Major depressive disorder (MDD) is estimated to affect approximately 17% of the population in the United States and is a growing and leading cause of disability worldwide.1–3 Despite these concerning trends, the pathophysiological mechanisms of depression remain unclear.1

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis are common in patients with MDD.4 HPA axis activation may have prognostic value and has been associated with increased risk of depression relapse and suicide.4 However, not all patients with MDD exhibit HPA alterations or the same HPA alterations.5 Similarly, some but not all patients with MDD also experience temporary structural changes in components of the axis, such as enlarged pituitary and adrenal glands, which normalize with treatment.4

HPA axis regulation is a complex process, involving feedback between its namesakes, the hypothalamus and the pituitary and adrenal glands, but it also receives input from the from the hippocampus, amygdala, bed nucleus of the stria terminalis, and paraventricular nuclei.4 Furthermore, different stressors, such as early life stress (ELS), may influence the HPA axis and development of MDD in adulthood.5

To further explore whether the alterations of the HPA axis that are commonly found in patients with MDD are due to ELS or whether the alterations are caused by the MDD itself, Angela Ceruso, a pharmacist at the University of the Basque Country in Vitoria, Spain, and colleagues conducted a systematic review that was recently published in Neuropsychobiology.5

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The investigators followed preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and included only studies whose design allowed comparison of HPA functioning in 4 groups: no-MDD/no-ELS, MDD/no-ELS, no-MDD/ELS, and MDD/ELS.5 They identified 8 articles that met these criteria.5

Among these studies, patients with MDD and ELS had a greater number of abnormalities in HPA functioning and were more likely than other groups to also report posttraumatic stress disorder (PTSD) comorbidity.5 Dysfunction of the HPA axis was also found in the no-MDD/ELS groups, indicating that ELS, rather than MDD, appears to drive HPA dysfunction.5

The authors emphasize the need to differentiate and study subtypes of MDD, especially complex-PTSD disorder, which appears to have been present among the studies in the review. The authors suggest that it would be interesting to study HPA axis dysfunction in patients who meet the criteria for complex PTSD (see Q&A below) and observe how they differ from patients with only ELS, MDD, or PTSD and healthy subjects.

To further explore this study and its importance in this evolving field, we spoke with Monica Martínez-Cengotitabengoa, PhD, MBPsS, senior author of the review. Dr Martínez-Cengotitabengoa is the research coordinator of The Psychology Clinic of East Anglia, Norwich, United Kingdom and a university professor of the Pharmacy Faculty at the University of the Basque Country.

The following Q&A was edited for clarity and length.

Why was it important to conduct this review?

Depression and childhood adverse experiences are problems that merit attention. MDD is one of the most commonly diagnosed mental disorders, and unfortunately, adverse childhood experiences (or early life stress, ELS) are highly prevalent and difficult to detect and prevent. Understanding the link between MDD, physiological alterations (HPA axis dysregulation) and ELS could help to find more effective treatments and develop prevention measures.

Why were the findings in HPA axis dysregulation variable across the 8 studies included in the review? How can this variability be addressed in future studies?

Different eligibility criteria and different techniques to measure the HPA axis activity are used in almost every study which makes it difficult to compare between them. It would be interesting to develop a standardized protocol.

Additionally, the analysis of the comorbidity between PTSD and MDD is not always made. Considering ELS may lead to PTSD, it is important to: a) not exclude patients diagnosed with PTSD or other anxiety disorders, b) consider the particular PTSD-MDD comorbidity, and if appropriate, to evaluate the possibility of including AXIS II diagnosis, in particular borderline personality disorder where ELS background and comorbid PTSD and MDD are very common.

What are the major challenges researchers encounter studying the connection between ELS and MDD/subtypes of MDD and the HPA axis? How is the research community working to overcome these challenges?

In addition to my earlier points, it is important to remember that mental health disorder diagnoses are useful constructs that are modified over time in order to better describe the clinical reality. The consequences of ELS, in extreme cases, may involve a complex sum of multiple symptoms whose manifestation is not necessarily constant over time. In fact, a new diagnostic entity known as “Complex post traumatic stress disorder” (code: 6B41) is now included in the 11th version of the International Classification of Diseases.6 The clinical picture composed by high ELS, PTSD and MDD may be now diagnosed as complex PTSD.

The fragmentation of diagnostic categories and the high presence of depressive symptoms in other diagnostic entities could potentially hinder the investigation of the relationship between MDD and the HPA functioning. Moreover, the high comorbidity of MDD with other disorders may entail that talking about “depressive episodes” or “high presence of depressive symptoms” to be more useful. A full comparison of HPA dysfunction present in “true” MDD and “depressive episodes” or “high presence of depressive symptoms” in other non-depressive disorders is needed.

What are the potential clinical implications of the findings linking ELS to PTSD/MDD and HPA dysfunction?

Finding a strong link between ELS and PTSD/MDD-HPA dysfunction would support diagnostic entities such as complex PTSD and highlight the relevance of environmental stress in some cases of organic/physiological dysfunction. Considering not all patients who suffered from ELS developed PTSD/MDD even in the presence of HPA axis dysfunction, it would be interesting to analyze which factors prevent them from developing these disorders. Knowing these factors could be useful to: a) detect those individuals who suffered from ELS and show HPA axis dysfunction, thus are at high risk of emerging PTSD/MDD, b) develop psychosocial interventions with a preventive purpose for those individuals who present with ELS and HPA axis dysfunction but have not fully developed any disorder yet, and c) improve combined treatment (psychotherapy and medication) considering that PTSD/MDD often respond poorly to medication alone.

What key points should practicing clinicians and psychiatrists take away from your review?

First, it is important to remember the frequent presence of ELS in MDD and the co-morbidity with PTSD. Second, ELS is associated with more HPA axis dysfunction, even in the absence of any disorder, and these patients are at higher risk of developing a disorder than the general population. Third, these patients tend to respond poorly to medication alone; integrated/combined treatment is often needed. Fourth, not everyone who suffered from ELS develops a mental health disorder; protective factors need to be detected and enhanced.

What should be the focus of future research regarding associations between ELS, PTSD and MDD and HPA dysfunction?

It would be interesting to design a prospective study to observe the HPA axis dysfunction present in those who suffered from ELS in order to answer the following questions: a) How and when can these HPA axis dysfunctions can be observed; b) Are HPA axis dysfunctions continuously present over time? Is hyperactivation after a stressful episode followed by hypoactivation? Does a single stressful episode lead to the same type of HPA axis dysfunction as multiple stressful episodes?; c) Does HPA axis dysfunction, qualitatively or quantitatively, correlate with the development of specific disorders?; d) Which factors protect some individuals from the development of MDD/PTSD?; e) Are psychosocial interventions helpful for prevention?; f) Can psychosocial interventions modify the course of HPA axis dysfunction or reverse its alteration?


1.      Wang F, Yang J, Pan F, Bourgeois JA, Huang JH. Editorial: Early Life Stress and Depression. Front psychiatry. 2019;10:964.

2.      Blazer DG, Kessler RC, McGonagle KA, Swartz MS. The prevalence and distribution of major depression in a national community sample: The National Comorbidity Survey. Am J Psychiatry. 1994;151(7):979-986.

3.      James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 Diseases and Injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858.

4.      Varghese FP, Brown ES. The hypothalamic-pituitary-adrenal axis in major depressive disorder: A brief primer for primary care physicians. Prim Care Companion J Clin Psychiatry. 2001;3(4):151-155.

5.      Ceruso A, Martínez-Cengotitabengoa M, Peters-Corbett A, Diaz-Gutierrez MJ, Martínez-Cengotitabengoa M. Alterations of the HPA Axis Observed in Patients with Major Depressive Disorder and Their Relation to Early Life Stress: A Systematic Review. Neuropsychobiology. 2020. doi:10.1159/000506484

6.      World Health Organization. ICD-11 – Mortality and Morbidity Statistics – 6B41 Complex Post Traumatic Stress Disorder. Published June 18, 2018. Accessed August 16, 2020.