The patient lounging on a psychoanalyst’s couch and rehashing childhood slights has been a long-held and now somewhat ersatz meme and cliché. However, childhood trauma is known to be a major factor in psychiatric illnesses of all kinds, including major depressive disorder (MDD). Adults with MDD reportedly have double the incidence rate of early life adversity (ELA) compared with healthy persons.1 ELA also has been shown to predict earlier onset of depression, higher risk of recurrence, a more severe disease course, and greater chronicity.1 Researchers are now exploring whether MDD in adulthood may be a latent symptom of an epigenetic alteration related to the impact of ELA on neurodevelopment.2,3
Because the hypothalamic-pituitary-adrenal (HPA) axis is the primary stress-response system, researchers are looking into the mechanisms of potential pathologic epigenetic modulation of the HPA axis as a basis for MDD. Findings by a multicenter team associated with Trinity College Dublin in Dublin, Ireland, demonstrated that hypermethylation at the glucocorticoid receptor gene (NR3C1) at exon 1F is apparent in MDD.2 The study authors explained that cortisol signaling via glucocorticord receptors is responsible for negative feedback inhibition of the HPA axis. Thus, the heightened HPA stress response in MDD, indicated by higher morning cortisol output, may be due to acquired glucocorticoid resistance.
The team examined two gene regions that have been implicated in HPA hyperactivity associated with MDD symptomatology: NR3C1 exon 1F and the FKBP5 intron 7. The study included 67 persons, including 33 patients with MDD (mean HAM-D score 21.94 ± 5.49) and 34 controls. Participants underwent a battery of clinical scales and instruments including the HAM-D-21, International Standard Classification of Education scale, Centre for Epidemiological Studies Depression Rating Scale, suicidality assessment, and the Childhood Trauma Questionnaire (CTQ). Participants who scored “moderate” on the CTQ were categorized as having had ELA. DNA methylation of NR3C1 exon 1F and the FKBP5 intron 7 was measured in whole blood via pyrosequencing, and associations between measures of ELA and the degree of methylation at specified gene regions (CG) were evaluated. Saliva samples also were collected at 5 time points within 24 hours to assess cortisol concentrations, including cortisol awakening response.
The researchers found that ELA was more prevalent among participants with MDD. This group had significantly higher CTQ global scores (P <.001) and CTQ scores related to emotional and physical neglect and abuse (P <.01). Mean NR3C1 exon 1F DNA methylation levels also were significantly (P <.05) increased. The degree of methylation was positively associated with morning cortisol concentrations, which were significantly higher than that seen in controls (P <.05).
DNA methylation levels at specific CG sites (CG37 and CG38) within NR3C1 exon 1F correlated with childhood emotional abuse severity to a significant degree in comparison with controls (P = .01 and P = .04, respectively). Correlations were not seen for other forms of abuse (ie, physical/sexual abuse or emotional/physical neglect). Although a literature-review meta-analysis y conducted earlier in the year found strong evidence of interactions between FKBP5 genotypes and early-life stress,3 no FKBP5 differences were seen between groups in the more recently published study.
The team concluded that epigenetic alterations at NR3C1 exon 1F may contribute to increased morning cortisol levels in persons with MDD and that ELA may play a role in this alteration. These findings may have implications in relation to early childhood interventions and later targeted pharmacotherapies for MDD.
1. Williams LM, Debattista C, Duchemin AM, et al. Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression. Transl Psychiatry. 2016;6:e799.
2. Farrell C, Doolin K, O' Leary N, et al. DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse. Psychiatry Res. 2018;265:341-348.
3. Wang Q, Shelton RC, Dwivedi Y. Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis. J Affect Disord. 2018;225:422-428.