Abstract
Previous studies have reported elevated concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients with major depression. Elevations of CSF CRF have also been reported in adult laboratory animals exposed to the stress of brief maternal deprivation or maternal neglect in the neonatal or preweaning period. The present study was designed to determine whether major depression and a history of perceived early adversity in childhood are independently associated with elevated CSF CRF concentrations in adults. In this case–control study, 27 medication-free adults with major depression and 25 matched controls underwent standardized lumbar puncture for collection of a single CSF sample at 1200. Subjects provided data about significant adverse early-life experiences and rated their global perceived level of stress during pre-school and preteen years on a six-point Likert scale. The mean difference in CSF CRF between depressed patients and controls did not reach statistical significance. In a regression model, perceived early-life stress was a significant predictor of CSF CRF, but depression was not. Perinatal adversity and perceived adversity in the preteen adversity years (ages 6–13 years) were both independently associated with decreasing CSF CRF concentrations. The relationship observed between perceived early-life stress and adult CSF CRF concentrations in this study closely parallels recent preclinical findings. More work is needed to elucidate the critical nature and timing of early events that may be associated with enduring neuroendocrine changes in humans.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Banki CM, Bissette G, Arato M, O'Connor L, Nemeroff CB (1987). Cerebrospinal fluid corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 144: 873.
Banki CM, Karmacsi L, Bissette G, Nemeroff CB (1992a). Cerebrospinal fluid neuropeptides in mood disorder and demetia. J Affect Disorders 25: 39–46.
Banki CM, Karmacsi L, Bissette G, Nemeroff CB (1992b). CSF corticotropin-releasing hormone and somatostatin in major depression: response to antidepressant treatment and relapse. Eur Neuropsychopharmacol 2: 107–113.
Breier A, Kelsoe Jr JR, Kirwin PD, Beller SA, Wolkowitz OM, Pickar D (1988). Early parental loss and development of adult psychopathology. Arch Gen Psychiatry 45: 987–993.
Browne A, Finkelhor D (1986). Impact of child sexual abuse: a review of the research. Psychol Bull 99: 66–77.
Buske-Kirschbaum A, Jobst S, Wilkes C, Hellhammer DH (2000). American Psychosomatic Society, Vol. Abstract number 1392. Savannah, GA.
Coplan J, Andrews M, Rosenblum L, Owens M, Friedman S, Gorman J et al (1996). Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: Implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci USA 93: 1619–1623.
Coplan JD, Smith EL, Altemus M, Scharf BA, Owens MJ, Nemeroff CB et al (2001). Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates. Biol Psychiatry 50: 200–204.
DeBellis MD, Gold PW, Geracioti TM, Listwak SJ, Kling MA (1993). Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am J Psychiatry 150: 656–657.
France RD, Urban B, Krishnan KRR, Bissette G, Banki CM, Nemeroff C et al (1988). CSF corticotropin-releasing factor-like immunoactivity in chronic pain patients with and without major depression. Biol Psychiatry 23: 86–88.
Garrick NA, Hill JL, Szele FG, Tomai TP, Gold PW, Murphy DL (1987). Corticotropin-releasing factor: a marked circadian rhythm in primate cerebrospinal fluid peaks in the evening and is inversely related to the cortisol circadian rhythm. Endocrinology 121: 1329–1334.
Geracioti Jr TD, Loosen PT, Orth DN (1997). Low cerebrospinal fluid corticotropin-releasing hormone concentrations in eucortisolemic depression. Biol Psychiatry 42: 165–174.
Geracioti TD, Orth DN, Ekhator NN, Blumenkopf B, Loosen PT (1992). Serial cerebrospinal fluid corticotrophin-releasing hormone concentrations in healthy and depressed humans. J Clin Endocrinol Metab 74: 1325–1330.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62.
Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB (2001). Altered pituitary–adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry 158: 575–581.
Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R et al (2000). Pituitary–adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284: 592–597.
Heim C, Newport DJ, Wagner D, Wilcox M, Miller AH, Nemeroff CB (2002). The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: a multiple regression analysis. Depression Anxiety 15: 117–125.
Hodgson DM, Knott B, Walker FR (2001). Neonatal endotoxin exposure influences HPA responsivity and impairs tumor immunity in Fischer 344 rats in adulthood. Pediatr Res 50: 750–755.
Holsboer F (1995). In: Bloom F, Kupfer D (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press, Ltd: New York. pp 957–999.
Hong SK, Gold PW, Herkenham M (1993). Hypothalamic paraventricular lesions decrease corticotropin-releasing hormone in the CSF and elevate TRH mRNA in the locus coeruleus (Abstract 31211). Soc Neurosci Abstr 19: 762.
Kalin NH, Shelton SE, Barksdale CM, Brownfield MS (1987). A diurnal rhythm in cerebrospinal fluid corticotropin-releasing hormone different from the rhythm of pituitary–adrenal activity. Brain Res 426: 385–391.
Kling MA, Roy A, Doran AR, Calabrese JR, Rubinow DR, Whitfield Jr HJ et al (1991). Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression: potential clinical implications. J Clin Endocrinol Metab 72: 260–271.
Ladd CO, Owens MJ, Nemeroff CB (1996). Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 137: 1212–1218.
Lee R, Kasckow J, Coccaro E (2002). American Psychiatric Association 155th Annual Meeting. Philadelphia, PA.
Mathew SJ, Coplan JD, Smith EL, Scharf BA, Owens MJ, Nemeroff CB et al (2002). Cerebrospinal fluid concentrations of biogenic amines and corticotropin-releasing factor in adolescent non-human primates as a function of the timing of adverse early rearing. Stress 5: 185–193.
Meany MJ, Aitken DH, Viau V, Sharma S, Sarrieau A (1989). Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glugogorticoid receptor binding in the rat. Neuroendocrinology 50: 597–604.
Meany MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C et al (1996). Early environmental regulation of forebrain glucocorticoid receptor gene expression: Implications for adrenocortical responses to stress. Dev Neurosci 18: 49–72.
Nemeroff C, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K et al (1984). Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226: 1342–1344.
Nemeroff CB, Bissette G, Akil H, Fink M (1991). Neuropeptide concentrations in the CSF of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, β-endorphin and somatostatin. Br J Psychiatry 158: 59–63.
Newport DJ, Stowe ZN, Nemeroff CB (2002a). Parental depression: animal models of an adverse life event. Am J Psychiatry 159: 1265–1283.
Newport DJ, Wilcox MM, Stowe ZN (2002b). Maternal depression: a child's first adverse life event. Semin Clin Neuropsychiatry 7: 113–119.
Petitto JM, Quade D, Evans DL (1992). Relationship of object loss during development to hypothalamic-pituitary–adrenal axis function during major affective illness later in life. Psychiatry Res 44: 227–236.
Pitts AF, Samuelson SD, Meller WH, Bissette G, Nemeroff CB, Kathol RG (1995). Cerebrospinal fluid corticotripin-releasing hormone, vasopressin, and oxytocin concentrations in treated patients with major depression and controls. Biol Psychiatry 38: 330–335.
Plotsky PM, Meaney MJ (1993). Early postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Mol Brain Res 18: 195–200.
Plotsky PM, Sanchez MM (2003). AAAS Annual Meeting. Denver, CO.
Post RM, Gold P, Rubinow DR, Ballenger JC, Bunney Jr WE, Goodwin FK (1982). Peptides in the cerebrospinal fluid of neuropsychiatric patients: an approach to central nervous system peptide function. Life Sci 31: 1–15.
Raphael KG, Widom CS, Lange G (2001). Childhood victimization and pain in adulthood: a prospective investigation. Pain 92: 283–293.
Reul JM, Stec I, Wiegers GJ, Labeur MS, Linthorst AC, Arzt E et al (1994). Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats. J Clin Invest 93: 2600–2607.
Risch SC, Lewine RJ, Kalin NH, Jewart RD, Risby ED, Caudle JM et al (1992). Limbic-hypothalamic-pituitary–adrenal axis activity and ventricular-to-brain ratio studies in affective illness and schizophrenia. Neuropsychopharmacology 6: 95–100.
Rosenblum LA, Paully GS (1984). The effects of varying environmental demands on maternal and infant behavior. Child Dev 55: 305–314.
Roy A, Pickar D, Paul S, Doran A, Chrousos GP, Gold PW (1987). CSF corticotropin-releasing hormone in depressed patients and normal control subjects. Am J Psychiatry 144: 641–645.
Rudorfer MV, Risby ED, Osman OT, Gold PW, Potter WZ (1991). Hypothalamic-pituitary–adrenal axis and monoamine transmitter activity in depression: a pilot study of central and peripheral effects of electroconvulsive therapy. Biol Psychiatry 29: 253–264.
Russek LG, Schwartz GE (1997a). Feelings of parental caring predict health status in midlife: a 35-year follow-up of the Harvard Mastery of Stress Study. J Behav Med 20: 1–13.
Russek LG, Schwartz GE (1997b). Perceptions of parental caring predict health status in midlife: a 35-year follow-up of the Harvard Mastery of Stress Study. Psychosom Med 59: 144–149.
Russek LG, Schwartz GE, Bell IR, Baldwin CM (1998). Positive perceptions of parental caring are associated with reduced psychiatric and somatic symptoms. Psychosom Med 60: 654–657.
Shanks N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, Ingram CD et al (2000). Early-life exposure to endotoxin alters hypothalamic-pituitary–adrenal function and predisposition to inflammation. Proc Natl Acad Sci USA 97: 5645–5650.
van Oers HJ, de Kloet ER, Levine S (1998). Early vs late maternal deprivation differentially alters the endocrine and hypothalamic responses to stress. Brain Res Dev Brain Res 111: 245–252.
Widerlov E, Bissette G, Nemeroff CB (1988). Monoamine metabolites, corticotropin releasing factor and somatostatin as CSF markers in depressed patients. J Affect Disord 14: 99–107.
Yehuda R, Golier J, Wong C, Grossman R (2001). American College of Neuropsychopharmacology 40th Annual Meeting. Waikoloa, HI.
Acknowledgements
This work was supported by a 1998 Young Investigator Award from NARSAD (LLC), and NIH grants MH-42088 (CBN), and MH-58922 (CBN). We gratefully acknowledge Jason Siniscalchi, MS and Kathleen Reilly, MS for assistance with data analysis, Julia C Burke, MSN, CS for excellent clinical care to research subjects, and Christine A Richard for administrative support. This work was presented in part at the annual meetings of the American College of Psychopharmacology (poster, 2001, Hawaii), the American Psychopathological Association (poster, 2002, NewYork City), the Society for Biological Psychiatry (poster, 2002, Philadephia), and the American Psychiatric Association (poster and industry-sponsored symposium, 2002, Philadelphia).
Author disclosures: Linda L Carpenter, MD discloses the following: payment for consultant services to Organon, Cephalon, GlaxosmithKline; grant/research support from Cyberonics, Pfizer, Merck, Corcept Therapeutics, Cephalon, Medtronics; speakers bureau honoraria from Cyberonics, Abbott, Pfizer, Somerset, Organon, Wyeth. Audrey R Tyrka MD, PhD reports no disclosures. Christopher McDougle, MD discloses research grants, consulting payments, and speakers bureau honoraria from Pfizer, Inc.; research grants, consulting payments, and speakers bureau honoraria from Janssen Pharmaceutica; research grants and consulting payments from Eli Lilly and Co.; speakers bureau honoraria from Bristol-Myers Squibb Co.; research grants from AstraZeneca; research grants and consulting payments from Repligen Corp. Robert T Malison, MD discloses a consulting payment from Pfizer, Inc. Michael J Owens, PhD discloses being a research grant recipient from GlaxoSmithKline, Pfizer Inc., Merck, UCB Pharma, NARSAD and NIH. He reports no standing consultancies or speakers bureau membership. Charles B Nemeroff MD, PhD discloses grants/research support from: Abbott Laboratories; AFSP; AstraZeneca; Bristol-Myers-Squibb; Eli Lilly; Forest Laboratories; GlaxoSmithKline; Janssen Pharmaceutica; Merck; NARSAD; NIMH; Pfizer Pharmaceuticals; Stanley Foundation/NAMI; Wyeth-Ayerst. Dr Nemeroff discloses receiving payments for consulting services to: Abbott Laboratories; Acadia Pharmaceuticals; AstraZeneca; Bristol-Myers-Squibb; Corcept; Cypress Biosciences; Cyberonics; Eli Lilly; Forest Laboratories; GlaxoSmithKline; Janssen Pharmaceutica; Merck; Neurocrine Biosciences; Novartis; NPS Pharmaceuticals Organon; Otsuka; Sanofi; Scirex; Somerset; Wyeth-Ayerst. Dr Nemeroff discloses receiving speakers bureau honoraria from: Abbott Laboratories; AstraZeneca; Bristol-Myers-Squibb; Eli Lilly; Forest Laboratories; GlaxoSmithKline; Janssen Pharmaceutica; Organon; Otsuka; Pfizer Pharmaceuticals; Wyeth-Ayerst. Dr Nemeroff is a stockholder with Corcept and Neurocrine Biosciences. Dr Nemeroff serves on the Board of Directors for the following: American Foundation for Suicide Prevention (AFSP); Cypress Biosciences; George West Mental Health Foundation; Novadel Pharma; Heinz C Prechter Fund for Manic Depression. Dr Nemeroff holds the following patents: (US 6,375,990 B1) for method and devices for transdermal delivery of lithium; method to estimate serotonin and norepinephrine transporter occupancy after drug treatment using patient or animal serum (provisional filing April, 2001). Lawrence H Price, MD discloses payment for consulting services to Pfizer, GlaxoSmithKline, Bristol-Myers Squibb; speakers bureau honoraria from GlaxoSmithKline, AstraZeneca; research support from Merck, Thuris, Medtronic, Cyberonics, and Cephalon.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Carpenter, L., Tyrka, A., McDougle, C. et al. Cerebrospinal Fluid Corticotropin-Releasing Factor and Perceived Early-Life Stress in Depressed Patients and Healthy Control Subjects. Neuropsychopharmacol 29, 777–784 (2004). https://doi.org/10.1038/sj.npp.1300375
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1300375
Keywords
This article is cited by
-
Maternal adverse childhood experiences impact fetal adrenal volume in a sex-specific manner
Biology of Sex Differences (2023)
-
Early life stress and development: potential mechanisms for adverse outcomes
Journal of Neurodevelopmental Disorders (2020)
-
Cerebrospinal fluid proteome evaluation in major depressive disorder by mass spectrometry
BMC Psychiatry (2020)
-
Lifestyle behaviour and prevalence of cardiovascular risk factors - a pilot study comparing Kiribati and European seafarers
BMC Public Health (2019)
-
Transitioning from acute to chronic pain: a simulation study of trajectories of low back pain
Journal of Translational Medicine (2019)
