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Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms.
Aims
We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls).
Method
Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (−1019, −1007, −681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF.
Results
Recent stress correlated positively with blood monocyte methylation at the −681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the −1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD.
Conclusions
These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.
The mainstay of treatment for late-life depression is antidepressant medication, although recently there have been some psychotherapies that have been developed specifically for the older patient, e.g. problem solving therapy, that have proved effective. Although tricyclic antidepressants (TCAs) are used much less frequently in younger patients, they still have a very important role in the treatment of late-life depression. The selective serotonin reuptake inhibitors (SSRIs) are the most prescribed class of antidepressants for late-life depression. Given the number of patients with late-life depression who do not respond to a trial of an antidepressant there is considerable opportunity to study augmentation strategies. This chapter discusses dysthymic disorder and sub-syndromal depressive disorder, which is a heterogenous group of milder forms of depression. In patients with depression and cognitive impairment, there is a need to understand pathophysiology, determine early prognostic indicators, and develop optimal treatment strategies.