The impact of early life stress on the hypothalamic-pituitary-adrenal axis in unipolar major depression: A systematic review
Lai Jiang, Lingfeng Xue, Mário F. Juruena
Abstract
Patients with major depressive disorder (MDD) tend to have abnormal hypothalamic-pituitary-adrenal axis (HPA) characterized by hypo- or hyperactivity, and early life stress (ELS) events influence the HPA axis, resulting in a heightened risk of depression. We conducted a systematic review evaluating the existing literature to summarise whether the HPA axis abnormalities in MDD are associated with ELS. This review was conducted following the PRISMA framework. In April 2024, searching was conducted on Ovid MEDLINE, Global Health, and APA PsycINFO. Keywords were based on three clusters of constructs: “HPA axis,” “MDD,” and “ELS.” Studies comparing the HPA axis activity in participants with and without unipolar depression and ELS were included. Quality assessment was conducted with the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool. Among the 17 included studies, 6 examined the naturalistic HPA axis activity, 7 conducted functional tests, and 4 performed psychosocial stress tests. The hypo- and hyperactive HPA axis was observed in most studies in depressed patients with ELS. Depressed patients with ELS and abused controls also manifested abnormal HPA axis activity compared to healthy controls. HPA axis abnormality is associated with depressive pathology, and ELS has an independent effect on the HPA axis. Posttraumatic stress disorder (PTSD) is associated with HPA axis hypoactivity either alone or as an MDD comorbidity. HPA axis hyperactivity in MDD with or without ELS may dampen over time, and an imbalance may implicate HPA axis abnormalities in depressed patients with ELS in the negative feedback. • ELS independently contributes to HPA axis dysfunction and increased depression risk. • HPA axis hyperactivity in MDD may diminish over time as an adaptive stress response. • PTSD comorbidity in MDD is linked to HPA axis hypoactivity, indicating a distinct subtype. • HPA dysregulation in MDD/ELS may result from impaired glucocorticoid feedback. • Sex differences and antidepressants significantly influence HPA axis findings.