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Rest-Activity Cycles in Childhood and Adolescent Depression
Rest-Activity Cycles in Childhood and Adolescent Depression ROSEANNE ARMITAGE, PH.D., ROBERT HOFFMANN, PH.D., GRAHAM EMSLIE, M.D., JEANNE RINTELMAN, B.S., JARRETTE MOORE, M.A., AND KELLY LEWIS, B.S.
ABSTRACT Objective: To quantify circadian rhythms in rest-activity cycles in depressed children and adolescents. Method: Restactivity cycles were evaluated by actigraphy over five consecutive 24-hour periods in 100 children and adolescents, including 59 outpatients with major depressive disorder (MDD) and 41 healthy normal controls. Total activity, total light exposure, and time spent in light at more than 1,000 lux were averaged over the recording period for each participant. Time series analysis was used to determine the amplitude and period length of circadian rhythms in rest-activity. Results: Overall, adolescents with MDD had lower activity levels, damped circadian amplitude, and lower light exposure and spent less time in bright light than healthy controls. Among children, those with MDD showed lower light exposure and spent less time in bright light, but only depressed girls showed damped circadian amplitude. The sex differences were substantially greater in the MDD group than in the normal control group. Conclusions: These results confirm damped circadian rhythms in children and adolescents with MDD and highlight the influence of gender and age on these measures. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(6):761–769. Key Words: rest-activity cycles, circadian rhythms, childhood depression, gender.
Sleep and biological rhythm abnormalities have been a key focus of theories on major depressive disorder (MDD) in adults for more than two decades. Beginning with the work of Goodwin et al. (1982), it was suggested that the sleep, temperature, and cortisol abnormalities evident in adults with MDD reflected a phase advance in the timing of circadian rhythms. Others have suggested that instability or irregularity of Accepted December 19, 2003. From the Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas. Drs. Armitage and Hoffmann are now at the University of Michigan in Ann Arbor. This research was supported by NIMH grant MH56593 (R.A.) and was conducted at the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas. The authors are grateful for the technical support of the Sleep Study Unit at University of Texas Southwestern Medical Center at Dallas, under the supervision of Darwynn D. Cole; for department support from Eric Nestler, M.D., Ph.D. (Chair); and for the secretarial support from Doris Benson. Correspondence to Dr. Armitage, Director, Sleep and Chronophysiology Laboratory, 2101 Commonwealth, Ann Arbor, MI 48105; e-mail: rosearmi@ umich.edu. 0890-8567/04/4306–0761©2004 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000122731.72597.4e
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sleep cycles and associated rhythms may be more characteristic of MDD than either a consistent phase advance or delay in circadian timing (Healy, 1987; Schulz and Lund, 1985; Siever and Davis, 1985). The majority of more recent studies, however, have not provided strong support for circadian abnormalities in temperature or endogenous cortisol secretion in adults with MDD (cf. Monk, 1993). Moreover, only one study has supported elevated cortisol at sleep onset in adolescents with MDD (Dahl et al., 1991). With regard to sleep laboratory findings, depressed adults show shorter rapid eye movement latencies, reduced slow-wave sleep, and increased sleep fragmentation, all of which point to abnormalities in the timing of the rapid eye movement-nonrapid eye movement sleep cycle (Armitage, 1995; Armitage et al., 1992, 1993a,b, 1999; Kupfer et al., 1984a,b, 1990; Reynolds and Kupfer, 1987; Reynolds et al., 1990). The findings in children and adolescents with MDD have been more equivocal. Although some studies have reported REM timing problems in early-onset MDD, prolonged sleep latency in adolescents is a more consistent finding (Birmaher and Heydl, 2001; Dahl, 1996). 761
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However, a closer examination of the EEG frequency structure in sleep and ultradian rhythms (shorter than 24 hours) has confirmed sleep abnormalities in depressed adults, in children and adolescents with MDD (Armitage et al., 2000a), and in those at risk of, but not yet ill with, MDD (Fulton et al., 2000; Morehouse et al., 2002). These findings provide strong support for the dysregulation hypothesis of depression and that a more general breakdown in biological rhythm in rest and activity underlies depression. Studies of motor activity rhythms have also consistently reported blunted circadian amplitude in depressed adults (cf. Goodwin and Jamieson, 1990) and in children and adolescents with nonseasonal depression (Teicher et al., 1993). The data from Teicher et al. (1993) go further to suggest that the ultradian components of locomotor rhythms are often more pronounced than circadian rhythms and that these findings were evident in both children and adolescents with MDD. Damped circadian amplitude was evident in adolescents but not in children. Interestingly, Glod et al. (1997) also reported blunted locomotor rhythms in children and adolescents with seasonal affective disorder, although this was not confirmed in adults with this disorder (Teicher et al., 1997). We have argued previously that abnormalities in ultradian rest-activity cycles may underlie both the sleep EEG and locomotor disturbances evident in MDD but that the effects may be gender specific (Armitage and Hoffmann 2001; Armitage et al., 2000a–c, 2001, 2002; Hoffmann et al., 2000). The sleep EEG frequency analyses do indicate a greater degree of ultradian rhythm disturbance among females with MDD, from early childhood to later adulthood but particularly in adolescence. These findings, coupled with the results from Teicher et al. (1993), suggest that locomotor rhythms in those with MDD should show both age and gender effects. The purpose of the current study was to evaluate rest-activity cycles and locomotor activity in 59 depressed children and 41 healthy controls. Of primary interest was an evaluation of gender differences and age-related differences in both patients and controls.
Child and Adolescent Psychiatry Outpatient Clinic. Rest-activity measurements were obtained from 100 children and adolescents, 8 to 17 years of age, including 59 outpatients diagnosed with unipolar, nonpsychotic MDD, single or recurrent, and 41 healthy normal controls (NCs). There were 28 females and 31 males in the sample of outpatients with MDD and 20 females and 21 males in the sample of healthy NCs. All patients were symptomatic and unmedicated at the time of the study. Independent sleep disorders by history or polysomnography were exclusionary for all participants. Diagnostic and demographic information is shown in Table 1. Note that there were no significant differences in age or education between groups. Diagnostic Procedures
METHOD
Patients for the study were scheduled for a full evaluation after a telephone screening for inclusion and exclusion criteria. The study was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center at Dallas. Before the initial interview, the study was explained and written informed consent was obtained from the parent(s) and assent from the patient. In addition to a structured psychiatric interview, the initial evaluation included a medical review of systems, a physical examination, routine laboratory tests, and neurological examination. The evaluation was completed during a 3-week period. At the initial visit, each patient and parent(s) were interviewed separately using the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime (K-SADSPL), a revision of the K-SADS (Kaufman et al., 1997). The K-SADS-PL is a semistructured DSM-IV–based diagnostic interview to establish that the patient met DSM-IV criteria for MDD and to identify other concurrent and lifetime psychiatric disorders. The final diagnoses were based on information from interviews of the parent(s) and child. Additionally, depressive symptom severity was assessed using the Children’s Depression Rating Scale-Revised (Poznanski et al., 1985). While the child was being interviewed, a separate interviewer obtained family history from the parent(s) using the Family History Diagnostic Interview. Patients completed two self-report scales for depression and anxiety, the Weinberg Screening Affective Scale–Short Form providing information on a patient’s perception of his/her problems based on 10 major symptom groups of depression (Weinberg and Emslie, 1988), and the Multidimensional Anxiety Scale for Children (March et al., 1997). The Children’s Global Assessment Scale assessed overall functioning (Shaffer et al., 1985). Tanner upper and lower body maturation (1–5 scores) was self-assessed by participants using the “Typical Progression of Pubertal Development Chart” adapted from Tanner (1962, 1978). Breast and pubic hair development was assessed for girls and genital and pubic hair development was assessed for boys. Note that Duke et al. (1980) have shown that children can reliably self-rate sexual maturation using these standard pictures. A third interview was conducted just before the sleep study to review psychiatric assessment and inventories. A Children’s Depression Rating Scale-Revised score of 40 or more was required for entry into the study. Further details on the clinical evaluation procedures are reported elsewhere (Emslie et al., 2001). All NC children and adolescents underwent the same initial psychiatric and medical evaluations as those with MDD and were scheduled for the laboratory tour after the first interview.
Subjects
Procedures
Participants were recruited through campus and community advertisement, by word of mouth, or during an initial visit to the
All participants agreed to follow their usual school week established by sleep history with bed- and rise-times schedules through-
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TABLE 1 Demographic and Clinical Features of the Sample by Diagnostic Group and Gender No. Age overall mean ≤12 yr ≥13 yr Tannera A B FGAS CGAS MASC CDRS BPRS No. of episodes Age at onset of 1st episode Length of current episode Suicide attempts Suicidal ideation Family history (%) Maternal MDD Paternal MDD Comorbid illness, no. (%) GAD OCD Dysthymia ODD Phobia Enuresis ADHD
MDD F
MDD M
NC F
NC M
28 12.3 ± 2.9 9.9 ± 1.4 15.0 ± 1.4
31 12.3 ± 3.0 9.5 ± 1.3 15.5 ± 1.6
21 12.4 ± 3.1 9.9 ± 1.7 14.9 ± 1.9
20 12.4 ± 2.5 10.3 ± 1.4 14.5 ± 1.3
2.9 ± 1.5 2.8 ± 1.6 61.4 ± 10.4 53.0 ± 7.3 54.2 ± 19.8 58.9 ± 11.1 33.0 ± 9.0 1.4 ± 0.7 11.1 ± 3.2 18.3 ± 7.1 0 2.3 ± 0.8
2.7 ± 1.5 2.8 ± 1.7 64.5 ± 11.9 52.5 ± 6.1 48.8 ± 16.1 57.1 ± 7.2 34.4 ± 8.4 1.4 ± 0.6 11.3 ± 3.3 18.5 ± 10.2 0 2.3 ± 0.6
3.5 ± 1.5 3.3 ± 1.5 91.7 ± 2.6 90.7 ± 4.1 33.1 ± 13.6 19.0 ± 2.3 2.4 ± 3.1 — — — — —
3.0 ± 1.6 2.9 ± 1.6 91.5 ± 6.0 90.7 ± 5.4 30.6 ± 14.7 18.4 ± 2.0 2.4 ± 2.8 — — — — —
64.3 17.9 17 (60.2) 1 0 7 0 0 1 8
45.2 12.9 16 (51.6) 2 1 4 1 1 0 7
Note: MDD F = depressed females; MDD M = depressed males; NC F = normal control females; NC M = normal control males; FGAS = Family Global Assessment Scale; CGAS = Children’s Global Assessment Scale; MASC = Multidimensional Anxiety Scale for Children; CDRS = Children’s Depression Rating Scale; BPRS = Brief Psychiatric Rating Scale; MDD = major depressive disorder; GAD = general anxiety disorder; OCD = obsessive-compulsive disorder; ODD = oppositional defiant disorder; ADHD = attention-deficit/hyperactivity disorder. a Tanner A is based on breast development for girls and genitalia for boys. Tanner B assesses development of pubic hair. out the study. They were informed that a deviation of more than one half hour would result in elimination from the study. With the exception of two children and three adolescents, all participants were tested Monday through Friday during the regular school year outside of holiday and vacation schedules. Actigraphs (Actiwatch-L, Mini-Mitter) were worn throughout the week, and sleep/wake diaries were collected daily during the home recording period. Actigraphs were set to begin at noon and end at 9 A.M. on the last morning of the recording. The actigraphs measured the number of movements that exceeded 0.01g (gravitation force per minute of recording). In addition, a photoconductive cell recorded light level exposure, measured in lux. All actigraphs were calibrated before recording to ensure comparability across subjects. Thresholds, sensitivities, scaling, and epoch lengths were held constant across all individual recordings. Actigraphs were not removed while showering or bathing. Subjects were asked to note in the diaries whether the actigraphs were removed, for how long, and for what purpose and to record any travel periods less than 15 minutes. Finally,
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subjects were instructed not to wear any clothing that covered up the watch face at any time during the recording period. The technical reliability of the actigraph was very high, with little loss of data. Subjects were compliant with the actigraphy procedures, resulting in the loss of very few data points. Of the 100 study participants, complete 5-day actigraphy data were available for 95 participants. For the remaining five subjects, 3 complete days of data were available. The additional days were excluded from analysis. The 24-hour blocks with missing data due to participants removing the watch were excluded from the analysis. Data Analysis Data were downloaded from the actigraphs at the end of the recording period. Initial data analyses were conducted with onboard Mini-Mitter software, computing the average activity count per epoch in the light and dark periods. Total daily light exposure was also computed for each day of recording, along with average
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light exposure and the amount of time in light above a 1,000-lux level across the recording period. The raw activity data per minute (time series) were also exported to SAS and subjected to Fourier-based spectral analysis for each individual subject to determine the circadian amplitude or strength of the 24-hour rhythms. Relative circadian amplitude was also computed (100 × amplitude/mean daily activity) to ensure that amplitude estimates were not biased by total activity (Teicher, et al., 1993). All data were coded for group (NC or MDD), gender, and age, using an arbitrary cut point of 12 to contrast children and adolescents. Average Tanner scores (upper body + lower body/2) were also used to evaluate maturational age by gender by group interaction. Analysis of variance (ANOVA) evaluated statistical differences, testing the group by gender by age interactions first, and simple interactions and main effects only if three-way interactions were not significant. Least-squares multiple comparisons contrasted differences between individual means only if a significant overall ANOVA effect was obtained to protect against type I errors.
RESULTS
Using an age cut point of 12, there were 15 girls and 11 boys in the 8- to 12-year-old MDD group. There were 10 girls and 11 boys in the 8- to 12-year-old NC group. The adolescent group had 13 girls and 14 boys with MDD and 10 NC girls and 10 NC boys all in the 13- to 17-year-old age range. Activity Levels
The means and standard deviations for all the activity measures are shown in Table 2 by group and age but collapsed across gender. The means indicate substantial age-related differences in activity, with lower total activity and lower activity in the light phase in the adolescents but with higher activity in the dark phase. Further, the difference in total activity between chil-
dren and adolescents was greater in the MDD group. Statistical analyses indicated that these effects were strongly moderated by gender. ANOVA revealed a significant gender by diagnostic group by age interaction for total activity (F7,92 = 2.2; p < .04) and for activity level during the light phase (F7,92 = 2.8; p < .02) but not during the dark phase (F7,92 = 1.1; p < .35). The three-way interaction for total daily activity is illustrated in Figure 1. Male children with MDD showed more total activity than the other groups of the same age range but differed significantly only from MDD girls (p < .03). Moreover, the differences in total activity between the age groups were most dramatic in the MDD males; adolescents had significantly lower activity than children (p < .001). By contrast, the difference between the child and adolescent groups were not significant for NC females (p < .23), NC males (p < .37), or MDD females (p < .22), accounting for the three-way interaction. Results were similar for activity in the light phase. Activity in the dark phase did show a main effect for age (F1,92 = 4.0; p < .05). Means indicated that activity during the dark was higher in adolescents than in children, in all groups, as is evident in Table 2. Note that the minimal and maximal values were lower in the MDD groups for all activity measures. Light Exposure
The means and standard deviations for average daily light level and the average time spent above a 1,000-lux threshold are shown in Table 2. Average light levels were lower in both children and adolescents with
TABLE 2 Means (and Standard Deviations) of Actigraphy Measures by Diagnostic Group (NC Versus MDD) and Age Group NC Children a
Activity total Avg. no. in light Avg. no. in dark Light avg.b (lux) Timec (min) Circadian period (h) Amplituded
18,313.6 (9,378.2) 386.0 (191.9) 25.2 (27.5) 847.9 (758.6) 99.6 (90.4) 24.30 (0.30) 2,865.3 (2,784.6)
MDD Adolescents
Children
Adolescents
14,461.4 (8,464.7) 288.2 (169.1) 38.2 (28.5) 832.7 (1,162.9) 81.4 (67.5) 24.09 (0.36) 1,467.8 (1,335.9)
18,888.2 (9,936.4) 389.9 (212.9) 28.5 (30.9) 597.9 (647.1) 64.0 (44.6) 23.98 (0.38) 3,311.5 (3,038.5)
11,626.7 (7,380.8) 236.7 (153.7) 40.6 (33.3) 408.1 (586.1) 50.3 (50.1) 24.18 (0.32) 987.1 (1,757.1)
a
Total number of events more than criterion × 103. Average time at more than 1,000 lux. c Average daily time spent at 1,000 or more lux. d Power (area under the curve) × 104. b
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Fig. 1 Total daytime activity counts over 5 days in children (filled bars) and adolescents (open bars) by gender and group. NC F = normal control females; MDD F = depressed females; NC M = normal control males; MDD M = depressed males.
MDD compared with controls. The between-group differences are illustrated in Figure 2. Young girls with MDD had lower light exposure than the other groups of children, whereas adolescent males in the NC group had the highest level of exposure, confirmed by multiple comparisons (p < .05). The NC males were also the only group to show more light exposure in the adolescents than in the children, accounting for the nearly significant three-way interaction (p < .06). Interestingly, adolescent NC girls and girls and boys with MDD were exposed mostly to indoor light levels. Only the adolescent NC males had sustained outdoor light exposure. However, no significant gender by diagnostic
Fig. 2 Day light level (lux) averaged over 5 days in children (filled bars) and adolescents (open bars) by group and gender. NC F = normal control females; MDD F = depressed females; NC M = normal control males; MDD M = depressed males.
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group by age interaction was obtained for this measure (F7,92 = 2.04; p < .06). The average time spent in bright light showed similar results. Also seen in Table 2, the MDD group spent roughly 30 minutes less on average in bright light than NCs, regardless of age. ANOVA indicated significant age by diagnostic group and gender by diagnostic group interactions (F3,96 = 3.1, 2.7; p < .05, respectively) but no significant three-way interaction (F7,92 = 1.6; p < .17). As seen with the average light level, NC adolescent males showed slightly more (4 minutes) time spent in bright light compared with children in this group. Although the means in Table 2 suggest equivalent age-related differences in the daily time spent in bright light in the MDD and NC groups, the greatest difference between children and adolescents was observed in the NC females. Girls in the NC group had an average of 90 minutes of bright light exposure, whereas adolescents in this group spent only 67 minutes in bright light (data not shown). Nevertheless, both male and female adolescents in the NC group still had more light exposure than their MDD counterparts (p < .05). Once again, the minimal and maximal values were lower in those with MDD than in the NCs for both light variable groups. Circadian Rhythm Measures
The means and standard deviations for the period length and the amplitude of circadian rest-activity rhythms are also shown in Table 2. Although children with MDD had a circadian rhythm that was 21 minutes shorter than that of NC children (23 hours 59 minutes versus 24 hours 20 minutes), this difference was not significant. The circadian period length did not appear to differ by age or diagnostic group. Further, ANOVA did not indicate significant main effects or interactions for this variable (p > .23). Collapsed across gender, the amplitude of circadian rhythms was lower in adolescents with MDD compared with NCs, as seen in Table 2. Children with MDD had higher amplitude rhythms than controls; however, a significant three-way interaction was obtained for this measure (F7,91 = 3.0; p < .006). Relative circadian amplitude adjusted for total activity also showed a three-way interaction (F7,91 = 3.8; p < .002) and is depicted in Figure 3. The means indicated that both female children and adolescents with MDD had lower relative amplitude circadian rhythms than all 765
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damped circadian amplitude compared with NCs (p < .05). Attention-Deficit/Hyperactivity Disorder Comorbidity
Fig. 3 Relative amplitude (power) of circadian (24-hour) rhythms in total activity in children (filled bars) and adolescents (open bars) averaged by group and gender. Amplitude determined by time series analysis (based on a fast Fourier transform) of activity count per minute throughout five consecutive 24-hour recording periods for each individual. NC F = normal control females; MDD F = depressed females; NC M = normal control males; MDD M = depressed males.
other groups, whereas MDD boys showed higher circadian amplitude than any other group. Multiple comparisons confirmed these differences (p < .05), except when comparing NC boys with MDD boys. In addition, Figure 3 also illustrates the dramatic age differences in circadian amplitude, evident in all groups. The difference between children and adolescents was, however, most pronounced in the MDD males, with more than 70% lower amplitude in the adolescents (p < .002), further contributing to the significant three-way interaction. Thus, circadian rhythms and light exposure were most abnormal in girls with MDD and evident even in preteens. Chronological Versus Maturational Age
To ensure that our arbitrary age cut point of 12 years did not produce an artificial distinction between groups, we also conducted an analysis of age using average upper and lower body Tanner scores. The three-way interactions (group by gender by developmental age) were evaluated for relative circadian amplitude, light exposure, and total activity. The outcome was strikingly similar to that obtained with chronological age (F7,69 = 3.1, 2.8, 2.4; p < .01, .02, .03, respectively), significantly lower circadian amplitude, light exposure, and total activity in prepubertal (Tanner 1 or 2) girls with MDD (p < .05). Pubertal (Tanner 4 or 5) but not prepubertal boys with MDD also showed 766
One further concern was the higher incidence of comorbid attention-deficit/hyperactivity disorder (ADHD) in the children with MDD, particularly with regard to the failure to find lower activity or damped circadian amplitude in young boys with MDD. We recomputed the analyses of the rest-activity measures excluding the three adolescents and 12 children who had morbid ADHD. Removing these subjects had only a small effect on results, reducing the overall probability due to the loss of degrees of freedom, but did not alter the effect size. For relative circadian amplitude, light exposure and activity levels, the resulting threeway interactions were (F7,85 = 2.7, 2.4; p < .03, 1.93; p < .07, respectively). Even excluding the outpatients with comorbid MDD, circadian amplitude was damped in preteen and teenage girls and in teenage boys with MDD. Thus, the failure to find damped amplitude rhythms in preteen depressed boys was not due to comorbid ADHD. DISCUSSION
To summarize the overall findings, adolescents with MDD had lower activity levels, damped circadian amplitude, and lower light exposure and spent less time in bright light than healthy controls. Among preteens, girls with MDD had lower light exposure, spent less time in bright light than controls, and showed lower circadian amplitude. By contrast, preteen boys with MDD had robust circadian amplitude. Most importantly, the same results were obtained with relative circadian amplitude, adjusted for mean activity levels. Thus, it is not just reduced activity that is evident in those with MDD. The results of the current study conform to those of Teicher et al. (1993), indicating that circadian amplitude was damped in adolescents with MDD. The Teicher et al. sample of control subjects was substantially smaller, patients were 2.5 to 3.4 years older than controls, and neither potential gender effects nor light levels were evaluated. Nevertheless, the rest-activity cycle data in the current study are remarkably similar to those shown in the Teicher et al. report. Damped circadian amplitude is likely to reflect weak entrainment to a 24-hour day and/or reduced J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:6, JUNE 2004
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exposure to zeitgebers (time cues and entrainment) (Teicher et al., 1993). Because the master circadian clock is strongly driven by light (Czeisler et al., 1989) and given the low light levels that appear to accompany damped amplitude, it suggests that increasing light exposure will enhance circadian amplitude. Additional clinical implications of these results are discussed below. Our findings are also in agreement with those of Glod et al. (1997) who reported blunted circadian amplitude but no phase disruption in children with seasonal affective disorder, although their study did not assess gender. Consistent with the dysregulation hypothesis of depression (Siever and Davis, 1985), we did not find evidence of a phase advance in circadian timing. The strong influence of gender obtained in the current study is also consistent with our previous reports on sleep data. The gender differences in the MDD group were substantially larger than those obtained in healthy controls overall. We have previously reported larger gender differences in adults with MDD compared with controls on several quantitative EEG measures during sleep (Armitage and Hoffmann, 2001; Armitage et al., 1999, 2000b,c). Further, we have also reported a greater degree of ultradian rhythm disturbance in females with MDD, in line with increased risk of MDD among women (Armitage and Hoffmann, 2001) and with studies of continuing biological vulnerability to recurrence that is greater in women. The data from the current study extend these gender differences to circadian rest-activity cycles. Even 8- to 12-year-old girls with MDD show damped circadian amplitude, whereas damped circadian rhythms were only evident in the adolescent boys with MDD. Interestingly, it is believed that the increased risk of MDD in females does not occur until after puberty, with equivalent risk of MDD in prepubertal boys and girls (Frank and Young, 2000; Kessler, 2000; Parry, 2000). Our data suggest that the developmental time course of biological rhythm abnormalities is different in boys and girls with MDD. Damped circadian restactivity cycles are evident earlier in females than in males with MDD. It is not clear, however, how (or whether) these biological abnormalities relate to the risk of MDD or to the clinical course of illness. A study of children at risk of MDD and longitudinal evaluations of those already ill are necessary to address these issues. Regardless of the outcome, the current study supports our previous findings that gender differences J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:6, JUNE 2004
are more dramatic in those with MDD (Armitage, 1995; Armitage and Hoffmann, 2001; Armitage et al., 1999, 2000b,c). Limitations
There are limitations to this study that need to be considered when interpreting data, most notably sample size. Splitting the groups by age and gender left only 10 to 17 subjects per cell. There is some concern that the findings may not generalize to a larger sample. Thus, it will be necessary to replicate our findings. Such efforts are currently underway. In addition, it is also necessary to determine whether the rest-activity abnormalities obtained in this study correlate with the amplitude and phase of other circadian measures such as temperature and cortisol. A constant routine or forced desynchrony paradigm would allow an assessment of the interaction of circadian and wake-dependent processes, including mood. Because recent work has demonstrated that circadian phase also affects mood regulation (Boivin et al., 1997), it would be of significance to include repeated mood assessments in further studies of circadian rhythms in depression. It will undoubtedly be necessary to manipulate light exposure and rest-activity cycles, including sleep-wake cycles to evaluate the clinical impact directly of these measures in depression and to further elucidate the mechanisms responsible for damped amplitude restactivity cycles. An additional limitation to this study is our inability to fully assess the influence of comorbidity on restactivity cycles. Although we reanalyzed our data excluding those with comorbid ADHD and found very similar results to full analysis, it is still possible that this and other comorbid illness could contribute to restactivity cycle parameters. Nonetheless, comorbid illness was not found to differentiate between the genders. Thus, comorbidity cannot account for the significant group by gender effects obtained in this study. Clinical Implications
The current study indicates that damped circadian amplitude is characteristic of teenagers with MDD and of preteen depressed girls. Because relative circadian amplitude was also found to be damped, it appears unlikely that increasing total activity alone would normalize circadian amplitude. The regularity of daytime 767
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and nighttime schedules, of the amount of light exposure, and of the timing of these events is more likely to have an impact on the strength of rhythms. The outcome of this study suggests that behavioral and chronobiological intervention may be of benefit in early-onset depression. Regularized sleep-wake schedules, structured daytime activity, and increased light exposure may serve to strengthen entrainment and to stabilize sleep-wake cycles. Ultimately, improving sleep and circadian rhythm regulation should the biological risk of depression, although any direct clinical benefit remains to be established. Disclosure: Dr. Armitage currently has two RO1 (MH54593 and MH061515). She currently serves on advisory boards for Pfizer and Takeda Pharmaceuticals. REFERENCES Armitage R (1995), Microarchitectural findings in sleep EEG in depression: diagnostic implications. Biol Psychiatry 37:72–84 Armitage R, Emslie GJ, Hoffmann RF et al. (2000a), Ultradian rhythms and temporal coherence in sleep EEG in depressed children and adolescents. Biol Psychiatry 47:338–350 Armitage R, Emslie GJ, Hoffmann RF, Rintelmann J, Rush AJ (2001), Delta sleep EEG in depressed adolescent females and healthy controls. J Affect Disord 63:139–148 Armitage R, Hoffmann RF (2001), Sleep EEG, depression and gender. Sleep Med Rev 5:237–246 Armitage R, Hoffmann RF, Emslie GJ, Weinberg WA, Mayes TL, Rush AJ (2002), Sleep microarchitecture as a predictor of recurrence in children and adolescents with depression. Int J Neuropsychopharmacol 5:217–228 Armitage R, Hoffmann R, Fitch T, Trivedi M, Rush AJ (2000b), Temporal characteristics of delta activity during NREM sleep in depressed outpatients and healthy adults: group and sex effects. Sleep 23:607– 617 Armitage R, Hoffmann RF, Rush AJ (1999), Biological rhythm disturbance in depression: temporal coherence of ultradian sleep EEG rhythms. Psychol Med 29:1435–1448 Armitage R, Hoffman R, Trivedi M, Rush AJ (2000c), Slow-wave activity in NREM sleep: sex and age effects in depressed outpatients and healthy controls. Psychiatry Res 95:201–213 Armitage R, Hudson A, Trivedi M, Rush AJ (1993a), Sex differences in the distribution of EEG frequencies during sleep: unipolar depressed outpatients. J Affect Disord 34:121–129 Armitage R, Roffwarg HP, Rush AJ (1993b), Digital period analysis of EEG in depression: periodicity, coherence, and interhemispheric relationships during sleep. Prog Neuropsychopharmacol Biol Psychiatry 17:363–372 Armitage R, Roffwarg HP, Rush AJ, Calhoun JS, Purdy DG, Giles DE (1992), Digital period analysis of sleep EEG in depression. Biol Psychiatry 31:52–68 Birmaher B, Heydl P (2001), Biological studies in depressed children and adolescents. Int J Neuropsychopharmacol 4:149–157 Boivin DB, Czeisler CA, Dijk D-J et al. (1997), Complex interaction of the sleep-wake cycle and circadian phase modulates mood in healthy subjects. Arch Gen Psychiatry 54:145–152 Czeisler CA, Kronauer RE, Allan JS et al. (1989), Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 244:1328–1333
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Dahl RE (1996), The regulation of sleep and arousal: development and psychopathology. Dev Psychopathol 8:3–27 Dahl RE, Ryan ND, Puig-Antich J et al. (1991), 24-hour cortisol measures in adolescents with major depression: a controlled study. Biol Psychiatry 30:25–36 Duke PM, Litt IF, Gross RT (1980), Adolescents’ self-assessment of sexual maturation. Pediatrics 66:918–920 Emslie GJ, Armitage R, Weinberg WA, Rush AJ, Mayes TL, Hoffmann RF (2001), Sleep polysomnography as a predictor of recurrence in children and adolescents with major depressive disorder. Int J Neuropsychopharmacol 4:159–168 Frank E, Young E (2000), Pubertal changes and adolescent challenges. Why do rates of depression rise precipitously for girls between ages 10 and 15 years? In: Gender and Its Effects on Psychopathology, Frank E, ed. Washington, DC: American Psychiatric Press, pp 85–102 Fulton MK, Armitage R, Rush AJ (2000), Sleep electroencephalographic coherence abnormalities in individuals at high risk for depression: a pilot study. Biol Psychiatry 47:618–625 Glod CA, Teicher MH, Polcari A, McGreenery CE, Ito Y (1997), Circadian rest-activity disturbances in children with seasonal affective disorder. J Am Acad Child Adolesc Psychiatry 36:188–195 Goodwin FK, Jamieson KR (1990), Manic-Depressive Illness. New York: Oxford University Press Goodwin FK, Wirz-Justice A, Wehr T (1982), Evidence that the pathophysiology of depression and the mechanism of action of antidepressant drugs involve alterations in circadian rhythms. Adv Biochem Psychopharmacol 31:1–11 Healy D (1987), Rhythm and blues. Neurochemical, neuropharmacological and neuropsychological implications of a hypothesis of circadian rhythm dysfunction in the affective disorders. Psychopharmacology 93:271–285 Hoffmann R, Hendrickse W, Rush AJ, Armitage R (2000), Slow-wave activity during NREM sleep in men with schizophrenia and major depressive disorders. Psychiatry Res 95:215–225 Kaufman J, Birmaher B, Brent D et al. (1997), Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL). Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988 Kessler RC (2000), Gender differences in major depression: epidemiological findings. In: Gender and Its Effects on Psychopathology, Frank E, ed. Washington, DC: American Psychiatric Press, pp 61–84 Kupfer DJ, Frank E, McEachran AB, Grochocinski VJ (1990), Delta sleep ratio: a biological correlate of early recurrence in unipolar affective disorder. Arch Gen Psychiatry 47:1100–1105 Kupfer DJ, Ulrich RF, Coble PA et al. (1984a), Application of an automated REM and slow wave sleep analysis: I. Normal and depressed subjects. Psychiatry Res 13:325–334 Kupfer DJ, Ulrich RF, Coble PA et al. (1984b), Application of an automated REM and slow wave sleep analysis. II. Testing the assumptions of the two-process model of sleep regulation in normal and depressed subjects. Psychiatry Res 13:335–343 March JS, Parker JDA, Sullivan K, Stallings P, Conners CK (1997), The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity. J Am Acad Child Adolesc Psychiatry 36:554–565 Monk TH (1993), Biological rhythms and depressive disorders. In: Biology of Depressive Disorders, Part A: A Systems Perspective, Mann JJ, Kupfer DJ, eds. New York: Plenum Press, pp 109–122 Morehouse RL, Kusumakar V, Kutcher SP, LeBlanc J, Armitage R (2002), Temporal coherence in ultradian sleep EEG rhythms in a neverdepressed, high-risk cohort of female adolescents. Biol Psychiatry 51:446–456 Parry BL (2000), Hormonal basis of mood disorders in women. In: Gender and Its Effects on Psychopathology, Frank E, ed. Washington, DC: American Psychiatric Press, pp 3–21 Poznanski EO, Freeman LN, Mokros HB (1985), Children’s Depression Rating Scale – Revised (September 1984) Psychopharmacol Bull 21:979– 989 Reynolds CF III, Kupfer DJ (1987), Sleep research in affective illness: state of the art circa 1987. Sleep 10:199–215
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Reynolds CF III, Kupfer DJ, Thase ME et al. (1990), Sleep, gender, and depression: an analysis of gender effects on the electroencephalographic sleep of 302 depressed outpatients. Biol Psychiatry 28:673–684 Schulz H, Lund R (1985), On the origin of early REM episodes in the sleep of depressed patients: a comparison of three hypotheses. Psychiatry Res 16:65–77 Shaffer D, Gould MS, Brasic J et al. (1985), A children’s global assessment scale (CGAS) (for children 4 to 16 years of age). Psychopharmacol Bull 21:747–748 Siever LJ, Davis KL (1985), Overview: toward a dysregulation hypothesis of depression. Am J Psychiatry 142:1017–1031
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Tanner JM (1962), Growth at Adolescence, 2nd ed. Springfield, IL: Charles C Thomas Tanner JM (1978), Fetus Into Man. Cambridge: Harvard University Press Teicher MH, Glod CA, Harper D et al. (1993), Locomotor activity in depressed children and adolescents: I. Circadian dysregulation. J Am Acad Child Adolesc Psychiatry 32:760–769 Teicher MH, Glod CA, Magnus E et al. (1997), Circadian rest-activity disturbances in seasonal affective disorder. Arch Gen Psychiatry 54:124– 130 Weinberg WA, Emslie GJ (1988), Weinberg Screening Affective Scale (WSAS and WSAS-SF). J Child Neurol 3:294–296
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ABSTRACT Objective: To quantify circadian rhythms in rest-activity cycles in depressed children and adolescents. Method: Restactivity cycles were evaluated by actigraphy over five consecutive 24-hour periods in 100 children and adolescents, including 59 outpatients with major depressive disorder (MDD) and 41 healthy normal controls. Total activity, total light exposure, and time spent in light at more than 1,000 lux were averaged over the recording period for each participant. Time series analysis was used to determine the amplitude and period length of circadian rhythms in rest-activity. Results: Overall, adolescents with MDD had lower activity levels, damped circadian amplitude, and lower light exposure and spent less time in bright light than healthy controls. Among children, those with MDD showed lower light exposure and spent less time in bright light, but only depressed girls showed damped circadian amplitude. The sex differences were substantially greater in the MDD group than in the normal control group. Conclusions: These results confirm damped circadian rhythms in children and adolescents with MDD and highlight the influence of gender and age on these measures. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(6):761–769. Key Words: rest-activity cycles, circadian rhythms, childhood depression, gender.
Sleep and biological rhythm abnormalities have been a key focus of theories on major depressive disorder (MDD) in adults for more than two decades. Beginning with the work of Goodwin et al. (1982), it was suggested that the sleep, temperature, and cortisol abnormalities evident in adults with MDD reflected a phase advance in the timing of circadian rhythms. Others have suggested that instability or irregularity of Accepted December 19, 2003. From the Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas. Drs. Armitage and Hoffmann are now at the University of Michigan in Ann Arbor. This research was supported by NIMH grant MH56593 (R.A.) and was conducted at the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas. The authors are grateful for the technical support of the Sleep Study Unit at University of Texas Southwestern Medical Center at Dallas, under the supervision of Darwynn D. Cole; for department support from Eric Nestler, M.D., Ph.D. (Chair); and for the secretarial support from Doris Benson. Correspondence to Dr. Armitage, Director, Sleep and Chronophysiology Laboratory, 2101 Commonwealth, Ann Arbor, MI 48105; e-mail: rosearmi@ umich.edu. 0890-8567/04/4306–0761©2004 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000122731.72597.4e
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sleep cycles and associated rhythms may be more characteristic of MDD than either a consistent phase advance or delay in circadian timing (Healy, 1987; Schulz and Lund, 1985; Siever and Davis, 1985). The majority of more recent studies, however, have not provided strong support for circadian abnormalities in temperature or endogenous cortisol secretion in adults with MDD (cf. Monk, 1993). Moreover, only one study has supported elevated cortisol at sleep onset in adolescents with MDD (Dahl et al., 1991). With regard to sleep laboratory findings, depressed adults show shorter rapid eye movement latencies, reduced slow-wave sleep, and increased sleep fragmentation, all of which point to abnormalities in the timing of the rapid eye movement-nonrapid eye movement sleep cycle (Armitage, 1995; Armitage et al., 1992, 1993a,b, 1999; Kupfer et al., 1984a,b, 1990; Reynolds and Kupfer, 1987; Reynolds et al., 1990). The findings in children and adolescents with MDD have been more equivocal. Although some studies have reported REM timing problems in early-onset MDD, prolonged sleep latency in adolescents is a more consistent finding (Birmaher and Heydl, 2001; Dahl, 1996). 761
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However, a closer examination of the EEG frequency structure in sleep and ultradian rhythms (shorter than 24 hours) has confirmed sleep abnormalities in depressed adults, in children and adolescents with MDD (Armitage et al., 2000a), and in those at risk of, but not yet ill with, MDD (Fulton et al., 2000; Morehouse et al., 2002). These findings provide strong support for the dysregulation hypothesis of depression and that a more general breakdown in biological rhythm in rest and activity underlies depression. Studies of motor activity rhythms have also consistently reported blunted circadian amplitude in depressed adults (cf. Goodwin and Jamieson, 1990) and in children and adolescents with nonseasonal depression (Teicher et al., 1993). The data from Teicher et al. (1993) go further to suggest that the ultradian components of locomotor rhythms are often more pronounced than circadian rhythms and that these findings were evident in both children and adolescents with MDD. Damped circadian amplitude was evident in adolescents but not in children. Interestingly, Glod et al. (1997) also reported blunted locomotor rhythms in children and adolescents with seasonal affective disorder, although this was not confirmed in adults with this disorder (Teicher et al., 1997). We have argued previously that abnormalities in ultradian rest-activity cycles may underlie both the sleep EEG and locomotor disturbances evident in MDD but that the effects may be gender specific (Armitage and Hoffmann 2001; Armitage et al., 2000a–c, 2001, 2002; Hoffmann et al., 2000). The sleep EEG frequency analyses do indicate a greater degree of ultradian rhythm disturbance among females with MDD, from early childhood to later adulthood but particularly in adolescence. These findings, coupled with the results from Teicher et al. (1993), suggest that locomotor rhythms in those with MDD should show both age and gender effects. The purpose of the current study was to evaluate rest-activity cycles and locomotor activity in 59 depressed children and 41 healthy controls. Of primary interest was an evaluation of gender differences and age-related differences in both patients and controls.
Child and Adolescent Psychiatry Outpatient Clinic. Rest-activity measurements were obtained from 100 children and adolescents, 8 to 17 years of age, including 59 outpatients diagnosed with unipolar, nonpsychotic MDD, single or recurrent, and 41 healthy normal controls (NCs). There were 28 females and 31 males in the sample of outpatients with MDD and 20 females and 21 males in the sample of healthy NCs. All patients were symptomatic and unmedicated at the time of the study. Independent sleep disorders by history or polysomnography were exclusionary for all participants. Diagnostic and demographic information is shown in Table 1. Note that there were no significant differences in age or education between groups. Diagnostic Procedures
METHOD
Patients for the study were scheduled for a full evaluation after a telephone screening for inclusion and exclusion criteria. The study was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center at Dallas. Before the initial interview, the study was explained and written informed consent was obtained from the parent(s) and assent from the patient. In addition to a structured psychiatric interview, the initial evaluation included a medical review of systems, a physical examination, routine laboratory tests, and neurological examination. The evaluation was completed during a 3-week period. At the initial visit, each patient and parent(s) were interviewed separately using the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime (K-SADSPL), a revision of the K-SADS (Kaufman et al., 1997). The K-SADS-PL is a semistructured DSM-IV–based diagnostic interview to establish that the patient met DSM-IV criteria for MDD and to identify other concurrent and lifetime psychiatric disorders. The final diagnoses were based on information from interviews of the parent(s) and child. Additionally, depressive symptom severity was assessed using the Children’s Depression Rating Scale-Revised (Poznanski et al., 1985). While the child was being interviewed, a separate interviewer obtained family history from the parent(s) using the Family History Diagnostic Interview. Patients completed two self-report scales for depression and anxiety, the Weinberg Screening Affective Scale–Short Form providing information on a patient’s perception of his/her problems based on 10 major symptom groups of depression (Weinberg and Emslie, 1988), and the Multidimensional Anxiety Scale for Children (March et al., 1997). The Children’s Global Assessment Scale assessed overall functioning (Shaffer et al., 1985). Tanner upper and lower body maturation (1–5 scores) was self-assessed by participants using the “Typical Progression of Pubertal Development Chart” adapted from Tanner (1962, 1978). Breast and pubic hair development was assessed for girls and genital and pubic hair development was assessed for boys. Note that Duke et al. (1980) have shown that children can reliably self-rate sexual maturation using these standard pictures. A third interview was conducted just before the sleep study to review psychiatric assessment and inventories. A Children’s Depression Rating Scale-Revised score of 40 or more was required for entry into the study. Further details on the clinical evaluation procedures are reported elsewhere (Emslie et al., 2001). All NC children and adolescents underwent the same initial psychiatric and medical evaluations as those with MDD and were scheduled for the laboratory tour after the first interview.
Subjects
Procedures
Participants were recruited through campus and community advertisement, by word of mouth, or during an initial visit to the
All participants agreed to follow their usual school week established by sleep history with bed- and rise-times schedules through-
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TABLE 1 Demographic and Clinical Features of the Sample by Diagnostic Group and Gender No. Age overall mean ≤12 yr ≥13 yr Tannera A B FGAS CGAS MASC CDRS BPRS No. of episodes Age at onset of 1st episode Length of current episode Suicide attempts Suicidal ideation Family history (%) Maternal MDD Paternal MDD Comorbid illness, no. (%) GAD OCD Dysthymia ODD Phobia Enuresis ADHD
MDD F
MDD M
NC F
NC M
28 12.3 ± 2.9 9.9 ± 1.4 15.0 ± 1.4
31 12.3 ± 3.0 9.5 ± 1.3 15.5 ± 1.6
21 12.4 ± 3.1 9.9 ± 1.7 14.9 ± 1.9
20 12.4 ± 2.5 10.3 ± 1.4 14.5 ± 1.3
2.9 ± 1.5 2.8 ± 1.6 61.4 ± 10.4 53.0 ± 7.3 54.2 ± 19.8 58.9 ± 11.1 33.0 ± 9.0 1.4 ± 0.7 11.1 ± 3.2 18.3 ± 7.1 0 2.3 ± 0.8
2.7 ± 1.5 2.8 ± 1.7 64.5 ± 11.9 52.5 ± 6.1 48.8 ± 16.1 57.1 ± 7.2 34.4 ± 8.4 1.4 ± 0.6 11.3 ± 3.3 18.5 ± 10.2 0 2.3 ± 0.6
3.5 ± 1.5 3.3 ± 1.5 91.7 ± 2.6 90.7 ± 4.1 33.1 ± 13.6 19.0 ± 2.3 2.4 ± 3.1 — — — — —
3.0 ± 1.6 2.9 ± 1.6 91.5 ± 6.0 90.7 ± 5.4 30.6 ± 14.7 18.4 ± 2.0 2.4 ± 2.8 — — — — —
64.3 17.9 17 (60.2) 1 0 7 0 0 1 8
45.2 12.9 16 (51.6) 2 1 4 1 1 0 7
Note: MDD F = depressed females; MDD M = depressed males; NC F = normal control females; NC M = normal control males; FGAS = Family Global Assessment Scale; CGAS = Children’s Global Assessment Scale; MASC = Multidimensional Anxiety Scale for Children; CDRS = Children’s Depression Rating Scale; BPRS = Brief Psychiatric Rating Scale; MDD = major depressive disorder; GAD = general anxiety disorder; OCD = obsessive-compulsive disorder; ODD = oppositional defiant disorder; ADHD = attention-deficit/hyperactivity disorder. a Tanner A is based on breast development for girls and genitalia for boys. Tanner B assesses development of pubic hair. out the study. They were informed that a deviation of more than one half hour would result in elimination from the study. With the exception of two children and three adolescents, all participants were tested Monday through Friday during the regular school year outside of holiday and vacation schedules. Actigraphs (Actiwatch-L, Mini-Mitter) were worn throughout the week, and sleep/wake diaries were collected daily during the home recording period. Actigraphs were set to begin at noon and end at 9 A.M. on the last morning of the recording. The actigraphs measured the number of movements that exceeded 0.01g (gravitation force per minute of recording). In addition, a photoconductive cell recorded light level exposure, measured in lux. All actigraphs were calibrated before recording to ensure comparability across subjects. Thresholds, sensitivities, scaling, and epoch lengths were held constant across all individual recordings. Actigraphs were not removed while showering or bathing. Subjects were asked to note in the diaries whether the actigraphs were removed, for how long, and for what purpose and to record any travel periods less than 15 minutes. Finally,
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subjects were instructed not to wear any clothing that covered up the watch face at any time during the recording period. The technical reliability of the actigraph was very high, with little loss of data. Subjects were compliant with the actigraphy procedures, resulting in the loss of very few data points. Of the 100 study participants, complete 5-day actigraphy data were available for 95 participants. For the remaining five subjects, 3 complete days of data were available. The additional days were excluded from analysis. The 24-hour blocks with missing data due to participants removing the watch were excluded from the analysis. Data Analysis Data were downloaded from the actigraphs at the end of the recording period. Initial data analyses were conducted with onboard Mini-Mitter software, computing the average activity count per epoch in the light and dark periods. Total daily light exposure was also computed for each day of recording, along with average
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light exposure and the amount of time in light above a 1,000-lux level across the recording period. The raw activity data per minute (time series) were also exported to SAS and subjected to Fourier-based spectral analysis for each individual subject to determine the circadian amplitude or strength of the 24-hour rhythms. Relative circadian amplitude was also computed (100 × amplitude/mean daily activity) to ensure that amplitude estimates were not biased by total activity (Teicher, et al., 1993). All data were coded for group (NC or MDD), gender, and age, using an arbitrary cut point of 12 to contrast children and adolescents. Average Tanner scores (upper body + lower body/2) were also used to evaluate maturational age by gender by group interaction. Analysis of variance (ANOVA) evaluated statistical differences, testing the group by gender by age interactions first, and simple interactions and main effects only if three-way interactions were not significant. Least-squares multiple comparisons contrasted differences between individual means only if a significant overall ANOVA effect was obtained to protect against type I errors.
RESULTS
Using an age cut point of 12, there were 15 girls and 11 boys in the 8- to 12-year-old MDD group. There were 10 girls and 11 boys in the 8- to 12-year-old NC group. The adolescent group had 13 girls and 14 boys with MDD and 10 NC girls and 10 NC boys all in the 13- to 17-year-old age range. Activity Levels
The means and standard deviations for all the activity measures are shown in Table 2 by group and age but collapsed across gender. The means indicate substantial age-related differences in activity, with lower total activity and lower activity in the light phase in the adolescents but with higher activity in the dark phase. Further, the difference in total activity between chil-
dren and adolescents was greater in the MDD group. Statistical analyses indicated that these effects were strongly moderated by gender. ANOVA revealed a significant gender by diagnostic group by age interaction for total activity (F7,92 = 2.2; p < .04) and for activity level during the light phase (F7,92 = 2.8; p < .02) but not during the dark phase (F7,92 = 1.1; p < .35). The three-way interaction for total daily activity is illustrated in Figure 1. Male children with MDD showed more total activity than the other groups of the same age range but differed significantly only from MDD girls (p < .03). Moreover, the differences in total activity between the age groups were most dramatic in the MDD males; adolescents had significantly lower activity than children (p < .001). By contrast, the difference between the child and adolescent groups were not significant for NC females (p < .23), NC males (p < .37), or MDD females (p < .22), accounting for the three-way interaction. Results were similar for activity in the light phase. Activity in the dark phase did show a main effect for age (F1,92 = 4.0; p < .05). Means indicated that activity during the dark was higher in adolescents than in children, in all groups, as is evident in Table 2. Note that the minimal and maximal values were lower in the MDD groups for all activity measures. Light Exposure
The means and standard deviations for average daily light level and the average time spent above a 1,000-lux threshold are shown in Table 2. Average light levels were lower in both children and adolescents with
TABLE 2 Means (and Standard Deviations) of Actigraphy Measures by Diagnostic Group (NC Versus MDD) and Age Group NC Children a
Activity total Avg. no. in light Avg. no. in dark Light avg.b (lux) Timec (min) Circadian period (h) Amplituded
18,313.6 (9,378.2) 386.0 (191.9) 25.2 (27.5) 847.9 (758.6) 99.6 (90.4) 24.30 (0.30) 2,865.3 (2,784.6)
MDD Adolescents
Children
Adolescents
14,461.4 (8,464.7) 288.2 (169.1) 38.2 (28.5) 832.7 (1,162.9) 81.4 (67.5) 24.09 (0.36) 1,467.8 (1,335.9)
18,888.2 (9,936.4) 389.9 (212.9) 28.5 (30.9) 597.9 (647.1) 64.0 (44.6) 23.98 (0.38) 3,311.5 (3,038.5)
11,626.7 (7,380.8) 236.7 (153.7) 40.6 (33.3) 408.1 (586.1) 50.3 (50.1) 24.18 (0.32) 987.1 (1,757.1)
a
Total number of events more than criterion × 103. Average time at more than 1,000 lux. c Average daily time spent at 1,000 or more lux. d Power (area under the curve) × 104. b
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Fig. 1 Total daytime activity counts over 5 days in children (filled bars) and adolescents (open bars) by gender and group. NC F = normal control females; MDD F = depressed females; NC M = normal control males; MDD M = depressed males.
MDD compared with controls. The between-group differences are illustrated in Figure 2. Young girls with MDD had lower light exposure than the other groups of children, whereas adolescent males in the NC group had the highest level of exposure, confirmed by multiple comparisons (p < .05). The NC males were also the only group to show more light exposure in the adolescents than in the children, accounting for the nearly significant three-way interaction (p < .06). Interestingly, adolescent NC girls and girls and boys with MDD were exposed mostly to indoor light levels. Only the adolescent NC males had sustained outdoor light exposure. However, no significant gender by diagnostic
Fig. 2 Day light level (lux) averaged over 5 days in children (filled bars) and adolescents (open bars) by group and gender. NC F = normal control females; MDD F = depressed females; NC M = normal control males; MDD M = depressed males.
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group by age interaction was obtained for this measure (F7,92 = 2.04; p < .06). The average time spent in bright light showed similar results. Also seen in Table 2, the MDD group spent roughly 30 minutes less on average in bright light than NCs, regardless of age. ANOVA indicated significant age by diagnostic group and gender by diagnostic group interactions (F3,96 = 3.1, 2.7; p < .05, respectively) but no significant three-way interaction (F7,92 = 1.6; p < .17). As seen with the average light level, NC adolescent males showed slightly more (4 minutes) time spent in bright light compared with children in this group. Although the means in Table 2 suggest equivalent age-related differences in the daily time spent in bright light in the MDD and NC groups, the greatest difference between children and adolescents was observed in the NC females. Girls in the NC group had an average of 90 minutes of bright light exposure, whereas adolescents in this group spent only 67 minutes in bright light (data not shown). Nevertheless, both male and female adolescents in the NC group still had more light exposure than their MDD counterparts (p < .05). Once again, the minimal and maximal values were lower in those with MDD than in the NCs for both light variable groups. Circadian Rhythm Measures
The means and standard deviations for the period length and the amplitude of circadian rest-activity rhythms are also shown in Table 2. Although children with MDD had a circadian rhythm that was 21 minutes shorter than that of NC children (23 hours 59 minutes versus 24 hours 20 minutes), this difference was not significant. The circadian period length did not appear to differ by age or diagnostic group. Further, ANOVA did not indicate significant main effects or interactions for this variable (p > .23). Collapsed across gender, the amplitude of circadian rhythms was lower in adolescents with MDD compared with NCs, as seen in Table 2. Children with MDD had higher amplitude rhythms than controls; however, a significant three-way interaction was obtained for this measure (F7,91 = 3.0; p < .006). Relative circadian amplitude adjusted for total activity also showed a three-way interaction (F7,91 = 3.8; p < .002) and is depicted in Figure 3. The means indicated that both female children and adolescents with MDD had lower relative amplitude circadian rhythms than all 765
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damped circadian amplitude compared with NCs (p < .05). Attention-Deficit/Hyperactivity Disorder Comorbidity
Fig. 3 Relative amplitude (power) of circadian (24-hour) rhythms in total activity in children (filled bars) and adolescents (open bars) averaged by group and gender. Amplitude determined by time series analysis (based on a fast Fourier transform) of activity count per minute throughout five consecutive 24-hour recording periods for each individual. NC F = normal control females; MDD F = depressed females; NC M = normal control males; MDD M = depressed males.
other groups, whereas MDD boys showed higher circadian amplitude than any other group. Multiple comparisons confirmed these differences (p < .05), except when comparing NC boys with MDD boys. In addition, Figure 3 also illustrates the dramatic age differences in circadian amplitude, evident in all groups. The difference between children and adolescents was, however, most pronounced in the MDD males, with more than 70% lower amplitude in the adolescents (p < .002), further contributing to the significant three-way interaction. Thus, circadian rhythms and light exposure were most abnormal in girls with MDD and evident even in preteens. Chronological Versus Maturational Age
To ensure that our arbitrary age cut point of 12 years did not produce an artificial distinction between groups, we also conducted an analysis of age using average upper and lower body Tanner scores. The three-way interactions (group by gender by developmental age) were evaluated for relative circadian amplitude, light exposure, and total activity. The outcome was strikingly similar to that obtained with chronological age (F7,69 = 3.1, 2.8, 2.4; p < .01, .02, .03, respectively), significantly lower circadian amplitude, light exposure, and total activity in prepubertal (Tanner 1 or 2) girls with MDD (p < .05). Pubertal (Tanner 4 or 5) but not prepubertal boys with MDD also showed 766
One further concern was the higher incidence of comorbid attention-deficit/hyperactivity disorder (ADHD) in the children with MDD, particularly with regard to the failure to find lower activity or damped circadian amplitude in young boys with MDD. We recomputed the analyses of the rest-activity measures excluding the three adolescents and 12 children who had morbid ADHD. Removing these subjects had only a small effect on results, reducing the overall probability due to the loss of degrees of freedom, but did not alter the effect size. For relative circadian amplitude, light exposure and activity levels, the resulting threeway interactions were (F7,85 = 2.7, 2.4; p < .03, 1.93; p < .07, respectively). Even excluding the outpatients with comorbid MDD, circadian amplitude was damped in preteen and teenage girls and in teenage boys with MDD. Thus, the failure to find damped amplitude rhythms in preteen depressed boys was not due to comorbid ADHD. DISCUSSION
To summarize the overall findings, adolescents with MDD had lower activity levels, damped circadian amplitude, and lower light exposure and spent less time in bright light than healthy controls. Among preteens, girls with MDD had lower light exposure, spent less time in bright light than controls, and showed lower circadian amplitude. By contrast, preteen boys with MDD had robust circadian amplitude. Most importantly, the same results were obtained with relative circadian amplitude, adjusted for mean activity levels. Thus, it is not just reduced activity that is evident in those with MDD. The results of the current study conform to those of Teicher et al. (1993), indicating that circadian amplitude was damped in adolescents with MDD. The Teicher et al. sample of control subjects was substantially smaller, patients were 2.5 to 3.4 years older than controls, and neither potential gender effects nor light levels were evaluated. Nevertheless, the rest-activity cycle data in the current study are remarkably similar to those shown in the Teicher et al. report. Damped circadian amplitude is likely to reflect weak entrainment to a 24-hour day and/or reduced J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:6, JUNE 2004
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exposure to zeitgebers (time cues and entrainment) (Teicher et al., 1993). Because the master circadian clock is strongly driven by light (Czeisler et al., 1989) and given the low light levels that appear to accompany damped amplitude, it suggests that increasing light exposure will enhance circadian amplitude. Additional clinical implications of these results are discussed below. Our findings are also in agreement with those of Glod et al. (1997) who reported blunted circadian amplitude but no phase disruption in children with seasonal affective disorder, although their study did not assess gender. Consistent with the dysregulation hypothesis of depression (Siever and Davis, 1985), we did not find evidence of a phase advance in circadian timing. The strong influence of gender obtained in the current study is also consistent with our previous reports on sleep data. The gender differences in the MDD group were substantially larger than those obtained in healthy controls overall. We have previously reported larger gender differences in adults with MDD compared with controls on several quantitative EEG measures during sleep (Armitage and Hoffmann, 2001; Armitage et al., 1999, 2000b,c). Further, we have also reported a greater degree of ultradian rhythm disturbance in females with MDD, in line with increased risk of MDD among women (Armitage and Hoffmann, 2001) and with studies of continuing biological vulnerability to recurrence that is greater in women. The data from the current study extend these gender differences to circadian rest-activity cycles. Even 8- to 12-year-old girls with MDD show damped circadian amplitude, whereas damped circadian rhythms were only evident in the adolescent boys with MDD. Interestingly, it is believed that the increased risk of MDD in females does not occur until after puberty, with equivalent risk of MDD in prepubertal boys and girls (Frank and Young, 2000; Kessler, 2000; Parry, 2000). Our data suggest that the developmental time course of biological rhythm abnormalities is different in boys and girls with MDD. Damped circadian restactivity cycles are evident earlier in females than in males with MDD. It is not clear, however, how (or whether) these biological abnormalities relate to the risk of MDD or to the clinical course of illness. A study of children at risk of MDD and longitudinal evaluations of those already ill are necessary to address these issues. Regardless of the outcome, the current study supports our previous findings that gender differences J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:6, JUNE 2004
are more dramatic in those with MDD (Armitage, 1995; Armitage and Hoffmann, 2001; Armitage et al., 1999, 2000b,c). Limitations
There are limitations to this study that need to be considered when interpreting data, most notably sample size. Splitting the groups by age and gender left only 10 to 17 subjects per cell. There is some concern that the findings may not generalize to a larger sample. Thus, it will be necessary to replicate our findings. Such efforts are currently underway. In addition, it is also necessary to determine whether the rest-activity abnormalities obtained in this study correlate with the amplitude and phase of other circadian measures such as temperature and cortisol. A constant routine or forced desynchrony paradigm would allow an assessment of the interaction of circadian and wake-dependent processes, including mood. Because recent work has demonstrated that circadian phase also affects mood regulation (Boivin et al., 1997), it would be of significance to include repeated mood assessments in further studies of circadian rhythms in depression. It will undoubtedly be necessary to manipulate light exposure and rest-activity cycles, including sleep-wake cycles to evaluate the clinical impact directly of these measures in depression and to further elucidate the mechanisms responsible for damped amplitude restactivity cycles. An additional limitation to this study is our inability to fully assess the influence of comorbidity on restactivity cycles. Although we reanalyzed our data excluding those with comorbid ADHD and found very similar results to full analysis, it is still possible that this and other comorbid illness could contribute to restactivity cycle parameters. Nonetheless, comorbid illness was not found to differentiate between the genders. Thus, comorbidity cannot account for the significant group by gender effects obtained in this study. Clinical Implications
The current study indicates that damped circadian amplitude is characteristic of teenagers with MDD and of preteen depressed girls. Because relative circadian amplitude was also found to be damped, it appears unlikely that increasing total activity alone would normalize circadian amplitude. The regularity of daytime 767
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and nighttime schedules, of the amount of light exposure, and of the timing of these events is more likely to have an impact on the strength of rhythms. The outcome of this study suggests that behavioral and chronobiological intervention may be of benefit in early-onset depression. Regularized sleep-wake schedules, structured daytime activity, and increased light exposure may serve to strengthen entrainment and to stabilize sleep-wake cycles. Ultimately, improving sleep and circadian rhythm regulation should the biological risk of depression, although any direct clinical benefit remains to be established. Disclosure: Dr. Armitage currently has two RO1 (MH54593 and MH061515). She currently serves on advisory boards for Pfizer and Takeda Pharmaceuticals. REFERENCES Armitage R (1995), Microarchitectural findings in sleep EEG in depression: diagnostic implications. Biol Psychiatry 37:72–84 Armitage R, Emslie GJ, Hoffmann RF et al. (2000a), Ultradian rhythms and temporal coherence in sleep EEG in depressed children and adolescents. Biol Psychiatry 47:338–350 Armitage R, Emslie GJ, Hoffmann RF, Rintelmann J, Rush AJ (2001), Delta sleep EEG in depressed adolescent females and healthy controls. J Affect Disord 63:139–148 Armitage R, Hoffmann RF (2001), Sleep EEG, depression and gender. Sleep Med Rev 5:237–246 Armitage R, Hoffmann RF, Emslie GJ, Weinberg WA, Mayes TL, Rush AJ (2002), Sleep microarchitecture as a predictor of recurrence in children and adolescents with depression. Int J Neuropsychopharmacol 5:217–228 Armitage R, Hoffmann R, Fitch T, Trivedi M, Rush AJ (2000b), Temporal characteristics of delta activity during NREM sleep in depressed outpatients and healthy adults: group and sex effects. Sleep 23:607– 617 Armitage R, Hoffmann RF, Rush AJ (1999), Biological rhythm disturbance in depression: temporal coherence of ultradian sleep EEG rhythms. Psychol Med 29:1435–1448 Armitage R, Hoffman R, Trivedi M, Rush AJ (2000c), Slow-wave activity in NREM sleep: sex and age effects in depressed outpatients and healthy controls. Psychiatry Res 95:201–213 Armitage R, Hudson A, Trivedi M, Rush AJ (1993a), Sex differences in the distribution of EEG frequencies during sleep: unipolar depressed outpatients. J Affect Disord 34:121–129 Armitage R, Roffwarg HP, Rush AJ (1993b), Digital period analysis of EEG in depression: periodicity, coherence, and interhemispheric relationships during sleep. Prog Neuropsychopharmacol Biol Psychiatry 17:363–372 Armitage R, Roffwarg HP, Rush AJ, Calhoun JS, Purdy DG, Giles DE (1992), Digital period analysis of sleep EEG in depression. Biol Psychiatry 31:52–68 Birmaher B, Heydl P (2001), Biological studies in depressed children and adolescents. Int J Neuropsychopharmacol 4:149–157 Boivin DB, Czeisler CA, Dijk D-J et al. (1997), Complex interaction of the sleep-wake cycle and circadian phase modulates mood in healthy subjects. Arch Gen Psychiatry 54:145–152 Czeisler CA, Kronauer RE, Allan JS et al. (1989), Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 244:1328–1333
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