Abstract
Previous work has demonstrated reliable electroencephalographic (EEG) sleep and hypothalamic-pituitary-adrenal (HPA) changes associated with adult major depressive disorder. These changes might be evident before clinical manifestation of the illness in at-risk persons. The aim of the study was to identify depression-related EEG sleep and HPA changes in healthy adolescents at high risk for depression, and to examine the relationship between EEG sleep (or HPA) changes and the onset of depression. Forty-eight adolescent volunteers with no personal history of a psychiatric illness, including depression, but who were at high risk for developing depression by virtue of parental depression (high-risk group), and 48 adolescent volunteers with no personal or family history of a psychiatric disorder (normal controls) were recruited. EEG sleep and HPA measures were collected on three consecutive evenings and nights at baseline. Clinical follow-up evaluations were conducted at regular intervals over a 5-year period. Compared with normal controls, adolescents at high risk for depression had shorter latency to rapid eye movement (REM) sleep, increased phasic REM sleep, more REM sleep and elevated nocturnal urinary-free cortisol (NUFC) excretion at baseline. Shorter REM latency, higher REM density and elevated NUFC (measured at baseline) were associated with the development of depression during follow-up. The findings that REM sleep abnormalities and elevated HPA activity occur before the onset of depression in at-risk adolescents suggest that these variables serve as vulnerability markers for the illness.
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References
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Press: Washington, DC.
Andreasen NC, Endicott J, Spitzer RL, Winokur G (1977). The family history method using diagnostic criteria. Arch Gen Psychiatry 34: 1229–1235.
Asnis GM, Halbreich U, Sachar EJ, Nathan RS, Ostrow LC, Novacenko H et al (1983). Plasma cortisol secretion and REM period latency in adult endogenous depression. Am J Psychiatry 140: 750–753.
Beck AT, Ward CH, Mendelson M, Muck M, Erbaugh J (1961). An inventory for measuring depression. Arch Gen Psychiatry 4: 561–571.
Benca RM, Obermeyer WH, Thisted RA, Gillin JC (1992). Sleep and psychiatric disorders: a meta-analysis. Arch Gen Psychiatry 49: 651–668.
Breslau N, Roth T, Rosenthal L, Andreski P (1996). Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 39: 411–418.
Buysse DJ, Angst J, Gama A, Ajdacic V, Eich D, Rossler W (2008). Prevalence, course and comorbidity of insomnia and depression in young adults. Sleep 31: 473–480.
Carroll BJ (2007). Regarding ‘the Munich vulnerability study on affective disorders: premorbid polysomnographic profile of affected high-risk probands. Biol Psychiatry 62: 703–704.
Cartwright RD (1983). Rapid eye movement sleep characteristics during and after mood-disturbing events. Arch Gen Psychiatry 40: 197–201.
Caspi a, Sudgen K, Moffitt TE, Taylor A, Craig IW, Harrington H et al (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301: 386–389.
Coble PA, Scher MS, Reynolds III CF, Day NL, Kupfer DJ (1988). Preliminary findings on the neonatal sleep of offspring of women with and without a prior history of affective disorder. Sleep Res 16: 120.
Dyer JG, Giles DE (1994). Familial influence in unipolar depression: effects of parental cognitions and social adjustment on adult offspring. Compr Psychiatry 35: 290–295.
Eaves L, Silberg J, Erkanli A (2003). Resolving multiple epigenetic pathways to adolescent depression. Child Psychol Psychiatry 44: 1006–1014.
Friess E, Modell S, Brunner H, Tagaya H, Lauer CJ (2008a). The Munich vulnerability study on affective disorders: microstructure of sleep in high-risk subjects. Eur Arch Psychiatry Clin Neurosci 258: 285–291.
Friess E, Schmid D, Modell S, Brunner H, Lauer CJ, Holsboer F et al (2008b). Dex/CRH-test response and sleep in depressed patients and healthy controls with and without vulnerability for affective disorders. J Psychiatr Res 42: 1154–1162.
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.
Germain A, Kupfer DJ (2008). Circadian rhythm disturbances in depression. Hum Pharmacol Clin Exp 23: 571–585.
Giles DE, Biggs MM, Rush AJ, Roffwarg HP (1988). Risk factors in families of unipolar depression, I: psychiatric illness and reduced REM latency. J Affect Disord 14: 51–59.
Giles DE, Etzel BA, Biggs MM (1990a). Risk factors in unipolar depression:II relation between proband REM latency and cognitions of relatives. Psychiatr Res 33: 39–49.
Giles DE, Jarrett RB, Rush AJ, Biggs MM, Roffwarg HP (1993). Prospective assessment of EEG sleep in remitted major depression. Psychiatr Res 46: 269–284.
Giles DE, Kupfer DJ (1994). Reduced REM latency: risk factor for first episode of depression. Sleep Res 23: 197.
Giles DE, Kupfer DJ, Rush AJ, Roffwarg HP (1998). Controlled comparison of electrophysiological sleep in families of probands with unipolar depression. Am J Psychiatry 155: 192–199.
Giles DE, Roffwarg HP, Dahl RE, Kupfer DJ (1992). EEG sleep abnormalities in depressed children: a hypothesis. Psychiatry Res 41: 53–63.
Giles DE, Roffwarg HP, Kupfer DJ, Rush AJ, Biggs MM, Etzel BA (1989). Secular trend in unipolar depressions: a hypothesis. J Affect Disord 16: 71–75.
Giles DE, Roffwarg HP, Rush AJ (1987). REM latency concordance in depressed family members. Biol Psychiatry 22: 907–910.
Giles DE, Roffwarg HP, Rush AJ, Guzick DS (1990b). Age-adjusted threshold values for reduced REM latency in unipolar depression using ROC analysis. Biol Psychiatry 27: 841–853.
Goodyer IM, Herbert J, Tamplin A, Altham PME (2000). Recent life events, cortisol, dehydroepiandrosterone and the onset of major depression in high-risk adolescents. Br J Psychiatry 177: 499–504.
Goodyer IM, Park RJ, Herbert J (2001). Psychosocial and endocrine features of chronic first-episode major depression in 8–16 year olds. Biol Psychiatry 50: 351–357.
Gottesman II, Gould TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160: 636–645.
Halligan SL, Herbert J, Goodyer I, Murray L (2007). Disturbances in morning cortisol secretion in association with maternal postnatal depression predict subsequent depressive symptomatology in adolescents. Biol Psychiatry 62: 40–46.
Halligan SL, Herbert J, Goodyer IM, Murray L (2004). Exposure to postnatal depression predicts elevated cortisol in adolescent offspring. Biol Psychiatry 55: 376–381.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62.
Hammen C, Shih JH, Brennan PA (2004). Intergenerational transmission of depression: test of an interpersonal stress model in a community sample. J Consult Clin Psychol 72: 511–522.
Harris TO, Borsanyi S, Messari S, Stanford K, Cleary SE, Shiers HM et al (2000). Morning cortisol as a risk factor for subsequent major depressive disorder in adult women. Br J Psychiatry 177: 505–510.
Hollingshead AB (1975). Four Factor Index of Social Status. Department of Sociology, Yale University: New Haven, CT.
Holsboer F (2001). Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 62: 77–91.
Ising M, Lauer CJ, Holsboer F, Modell S (2005). The Munich vulnerability study on affective disorders: premorbid neuroendocrine profile of affected high-risk probands. J Psychiatr Res 39: 21–28.
Ivanenko A, Johnson K (2008). Sleep disturbances in children with psychiatric disorders. Sem Pediatr Neurol 15: 70–78.
Joiner TE (2006). The Interpersonal, Cognitive, and Social Nature of Depression. Lawrence Erilbaum Associates: Mahwah, New Jersey.
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P et al (1997). Schedule for Affective Disorders and Schizophrenia for School-aged Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36: 980–988.
Kaufman J, Martin A, King RA, Charney D (2001). Are child-, adolescent-, and adult-onset depression one and the same disorder? Biol Psychiatry 49: 980–1001.
Kendler KS, Gardner CO, Neale MC, Prescott CA (2001). Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? Psychol Med 31: 605–616.
Kessler RC, Avenevoli S, Merikangas KR (2001). Mood disorders in children and adolescents: an epidemiologic perspective. Biol Psychiatry 49: 1002–1014.
Kimura M, Winkelmann J (2007). Genetics of sleep and sleep disorders. Cell Mol Life Sci 64: 1171–1173.
Kirschbaum C, Wust S, Faig H-G, Hellhammer DH (1992). Heritability of cortisol responses to human corticotrophin-releasing hormone, ergometry, and psychological stress in humans. J Clin Endocrinol Metab 75: 1526–1530.
Kupfer DJ, Foster G, Reich L, Thompson KS, Weiss B (1976). EEG sleep changes as predictors in depression. Am J Psychiatry 133: 622–626.
Lauer C, Schreiber W, Holsboer F, Krieg J-C (1995). In quest of identifying vulnerabilitiy markers for psychiatric disorders by all-night polysomnography. Arch Gen Psychiatry 52: 145–153.
Lauer CJ, Bronisch T, Kainz M, Schreiber W, Holsboer F (1997). Pre-morbid psychometric profile of subjects at high familial risk for affective disorder. Psychol Med 27: 355–362.
Lauer CJ, Modell S, Schreiber W, Krieg J-C, Holsboer F (2004). Prediction of the development of a first major depressive episode with a rapid eye movement sleep induction test using the cholinergic agonist RS86. J Clin Psychopharmacol 24: 356–357.
Mannie ZN, Harmer CJ, Cowen PJ (2007). Increased waking salivary cortisol levels in young people at familial risk for depression. Am J Psychiatry 164: 617–621.
Mathew SJ, Coplan JD, Goetz RR, Feder A, Greenwald S, Dahl RE et al (2003). Differentiating depressed adolescent 24 h cortisol secretion in light of their adult clinical outcome. Neuropsychopharmacology 28: 1336–1343.
Meikle AW, Stringham JD, Woodward MG, Bishop DT (1988). Heritability of variation of plasma cortisol levels. Metab 37: 514–517.
Modell S, Ising M, Holsboer F, Lauer CJ (2005). The Munich vulnerability study on affective disorders: premorbid polysomnographic profile of affected high-risk probands. Biol Psychiatry 58: 694–699.
Modell S, Lauer CJ, Schreiber W, Huber J, Kreig J-C, Holsboer F (1998). Hormonal response pattern in the combined DEX/CRH test is stable over time in subjects at high familial risk for affective disorders. Neuropsychopharmacology 18: 253–262.
Monroe SM, Harkness K, Simons AD, Thase ME (2001). Life stress and the symptoms of major depression. J Nerv Ment Dis 189: 168–175.
Monroe SM, Thase ME, Simons AD (1992). Social factors and the psychobiology of depression: relations between life stress and rapid eye movement sleep latency. J Abnorm Psychol 101: 528–537.
Morehouse RL, Kusumakar V, Kutcher SP, LeBlanc J, Armitage R (2002). Temporal coherence in ultradian sleep EEG rhythms in a never-depressed, high-risk cohort of female adolescents. Biol Psychiatry 51: 446–456.
Ouellet-Morin I, Boivin M, Dionne G, Lupien SJ, Arsenault L, Barr RG et al (2008). Variations in heritability of cortisol reactivity to stress as a function of early familial adversity among 19-month-old twins. Arch Gen Psychiatry 65: 211–218.
Perlis ML, Giles DE, Buysse DJ, Thase ME, Tu X, Kupfer DJ (1997). Which depressive symptoms are related to which sleep electroencephalographic variables? Biol Psychiatry 15: 904–913.
Perlis ML, Giles DE, Fleming G, Drummond SPA, James SP (1995). Sustained facial muscle activity during REM sleep in depressed subjects and its correlations with self-reported depression. J Affect Disord 35: 163–171.
Poland RE, McCracken JT, Lutchmansingh P, Lesser IM, Tondo L, Edwards C et al (1997). Differential response of rapid eye movement sleep to cholinergic blockade by scopolamine in currently depressed, remitted and normal control subjects. Biol Psychiatry 41: 929–938.
Poland RE, McCracken JT, Lutchmansingh P, Tondo L (1992). Relationship between REM sleep latency and nocturnal cortisol concentrations in depressed patients. J Sleep Res 1: 54–57.
Poland RE, Rubin RT (1982). Saliva cortisol levels following dexamethasone administration in endogenously depressed patients. Life Sci 30: 177–181.
Rao U (2006). Development and natural history of pediatric depression: treatment implications. Clin Neuropsychiatry 3: 194–204.
Rao U, Chen L-A (2009). Characteristics, correlates and outcomes of childhood and adolescent depressive disorders. Dialogues Clin Neurosci 11: 91–108.
Rao U, Dahl RE, Ryan ND, Birmaher B, Williamson DE, Giles DE et al (1996). The relationship between longitudinal clinical course and sleep and cortisol changes in adolescent depression. Biol Psychiatry 40: 474–484.
Rao U, McCracken JT, Lutchmansingh P, Edwards C, Poland RE (1997). Electroencephalographic sleep and urinary free cortisol in adolescent depression: a preliminary report of changes from episode to recovery. Biol Psychiatry 41: 369–373.
Rao U, Poland RE (2008). EEG sleep and HPA changes from episode to recovery in depressed adolescents. J Child Adolesc Psychopharmacol 18: 607–613.
Rechtschaffen A, Kales A (1968). A Manual of Standardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects. National Institutes of Health: Bethesda, MD.
Robert JJ, Hoffmann RF, Emslie GJ, Hughes C, Rintelmann J, Moore J et al (2006). Sex and age differences in sleep macroarchitecture in childhood and adolescent depression. Sleep 29: 351–358.
Rush AJ, Thase ME, Dubé S (2003). Research issues in the study of difficult to treat depression. Biol Psychiatry 53: 743–753.
Schmid DA, Brunner H, Lauer CJ, Uhr M, Yassouridis A, Holsboer F et al (2008). Acute cortisol administration increases sleep depth and growth hormone release in patients with major depression. J Psychiatr Res 42: 991–999.
Schreiber W, Lauer CJ, Krumrey K, Holsboer F, Krieg J-C (1992). Cholinergic REM sleep induction test in subjects at high risk for psychiatric disorders. Biol Psychiatry 32: 79–90.
Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H et al (1983). A Children's Global Assessment Scale (C-GAS). Arch Gen Psychiatry 40: 1228–1231.
Shapiro R, Keller M (1979). Longitudinal Interval Follow-Up Evaluation (LIFE). Massachusetts General Hospital: Boston, MA.
Shapiro SS, Wilk MB (1965). An analysis of variance test for normality (complete samples). Biometrika 52: 591–611.
Simons AD, Gordon JS, Monroe SM, Thase ME (1995). Toward an integration of psychologic, social, and biologic factors in depression: effects of outcome and course of cognitive therapy. J Consult Clin Psychol 63: 369–377.
Sitaram N, Dube S, Keshavan M, Davies A, Reynal P (1987). The association of supersensitivity cholinergic REM-induction and affective illness within pedigrees. J Psychiatr Res 21: 487–497.
Steiger A (2007). Neurochemical regulation of sleep. J Psychiatr Res 41: 537–552.
Thase ME, Kupfer DJ, Buysse DJ, Frank E, Simons AD, McEachran AB et al (1995). Electroencephalographic sleep profiles in single episode and recurrent unipolar forms of major depression: I. Comparison during acute depressive states. Biol Psychiatry 38: 506–515.
Thompson WD, Orvaschel H, Prusoff BA, Kidd KK (1982). An evaluation of the family history method for ascertaining psychiatric disorders. Arch Gen Psychiatry 39: 53–58.
Tsuno N, Besset A, Ritchie K (2005). Sleep and depression. J Clin Psychiatry 66: 1254–1269.
Uher R (2008). The implications of gene-environment interactions in depression: will cause inform cure?. Mol Psychiatry 13: 1070–1078.
Young AH (2004). Cortisol in mood disorders. Stress 7: 205–208.
Zalsman G, Oquendo MA, Greenhill L, Goldberg PH, Kamali M, Martin A et al (2006). Neurobiology of depression in children and adolescents. Child Adolesc Psychiatr Clin N Am 15: 843–868, vii–viii.
Acknowledgements
This work was supported, in part, by Grants DA14037, DA15131, DA17804, DA17805, MH01419, MH62464, and MH68391 from the National Institutes of Health, from the National Alliance for Research on Schizophrenia and Affective Disorders, and by the Sarah M and Charles E. Seay Endowed Chair in Child Psychiatry at UT Southwestern Medical Center. We also thank Li-Ann Chen, MA, for technical support.
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Rao, U., Hammen, C. & Poland, R. Risk Markers for Depression in Adolescents: Sleep and HPA Measures. Neuropsychopharmacol 34, 1936–1945 (2009). https://doi.org/10.1038/npp.2009.27
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DOI: https://doi.org/10.1038/npp.2009.27
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