Skip to main content

The Role of Early Life Stress in HPA Axis and Depression

Abstract

Considerable evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that early life stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of early life stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression with early life stress. Thus, more studies are needed to elucidate this issue.

Keywords

  • Early life stress
  • Childhood trauma
  • Depression
  • Hypothalamic-pituitary-adrenal axis
  • Cortisol

This is a preview of subscription content, access via your institution.

References

  • Arana GW, Baldessarini RJ, Omsteen M. The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Arch Gen Psychiatry. 1985;42:1193–204.

    CrossRef  CAS  Google Scholar 

  • Asgeirsdottir BB, Sigfusdottir ID, Gudjonsson GH, Sigurdsson JF. Associations between sexual abuse and family conflict/violence, self-injurious behavior, and substance use: the mediating role of depressed mood and anger. Child Abuse Negl. 2011;35:210–9.

    CrossRef  Google Scholar 

  • Baes CW, Martins CM, Tofoli SM, Juruena MF. Early life stress in depressive patients: HPA axis response to GR and MR agonist. Front Psych. 2014;5:2.

    Google Scholar 

  • Baes CVW, Tofoli SMC, Martins CMS, Juruena MF. Assessment of the hypothalamic–pituitary–adrenal axis activity: glucocorticoid receptor and mineralocorticoid receptor function in depression with early life stress – a systematic review. Acta Neuropsychiatrica. 2012;24:4–15.

    CrossRef  Google Scholar 

  • Banki CM, Karmascia L, et al. CSF corticotropin-releasing hormone and somatostatin in major depression: response to antidepressant treatment and relapse. Eur Neuropsychopharmacol. 1992;2(2):107–13.

    CrossRef  CAS  Google Scholar 

  • Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, Sapareto E, Ruggiero J. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatr. 1994;151:1132–6.

    CrossRef  CAS  Google Scholar 

  • Bernstein DP, Stein JA, Newcomb MD, et al. Development and validation of a brief screening version of the childhood trauma questionnaire. Child Abuse Negl. 2003;27:169–90.

    CrossRef  Google Scholar 

  • Carnes M, Kalin NH, et al. Pulsatile ACTH secretion: variation with time of day and relationship to cortisol. Peptides. 1988;9(2):325–31.

    CrossRef  CAS  Google Scholar 

  • Carpenter LL, Carvalho JP, Tyrka AR, Wier LM, Mello AF, Mello MF, et al. Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment. Biol Psychiatry. 2007;62:1080–7.

    CrossRef  CAS  Google Scholar 

  • Carpenter LL, Tyrka AR. Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects. Neuropsychopharmacology. 2004;29(4):777–84.

    CrossRef  CAS  Google Scholar 

  • Carroll BJ, Martin FIR, Davies BM. Resistance to suppression by dexamethasone of plasma II OCHS levels in severe depressive illness. Br Med J. 1968;1:285–8.

    CrossRef  Google Scholar 

  • Cohen P, Brown J, Smaile E. Child abuse and neglect and the development of mental disorders in the general population. Dev Psychopathol. 2001;13(4):981–99.

    CAS  PubMed  Google Scholar 

  • Cowan CS, Callaghan BL, Kan JM, et al. The lasting impact of early-life adversity on individuals and their descendants: potential mechanisms and hope for intervention. Genes Brain Behav. 2016;15:155–68.

    CrossRef  CAS  Google Scholar 

  • De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998;19:269–301.

    PubMed  Google Scholar 

  • de Quervain D, Schwabe L, Roozendaal B. Stress, glucocorticoids and memory: implications for treating fear-related disorders. Nat Rev Neurosci. 2017;18(1):7–19.

    CrossRef  Google Scholar 

  • Debono M, Ghobadi C, et al. Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab. 2009;94(5):1548–54.

    CrossRef  CAS  Google Scholar 

  • Deuschle M, Schweiger U, Weber B, et al. Diurnal activity and pulsatility of the hypothalamus—pituitary—adrenal system in male depressed patients and healthy controls. J Clin Endocrinol Metab. 1997;82:234–8.

    CrossRef  CAS  Google Scholar 

  • Diorio D, Viau V, Meaney MJ. The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci. 1993;13:3839–47.

    CrossRef  CAS  Google Scholar 

  • Egliston KA, McMahon C, Austin MP. Stress in pregnancy and infant HPA axis function: conceptual and methodological issues relating to the use of salivary cortisol as an outcome measure. Psychoneuroendocrinology. 2007;32:1–13.

    CrossRef  CAS  Google Scholar 

  • Fava GA, Park SK, Sonino N. Treatment of recurrent depression. Expert Rev Neurother. 2006;6:1735–40.

    CrossRef  CAS  Google Scholar 

  • Flandreau EI, Ressler KJ, Owens MJ, Nemeroff CB. Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus. Psychoneuroendocrinology. 2012;37(1):27–38.

    CrossRef  CAS  Google Scholar 

  • Friedrich W. Behavioral manifestations of child sexual abuse. Child Abuse Negl. 1998;22:523–31.

    CrossRef  CAS  Google Scholar 

  • Frodl T, Reinhold E, Koutsouleris N, Reiser M, Meisenzahl EM. Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. J Psychiatr Res. 2010;44:799–807.

    CrossRef  Google Scholar 

  • Geracioti TD, Loosen PT, Gold PW, Kling MA. Cortisol, thyroid hormone, and mood in atypical depression: a longitudinal case study. Biol Psychiatry. 1992;31(5):515–9.

    CrossRef  Google Scholar 

  • Gibb BE, Chelminski I, Zimmerman M. Childhood emotional, physical, and sexual abuse, and diagnoses of depressive and anxiety disorders in adult psychiatric outpatients. Depress Anxiety. 2007;24:256–63.

    CrossRef  Google Scholar 

  • Gibbons JL. Cortisol secretion rate in depressive illness. Arch Gen Psychiatry. 1964;10:572–5.

    CrossRef  CAS  Google Scholar 

  • Gladstone GL, Parker GB, Mitchell PB, Malhi GS, Wilhelm K, Austin MP. Implications of childhood trauma for depressed women: an analysis of pathways from childhood sexual abuse to deliberate self-harm and revictimization. Am J Psychiatry. 2004;161:1417–25.

    CrossRef  Google Scholar 

  • Glover V, O’Connor TG. Effects of antenatal stress and anxiety: implications for development and psychiatry. Br J Psychiatry. 2002;180:389–91.

    CrossRef  Google Scholar 

  • Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2015;20:32–47.

    CrossRef  CAS  Google Scholar 

  • Gold PW, Chrousos G, et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry. 1984;141(5):619–27.

    CrossRef  CAS  Google Scholar 

  • Grandjean P, Heindel JJ. In utero and early-life conditions and adult health and disease. N Engl J Med. 2008;359:1523; author reply 1524.

    CrossRef  CAS  Google Scholar 

  • Hayden EP, Klein DN. Outcome of dysthymic disorder at 5-year follow-up: the effect of familial psychopathology, early adversity, personality, comorbidity, and chronic stress. Am J Psychiatry. 2001;158:1864–70.

    CrossRef  CAS  Google Scholar 

  • Hayes PE, Ettigi P. Dexamethasone suppression test in diagnosis of depressive illness. Clin Pharm. 1983;2(6):538–45.

    CAS  PubMed  Google Scholar 

  • Heim C, Nemeroff CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry. 2001;49:1023–39.

    CrossRef  CAS  Google Scholar 

  • Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, Nemeroff CB. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. J Am Med Assoc. 2000;284:592–7.

    CrossRef  CAS  Google Scholar 

  • Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology. 2008;33:693–710.

    CrossRef  CAS  Google Scholar 

  • Hoek HW, Brown AS, Susser E. The Dutch famine and schizophrenia spectrum disorders. Soc Psychiatry Psychiatr Epidemiol. 1998;33:373–9.

    CrossRef  CAS  Google Scholar 

  • Holsboer-Trachsler E, Stohler R, Hatzinger M. Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression. Psychiatry Res. 1991;38(2):163–71.

    CrossRef  CAS  Google Scholar 

  • Juruena MF. Early-life stress and HPA axis trigger recurrent adulthood depression. Epilepsy Behav. 2014;38:148–59.

    CrossRef  Google Scholar 

  • Juruena MF, Cleare AJ, Papadopoulos AS, Poon L, Lightman S, Pariante CM. Different responses to Dex and prednisolone in the same depressed patients. Psychopharmacology. 2006;189(2):225–35.

    CrossRef  CAS  Google Scholar 

  • Juruena MF, Cleare AJ, Papadopoulos AS, Poon L, Lightman S, Pariante CM. The prednisolone suppression test in depression: dose— response and changes with antidepressant treatment. Psychoneuroendocrinology. 2010;35(10):1486–91.

    CrossRef  CAS  Google Scholar 

  • Juruena MF, Pariante CM, Papadopoulos AS, Poon L, Lightman S, Cleare AJ. Prednisolone suppression test in depression: a prospective study of the role of HPA axis dysfunction in treatment resistance. Br J Psychiatry. 2009;194:342–9.

    CrossRef  Google Scholar 

  • Koss MP, Bailey JA, Yan NP. Depression and PTSD in survivors of male violence: research and training initiatives to facilitate recovery. Psychol Women Q. 2003;27:130–42.

    CrossRef  Google Scholar 

  • Lara ME, Klein DN, Kasch KL. Psychosocial predictors of the short-term course and outcome of major depression: a longitudinal study of a nonclinical sample with recent-onset episodes. J Abnorm Psychol. 2000;109:644–50.

    CrossRef  CAS  Google Scholar 

  • Leverich GS, McElroy SL, Suppes T, Keck PE Jr, Denicoff KD, Nolen WA, Altshuler LL, Rush AJ, Kupka R, Frye MA, Autio KA, Post RM. Early physical and sexual abuse associated with an adverse course of bipolar illness. Biol Psychiatry. 2002;51:288–97.

    CrossRef  Google Scholar 

  • Lupien SJ, McEwen BS, Gunnar MR, et al. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–45.

    CrossRef  CAS  Google Scholar 

  • Martins CMS, Tofoli SMC, Baes CVW, Juruena MF. Analysis of the occurrence of early life stress in adult psychiatric patients: a systematic review. Psychol Neurosci. 2011;4:219–27.

    CrossRef  Google Scholar 

  • Mclaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, Kessler RC. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication associations with persistence of DSM-IV disorders. Arch Gen Psychiatry. 2010;67:113–23.

    CrossRef  Google Scholar 

  • Mello AF, Faria AA, Mello AF, Carpenter LL, Tyrka AR, Price LH, Carpenter LL, Del Porto JÁ. Childhood maltreatment and adult psychopathology: pathways to hypothalamic-pituitary-adrenal axis dysfunction. Rev Bras Psiquiatr. 2009;31:S41–8.

    CrossRef  Google Scholar 

  • Mello AF, Juruena MF, Pariante CM, Tyrka AR, Price LH, Carpenter LL, Del Porto JA. Depression and stress: this there an endophenotype? Rev Bras Psiquiatr. 2007;29:13–8.

    CrossRef  Google Scholar 

  • Mullen PE, Martin JL, Anderson JC, Romans SE, Herbison GP. The long-term impact of the physical, emotional, and sexual abuse of children: a community study. Child Abuse Negl. 1996;20:7–21.

    CrossRef  CAS  Google Scholar 

  • Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatr. 2011;169:141–51.

    CrossRef  Google Scholar 

  • Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry. 2012;169:141–51.

    CrossRef  Google Scholar 

  • Neigh GN, Gillespie CF, Nemeroff CF. The neurobiological toll of child abuse and neglect. Trauma Violence Abuse. 2009;10:389–410.

    CrossRef  Google Scholar 

  • Nemeroff CB. The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry. 1996;1(4):336–42.

    CAS  PubMed  Google Scholar 

  • Nemeroff CB, Heim CM, Thase ME, Klein DN, Rush AJ, Schatzberg AF, Ninan PT, McCullough JP Jr, Weiss PM, Dunner DL, Rothbaum BO, Kornstein S, Keitner G, Keller MB. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci U S A. 2003;100(24):14293–6.

    CrossRef  CAS  Google Scholar 

  • Nemeroff CB, Widerlov E, Bissette G, et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science. 1984;226:1342–4.

    CrossRef  CAS  Google Scholar 

  • Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol. 2005;20:345–52.

    CrossRef  CAS  Google Scholar 

  • Pariante CM, Papadopoulos AS, Poon L, Checkley SA, English J, Kerwin RW, Lightman S. A novel prednisolone suppression test for the hypothalamic-pituitary— adrenal axis. Biol Psychiatry. 2002;51:922–30.

    CrossRef  CAS  Google Scholar 

  • Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron. 2005;48:175–87.

    CrossRef  CAS  Google Scholar 

  • Ribeiro SC, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry. 1993;150:1618–29.

    CrossRef  CAS  Google Scholar 

  • Saridjan NS, Huizink AC, Koetsier JA, Jaddoe VW, Mackenbach JP, Hofman A, et al. Do social disadvantage and early family adversity affect the diurnal cortisol rhythm in infants? The generation R study. Horm Behav. 2010;57:247–54.

    CrossRef  CAS  Google Scholar 

  • Stetler C, et al. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med. 2013;73:114–26.

    CrossRef  Google Scholar 

  • Teicher MH. Wounds that do not heal: the neurobiology of child abuse. Sci Am. 2002;286(3):68–75; (edition 1).

    CrossRef  Google Scholar 

  • Tofoli SMC, Baes CVW, Martins CMS, Juruena MF. Early life stress, HPA axis, and depression. Psychol Neurosci. 2011;4:229–34.

    CrossRef  Google Scholar 

  • Tunnard C, Rane LJ, Wooderson SC, Markopoulou K, Poon L, Fekadu A, Juruena MF, Cleare AJ. The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression. J Affect Disord. 2014;152:122–30.

    CrossRef  Google Scholar 

  • Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10(6):397–409.

    CrossRef  CAS  Google Scholar 

  • Veenendaal MV, Painter RC, de Rooij SR, et al. Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine. BJOG. 2013;120:548–53.

    CrossRef  CAS  Google Scholar 

  • Vitolo YLC, Fleitlich-Bilyk B, Goodman R, Bordin IAS. Parental beliefs and child-rearing attitudes and mental problems among school children. Rev Saude Publica. 2005;39:716–24.

    CrossRef  Google Scholar 

  • Vreeburg SA, Hoogendijk WJ, van Pelt J, Derijk RH, Verhagen JC, van Dyck R, Smit JH, Zitman FG, Penninx BW. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry. 2009;66:617–26.

    CrossRef  CAS  Google Scholar 

  • WHO. Depression and other common mental disorders. Geneva: Global Health Estimates; 2017.

    Google Scholar 

  • Wiersma JE, Hovens JG, van Oppen P, Giltay EJ, van Schaik DJ, Beekman AT, Penninx BW. The importance of childhood trauma and childhood life events for chronicity of depression in adults. J Clin Psychiatry. 2009;70:983–9.

    CrossRef  Google Scholar 

  • Wise LA, Zierler S, Krieger N, Harlow BL. Adult onset of major depressive disorder in relation to early life violent victimisation: a case–control study. Lancet. 2001;358:881–7.

    CrossRef  CAS  Google Scholar 

  • Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H. Mineralocorticoid receptor function in major depression. Arch Gen Psychiatry 2003;60:24–8.

    CrossRef  CAS  Google Scholar 

  • Zavaschi MLS, Satler F, Poester D, Vargas CF, Piazenski R, Rohde LAP, Eizirik CL. Association between childhood loss trauma and depression in adulthood. Rev Bras Psiquiatr. 2002;24:189–95.

    CrossRef  Google Scholar 

  • Zisook S, Lesser IM, Lebowitz B, Rush AJ, Kallenberg G, Wisniewski SR, Nierenberg AA, Fava M, Luther JF, Morris DW, Trivedi MH. Effect of antidepressant medication treatment on suicidal ideation and behavior in a randomized trial: an exploratory report from the combining medications to enhance depression outcomes study. J Clin Psychiatry. 2011;72:1322–32.

    CrossRef  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mario F. Juruena .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Juruena, M.F., Cleare, A.J., Young, A.H. (2018). The Role of Early Life Stress in HPA Axis and Depression. In: Kim, YK. (eds) Understanding Depression . Springer, Singapore. https://doi.org/10.1007/978-981-10-6580-4_5

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-6580-4_5

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-6579-8

  • Online ISBN: 978-981-10-6580-4

  • eBook Packages: MedicineMedicine (R0)