Role of Epigenetic Modulation in the Etiology of Major Depressive Disorder

Question:

"Is there a role for epigenetic modulation in the etiology of major depressive disorder?"

Vladimir Maletic, MD:

Most likely, yes! During the life cycle of the cell, in response to metabolic perturbations or meaningful environmental changes, profound alterations in gene expression take place—epigenetic modification mediates these processes. Epigenetic modulation is a biological underpinning of cell differentiation; it can also be precipitated by significant events in one’s life such as abuse, neglect, extreme poverty, and family dysfunction. In some way, regulation of gene expression mirrors our life experience. Dramatic events in our early childhood appear to leave deeper epigenetic "marks" than adverse events taking place later in our lives. ¹

How is it that our gene expression becomes "reprogrammed"? Our genes, built into sections of DNA strand, are enwrapped by a polypeptide "sleeve" composed of histones. Methylation of histone and/or DNA makes them virtually inaccessible for transcription—the gene is silenced! Acetylation of histone facilitates gene transcription; deacetylation turns it off. A very simplified scenario would suggest that major life events, represented by their chemical correlates, alter the molecular milieu surrounding the cells and consequently cause intracellular signaling cascades, ultimately leaving their specific imprint by changing the pattern of gene expression. ^2-4

An intriguing study by Fraga et al. found that due to divergent pattern of histone acetylation and methylation, thus turning their genes on or off, a pair of identical twins after several decades remained identical in name only. ⁵ A recent preclinical study indicated that mice subjected to chronic and unpredictable maternal separation developed a behavioral pattern reminiscent of depression. Not only did these depressive-like behaviors persist into adulthood, they were propagated to subsequent generations suggesting that epigenetically acquired traits may be passed on to progeny. ⁶

Let’s now examine some of the evidence indicating that epigenetic modulation may have a role in etiopathogenesis of major depressive disorder (MDD). A recent human study focusing on epigenetic modification of a serotonin transporter related gene (5HTTLPR) noted that complete or partial methylation of surrounding histone substantially reduced 5-HTT activity. ⁷ This is of particular interest since 5HTT-linked polymorphic region (5-HTTLPR) alleles have been associated with a number of different neuropsychiatric conditions, including depression, bipolar and anxiety disorders, chronic pain, fibromyalgia, attention-deficit/hyperactivity disorder, insomnia, and substance abuse.

Another study assessed depressed mood in a group of women during the second and third trimesters of pregnancy, using the Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale for Depression (HAM-D). The methylation status of 5-HTTLPR and brain-derived neurotrophic factor (BDNF)-related genes was assessed in third trimester maternal peripheral leukocytes and in umbilical cord leukocytes collected from their infants at birth. A gene regulating methyl-tetra-hydro-folate reductase (MTHFR)—an enzyme with a key role in the synthesis of methyl group donors (and therefore influential in epigenetic methylation)—was also studied. Future mothers with the MTHFR 677TT genotype (less functional allele) had greater second trimester depressed mood. Increased second trimester maternal depressed mood (reflected in EPDS scores) was associated with decreased maternal and infant 5-HTT promoter methylation! ⁸ Less functional genetic variant of 5HTT promoter was inadequately silenced. These findings suggest that maternal depression via altered epigenetic processes may contribute to developmental programming of infant behavior in utero.

In a separate study, adoptees now in their late thirties experienced a greater sense of loss and trauma if their less functional 5-HTTLPR "ss" allele was lightly methylated, or conversely, if their high-functioning "l/l" allele was "silenced" by heavy methylation. ⁹ Maltreatment during childhood was also found to be associated with methylation of a gene regulating synthesis of an important neurotrophic factor (BDNF) in prefrontal cortex (PFC). ¹⁰ Diminished BDNF concentration in PFC has been a consistent finding in postmortem studies of patients with depression.

Adults who have experienced adversity in the childhood, such as neglect, family violence, physical and sexual abuse, are much more likely to develop depression in the face of a current stressful event, according to a recent research report. ¹¹ A landmark prospective study evaluated the impact of early-life adversity on the likelihood of developing adult depression and general medical conditions. Adults who suffered adversity in their childhood were much more likely to develop MDD, but also clustering of metabolic and inflammatory markers several decades later! Furthermore, authors reported a "dose-response" relationship between the number of adverse childhood experiences and the likelihood of developing subsequent pathology. ¹²

A paper stemming from a prospective National Collaborative Perinatal Project (mean age=34 at follow-up, final N=482) noted an association between objectively measured affective quality of the mother-infant interaction (rated by an observer when infants were 8 months old), and adult mental health. Highly affectionate parent-child interaction at the age of 8 months was associated with reduced anxiety and somatization in adults (measured by a standardized instrument) three decades later! ¹³

In summary, accumulating evidence points to a dramatic impact of early-life adversity on the adult mental and even general medical health. Most likely, early events left an epigenetic “imprint” manifest in mind and bodily function decades later. It appears that the same epigenetic processes, which assist with cellular differentiation at the microscopic level, may also play a role in the differentiation of the major bodily regulatory systems, and even personality at the macroscopic level.

–Vladimir Maletic, MD

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