Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study.

CONTEXT There is a central belief that depression is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in higher cortisol levels. However, results are inconsistent. OBJECTIVE To examine whether there is an association between depression and various cortisol indicators in a large cohort study. DESIGN, SETTING, AND PARTICIPANTS Data are from 1588 participants of the Netherlands Study of Depression and Anxiety who were recruited from the community, general practice care, and specialized mental health care. Three groups were compared: 308 control subjects without psychiatric disorders, 579 persons with remitted (no current) major depressive disorder (MDD), and 701 persons with a current MDD diagnosis, as assessed using the DSM-IV Composite International Diagnostic Interview. MAIN OUTCOME MEASURES Cortisol levels were measured in 7 saliva samples to determine the 1-hour cortisol awakening response, evening cortisol levels, and cortisol suppression after a 0.5-mg dexamethasone suppression test. RESULTS Both the remitted and current MDD groups showed a significantly higher cortisol awakening response compared with control subjects (effect size [Cohen d] range, 0.15-0.25). Evening cortisol levels were higher among the current MDD group at 10 pm but not at 11 pm. The postdexamethasone cortisol level did not differ between the MDD groups. Most depression characteristics (severity, chronicity, symptom profile, prior childhood trauma) were not associated with hypothalamic-pituitary-adrenal axis activity except for comorbid anxiety, which tended to be associated with a higher cortisol awakening response. The use of psychoactive medication was generally associated with lower cortisol levels and less cortisol suppression after dexamethasone ingestion. CONCLUSIONS This large cohort study shows significant, although modest, associations between MDD and specific hypothalamic-pituitary-adrenal axis indicators. Because a higher cortisol awakening response was observed among both subjects with current MDD and subjects with remitted MDD, this may be indicative of an increased biological vulnerability for depression.

[1]  J. Tijssen,et al.  Thyroid and adrenal axis in major depression: a controlled study in outpatients. , 2005, European journal of endocrinology.

[2]  J. Krystal,et al.  Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the Archives of General Psychiatry. , 2004, Archives of general psychiatry.

[3]  J. Markowitz,et al.  The 16-Item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression , 2003, Biological Psychiatry.

[4]  F. Hucklebridge,et al.  Exploration of the awakening cortisol response in relation to diurnal cortisol secretory activity. , 2001, Life sciences.

[5]  G. Chrousos,et al.  In vitro and in vivo effects of the triazolobenzodiazepine alprazolam on hypothalamic-pituitary-adrenal function: pharmacological and clinical implications. , 1990, The Journal of clinical endocrinology and metabolism.

[6]  P. Cuijpers,et al.  The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods , 2008, International journal of methods in psychiatric research.

[7]  O. Cameron,et al.  Effect of comorbid anxiety disorders on the Hypothalamic-Pituitary-Adrenal axis response to a social stressor in major depression , 2004, Biological Psychiatry.

[8]  P. Cowen,et al.  Increased waking salivary cortisol levels in young people at familial risk of depression. , 2007, The American journal of psychiatry.

[9]  B. Netterstrøm,et al.  Progression in intima media thickness—the significance of hormonal biomarkers of chronic stress , 2005, Psychoneuroendocrinology.

[10]  R. de Graaf,et al.  Pathways to comorbidity: the transition of pure mood, anxiety and substance use disorders into comorbid conditions in a longitudinal population-based study. , 2004, Journal of affective disorders.

[11]  C. Kirschbaum,et al.  The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm. , 1999, Life sciences.

[12]  C. Nemeroff,et al.  The neurobiology of depression: inroads to treatment and new drug discovery. , 2005, The Journal of clinical psychiatry.

[13]  A Hofman,et al.  Salivary cortisol is related to atherosclerosis of carotid arteries. , 2008, The Journal of clinical endocrinology and metabolism.

[14]  C. Kirschbaum,et al.  Increased free cortisol secretion after awakening in chronically stressed individuals due to work overload , 1998 .

[15]  L. Sher.  Daily hassles, cortisol, and the pathogenesis of depression. , 2004, Medical hypotheses.

[16]  R. Lazarus,et al.  Comparison of two modes of stress measurement: Daily hassles and uplifts versus major life events , 1981, Journal of Behavioral Medicine.

[17]  A. Schatzberg,et al.  The Roles of Glucocorticoid and Dopaminergic Systems in Delusional (Psychotic) Depression a , 1988, Annals of the New York Academy of Sciences.

[18]  J. Calabrese,et al.  The relevance of the in- versus outpatient status for studies on HPA-axis in depression: Spontaneous hypercortisolism is a feature of major depressed inpatients and not of major depression per se , 1994, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[19]  J D Veldhuis,et al.  Pathophysiology of hypercortisolism in depression , 2007, Acta psychiatrica Scandinavica. Supplementum.

[20]  G. Miller,et al.  Blunted cortisol response to awakening in mild to moderate depression: regulatory influences of sleep patterns and social contacts. , 2005, Journal of abnormal psychology.

[21]  A. Young,et al.  The dex/CRH test—Is it better than the DST? , 2006, Psychoneuroendocrinology.

[22]  A. Young,et al.  Hypothalamic–pituitary–adrenal axis function in patients with chronic depression , 2002, Psychological Medicine.

[23]  Jeffrey E. Grice,et al.  Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change , 2004 .

[24]  E. Robins,et al.  Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups. A multicenter study. , 1984, Archives of general psychiatry.

[25]  P. Cowen,et al.  Enhanced early morning salivary cortisol in neuroticism. , 2005, The American journal of psychiatry.

[26]  A. Bouhuys,et al.  Urinary free cortisol excretion in elderly persons with minor and major depression , 2001, Psychiatry Research.

[27]  O. Wolf,et al.  The cortisol awakening response is blunted in psychotherapy inpatients suffering from depression , 2006, Psychoneuroendocrinology.

[28]  Constantine G. Lyketsos,et al.  The Life Chart Interview: A standardized method to describe the course of psychopathology. , 1994 .

[29]  H. Akil,et al.  Increased evening activation of the hypothalamic-pituitary-adrenal axis in depressed patients. , 1994, Archives of general psychiatry.

[30]  E. D. de Kloet,et al.  Hormones and the stressed brain. , 2004, Annals of the New York Academy of Sciences.

[31]  F. Holsboer,et al.  Antidepressants and hypothalamic-pituitary-adrenocortical regulation. , 1996, Endocrine reviews.

[32]  J. V. van Meurs,et al.  Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection. , 1997, American journal of ophthalmology.

[33]  A. Rush,et al.  Clinical and demographic features of atypical depression in outpatients with major depressive disorder: preliminary findings from STAR*D. , 2005, The Journal of clinical psychiatry.

[34]  Johannes Berkhof,et al.  Cortisol Responses to Daily Events in Major Depressive Disorder , 2003, Psychosomatic medicine.

[35]  J. Violanti,et al.  Area Under the Curve and Other Summary Indicators of Repeated Waking Cortisol Measurements , 2007, Psychosomatic medicine.

[36]  H. Roffwarg,et al.  Disrupted 24-hour patterns of cortisol secretion in psychotic depression. , 1973, Archives of general psychiatry.

[37]  A. Steptoe,et al.  The cortisol awakening response in relation to objective and subjective measures of waking in the morning , 2008, Psychoneuroendocrinology.

[38]  T. Baghai,et al.  Influence of mirtazapine on urinary free cortisol excretion in depressed patients , 2003, Psychiatry Research.

[39]  D. Mohr,et al.  Depression and cortisol responses to psychological stress: A meta-analysis , 2005, Psychoneuroendocrinology.

[40]  J. Os,et al.  Susceptibility to Depression Expressed as Alterations in Cortisol Day Curve: A Cross-Twin, Cross-Trait Study , 2008, Psychosomatic medicine.

[41]  B. Carroll,et al.  A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. , 1981, Archives of general psychiatry.

[42]  Jacob Cohen.  Statistical Power Analysis , 1992 .

[43]  J. Romijn,et al.  Automated measurement of salivary cortisol. , 2003, Clinical chemistry.

[44]  B. Penninx,et al.  Depression and cardiac mortality: results from a community-based longitudinal study. , 2001, Archives of general psychiatry.

[45]  A. Beck,et al.  Assessment of suicidal intention: the Scale for Suicide Ideation. , 1979, Journal of consulting and clinical psychology.

[46]  A. Young,et al.  Hypothalamic-pituitary-adrenal axis and bipolar disorder. , 2005, The Psychiatric clinics of North America.

[47]  P. Cowen,et al.  Increase in concentration of waking salivary cortisol in recovered patients with depression. , 2003, The American journal of psychiatry.

[48]  R. Morriss,et al.  A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls. , 1998, Journal of affective disorders.

[49]  C. Kirschbaum,et al.  Salivary cortisol in psychoneuroendocrine research: Recent developments and applications , 1994, Psychoneuroendocrinology.

[50]  E. Fliers,et al.  Glucocorticoids and Relapse of Major Depression (Dexamethasone/Corticotropin-Releasing Hormone Test in Relation to Relapse of Major Depression) , 2006, Biological Psychiatry.

[51]  G. Chrousos,et al.  Chronic imipramine is associated with diminished hypothalamic-pituitary-adrenal axis responsivity in healthy humans. , 1997, The Journal of clinical endocrinology and metabolism.

[52]  A. Beekman,et al.  Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis , 2006, Diabetologia.

[53]  J. Davis,et al.  DST studies in psychotic depression: a meta-analysis. , 1997, The American journal of psychiatry.

[54]  P. Cowen,et al.  Increased salivary cortisol after waking in depression , 2005, Psychopharmacology.

[55]  A. Rush,et al.  The Inventory of Depressive Symptomatology (IDS): psychometric properties , 1996, Psychological Medicine.

[56]  M. Wong,et al.  Corticotropin Releasing Hormone in the Pathophysiology of Melancholic and Atypical Depression and in the Mechanism of Action of Antidepressant Drugs , 1995, Annals of the New York Academy of Sciences.

[57]  C. Kirschbaum,et al.  Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change , 2003, Psychoneuroendocrinology.

[58]  O. Meijer,et al.  Therapy Insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression? , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[59]  D. Kurcgant,et al.  Cytokine profiles in women with different subtypes of major depressive disorder. , 2007, Journal of psychiatric research.

[60]  D. Hellhammer,et al.  Self-Reported Depressive Symptoms and Stress Levels in Healthy Young Men: Associations With the Cortisol Response to Awakening , 2003, Psychosomatic medicine.

[61]  E. Ronald de Kloet,et al.  Hormones and the Stressed Brain , 2004 .

[62]  G. Winokur,et al.  Differences in plasma ACTH and cortisol between depressed patients and normal controls , 1985, Biological Psychiatry.

[63]  J. Mendels,et al.  Neuroendocrine regulation in depression. I. Limbic system-adrenocortical dysfunction. , 1976, Archives of general psychiatry.

[64]  B. Ainsworth,et al.  International physical activity questionnaire: 12-country reliability and validity. , 2003, Medicine and science in sports and exercise.

[65]  P. Costa,et al.  Domains and facets: hierarchical personality assessment using the revised NEO personality inventory. , 1995, Journal of personality assessment.