The Relationship Between Longitudinal Clinical Course and Sleep and Cortisol Changes in Adolescent Depression

Uma Rao, Ronald E. Dahl, Neal D. Ryan, Boris Birmaher, Douglas E. Williamson,

Donna E. Giles, Radhika Rao, Joan Kaufman, and Beverly Nelson

This study examined the relationship between longitudinal clinical course and sleep and cortisol findings in adolescent unipolar major depressive disorder (MDD). Subjects were 28 adolescents (15.4 +- 1.3 years) systematically diagnosed with unipolar MDD and 35 group-matched normal controls who participated in EEG sleep and neuroendocrine studies. Follow-up clinical assessments were conducted 7.0 + 0.5 years later in 94% of the original cohort. Although initial group comparisons failed to show significant differences in biologic measures, analyses incorporating clinical follow-up reveal that changes in sleep and cortisoI measures are associated with differential longitudinal course. Normal controls who would develop depression after the biologic studies had shown significantly higher density of rapid eye movements (REM) and a trend for reduced REM latency compared to controls with no psychiatric disorder at follow-up. Depressed subjects with a recurrent unipolar course showed a trend towards elevated plasma cortisol near sleep onset compared to MDD subjects with no further episodes during the follow-up interval.

Key Words: Depression, adolescent, onset, recurrence, EEG sleep, cortisol

BIOL PSYCHIATRY 1996;40:474--484

Introduction We have conducted a controlled follow-up study of a cohort of well-characterized adolescents with unipolar major depression and group-matched normal controls with a clinical reassessment in early adulthood. Subjects were initially studied using systematic diagnostic and multidi-

From the University of Pittsburgh School of Medicine, Western Psychiatric Institute & Clinic, Pittsburgh, PA.

Address reprint requests to Uma Rao, Department of Psychiatry and Biobehavioral Sciences, UCLA Neuropsychiatric Institute and Hospital, Room 68-237, 760 Westwood Plaza, Los Angeles, CA 90024-1759.

Received May 8, 1995; revised August 10, 1995.

mensional psychobiologic (EEG sleep and neuroendo- crine) assessments during adolescence. Initial comparison of depressed and control groups did not show significant differences on any of the major sleep or cortisol variables. Six to eight years after the initial study, clinical course and psychiatric outcome were assessed in both depressed and control groups. The predictive utility of EEG sleep and neuroendocrine regulation with regard to the longitudinal clinical course was examined in this report.

EEG sleep changes associated with adult major depres- sive disorder (MDD) are among the best replicated find- ings in biological psychiatry (Reynolds and Kupfer 1987).

© 1996 Society of Biological Psychiatry 0006-3223/96/$15.00 SSDI 0006-3223(95)00481-5

Sleep, Cortisol and Adolescent Depression BIOL PSYCHIATRY 475 1996;40:474-484

The most reliable and predictable sleep abnormalities of adult depression include sleep continuity disturbances, earlier onset of rapid eye movement (REM) sleep, in- creased REM time, higher REM density, and diminished slow-wave sleep (Reynolds and Kupfer 1987). Similarly, numerous investigations have presented evidence of hy- pothalamic-pituitary-adrenal (HPA) axis dysregulation and/or cortisol hypersecretion in adult major depression (Halbreich et al 1985; Holsboer 1989; Jarrett et al 1983; Kathol et al 1989; Linkowski et al 1985; Pfohl et al 1985; Rubin et al 1987; Young et al 1994).

In contrast to the well-replicated abnormalities in EEG sleep and plasma cortisol in adult depression, controlled investigations of adolescent cohorts with MDD have shown relatively few EEG sleep or cortisol changes. Although none of the adolescent studies showed the full constellation of EEG sleep findings in adult depression, individual abnormalities have been observed in some studies. Of nine controlled adolescent sleep investigations, only five studies have found reduced REM latency, with two studies observing higher REM density and three studies reporting decreased sleep efficiency (Appelboom- Fondu et al 1988; Dahl et al 1990, 1995; Emslie et al 1994; Goetz et al 1987; Khan and Todd 1990; Kutcher et al 1992; Lahmeyer et al 1983; Riemann et al 1995). Five of the studies reported longer sleep latency associated with depression, two studies found increase in the number of REM periods and none observed changes in slow-wave sleep. Cashman and colleagues (1986) reported higher REM density in depressed adolescents compared to his- torical controls studied in the same laboratory.

With respect to plasma cortisol, one study reported elevated cortisol secretion surrounding sleep onset, when the HPA axis is normally quiescent, which occurred largely in a subgroup of suicidal/inpatient depressed ado- lescents (Dahl et al 1991). Two other adolescent studies found no differences in baseline cortisol secretion between depressed and control subjects (Dahl et al 1989; Kutcher et al 1991). Nonsuppression of cortisol to exogenous dexa- methasone (DST nonsuppression) is also infrequent in adolescent MDD (for a review, see Dahl et al 1992). Taken together, these results suggest that the adult pattern of EEG sleep and plasma cortisol abnormalities are only variably expressed in adolescent depression; that is, there is substantial heterogeneity in sleep and HPA axis findings in adolescent cohorts.

Several possibilities have been considered to explain the variability in sleep and cortisol findings in depressed adolescents. One prominent factor is the role of matura- tion. Both EEG sleep and the HPA system are profoundly influenced by maturational changes (Ehlers and Kupfer 1989; Feinberg 1974; Gillin et al 1981; Halbreich et al 1984; Knowles and MacLean 1990; Lauer et al 1991).

Further, alterations associated with depression are similar to those associated with normal aging (Davis et al 1984; Gillin et al 1981; Halbreich et al 1984; Reynolds and Kupfer 1987; Ulrich et al 1980). Evidence from cross- sectional data across the life span suggest that age and depression may interact to produce sleep and cortisol abnormalities in major depression (Asnis et al 1981; Benca et al 1992; Gillin et al 1981; Goetz et al 1987, 1991; Halbreich et al 1984; Keitner et al 1992; Knowles and MacLean 1990; Maes et al 1991). In addition to physio- logic maturity, familial/genetic influences on sleep and HPA axis regulation together with familial loading for depression may contribute significant variance to observed changes in EEG sleep and plasma cortisol (Giles et al 1989, 1992; Krieg et al 1990; Lauer et al 1995).

Another possibility for discrepant findings in sleep and plasma cortisol in depressed adolescents is greater heter- ogeneity in the clinical spectrum of early onset depression (Dahl et al 1990). For example, rates of future bipolar disorder are increased in adolescent depression when compared to adult samples (Akiskal et al 1983; Geller et al 1994; Kovacs and Gatsonis 1989; Strober and Carlson 1982; Strober et al 1993). In adults, sleep and cortisol changes have been best replicated in patients with unipolar MDD, whereas findings in bipolar depression are more variable (Giles et al 1986; Lauer et al 1992; Linkowski et al 1985; Schatzberg et al 1983; Thase et al 1989). Furthermore, it has recently been shown in adults that certain sleep abnormalities (e.g., reduced REM latency) may be present prior to the onset of first MDD episode (Giles and Kupfer 1994). It is possible that at least in some controlled adolescent sleep studies, inclusion of depressed adolescents with latent bipolar disorder and/or normal subjects who are at risk for depression may mask differ- ences between "depressed" and "control" groups.

EEG sleep and/or cortisol measures in depressed ado- lescent subjects may vary with respect to clinical course. For instance, certain sleep abnormalities, including re- duced REM latency and diminished slow-wave sleep were more prominent in adult depressed patients who may be vulnerable to recurrent MDD episodes (Giles et al 1987a; Grunhaus et al 1994; Kupfer et al 1990; Reynolds et al 1989). Similarly, other investigators have reported that higher cortisol secretion and persistent nonsuppression of cortisol in response to dexamethasone predicted recur- rence of depressive episodes (Charles et al 1989; Holsboer et al 1983; Jarrett et al 1983; Papakostas et al 1981; Schweitzer et al 1987; Targum 1983).

In summary, specific factors that mediate the high variability among sleep and cortisol studies in depressed adolescents have not been clearly delineated; however, there is preliminary support for the role of maturation, familial/genetic factors, and longitudinal clinical course as

476 BIOL PSYCHIATRY U. Rao et al 1996:40:474-484

important factors. This study was specifically designed to: 1) examine the utility of sleep and cortisol findings as predictors of outcome in both depressed and normal adolescents; and 2) reassess initial sleep and cortisol data based on refinements of diagnosis with information from prospective clinical course.

Methods and Materials

Methods for the Initial Study

The methods for the initial study have been described in detail elsewhere (Dahl et al 1990, 1991), and are reviewed here briefly. The assessments for the depressed cohort included present episode and lifetime diagnoses versions of the Schedule for Affective Disorders and Schizophrenia for school-age children both with the adolescent and a parent (K-SADS-P, Chambers et al 1985; K-SADS-E, Orvaschel et al 1982). A second K-SADS-P was repeated 10-14 days later by an independent clinician, "blind" to the earlier assessment, to establish the stability of depres- sive and other symptoms. Normal controls were assessed with the K-SADS-E using the adolescent and a parent as informants. All subjects had comprehensive pediatric as- sessments, including medical history, physical examina- tion, and laboratory tests.

The depressed subjects were included in the study if they met Research Diagnostic Criteria (RDC) (Spitzer et al 1978) for MDD on both K-SADS-P evaluations. De- pressed adolescents with a previous or current history of mania and/or hypomania were excluded. Normal controls were included only if they had no evidence of current or past psychiatric disorder. All adolescents were between the ages of 12-18 and Tanner Stage III, IV or V of pubertal development (Marshall and Tanner 1969, 1970).

Exclusion criteria for both groups included medication or substance use in the past 2 weeks, significant medical or neurologic illness, weight greater than 150% of ideal body weight for age and sex, weight or height less than the third percentile, and IQ less than 70. In addition, depressed adolescents who met DSM-III criteria (American Psychi- atric Association 1980) for anorexia nervosa, bulimia nervosa, autism, schizophrenia, and/or schizoaffective dis- order were excluded.

Sleep and Neuroendocrine Protocol for the Initial Study

The sample consisted of 28 subjects (10 males and 18 females) with unipolar MDD (15.4 ___ 1.3 years) and 35 normal controls (14 males and 21 females), matched for age and sex, studied in the Child/Adolescent Sleep and Neuroendocrine Laboratory. Sleep was recorded polysom- nographically for 3 consecutive nights using methods described previously (Dahl et al 1990). Sleep records were

scored visually in 30-second epochs using the standard- ized criteria reported by Rechtschaffen and Kales (1968). An indwelling venous catheter was inserted the morning after the second night of sleep for 24-hour neuroendocrine study overlapping with the third night of sleep. Blood samples for cortisol assays were drawn at 20-minute intervals through a three-way stop-cock system (Dahl et al 1991). Cortisol levels were determined by radioimmuno- assay (RIA).

Overview of Initial EEG Sleep and Plasma Cortisol Findings

Group comparisons between the depressed subjects and normal controls had not revealed statistically significant differences for any of the major sleep summary variables (Dahl et al 1990); however, a subgroup of MDD adoles- cents who were suicidal (n = 11/28, 39%) (the majority of whom were inpatients) had significantly prolonged sleep latency and increased REM density with a trend for reduced REM latency compared to both nonsuicidal de- pressed and control groups (Dahl et al 1990). In addition, the suicidal depressed subjects had a significantly higher percentage of 24-hour cortisol secretion within 180 min- utes of sleep onset compared to nonsuicidal depressed patients and normal controls (Dahl et al 1991). Estimates of depressive severity or type of depression (including endogenous vs. nonendogenous, melancholic vs. nonmel- ancholic, and psychotic vs. nonpsychotic) did not account for the sleep or cortisol changes in the suicidal/inpatient subjects (Dahl et al 1990, 1991).

Follow-up Methods

Sample

All 28 subjects initially identified with unipolar MDD and the 35 normal controls were located. Twenty-six subjects from the depressed group (93% of the original cohort) and 33 normal controls (94%) consented and completed the clinical follow-up study. The depressed group consisted of 9 men and 17 women (19 white/7 nonwhite) with a mean age of 22.4 - 1.5 years. There were 13 men and 20 women (31 white/2 nonwhite) with a mean age of 21.9 +- 1.7 years in the control group.

Assessment of Major Psychiatric Disorders

Lifetime diagnoses of major psychiatric disorders were ascertained using the Schedule for Affective Disorders and Schizophrenia--Lifetime version (SADS-L) (Spitzer and Endicott 1978), and supplemented with the K-SADS-E to obtain information on childhood-onset disorders (Orvas- chel et al 1982). The SADS-L was modified to obtain information on the age of onset, duration, symptom

Sleep, Cortisol and Adolescent Depression BIOL PSYCHIATRY 477 1996;40:474 -484

severity, and treatment for each MDD episode. Evalua- tions were made "blind" to the original diagnostic and psychobiologic status by three experienced clinical inter- viewers. Information was obtained from both the proband and a parent. All interviews were audiotaped. Consensus diagnoses were made taking information from both inter- views and using the DSM-III-R criteria (American Psy- chiatric Association 1987), with the additional require- ment for evidence of help-seeking and/or functional impairment in work, school, familial and/or extra-familial relationships. Discrepancies were resolved by reinterview- ing both informants. Medical records were obtained in cases where there was previous treatment.

All the audiotapes were reviewed by an independent child psychiatrist (UR) along with the available medical records. "Best estimate" of the number of previous epi- sodes of MDD and other psychiatric diagnoses were made using the DSM-III-R criteria with additional requirement for functional impairment, using information from all available sources (Leckman et al 1982). To examine the reliability of "best estimate" diagnoses, 20% of the inter- view tapes were randomly selected and reviewed by another independent child psychiatrist (BB). The concor- dance of "best estimate" diagnoses was 100%.

Clinical Outcome at Follow-up

Major findings of clinical outcome at follow-up have been described (Rao et al 1995). Based on our a priori hypoth- esis that one possibility for variable sleep and cortisol findings in unipolar depressed adolescent cohorts was latent bipolar disorder (Dahl et al 1990), MDD subjects who switched to bipolar disorder (n = 5) were removed from data analyses. Also excluded were controls who developed a major psychiatric disorder other than a diag- nosis of unipolar depression (n = 3) (all three had primary substance abuse disorder). The remaining unipolar de- pressed group (n = 21) was then divided into those who had no further depressive episodes over the follow-up period (n = 6, 29%) and those who continued to have a recurrent unipolar course (n = 15, 71%). The controls (n -: 30) were separated into those with no lifetime major psychiatric disorder at follow-up (n = 23, 77%) and those who developed unipolar depression over the interval period (n = 7, 23%).

Choice of Biologic Variables and Statistical Methods

Prior to any analyses incorporating clinical course infor- mation, a decision was made to focus on a small subset of biologic variables from the original study. This decision was made because of the potentially large number of

statistical comparisons and relatively modest sample sizes available. Four summary variables were selected for these analyses based on those variables which had appeared promising in subgroup analyses in the original studies (Dahl et al 1990, 1991). These included three variables from the baseline night (night 2) EEG sleep measures (sleep latency, REM latency, and REM density), and one variable from the 24-hour plasma cortisol (collected on day 3 and night 3) focusing on the 180-minute window surrounding sleep onset. These four variables were then examined in relation to clinical diagnoses over the fol- low-up interval.

Sleep data had been incomplete due to technical diffi- culties in two subjects from the initial MDD group and five initial controls, reducing the sample sizes to 19 and 25, respectively, for sleep analyses. There were more than 8 missing data points for plasma cortisol (out of a total of 72 draws) in two MDD subjects and two controls, reduc- ing the sample sizes to 19 and 28, respectively for the cortisol analyses. The problem of missing data was mini- mal in the remaining cases.

For all summary variables, data were examined for normality using the Shapiro-Wilk's W statistic (Shapiro and Wilk 1965). In cases of significantly non-normal distributions, logarithm transformations were performed to normalize the data prior to the application of statistical tests for significance. One-way analysis of variance (ANOVA) was utilized for group comparisons on contin- uous variables. Group comparisons for categorical vari- ables were done using Yates corrected chi square test (X2), and Fisher's Exact Test (FET) was used when the mini- mum estimated cell size for any cell was 5 or less. Associations between dimensional variables were exam- ined using the Pearson's product moment correlation test. All statistical tests were two-tailed with alpha set at 0.05.

The four groups identified at follow-up were: 1) MDD subjects with no further depressive episodes during the follow-up interval; 2) MDD subjects with a recurrent unipolar course; 3) controls with no lifetime disorder at follow-up; and 4) controls with new onset unipolar depres- sion. Groups were compared on demographic characteris- tics and were not significantly different with respect to age at initial study, follow-up interval, sex distribution or racial composition. The four groups were then compared on the four EEG sleep and plasma cortisol measures described above.

Results

Relationship Between Prospective Clinical Course and Adolescent Sleep and Cortisol Measures

The mean sleep and cortisol values for the four groups are presented in Table 1. As shown in Table 1, there was

478 BIOL PSYCHIATRY U. Rao et al 1996;40:474-484

Table 1. Adolescent EEG Sleep and Plasma Cortisol Measures, and Clinical Outcome at Follow-up a

Variables

MDDs with no MDDs with Controls who Controls with no further episodes recurrent unipolar developed psychopathology

at follow-up course depression at follow-up (n = 6) (n = 13) (n = 5) (n = 23) b F p

Sleep latency c 17.9 - 19.9 25.0 ± 13.5 21.6 ± 14.5 REM latency C 81.0 -+ 45.4 76.8 ± 31.2 67.3 ± 20.2 REM density 1.3 - 0.2 1.4 ± 0.2 1.5 ± 0.3 Percentage of 24-hour 7.3 ± 5.3 10.8 ± 4.7 8.7 ± 5.2

cortisol near sleep onset c

18.2 1.1 0.38 104.1 --- 48.2 1.8 0.15

1.1 --- 0.3 4.6 0.008 6.7 ± 2.7 2.9 0.05

aValues are means (_+SD). t'Sample size (n = 20) for sleep variables. CAnalyses were performed on the logarithm. MDDs = patients with major depressive disorder.

significant variabili ty among the four groups for REM d e n s i t y ( F 3 , 4 0 = 4.6, p -< 0.01) and percentage of 24-hour secretion of cortisol near sleep o n s e t (F3,43 = 2.9, p --< 0.05). A priori, there was an interest in examining the relationship of biologic variables with regard to new onset of depression among the controls and recurrence of de- pressive episodes within the unipolar group. Therefore, controls who would develop depression over the 6- to 8-year interval were compared to controls who had no psychopathology at follow-up, and MDD subjects with no further episodes over the follow-up interval were com- pared to MDD subjects with a recurrent unipolar course on the sleep and cortisol measures.

Controls who would develop depression over the fol- low-up interval had significantly higher REM density compared to controls with no disorder at follow-up (1.5 ___ 0.3 vs. 1.1 _+ 0.3, t4o = 2.9, p -< 0.005). The two groups did not significantly differ with respect to sleep latency, REM latency, and cortisol secretion around sleep onset; however, as depicted in Figure 1, there was a trend for controls with new-onset depression to have reduced REM

latency compared to controls without psychopathology (67.3 _+ 20.2 vs. 104.1 _+ 48.2 minutes, t4o = 1.8, p -< O.O8).

Depressed subjects with a recurrent unipolar course over the follow-up period did not significantly differ from MDD subjects with no further episodes on any of the sleep or cortisol variables; however, there was a trend for unipolar MDD subjects with a recurrent course to have higher percentage of 24-hour cortisol secretion surround- ing sleep onset compared to depressed subjects with no

further episodes (10.8 + 4.7 vs. 7.3 - 5.3, t43 = 1.9, p -< 0.06).

The prevalence of reduced REM latency and hypercor- t isolemia (elevated cortisol near sleep onset) was exam- ined in this adolescent sample. In addition, the predictive value of reduced REM latency and elevated cortisol near sleep onset regarding onset and recurrence of unipolar depression was also explored. Based on data from Giles et

al (1990) using Receiver Operator Characteristic (ROC) analysis of age-adjusted REM latency distribution in normal and depressed populations, a second night REM latency value of -<70 minutes was considered abnormal. Within the initial control group, 11/25 (44%) subjects had reduced REM latency. Four of 11 controls with reduced REM latency (37%) developed depression, whereas only 1/14 (7%) controls with nonreduced REM latency devel- oped depression over the 6- to 8-year period (FET = NS). Within the initial depressed group, 10/19 (53%) had

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Continuous Initial Normals Normals with Depression (n=20) (n=5)

Figure l. REM latency in normal controls with no psychopa- thology at follow-up (continuous normals) and controls who developed depression in the 6- to 8-year interval after the sleep studies.

Sleep, Cortisol and Adolescent Depression BIOL PSYCHIATRY 479 1996;40:474-484

reduced REM latency. Seven of 10 depressed subjects who demonstrated reduced REM latency (70%) had one or more depressive episodes, and 6/9 (67%) subjects with nonreduced REM latency also had a recurrence during the follow-up period (FET = NS).

With respect to cortisol, no normative data are available in adolescent cohorts. Any value above 1 standard devia- tion from the normal mean was selected as elevated secretion. Within the control group, 3/28 (11%) had elevated cortisol near sleep onset. Two of the three controls with elevated cortisol (67%) developed depres- sion, while only 3/25 (12%) controls with normal cortisol developed depression (FET = NS). Within the depressed group, 6/19 (32%) subjects had elevated cortisol secretion around sleep onset. Five of six MDD subjects with elevated cortisol (83%) had a recurrent course, and 8/13 (62%) with normal cortisol also had a recurrence (FET = NS).

Reexamination of Initial Diagnostic Comparisons Incorporating Follow-up Information

In some adolescents, depressive disorder may be brief; such individuals would not be included in adult studies on depression. Similarly, adolescent controls who would develop depression would not be included as normal controls. The design of the current study allowed data on clinical course to be used to classify subjects assessed during adolescence. We could therefore compare "true" recurrent unipolar subjects and "true" normal controls. That is, 15 of the subjects initially diagnosed as MDD had recurrent unipolar course in longitudinal follow-up, while 23 of the controls were free of psychopathology through- out the follow-up interval.

Comparing these two groups, adolescent subjects with a prospective course of recurrent unipolar depression had significantly increased REM density compared to "true" normal controls (1.4 _ 0.2 vs. 1.1 _ 0.3, t31 = 2.9, p --< 0.01). In addition, the recurrent unipolar group had a higher percentage of 24-hour cortisol secretion near sleep onset (10.8 ± 4.7 vs. 6.7 +-- 2.7, t34 = 3.1, p -< 0.005). Moreover, there was a trend for the depressed group to have prolonged sleep latency (25.0 ± 13.5 vs. 18.2 + 1 0 . 4 , t31 : 1.7,p --< 0.10) and lower REM latency (76.8 ___ 31.2 vs. 104.1 __+ 48.2, t31 = 1.8, p --< 0.10) compared to the controls.

Relationship between Sleep and HPA axis Dysregulation in Recurrent Unipolar Depression

Reduced REM latency and overactivity of the HPA system have been reported to occur simultaneously in adult depressed patients. The relationship between reduced

REM latency (---70 minutes) and elevated cortisol sur- rounding sleep onset (more than one standard deviation above the normal mean) was explored in the cohort of depressed subjects who had a recurrent unipolar course (n = 13). There was a modest correlation between the two variables (Pearson R = -0.48, p --< 0.10). Four of seven subjects with reduced REM latency (57%) also had corti- sol hypersecretion, whereas 1/6 (17%) subjects with nor- mal REM latency had cortisol hypersecretion (FET, NS).

Association of Sleep and Cortisol Parameters with Suicidality during the Follow-up Period

Since EEG sleep and plasma cortisol changes were asso- ciated with suicidal depression in the initial analyses, the relationship of initial sleep and plasma cortisol variables were examined with respect to suicidality over the fol- low-up interval. MDD subjects who were suicidal over the interval period (n = 6) were not significantly different from MDD subjects without suicidality (n = 13) on any of the major sleep or cortisol variables.

Discussion

This is the first study to report on the relationship between baseline sleep and plasma cortisol measures, and prospec- tive clinical course of adolescent unipolar depression. The results are consistent with two conclusions: 1) Within the heterogeneous diagnostic classification that comprises ad- olescent MDD, there exists a group of patients concordant for both recurrent unipolar course, and sleep and HPA axis dysregulation; and 2) certain EEG sleep abnormalities (including reduced REM latency and increased REM density) may be present prior to the onset of depression in adolescents. Taken together, the above-described study has shown that longitudinal clinical course can clarify and reduce the heterogeneity observed in EEG sleep and plasma cortisol measures in depressed and normal control adolescent samples.

The most provocative finding in this study is the observation of reduced REM latency and increased REM density in some normal controls who would go on to develop depression. Reduced REM latency was observed in 80% of controls who later developed depression. In adults, reduced REM latency has been demonstrated both at baseline and on cholinergic stimulation in psychiatri- cally healthy subjects who may be at high risk for depression by virtue of family history (Giles et al 1989; Schreiber et al 1992; Sitaram et al 1987). Further, Giles and Kupfer (1994) have shown that unaffected adult relatives of depressed probands who have reduced REM latency may be at substantially increased risk for devel- oping new onset depression compared to relatives with

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nonreduced REM latency. Lauer et al (1995) recently reported diminished slow-wave sleep and higher REM density in high-risk adult subjects with no personal history of depression. Similarly, in a pilot study, McCracken and Poland (personal communication, February 8, 1995) ob- served that healthy adolescent offspring of depressed probands had significantly increased REM density with a trend for diminished slow-wave sleep compared to ado- lescents with no personal or family history of depression. Future prospective research on large high-risk samples can further our understanding on the significance of reduced REM latency, increased REM density, and diminished slow-wave sleep as markers for depression. The most robust finding in our study and in the investigation described by Lauer et al (1995) was increased REM density in the high-risk and depressed groups. In a study that examined the relationship between EEG sleep mea- sures and age in both depressed and normal subjects ranging from 18-65 years, Lauer and colleagues (1991) reported that REM density did not vary with age and that REM density was significantly higher in depressed pa- tients compared to normal controls across all age groups. Lauer et al (1991) have hypothesized that REM density may be a more likely candidate for a biological marker for major depression compared to other EEG sleep measures.

Once identified during an episode of depression, re- duced REM latency has been shown to predict recurrence of MDD episodes in adult patients (Giles et al 1987a; Grunhaus et al 1994; Reynolds et al 1989). Similarly, other sleep measures, such as a reduced ratio of delta waves in the first nonREM period compared to the second nonREM period, may also predict vulnerability to recur- rence (Kupfer et al 1990). In our study, we did not find that reduced REM latency had prognostic value in adoles- cent unipolar depression once the disorder was manifest. One possibility for this variation from adult studies is the small sample of depressed subjects in this study. Another possibility is that both REM latency and slow-wave sleep are influenced by age (Benca et al 1992; Dahl et al 1990; Gillin et al 1981; Goetz et al 1987, 1991; Knowles and MacLean 1990; Lauer et al 1991), and it may be only in the context of a fully matured central nervous system that these parameters have robust prognostic significance. The length of the follow-up period may also modify the effect of EEG sleep parameters on recurrence of depressive episodes. The above-referenced adult studies that reported on the predictive value of reduced REM latency and decreased delta ratio on MDD recurrence(s) had short follow-up intervals ranging from 3 months to 2 years, whereas in our investigation the follow-up period was 6 years or longer. When Giles et al (1987a) followed their sample for longer intervals, the effect of reduced REM latency on recurrence was attenuated because virtually all

subjects ultimately had a recurrence (Giles et al, unpub- lished data). Therefore, EEG sleep abnormalities may be more useful in predicting early recurrence.

There was a trend for depressed subjects with a recur- rent course to have elevated cortisol near sleep onset. This finding is consistent with investigations in adult depressed patients where higher secretion of cortisol around sleep onset and persistent nonsuppression of cortisol in response to dexamethasone following successful treatment of de- pressive episodes have been shown to indicate vulnerabil- ity to early relapses (Charles et al 1989; Holsboer et al 1983; Jarrett et al 1983; Papakostas et al 1981; Schweitzer et al 1987; Targum 1983). Similar to the effect of REM latency, however, several depressed patients with normal cortisol also had a recurrence by the end of the follow-up period. These data suggest that there may be multiple pathways that determine morbidity in unipolar depression, and that reduced REM latency and elevated cortisol near sleep onset may be important factors in the context of a series of related (other sleep and cortisol) and independent (e.g., psychological and psychosocial) factors. Although dysregulation of the HPA axis is considered to be "state" related, the observation of cortisol hypersecretion specif- ically in some controls who would later develop depres- sion is provocative. Elevated cortisol response to cortico- tropin-releasing hormone has also been reported in some adult healthy subjects who were at high risk for depression (Kreig et al 1990). Further investigations are necessary to clarify the relationship between HPA overactivity and susceptibility to depression.

We have shown that reduced REM latency and elevated cortisol near sleep onset occurred simultaneously in de- pressed adolescents who were at risk for a recurrent unipolar course. This finding is consistent with investiga- tions in adult depressed patients where reduced REM latency was often found to be associated with HPA overactivity (Annseau et al 1984; Asnis et al 1983; Feinberg and Carroll 1984; Giles et al 1987b; Kerkhofs et al 1986; Kupfer et al 1984; Mendlewicz et al 1984; Poland et al 1992; Rush et al 1982; Shipley et al 1989). These results suggest that a common system such as the central cholinergic system may link sleep, HPA axis, and affec- tive dysregulation (reviewed in Janowsky and Risch 1987).

Prospective clinical course was certainly helpful in reducing the heterogeneity of certain sleep and cortisol measures in both depressed and control groups. As often observed in adult patients, the depressed subjects who would go on to have a recurrent unipolar course had demonstrated greater degree of sleep and cortisol abnor- malities in this study. After controlling for clinical course (specifically latent bipolar disorder), the prevalence of reduced REM latency in the depressed sample (53%) is

Sleep, Cortisol and Adolescent Depression BIOL PSYCHIATRY 481 1996;40:474-484

comparable to that seen in adult depression (about 50%) (Giles et al 1987b, 1989, 1990). Further, after controlling for nonrecurrent depression, the prevalence of elevated cortisol near sleep onset in recurrent unipolar subjects (38%) is also comparable to DST nonsuppression rate in adult depression (approximately 40%) (Giles et al 1987b; Keitner et al 1992).

In contrast to the above, the prevalence of reduced REM latency in our control sample (44%) was substantially higher than that seen in adult normal control population (5%-20%) (Giles et al 1989, 1990). As noted above, familial loading for depression and biologic dysregulation in the family of origin may contribute significant variance to observed EEG sleep changes in depression (Giles et al 1989, 1992; Lauer et al 1995). The effects of both familial loading and sleep dysregulation in the biologic parents on adolescent EEG sleep patterns is currently being investi- gated in this cohort. Parental major depression has been found in a substantial subset of subjects who were initially identified as controls but later developed depression. As described earlier, these controls showed evidence of EEG sleep abnormalities prior to the onset of depression. Some controls who had not developed any psychopathology at follow-up also have family history of depression. In their longitudinal study, Giles et al (unpublished data) have found that normal controls with reduced REM latency were at increased risk for new onset of depression com- pared to controls with nonreduced REM latency. These findings underscore the need for careful screening of controls for family history in investigations of juvenile cohorts.

These results should be interpreted within the context of study limitations. 1) The sample sizes are small. There- fore, the findings should be viewed cautiously. In an attempt to minimize Type I error and based on our a priori hypotheses, only those EEG sleep and plasma cortisol variables that appeared promising in a subgroup of de- pressed adolescents in earlier comparisons were used. 2)

Although the study had a prospective design, the fol- low-up interval ranged from 6 - 8 years, leading to possi- ble retrospective recall bias in charting the clinical course. Within this limitation, every effort was made to obtain accurate history from multiple sources, including pro- bands, parents, and medical records by experienced clini- cians. In addition, all audiotapes of clinical interviews and other sources of information were carefully reviewed by the investigators. Moreover, our findings on clinical course in this sample were comparable to results from other prospective studies on the natural history of early- onset depression where frequent follow-up intervals were used (Kovacs et al 1984 a,b; McCauley et al 1993; Rao et al 1995; Strober et al 1993).

The results from this study should be placed in the context of other EEG sleep and plasma cortisol findings in adolescent and adult depressed samples. Although pro- spective clinical course was useful in clarifying and reducing the heterogeneity of some sleep and cortisol variables, our findings as well as those of other adolescent studies are not as robust as those found in adult depressed samples. More specifically, slow-wave sleep deficits and increase in the mean 24-hour cortisol have not been shown in adolescent depression (Appelboom-Fondu et al 1988; Dahl et al 1989, 1990, 1991, 1995; Emslie et al 1994; Goetz et al 1987; Khan and Todd 1990; Kutcher et al 1991, 1992; Lahmeyer et al 1983; Riemann et al 1995). As noted above, age strongly affects the relationship between sleep and cortisol secretory patterns, and mood disorders. The effects of both physiologic maturation and clinical course on EEG sleep and HPA axis are the focus of our next investigation on this cohort.

This study was supported in part by Grants MH30915, AA08746 and MH41712.

The authors acknowledge with gratitude the assistance received from Laura Trubnick, BS, in locating and recruiting the subjects, and from Lorah Dorn, PhD, in reviewing the manuscript.

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