Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review

The link between the abnormalities of the Hypothalamic-pituitary-adrenal (HPA) axis and depression has been one of the most consistently reported findings in psychiatry. At the same time, multiple studies have demonstrated a stronger association between the increased activation of HPA-axis and melancholic, or endogenous depression subtype. This association has not been confirmed for the atypical subtype, and some researchers have suggested that as an antinomic depressive subtype, it may be associated with the opposite type, i.e. hypo-function, of the HPA-axis, similarly to PTSD. The purpose of this systematic review is to summarise existing studies addressing the abnormalities of the HPA-axis in melancholic and/or atypical depression.

We conducted a systematic review in the literature by searching MEDLINE, PsycINFO, OvidSP and Embase databases until June 2017. The following search items were used: "hypothalamic-pituitary-adrenal" OR "HPA" OR "cortisol" OR "corticotropin releasing hormone" OR "corticotropin releasing factor" OR "glucocorticoid*" OR "adrenocorticotropic hormone" OR "ACTH" AND "atypical depression" OR "non-atypical depression" OR "melancholic depression" OR "non-melancholic depression" OR "endogenous depression" OR "endogenomorphic depression" OR "non-endogenous depression". Search limits were set to include papers in English or German language published in peer-reviewed journals at any period. All studies were scrutinized to determine the main methodological characteristics, and particularly possible sources of bias influencing the results reported.

We selected 48 relevant studies. Detailed analysis of the methodologies used in the studies revealed significant variability especially regarding the samples' definition comparing the HPA axis activity of melancholic patients to atypical depression, including healthy controls. The results were subdivided into 4 sections: (1) 27 studies which compared melancholic OR endogenous depression vs. non-melancholic or non-endogenous depression or controls; (2) 9 studies which compared atypical depression or atypical traits vs. non-atypical depression or controls; (3) 7 studies which compared melancholic or endogenous and atypical depression subtypes and (4) 5 studies which used a longitudinal design, comparing the measures of HPA-axis across two or more time points. While the majority of studies did confirm the association between melancholic depression and increased post-challenge cortisol levels, the association with increases in basal cortisol and basal ACTH were less consistent. Some studies, particularly those focusing on reversed vegetative symptoms, demonstrated a decrease in the activity of the HPA axis in atypical depression compared to controls, but the majority did not distinguish it from healthy controls.

In conclusion, our findings indicate that there is a difference in the activity of the HPA-axis between melancholic and atypical depressive subtypes. However, these are more likely explained by hypercortisolism in melancholia; and most often normal than decreased function in atypical depression. Further research should seek to distinguish a particular subtype of depression linked to HPA-axis abnormalities, based on symptom profile, with a focus on vegetative symptoms, neuroendocrine probes, and the history of adverse childhood events. New insights into the dichotomy addressed in this review might be obtained from genetic and epigenetic studies of HPA-axis related genes in both subtypes, with an emphasis on the presence of vegetative symptoms.