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Electroencephalographic sleep and urinary free cortisol in adolescent depression: A preliminary report of changes from episode to recovery
Electroencephalographic Sleep and Urinary Free Cortisol in Adolescent Depression: A Preliminary Report of Changes from Episode to Recovery Uma Rao, James T. McCracken, Preetam Lutchmansingh, Carla Edwards, and Russell E. Poland Key W o r d s :
Adolescence, depression, sleep, cortisol, episode, recovery
BIOL PSYCHIATRY 1997;41:369-373
Introduction Electroencephalographic (EEG) sleep and hypothalamic-pituitary-adrenal (HPA) axis changes associated with adult major depressive disorder (MDD) are among the best replicated findings in biological psychiatry (Holsboer 1995; Reynolds and Kupfer 1987). More recently, attention has shifted to the question as to whether or not sleep and HPA axis changes observed in depression are exclusively present during the depressive episode (state related) or may persist after clinical remission (traitlike). The delineation of state-dependent and state-independent correlates of depression would be relevant for models of biologic vulnerability, course of illness, and prediction of treatment response. Longitudinal studies of adult depressed patients have shown that most EEG sleep measures are relatively stable from episode to clinical remission (Buysse et al 1992; Giles et al 1993; Lee et al 1993; Riemann and Berger 1989; Rush et al 1986; Schultz et al 1979; Steiger et al 1989; Thase et al 1994). In contrast, changes in the HPA axis appear to be state-related (Gerken et al 1985; Greden et al 1983; Holsboer et al 1982; Steiger et al 1989; Targum 1983). In contrast to adults, the question of whether EEG sleep and HPA axis changes are associated with adolescent depression From the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California (JTM, PL, CE, REP); and Department of Psychiatry and Biobehavioral Sciences, UCLA Neuropsychiatric InstitUte, Los Angeles, California (UR, JTM, REP). Address reprint requests to Uma Rao, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759. Received February 5, 1996; revised September 6, 1996.
© 1997 Society of Biological Psychiatry
remains unsettled. Studies have reported inconsistent differences between depressed and control subjects (for reviews, see Dahl et al 1990, 1992; McCracken et al 1996). Aside from methodological differences in assessment procedures, clinical course may contribute significant variance to observed changes in EEG sleep as well as HPA axis function in adolescent cohorts (Rao et al 1996 ). Therefore, longitudinal sleep and neuroendocrine studies not only would be potentially useful in advancing our knowledge of the etiology and pathophysiology of juvenile mood disorders, but may also be helpful in the clarification of developmental continuities and discontinuities in the psychobiology of affective disorders. In this preliminary communication, we report on EEG sleep and nocturnal urinary free cortisol (UFC) in 5 adolescent subjects studied during an episode of MDD as well as in remission. These subjects were included as part of a larger controlled study of EEG sleep and neuroendocrine function in adolescent and adult depression. Baseline sleep findings in the larger adolescent sample (n = 20) have been described (McCracken et al, in press).
Methods and Materials The methods for the initial study have been described in detail elsewhere (McCracken et al, in press), and are reviewed here briefly. When depressed, all 5 subjects (4 female and 1 male) had fulfilled DSM-III-R criteria for MDD by clinical as well as structured (the Schedule for Affective Disorders and Schizophrenia for School-Age Children, K-SADS-E) interviews. Severity 0006-3223/97/$17.00 PII S0006-3223(96)00430-1
370
BIOL PSYCHIATRY 1997;41:369-373
ratings on the Hamilton Depression Rating Scale (HDRS) indicated that the depressive symptoms were of moderate to severe degree (20.4 ± 4.6; range 15-29). All 5 subjects were outpatients. Of the 5 adolescents, 4 were in their first episode of depression and 1 patient had two prior episodes. None of the subjects had a previous history of mania, hypomania, or substance abuse. The mean age of the sample was 16.2 ± 1.9 (range 14-19) years. The sleep and neuroendocrine protocol consisted of two 2-night sessions, spaced approximately 1 week apart. Night 1 was considered an adaptation night. On night 2, at 11:00 PM immediately prior to lights out, subjects were administered either saline or scopolamine (4.5 I~g/kg) by intramuscular injection in a double-blind randomized fashion. Urine was collected from 11:00 PM-7:00 AM. Sleep records were scored visually in 30-sec epochs using the standardized criteria reported by Rechtschaffen and Kales (1968). UFC was assayed using the radioimmunoassay method as described previously (Rubin et al 1987). For reinvestigation during remission, the study criteria included: 1) complete remission from MDD for -->3 months; 2) medication-free for a minimum of 6 months; 3) a HDRS score <--6 on six consecutive evaluations performed at 2-week intervals; and 4) normal physical examination and laboratory tests. To ensure that the subjects were potentially not at risk for recurrence at the time of sleep studies, they continued to have clinical evaluations every 2 weeks for 3 additional months after completion of the sleep studies.
Statistical Analysis For this report, sleep and UFC data only from the placebo night will be presented. REM latency was defined as the time between the first minute of stage 2 or deeper sleep (followed by at least 9 rain of stage 2 or deeper sleep, and interrupted by no more than 1 rain of waking or stage 1) and the first REM period greater than or equal to 3 min. Use of other definitions of REM latency (more lenient criteria as well as controlling for any intervening awake time) did not lead to significant changes in values. Since the study used a within-subject repeated-measures design, the T~ and T 2 measures from the depressed subjects were compared using paired two-tailed t tests. Sleep and UFC variables only from night 2 were included in the analyses. As a second test of stability, the primary dependent variables (from TI and T z) were examined by scatterplots, and Pearson's productmoment correlation coefficients were calculated. All analyses were performed on log-transformed data. To examine the association between EEG sleep and UFC measures, Pearson's product-moment correlation coefficients were calculated for these variables at Ta and T 2.
Results Sample Characteristics at Follow-Up The sleep and UFC assessments during the recovery phase were performed approximately 18.8 ± 10•9 (range 8-31) months after
Brief Reports
the initial protocol. The mean HDRS score at follow-up was 0.4 --_ 0.6 (range 0-1). Four of the 5 patients had received no psychotropic medication and were treated with psychosocial interventions. One subject, treated with amitriptyline, was medication-free for 6 months. None of the subjects had a relapse or recurrence since the index assessment.
Effect of Depressive State on Baseline EEG Sleep and Urinary Free Cortisol As shown in Table 1, with the exception of a decrease in awake time during recovery (31.9 - 26.7 rain during the episode and 9.6 -+ 6.8 min on recovery, t4 = 2.92, p --< .05), there were no significant differences in sleep continuity, sleep architecture, or REM sleep measures from episode to recovery. Stage 4 sleep showed a trend for reduction during the recovery state (20.9 ± 4.6 vs. 15.9 ± 6.1, t4 = 2.26,p <- .10). All major sleep variables showed modest to high correlations between pre- and postassessments (e.g., r = .82 for REM latency; r = .69 for stage 4 sleep), with the exception of sleep continuity (Pearson r ranging .25 .74) and REM density (r = .09) measures. With respect to nocturnal UFC, both measures of excretion were significantly diminished during the recovery phase compared to the depressive state (mean 11.0 I~g with a standard deviation of 9.3 during the episode and 3.9 - 1.9 Ixg on recovery for total excretion, t4 = 3.00, p -< .05; 50.7 - 46.5 ng/mL and 13.1 ± 4.7, respectively for UFC concentration, t4 = 2.68, p -< •10). There was a high correlation between T 1 and T 2 evaluations for total UFC excretion (r = .81).
Relationship between EEG Sleep and UFC Measures Examination of the association between EEG sleep and UFC measures during episode and recovery times showed that stage 1 sleep was significantly correlated with total UFC during the episode (r = .93, p <- .05). Total UFC was modestly correlated with awake time during the depressive phase (r = .51, ns). Total UFC was also associated with REM latency during the depressive as well as the remission states (r = - . 6 4 during the depressive episode; r = - . 5 5 during recovery).
Discussion To our knowledge, this is the first study to report on EEG sleep and UFC measures in adolescent depression during episode and in remission. The findings of the study are very tentative due to the small sample size; however, the results from this preliminary ongoing investigation suggest that, in this limited sample, most sleep variables in adolescent depression remain relatively stable from episode to recovery (traitlike), whereas UFC measures may be state related. The results from this study are comparable to findings from investigations with adult patients• From various samples of adult depressives, including cross-sectional comparison of remitted patients with healthy controls (Hauri et al 1974;
Brief Reports
BIOL PSYCHIATRY 1997;41:369-373
371
Table 1. Selected EEG Sleep and Urinary Cortisol Measures in Depressed and Remitted Adolescents Variables Sleep continuity Total study time (min) Total sleep time (min) Sleep latency (min) Sleep efficiency (%) Number of arousals Awake time (min) Sleep architecture Stage 1 (%) Stage 2 (%) Stage 3 (%) Stage 4 (%) REM sleep (%) REM sleep REM latency (min) REM activity (units) REM density (ut/min) REM duration (rain) Number of episodes Nocturnal UFC Total (~g) ng/mL of urine
MDD subjects in episode
MDD subjects in remission
T I VS. T 2 (paired t)
T t vs. T 2 (Pearson r)
477.6 445.7 _ 13.2 93.0 16.6 ± 31.9 ±
460.7 - 16.0 444.9 _+ 12.1 10.3 _ 6.1 96.0 ___2.0 23.6 __ 23.8 9.6 +- 6.8
2.23`" 0.03 0.07 -1.28 -0.13 2.92b
-.33 .69 -.25 .28 .74 .26
3.1 ___2.0 49.9 _+ 3.1 4.3 ± 1.8 15.9 ± 6.1 26.6 - 7.5
-0.38 -1.44 0.45 2.26" -0.72
.73 .31 -.36 .69 .59
-1.42 -0.84 -0.66 -0.57 1.89
.82 -.50 -.09 .46 .81
2.6 47.4 4.8 20.9 24.1
2.3 26.0 11.8 6.0 7.9 26.7
± 1.5 _ 3.5 +_ 1.6 - 4.6 _ 4.0
83.3 -+ 34.0 229.8 -+ 117.1 2.1 - 0.9 109.6 + 22.0 4.6 -+ 0.6 11.0 -+ 9.3 50.7 - 46.5
93.8 268.8 2.5 119.1 4.0
_+ 30.3 _+ 51.7 _+ 1.0 ± 34.5 +_ 1.2
3.9 _+ 1.9 13.1 ± 4.7
3.00b 2.68a
.81 -.22
Values are actual mean ± SD for comparison purposes; transformations were performed prior to tests of significance. UFC, urinary free cortisol; ut, units; min, minute.
Op<- .10. bp < .05.
Poland et al in press), single-episode cases versus those with recurrent illness (Giles et al 1989; Thase et al 1995), and prospective follow-up of individual subjects through recovery or into a subsequent episode (Buysse et al 1992; Giles et al 1993; Kupfer et al 1988; Lee et al 1993; Poland et al, unpublished data; Riemann and Berger 1989; Rush et al 1986; Schultz et al 1979; Steiger et al 1989; Thase et al 1994), there is an emerging consensus that EEG sleep disruptions associated with depression are remarkably stable from episode to recovery. It is possible, however, that some EEG sleep changes (or their severity) are state related, and that the changes are too subtle to be detected by visual scoring methods (Buysse et al 1992). Nevertheless, the consensus from the above-mentioned studies that some EEG sleep differences may be trait markers for depression is supported by the demonstration of sleep abnormalities prior to the first episode of depression (Giles and Kupfer 1994; Ran et al 1996), as well as in healthy subjects with high familial risk for depression (Lauer et al 1995; McCracken et al, unpublished data). In contrast to the stability of sleep measures, studies examining HPA function highlight the state-related quality of this system in relation to adult depression (Gerken et al 1985; Greden et al 1983; Holsboer et al 1982; Steiger et al 1989; Targum 1983). In the reported sample, there was a trend for slow-wave sleep to be further reduced during recovery. Similarly, in an EEG sleep study of prepubertal depression, Puig-Antich et al (1983) had observed significantly reduced REM latency in recovered chil-
dren compared to their depressive state, suggesting that shortened REM latency (or possibly reduced delta sleep) is a "scar" marker for previous depressive episode(s) or recurrence risk. It is to be noted, however, that developmental effects on EEG sleep (including REM latency and slow-wave sleep) are profound (Dahl et al 1990; Knowles and MacLean 1990). In the study by Puig-Antich et al (1983) as well as in our study, the chronological age of the depressed patients at the time of follow-up evaluation was greater than 6 months compared to their age at initial assessment. In this sample, we have found a modest correlation between age and stage 4 sleep (r = -.65). Longitudinal investigations with large samples of depressed as well as healthy youngsters can be potentially helpful in separating normative developmental changes from the effects of clinical course. Our finding of normalization of HPA function in remitted state is at variance with that of Puig-Antich et al (1989), where 24-hour plasma cortisol in prepubertal depressed patients did not differ between episode and recovery states. Given the high documented relapse potential of juvenile depressives, it is possible that absence of change in plasma cortisol values during recovery in earlier samples of prepubertal patients reflected a potential for relapse (Rao et al 1996; Targum 1983), rather than a difference in psychobiology of the disorder from adults. As noted in previous studies, there was an inverse relationship between REM latency and cortisol measures (Poland et al 1992; Rao et al 1996). Other sleep measures (e.g., awake time and stage 1 sleep) were also correlated with urinary cortisol, suggesting
372
BIOLPSYCHIATRY 1997;41:369-373
that sleep and HPA axis may be regulated through a common mechanism in depression. In summary, this investigation has shown that EEG sleep parameters in adolescent depression appear to be stable from episode to recovery, whereas measures of HPA function are state related. These results are quite preliminary, but support the continuity of some sleep and HPA abnormalities between adolescent and adult depression.
Brief Reports
This study was supported in part by grants MH00722, MH34471, and MH00534 from the National Institute of Mental Health, and the General Clinical Research Center Grant RR00425 from the National Institutes of Health. The authors thank Ms. Debbie Hanaya and Ms. Margie Greenwald for their expert administrative assistance.
References Buysse DJ, Kupfer DJ, Frank E, Monk TH, Ritenour A (1992): Electroencephalographic sleep studies in depressed outpatients treated with interpersonal psychotherapy: II. Longitudinal studies at baseline and recovery. Psychiatry Res 40:2740. Dahl RE, Puig-Antich J, Ryan ND, et al (1990): EEG sleep in adolescents with major depression: The role of suicidality and inpatient status. J Affect Disord 19:63-75. Dahl RE, Kaufman J, Ryan ND, et al (1992): The dexamethasone suppression test in children and adolescents: A review and a controlled study. Biol Psychiatry 32:109-126. Gerken A, Maier W, Holsboer F (1985): Weekly monitoring of dexamethasone suppression response in depression: Its relationship to change of body weight and psychopathology. Psychoneuroendocrinology 10:261-271. Giles DE, Kupfer DJ (1994): Reduced REM latency: Risk factor for first episode of depression. Sleep Res 23:197. Giles DE, Etzel BA, Reynolds CF, Kupfer DJ (1989): Stability of polysomnographic parameters in unipolar depression: A cross-sectional report. Biol Psychiatry 25:807-810. Giles DE, Jarrett RB, Rush AJ, Biggs MM, Roffwarg HP (1993): Prospective assessment of EEG sleep in remitted major depression. Psychiatry Res 46:269-284. Greden JF, Gardner R, King D, Grunhaus L, Kronfol G, Carroll BJ (1983): Dexamethasone suppression tests in antidepressant treatment of melancholia: The process of normalization and test-retest reproducibility. Arch Gen Psychiatry 40:493500. Hauri P, Chernik D, Hawkins D, Mendels J (1974): Sleep in depressed patients in remission. Arch Gen Psychiatry 31: 386-391. Holsboer F (1995): Neuroendocrinology of mood disorders. In Bloom FE, Kupfer DJ (eds), Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, pp 957-969. Holsboer F, Liebl R, Hofschuster E (1982): Repeated dexamethasone during depressive illness: Normalization of test result compared with clinical improvement. J Affect Disord 4:93101. Knowles JB, MacLean AW (1990): Age-related changes in sleep in depressed and healthy subjects. Neuropsychopharmacology 3:251-259. Kupfer DJ, Frank E, Grochocinski VJ, Gregor M, McEachran AB (1988): Electroencephalographic sleep profiles in recurrent depression: A longitudinal investigation. Arch Gen Psychiatry 45:678-681.
Lauer CJ, Schreiber W, Holsboer F, Krieg J-C (1995): In quest of identifying vulnerability markers for psychiatric disorders by all-night polysonmography. Arch Gen Psychiatry 52:145153. Lee JH, Reynolds CF, Hoch CC, et al (1993): Electroencephalographic sleep in recently remitted, elderly depressed patients in double-blind placebo-maintenance therapy. Neuropsychopharmacology 8:143-150. McCracken JT, Poland RE, Lutchmansingh P, Edwards C (in press): Sleep EEG abnormalities in adolescent depressives: Effects of scopolamine. Biol Psychiatry. Poland RE, McCracken JT, Lutchmansingh P, Tondo L (1992): Relationship between REM sleep latency and nocturnal cortisol concentrations in depressed patients. J Sleep Res 1:5457. Poland RE, McCracken JT, Lutchmansingh P, et al (in press): Differential response of REM sleep to cholinergic blockade by scopolamine in currently depressed, remitted, and normal control subjects. Biol Psychiatry. Puig-Antich J, Goetz R, Hanlon C, Tabrizi MA, Davies M, Weitzman ED (1983): Sleep architecture and REM sleep measures in prepubertal major depressives: Studies during recovery from the depressive episode in a drug-free state. Arch Gen Psychiatry 40:187-192. Puig-Antich J, Dahl R, Ryan N, et al (1989): Cortisol secretion in prepubertal children with major depressive disorder: Episode and recovery. Arch Gen Psychiatry 46:801-809. Rao U, Dahl RE, Ryan ND, et al (1996): The relationship between longitudinal clinical course and sleep and cortisol changes in adolescent depression. Biol Psychiatry 40:474484. Rechtschaffen A, Kales A (1968): A Manual of Standardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects. Bethesda, MD: National Institutes of Health. Reynolds CF, Kupfer DJ (1987): Sleep research in affective illness: State of the art circa 1987. Sleep 10:199-215. Riemann D, Berger M (1989): EEG sleep in depression and in remission and the REM sleep response to the cholinergic agonist RS 86. Neuropsychopharmacology 2:145-152. Rubin RT, Poland RE, Lesser IM, Winston RA, Blodgett N (1987): Neuroendocrine aspects of primary endogenous depression: I. Cortisol secretory dynamics in patients and matched controls. Arch Gen Psychiatry 44:328-336. Rush AJ, Erman MK, Giles DE, et al (1986): Polysomnographic
Brief Reports
findings in recently drug-free and clinically remitted depressed patients. Arch Gen Psychiatry 43:878-884. Schulz H, Lund R, Cording C, Dirlich G (1979): Bimodal distribution of REM sleep latencies in depression. Biol Psychiatry 14:595-600. Steiger A, von Bardeleben U, Herth T, Holsboer F (1989): Sleep EEG and nocturnal secretion of cortisol and growth hormone in male patients with endogenous depression before treatment and after recovery. J Affect Disord 16:189-195. Targum SD (1983): The application of serial neuroendocrine
BIOLPSYCHIATRY 1997;41:369-373
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challenge studies in the management of depressive disorder. Biol Psychiatry 18:3-19. Thase ME, Reynolds CF, Frank E, et al (1994): Polysomnographic studies of unmedicated depressed men before and after treatment with cognitive behavior therapy. Am J Psychiatry 151:1615-1622. Thase ME, Kupfer DI, Buysse DJ, et al (1995): Electroencephaiographic sleep profiles in single-episode and recurrent unipolar forms of major depression: I. Comparison during acute depressive states. Biol Psychiatry 38:506-515.
Adolescence, depression, sleep, cortisol, episode, recovery
BIOL PSYCHIATRY 1997;41:369-373
Introduction Electroencephalographic (EEG) sleep and hypothalamic-pituitary-adrenal (HPA) axis changes associated with adult major depressive disorder (MDD) are among the best replicated findings in biological psychiatry (Holsboer 1995; Reynolds and Kupfer 1987). More recently, attention has shifted to the question as to whether or not sleep and HPA axis changes observed in depression are exclusively present during the depressive episode (state related) or may persist after clinical remission (traitlike). The delineation of state-dependent and state-independent correlates of depression would be relevant for models of biologic vulnerability, course of illness, and prediction of treatment response. Longitudinal studies of adult depressed patients have shown that most EEG sleep measures are relatively stable from episode to clinical remission (Buysse et al 1992; Giles et al 1993; Lee et al 1993; Riemann and Berger 1989; Rush et al 1986; Schultz et al 1979; Steiger et al 1989; Thase et al 1994). In contrast, changes in the HPA axis appear to be state-related (Gerken et al 1985; Greden et al 1983; Holsboer et al 1982; Steiger et al 1989; Targum 1983). In contrast to adults, the question of whether EEG sleep and HPA axis changes are associated with adolescent depression From the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California (JTM, PL, CE, REP); and Department of Psychiatry and Biobehavioral Sciences, UCLA Neuropsychiatric InstitUte, Los Angeles, California (UR, JTM, REP). Address reprint requests to Uma Rao, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759. Received February 5, 1996; revised September 6, 1996.
© 1997 Society of Biological Psychiatry
remains unsettled. Studies have reported inconsistent differences between depressed and control subjects (for reviews, see Dahl et al 1990, 1992; McCracken et al 1996). Aside from methodological differences in assessment procedures, clinical course may contribute significant variance to observed changes in EEG sleep as well as HPA axis function in adolescent cohorts (Rao et al 1996 ). Therefore, longitudinal sleep and neuroendocrine studies not only would be potentially useful in advancing our knowledge of the etiology and pathophysiology of juvenile mood disorders, but may also be helpful in the clarification of developmental continuities and discontinuities in the psychobiology of affective disorders. In this preliminary communication, we report on EEG sleep and nocturnal urinary free cortisol (UFC) in 5 adolescent subjects studied during an episode of MDD as well as in remission. These subjects were included as part of a larger controlled study of EEG sleep and neuroendocrine function in adolescent and adult depression. Baseline sleep findings in the larger adolescent sample (n = 20) have been described (McCracken et al, in press).
Methods and Materials The methods for the initial study have been described in detail elsewhere (McCracken et al, in press), and are reviewed here briefly. When depressed, all 5 subjects (4 female and 1 male) had fulfilled DSM-III-R criteria for MDD by clinical as well as structured (the Schedule for Affective Disorders and Schizophrenia for School-Age Children, K-SADS-E) interviews. Severity 0006-3223/97/$17.00 PII S0006-3223(96)00430-1
370
BIOL PSYCHIATRY 1997;41:369-373
ratings on the Hamilton Depression Rating Scale (HDRS) indicated that the depressive symptoms were of moderate to severe degree (20.4 ± 4.6; range 15-29). All 5 subjects were outpatients. Of the 5 adolescents, 4 were in their first episode of depression and 1 patient had two prior episodes. None of the subjects had a previous history of mania, hypomania, or substance abuse. The mean age of the sample was 16.2 ± 1.9 (range 14-19) years. The sleep and neuroendocrine protocol consisted of two 2-night sessions, spaced approximately 1 week apart. Night 1 was considered an adaptation night. On night 2, at 11:00 PM immediately prior to lights out, subjects were administered either saline or scopolamine (4.5 I~g/kg) by intramuscular injection in a double-blind randomized fashion. Urine was collected from 11:00 PM-7:00 AM. Sleep records were scored visually in 30-sec epochs using the standardized criteria reported by Rechtschaffen and Kales (1968). UFC was assayed using the radioimmunoassay method as described previously (Rubin et al 1987). For reinvestigation during remission, the study criteria included: 1) complete remission from MDD for -->3 months; 2) medication-free for a minimum of 6 months; 3) a HDRS score <--6 on six consecutive evaluations performed at 2-week intervals; and 4) normal physical examination and laboratory tests. To ensure that the subjects were potentially not at risk for recurrence at the time of sleep studies, they continued to have clinical evaluations every 2 weeks for 3 additional months after completion of the sleep studies.
Statistical Analysis For this report, sleep and UFC data only from the placebo night will be presented. REM latency was defined as the time between the first minute of stage 2 or deeper sleep (followed by at least 9 rain of stage 2 or deeper sleep, and interrupted by no more than 1 rain of waking or stage 1) and the first REM period greater than or equal to 3 min. Use of other definitions of REM latency (more lenient criteria as well as controlling for any intervening awake time) did not lead to significant changes in values. Since the study used a within-subject repeated-measures design, the T~ and T 2 measures from the depressed subjects were compared using paired two-tailed t tests. Sleep and UFC variables only from night 2 were included in the analyses. As a second test of stability, the primary dependent variables (from TI and T z) were examined by scatterplots, and Pearson's productmoment correlation coefficients were calculated. All analyses were performed on log-transformed data. To examine the association between EEG sleep and UFC measures, Pearson's product-moment correlation coefficients were calculated for these variables at Ta and T 2.
Results Sample Characteristics at Follow-Up The sleep and UFC assessments during the recovery phase were performed approximately 18.8 ± 10•9 (range 8-31) months after
Brief Reports
the initial protocol. The mean HDRS score at follow-up was 0.4 --_ 0.6 (range 0-1). Four of the 5 patients had received no psychotropic medication and were treated with psychosocial interventions. One subject, treated with amitriptyline, was medication-free for 6 months. None of the subjects had a relapse or recurrence since the index assessment.
Effect of Depressive State on Baseline EEG Sleep and Urinary Free Cortisol As shown in Table 1, with the exception of a decrease in awake time during recovery (31.9 - 26.7 rain during the episode and 9.6 -+ 6.8 min on recovery, t4 = 2.92, p --< .05), there were no significant differences in sleep continuity, sleep architecture, or REM sleep measures from episode to recovery. Stage 4 sleep showed a trend for reduction during the recovery state (20.9 ± 4.6 vs. 15.9 ± 6.1, t4 = 2.26,p <- .10). All major sleep variables showed modest to high correlations between pre- and postassessments (e.g., r = .82 for REM latency; r = .69 for stage 4 sleep), with the exception of sleep continuity (Pearson r ranging .25 .74) and REM density (r = .09) measures. With respect to nocturnal UFC, both measures of excretion were significantly diminished during the recovery phase compared to the depressive state (mean 11.0 I~g with a standard deviation of 9.3 during the episode and 3.9 - 1.9 Ixg on recovery for total excretion, t4 = 3.00, p -< .05; 50.7 - 46.5 ng/mL and 13.1 ± 4.7, respectively for UFC concentration, t4 = 2.68, p -< •10). There was a high correlation between T 1 and T 2 evaluations for total UFC excretion (r = .81).
Relationship between EEG Sleep and UFC Measures Examination of the association between EEG sleep and UFC measures during episode and recovery times showed that stage 1 sleep was significantly correlated with total UFC during the episode (r = .93, p <- .05). Total UFC was modestly correlated with awake time during the depressive phase (r = .51, ns). Total UFC was also associated with REM latency during the depressive as well as the remission states (r = - . 6 4 during the depressive episode; r = - . 5 5 during recovery).
Discussion To our knowledge, this is the first study to report on EEG sleep and UFC measures in adolescent depression during episode and in remission. The findings of the study are very tentative due to the small sample size; however, the results from this preliminary ongoing investigation suggest that, in this limited sample, most sleep variables in adolescent depression remain relatively stable from episode to recovery (traitlike), whereas UFC measures may be state related. The results from this study are comparable to findings from investigations with adult patients• From various samples of adult depressives, including cross-sectional comparison of remitted patients with healthy controls (Hauri et al 1974;
Brief Reports
BIOL PSYCHIATRY 1997;41:369-373
371
Table 1. Selected EEG Sleep and Urinary Cortisol Measures in Depressed and Remitted Adolescents Variables Sleep continuity Total study time (min) Total sleep time (min) Sleep latency (min) Sleep efficiency (%) Number of arousals Awake time (min) Sleep architecture Stage 1 (%) Stage 2 (%) Stage 3 (%) Stage 4 (%) REM sleep (%) REM sleep REM latency (min) REM activity (units) REM density (ut/min) REM duration (rain) Number of episodes Nocturnal UFC Total (~g) ng/mL of urine
MDD subjects in episode
MDD subjects in remission
T I VS. T 2 (paired t)
T t vs. T 2 (Pearson r)
477.6 445.7 _ 13.2 93.0 16.6 ± 31.9 ±
460.7 - 16.0 444.9 _+ 12.1 10.3 _ 6.1 96.0 ___2.0 23.6 __ 23.8 9.6 +- 6.8
2.23`" 0.03 0.07 -1.28 -0.13 2.92b
-.33 .69 -.25 .28 .74 .26
3.1 ___2.0 49.9 _+ 3.1 4.3 ± 1.8 15.9 ± 6.1 26.6 - 7.5
-0.38 -1.44 0.45 2.26" -0.72
.73 .31 -.36 .69 .59
-1.42 -0.84 -0.66 -0.57 1.89
.82 -.50 -.09 .46 .81
2.6 47.4 4.8 20.9 24.1
2.3 26.0 11.8 6.0 7.9 26.7
± 1.5 _ 3.5 +_ 1.6 - 4.6 _ 4.0
83.3 -+ 34.0 229.8 -+ 117.1 2.1 - 0.9 109.6 + 22.0 4.6 -+ 0.6 11.0 -+ 9.3 50.7 - 46.5
93.8 268.8 2.5 119.1 4.0
_+ 30.3 _+ 51.7 _+ 1.0 ± 34.5 +_ 1.2
3.9 _+ 1.9 13.1 ± 4.7
3.00b 2.68a
.81 -.22
Values are actual mean ± SD for comparison purposes; transformations were performed prior to tests of significance. UFC, urinary free cortisol; ut, units; min, minute.
Op<- .10. bp < .05.
Poland et al in press), single-episode cases versus those with recurrent illness (Giles et al 1989; Thase et al 1995), and prospective follow-up of individual subjects through recovery or into a subsequent episode (Buysse et al 1992; Giles et al 1993; Kupfer et al 1988; Lee et al 1993; Poland et al, unpublished data; Riemann and Berger 1989; Rush et al 1986; Schultz et al 1979; Steiger et al 1989; Thase et al 1994), there is an emerging consensus that EEG sleep disruptions associated with depression are remarkably stable from episode to recovery. It is possible, however, that some EEG sleep changes (or their severity) are state related, and that the changes are too subtle to be detected by visual scoring methods (Buysse et al 1992). Nevertheless, the consensus from the above-mentioned studies that some EEG sleep differences may be trait markers for depression is supported by the demonstration of sleep abnormalities prior to the first episode of depression (Giles and Kupfer 1994; Ran et al 1996), as well as in healthy subjects with high familial risk for depression (Lauer et al 1995; McCracken et al, unpublished data). In contrast to the stability of sleep measures, studies examining HPA function highlight the state-related quality of this system in relation to adult depression (Gerken et al 1985; Greden et al 1983; Holsboer et al 1982; Steiger et al 1989; Targum 1983). In the reported sample, there was a trend for slow-wave sleep to be further reduced during recovery. Similarly, in an EEG sleep study of prepubertal depression, Puig-Antich et al (1983) had observed significantly reduced REM latency in recovered chil-
dren compared to their depressive state, suggesting that shortened REM latency (or possibly reduced delta sleep) is a "scar" marker for previous depressive episode(s) or recurrence risk. It is to be noted, however, that developmental effects on EEG sleep (including REM latency and slow-wave sleep) are profound (Dahl et al 1990; Knowles and MacLean 1990). In the study by Puig-Antich et al (1983) as well as in our study, the chronological age of the depressed patients at the time of follow-up evaluation was greater than 6 months compared to their age at initial assessment. In this sample, we have found a modest correlation between age and stage 4 sleep (r = -.65). Longitudinal investigations with large samples of depressed as well as healthy youngsters can be potentially helpful in separating normative developmental changes from the effects of clinical course. Our finding of normalization of HPA function in remitted state is at variance with that of Puig-Antich et al (1989), where 24-hour plasma cortisol in prepubertal depressed patients did not differ between episode and recovery states. Given the high documented relapse potential of juvenile depressives, it is possible that absence of change in plasma cortisol values during recovery in earlier samples of prepubertal patients reflected a potential for relapse (Rao et al 1996; Targum 1983), rather than a difference in psychobiology of the disorder from adults. As noted in previous studies, there was an inverse relationship between REM latency and cortisol measures (Poland et al 1992; Rao et al 1996). Other sleep measures (e.g., awake time and stage 1 sleep) were also correlated with urinary cortisol, suggesting
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that sleep and HPA axis may be regulated through a common mechanism in depression. In summary, this investigation has shown that EEG sleep parameters in adolescent depression appear to be stable from episode to recovery, whereas measures of HPA function are state related. These results are quite preliminary, but support the continuity of some sleep and HPA abnormalities between adolescent and adult depression.
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This study was supported in part by grants MH00722, MH34471, and MH00534 from the National Institute of Mental Health, and the General Clinical Research Center Grant RR00425 from the National Institutes of Health. The authors thank Ms. Debbie Hanaya and Ms. Margie Greenwald for their expert administrative assistance.
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