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Susceptibility to Depression Expressed as Alterations in Cortisol Day Curve: A Cross-Twin, Cross-Trait Study

From the Department of Psychiatry and Neuropsychology (M.W., I.M.-G., N.J., G.K., P.D., R.M., F.P., N.N., J.V.O.), South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University, Maastricht, Netherlands; Faculty of Psychology (N.J.), Open University of the Netherlands, Heerlen, Netherlands; Department of Human Genetics (C.D., R.V.), University Hospital Gasthuisberg, Katholieke Universiteit, Leuven, Belgium; and the Division of Psychological Medicine (J.V.O), Institute of Psychiatry, London, UK.

Address correspondence and reprint requests to M.C. Wichers, Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University, Vijverdalseweg 1, Concorde Building, Maastricht, Netherlands. E-mail: m.wichers{at}sp.unimaas.nl

Objective: To examine, using a cross-twin cross-trait design, the hypotheses 1) that the genetic and environmental susceptibility to depression is expressed, in part, as alterations in cortisol day curves and 2) that cortisol abnormalities are not merely the consequence of depressive states or the stressors associated with its onset. Alteration of diurnal secretion of cortisol is a possible endophenotype of depression, as depressed patients show alterations in cortisol dynamics over the day.

Methods: Salivary cortisol measurements were obtained in a sample of 279 twin pairs at 10 random times a day for 5 days. A structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4^th Edition) axis I mood disorder (SCID) was administered. Using multilevel regression analysis, the moderating influence of a lifetime diagnosis of depression in the co-twin on the association between time of day and cortisol concentrations in the proband twin was examined.

Results: Diurnal variation in cortisol in the proband twin differed as a function of lifetime diagnosis of depression in the co-twin. In addition, this moderating effect was significantly stronger for dizygotic than for monozygotic twins.

Conclusions: Probands of co-twins with lifetime depression have a different diurnal cortisol profile than those without, suggesting that altered hypothalamic-pituitary-adrenal axis functioning is an indicator of depression susceptibility.

Key Words: depression • cross-twin cross-trait method • cortisol • endophenotype • epigenetics

Abbreviations: DZ = dizygotic; ESM = experience sampling method; FDR = first-degree relative; GR = glucocorticoid receptor; HPA = hypothalamic-pituitary-adrenal; MDD = major depressive disorder; MZ = monozygotic; SCID = structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4^th Edition) disorders.

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