage 2 sleep Ž% . Stage 3 sleep Ž% . Stage 4 sleep Ž% . REM sleep Ž% .

African-American Ž N s 21 .

99

2.0 " 0.8 84.3 " 25.1 3.8 " 0.8

1.4 " 0.7 64.2 " 19.9 3.7 " 1.0

94.0 " 65.4 175.3 " 100.5

Placebo

SCOP

Placebo

Hispanic Ž N s 20 . SCOP

1.9 " 0.7

3.2 " 1.0

4.3 " 0.7

55.9 " 20.1 105.0 " 21.7

1.8 " 1.0

2.0 " 0.6

3.5 " 0.6

4.3 " 0.6

71.7 " 30.1 104.1 " 26.7

1.7 " 0.7

3.5 " 0.7

70.3 " 18.0

1.7 " 0.6

91.1 " 43.6 211.5 " 92.5 119.5 " 65.5 207.4 " 85.4 120.7 " 58.9

SCOP

Caucasian Ž N s 37 .

0.18

b

a

0.89

1.65

0.95

10.53UUU 3.31

0.01

2.22

4.88UUU e

0.40

2.15

Gender Group

7.58UU

Age

Repeated measurement ANCOVA

Note: ANCOVAs Analysis of co-variance; SCOP s scopolamine; U PF 0.05; UU PF 0.01; UUU PF 0.005; †P F 0.001; ‡ P F 0.0001. African-Americans and Asians differed significantly from Caucasians. c African-Americans differed significantly from Caucasians and Hispanics. d Asians differed significantly from all other ethnic groups. e African-Americans differed significantly from Caucasians; Asians differed significantly from Caucasians and Hispanics.

REM (all episodes) REM activity 196.3 " 97.6 Žunits . REM density 2.0 " 0.6 Žunitsrmin . REM duration 94.1 " 27.7 Žmin . No. of REM 4.3 " 1.1 episodes

Placebo

Placebo

SCOP

Asian Ž N s 17 .

African-American Ž N s 21 .

Table 2 Ž Continued.

1.29

16.04‡ 0.42

22.82‡ 0.51

0.07

10.97† 0.17

SCOP Drug = group interaction

100 R.E. Poland et al. r Psychiatry Research 88 (1999) 95]105

R.E. Poland et al. r Psychiatry Research 88 (1999) 95]105

Fig. 1. Percent stage 4 sleep Žmean " S.D.. in AfricanAmerican, Asian, Caucasian and Hispanic male and female patients with major depression ŽU PF 0.005 between AfricanAmerican males and females..

the effects of age and gender, compared with C subjects, duration of REM sleep over the entire night was significantly reduced in AA and AS subjects at baseline. AS subjects also were significantly different from H subjects with respect to total REM duration. Moreover, there was a tendency for AA and AS subjects to have fewer REM episodes compared with C and H subjects Ž71% AA, 65% AS, 86% C and 90% H had four REM episodes.. Scopolamine consistently prolonged REM latency, reduced REM activity and REM density, and suppressed REM sleep. Only REM latency, total REM activity, total REM duration and number of REM episodes showed statistical significance, however. No significant differential responses to scopolamine were found. REM duration for the first four REM periods is shown in Fig. 2. During the first three REM periods, AA and AS subjects had considerably less REM sleep in comparison with C and, to a lesser extent, H subjects. However, during the fourth REM period, the pattern was reversed. AA and AS subjects had more REM sleep than C and H subjects. A repeated measures ANOVA, controlling for age and gender, showed a significant ethnicity by REM episode interaction Ž F9,210 s 2.75, PF 0.005.. Thus, not only was the duration of REM sleep different, for both individual REM episodes and overall, but the distribution of REM

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Fig. 2. REM duration profiles during the night in AfricanAmerican ŽAA., Asian ŽAS., Caucasian ŽC., and Hispanic ŽH. patients with major depression Ž P F 0.005 between REM episodes 1 and 3 for discriminating AA and AS from C and H; PF 0.05 between REM episodes 1 and 4 for distinguishing AA and AS from C and H..

sleep across the night also differed. Although the absolute values of REM sleep were reduced, essentially similar findings were observed following scopolamine administration Ždata not shown.. In addition to controlling for the effects of age and gender, the potential roles of other confounding factors, including weight, height and HAM-D score, on cross-ethnic differences in REM sleep were evaluated. None of these co-variates showed a significant effect. After controlling for these factors, AA and AS subjects continued to have significantly reduced REM sleep as compared to C subjects, and AS subjects differed significantly from H subjects as well Ž F3,87 s 4.76, PF 0.05.. The findings held up when percent of REM sleep was examined Ž F3,87 s 4.16, PF 0.01.. Since AS subjects also had decreased sleep efficiency and total sleep time as well as increased wakefulness, which could affect REM sleep, these variables also were entered into the model and the group differences persisted Ž F1,83 s 3.91, PF 0.05.. 3.3. Relationship between sleep ¨ ariables and potential confounding factors In order to confirm the findings of ethnic influences on REM sleep and other sleep variables

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in the full sample, the C subsample was reduced in size to more closely match the other ethnic groups with respect to age and gender, and the resulting data were re-analyzed. The pattern of results did not change. There was no significant effect of order of administration of placebo vs. scopolamine in the total sample or in any ethnic group. None of the sleep measures were influenced by the HAM-D score in the full sample or in the individual ethnic groups, and there was no influence of educational level on the results.

4. Discussion The study examined the influence of ethnicity on baseline EEG sleep measures and their responses following scopolamine administration in four major ethnic groups. For the most part, baseline EEG sleep measures were remarkably similar across ethnic groups. REM sleep was less in AA and AS subjects compared with C and H subjects. AA subjects also had prolonged sleep latency, and AS subjects had diminished sleep efficiency and total sleep time. Contrary to our hypothesis, scopolamine did not differentially affect the sleep variables significantly across ethnicity. Only two other studies, to our knowledge, have addressed the issue of ethnicity and EEG sleep changes in depression ŽMendlewicz and Kerkhofs, 1991; Giles et al., 1998.. Consistent with our findings, Giles et al. Ž1998. reported that AA depressed patients have less REM sleep compared with C patients. These findings should be interpreted in the context of the study limitations. The samples, specifically the ethnic-minority groups, were of modest size, thereby limiting statistical power to detect other cross-ethnic differences. In addition, several variables were examined without controlling for multiple comparisons. Therefore, these findings should be considered preliminary until they are confirmed in larger samples with more rigorous statistical approaches. The samples varied with respect to age and gender distribution. However, effects of age and gender were controlled in the analyses, and reducing the C sample size to match the other groups on age and gender

distribution essentially confirmed cross-ethnic differences observed in the full sample. Finally, the clinical significance of cross-ethnic differences in EEG sleep of depressed patients is unclear. Despite these issues, the study also has considerable strengths. To our knowledge, this is the first study to assess EEG sleep patterns in four major ethnic groups at a single site. The criteria for inclusion were rigorous, particularly with regard to ethnic classification and medical and psychiatric comorbidity. It would be important to determine whether the observed cross-ethnic differences in REM sleep are related to depression or also occur in normal controls. We have preliminary baseline EEG sleep data from a group of normal volunteers who were studied in the same laboratory as controls for a variety of psychobiological studies, including this investigation. In those controls, there was a trend for AA and AS subjects also to have less REM sleep compared with C and H subjects ŽRao et al., 1999.. Similar to findings in this study, male AA normal volunteers had diminished stage 4 sleep ŽRao et al., 1999.. Preliminary comparisons between normal volunteers and depressed patients across the four ethnic groups do not support ethnicity by diagnosis interactions in the manifestation of cross-ethnic variations in EEG sleep ‘abnormalities’ associated with depression ŽRao et al., unpublished data.. Nevertheless, a larger investigation comprising both depressed patients and normal controls, matched on age, gender and ethnicity, would be helpful in resolving whether ethnicity and depressive illness interact to produce differential EEG sleep patterns across ethnic groups. Cross-ethnic variations in sleep profiles have potential implications for the treatment of depressive illness in patients from different ethnic backgrounds ŽThase, 1998.. Different antidepressants have distinctly different effects on sleep ŽVogel et al., 1990, 1998; Ware and Pittard, 1990; Nofzinger et al., 1995; Sharpley and Cowen, 1995; Sharpley et al., 1996; Rush et al., 1998.. For instance, selective serotonin re-uptake inhibitors ŽSSRIs. strongly suppress REM sleep, and also may worsen sleep maintenance and reduce slowwave sleep ŽSharpley et al., 1996; Rush et al.,

R.E. Poland et al. r Psychiatry Research 88 (1999) 95]105

1998.. In contrast, nefazodone and bupropion tend to preserve REM sleep and may improve sleep efficiency ŽNofzinger et al., 1995; Sharpley et al., 1996; Rush et al., 1998; Vogal et al., 1998.. Other antidepressants, including tricyclic agents and trazodone, can enhance slow-wave sleep ŽMontgomery et al., 1983; Ware and Pittard, 1990; Reynolds et al., 1991.. The differential effects of antidepressants on sleep architecture, coupled with cross-ethnic differences in sleep, might have implications for determining treatment strategies. According to the available data, AA and AS subjects have less REM sleep compared with C and H subjects. It is possible that these two ethnic groups might be more sensitive to antidepressants that robustly suppress REM sleep. There is some evidence that AA and AS subjects are more sensitive to antidepressants ŽRaskin and Crook, 1975; Kleinman, 1981; Rosenblat and Tang, 1987; Lin and Poland, 1995; Lesser et al., 1997; Varner et al., 1998; Wood, 1998.. Thus, the greater sensitivity of these ethnic groups to pharmacologic treatment might be mediated by their having less REM sleep to begin with, as well as possibly showing a greater sensitivity to REM sleep suppression by antidepressants. Similarly, AA males might be more sensitive to agents which reduce slow-wave sleep. Controlled studies should address this clinically relevant question in the future. Ethnicity-sensitive treatment guidelines based on EEG sleep profiles might reduce treatment-related sleep difficulties and enhance treatment compliance ŽKleinman, 1981; Marcos and Cancro, 1982; Lin and Poland, 1995; Lesser et al., 1997.. These data do not help in the differentiation between geneticrbiological and socio-cultural factors associated with inter-ethnic differences in EEG sleep profiles, particularly in REM sleep. Studies examining genetic influence Žs. on REM sleep regulation are contradictory, with some studies suggesting that at least some aspects of REM sleep regulation are heritable ŽWebb and Campbell, 1983; Hori, 1986., whereas other investigations find non-genetic factors more influential ŽLinkowski et al., 1991.. Physical characteristics, such as, weight, height, and body surface area,

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which correlate highly in identical twins and within ethnic groups, have been shown to influence some components of REM sleep regulation ŽAdam, 1977; Ohkawa and Nakazawa, 1982; Hori, 1986.. After controlling for these physical as well as other potential confounding clinical Že.g. depression severity. and sleep variables Žnamely, crossethnic differences in sleep efficiency, total sleep time and awake time., the ethnic variations in REM sleep persisted. Counter to expectation, AS subjects had relatively more sleep continuity disturbances and less REM sleep in spite of being the youngest age group. Future investigations should address the issue of interactions between biological and socio-cultural forces in determining the cross-ethnic variations in sleep patterns. In summary, REM sleep was considerably less in AA and AS depressed patients compared with their C and, to a lesser extent, H counterparts. These differences probably reflect ethnic variations in REM sleep organization rather than the effect of depressive disorder. A larger controlled study is needed to examine the interaction Žs. between ethnicity and depressive illness. Although the mechanisms underlying the REM sleep differences are unclear, it does not appear that the differences are mediated by muscarinic cholinergic mechanisms, at least as reflected by the REM sleep responses to scopolamine. The extent to which ethnic differences in response to antidepressants are due to interactions between pharmacogenetic and pharmacodynamic factors remains to be determined.

Acknowledgements This study was supported in part by the NIMHrNIH Research Center on the Psychobiology of Ethnicity MH47193, MH34471, NIMH Research Scientist Development Award MH00534 Žto REP., NIMH Scientist Development Award MH01419 Žto UR., and NIH General Clinical Research Center Grant RROO425. We thank Manny Madamba for excellent technical assistance and Debbie Hanaya for expert administrative support.

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