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According to the Fifth Edition Diagnostic and Statistical Manual of Mental Disorders (DSM-V), major depressive disorder (MDD) is characterized by five or more depressive symptoms over a two week period; symptoms include depressed mood, diminished interest in daily activities, significant weight loss, feelings of worthlessness or guilt, diminished concentration, recurrent suicidal ideation, insomnia, psychomotor retardation, and other symptoms causing clinically significant impairment in daily functioning. Other depressive disorders also exist within the diagnostic criteria of the DSM-V, with differing characteristic etiology, duration, and timing. Classification of depressive disorders continues to change as more becomes known about the etiology these disorders. The heterogeneous nature of depression symptoms and its complexity further complicates classification based on current standards of practice.

As of April 2016, the World Health Organization reported that an estimated 350 million people globally suffer from depression, making depression a leading cause of disability. An estimated 800,000 people die due to suicide each year, making it the leading cause of death in 15-29 year olds. Currently, less than half of the individuals worldwide afflicted with depression have access to sufficient treatments, although effective treatments are well known. Thus, research into better evaluation of exposures associated with the development of MDD and other mental illnesses may hold key public health opportunities to ameliorate the effect of depression on the global burden of disease through novel interventions. Lack of progress around genetic research into development of MDD and other depressive disorders has largely swayed current research endeavors towards the field of epigenetics.

History
As early as 1975, Dr. Robin Holliday and J.E. Pugh recognized the implications of epigenetic mechanisms in the expression and regulation of chromosomes, firstly through the framework of DNA methylation and imprinting. Though the term “epigenetics” was coined in the 1940’s by Waddington in an attempt to describe cell differentiation from a common genome, it has come to encompass all regulatory mechanisms that may act on genomic material, without directly interfering with the coding sequence itself. These mechanisms may include DNA methylation, silencing of maternal or paternal alleles through imprinting, histone modification, or action through non-coding RNAs.

Furthermore, the connection between transcriptional regulation mechanisms and depression was robustly studied as of a 2004 review, which clearly outlined the influence life stress could have on multiple systems implicated in depression, including those involved in cellular resilience, cell death or atrophy, and neuroplasticity across many regions of the brain. Charney emphasized the importance of developing a “comprehensive model of vulnerability to depression” in order to facilitate development of more targeted treatments. Through inclusion of genetic predisposition and psychosocial stress in such a model, it would be possible to create diagnostic classification system for depressive disorder which highlights the exact structural or functional abnormalities that give rise to the condition. Arguably, the elucidation of the specific epigenetic mechanisms at work that encompass this complex interplay could facilitate such an endeavor.

Lack of Common Genotype
Extensive studies have been conducted over the past decade in an effort to further elucidate the etiology of major depressive disorder and other mental illnesses. A 2011 genome-wide study identified a possible significant linkage to chromosome 3p25-26 in families with sibling pairs afflicted with severe recurrent major depression, however subsequent association mapping did not yield further significant results. Twin concordance studies estimate the heritability of major depression to be about 40%, suggesting that other non-genetic factors, such as environmental influences across the life course, may also be implicated in risk for depression. The interplay between well-studied genetic components of depression and environmental stressors associated with situational depression is the current focus of many contemporary studies into the epigenetic mechanisms that impact the development of depressive disorders. The persistence of many depressive symptoms also suggest that the more stable effects of epigenetic regulation may be at work to modify chromatin expression.

Modern genome-wide association studies have not been able to determine a single risk allele associated with major depression, making it difficult to generate genetic animal mutant models for depression. However, many animal models exist for the purpose of modeling various stress exposures to study their impact on development of depressive disorders. Reviews of research involving rodent models of depression ultimately are in line with those of human research, and it has been shown that the neurobiological profiles of various stress models, particularly in cases of social deprivation and maternal separation models, may vary depending on stage of development. Ultimately, most animal studies of varying stress conditions continue to highlight the need for further study into the exact mechanisms involved in the development of depressive behaviors, and how progression through the life course and social environmental factors may alter their development. Transmission through generations and difference of symptoms depending on developmental stage further implicate epigenetic mechanisms at work in depressive disorders, and open the doors for future treatments to target structural aspects of the genome.

Role of DNA Methylation in Depressive Disorders
Numerous studies in recent years have examined the effects that DNA methylation, which is typically inhibitive of gene expression, has on depressive phenotype and presentation of suicidality, which is associated with more severe cases of depressive disorders. The nature of DNA methylation lends to this epigenetic change being considered more stable than others, since it is largely irreversible, unlike histone modifications.

The large majority of the sixteen studies examined in a 2015 review of existing literature on epigenetic changes in depression and suicide found an association between epigenetic alterations and depression and suicide, with only two studies showing inconclusive results. Among the studies, three specifically looked at methylation across specific CpG methylation sites, and found that transcriptive dysregulation through methylation pathways was associated with depression and suicidality.

One study focusing primarily on subjects currently not taking medication to treat their MDD conducted genome-wide DNA methylation profiling, and found significant differences across 363 unique CpG methylation sites. All sites showed significant hypomethylation in depressed patients when compared to controls. Numata was able to preliminarily demonstrate that these methylation sites could be used as biomarkers in the diagnosis of MDD. Another study in particular examined the DNA methylation levels at the monoamine oxidase A (MAOA) and NR3C1 regions. MAOA is located on the X-chromosome and encodes for an oxidase mitochondrial enzyme involved in the metabolism of neurotransmitters like dopamine, serotonin, and norepinephrine. NR3C1 codes for a glucocorticoid receptor involved in inhibition of hypothalamic-pituitary-adrenal function. Hypermethylation of NR3C1 and hypomethylation of MAOA has been associated with increased risk of depression as a result of childhood adversity. Melas found that early parental death or childhood trauma was associated with epigenetic changes to the MAOA locus and to the NR3C1 locus.

In line with many previous studies, a matched control study conducted by Del Osso identified brain derived neurotrophic factor, which is associated with brain development and neuroplasticity, (BDNF) as another site of epigenetic regulation affecting risk for depression. Methylation levels at the BDNF locus were significantly higher in depressed patients than in manic/mixed patients, both of which showed higher methylation levels than the control. A separate study found that BDNF promoter methylation was higher in individuals with suicidal ideation or who had had a previous suicide attempt. Overall, these studies and many more clearly outline a significant association between BDNF hypermethylation and depression, particularly for cases in which suicidality is evident. Although many of these studies are preliminary and much more can be done to solidify these associations, BDNF methylation offers an area of focus for new targeted therapies. Aside from BDNF and MAOA, altered glucose metabolism as a result of differential expression of insulin independent glucose transporter 1 (GLUT1) and insulin-dependent glucose transporter 4 (GLUT 4) have also been implicated in the development of depressive disorders. A 2016 study measured the levels of methylation at GLUT 1 and GLUT 4 promoter regions, and found that enhanced methylation was more common in depressed patients than in control patients for GLUT 1, but not GLUT 4. These findings imply a relationship between altered glucose metabolism as a result of differential GLUT 1 expression and MDD. Other studies linking the development of type-2 diabetes and all-cause dementia with an association to depression are consistent with these findings of differential GLUT 1 expression.

It has also been demonstrated that adverse life events outside of the life course of a particular individual can also impact the development of depression. Maternal responsiveness to stress and maternal depressive symptoms have been shown to also alter epigenetics in infants in both animal models and humans. Researchers have shown that there may be environmental factors that alter the epigenetic DNA methylation of 11-HSD2 and NR3C1, which impact the HPA axis function of the infant. There is evidence supporting a social buffering hypothesis where the mother’s response to stress can alter the regulation of an infant’s HPA axis, thus ameliorating any adverse effects on the infant from a mother’s depressive symptoms through proper mother-infant interaction.

Each of these DNA methylation mechanisms offers possible linkage between stressful life events and neurobiological changes. These mechanism possibly explain how inflammatory processes and neuroplasticity, which have long been linked to depression, are altered epigenetically in such a way that stressful or adverse life experiences “enter the body” in a stable and long-lasting manner from childhood through adulthood, impacting the pathogenesis of depression. They also offer further insight into a more accurate, specific classification system for depressive disorders, characterizing them based on neurobiological presentation of epigenetic changes rather than simply on duration of symptoms and other conditions.

Histone Modification and other Chromatin Regulatory Pathways in Depression
Posttranslational histone modifications are one of the most important regulatory mechanisms for chromatin. Acetylation of histone lysine residues generally promote transcription, while methylation or phosphorylation of lysine or arginine residues can either promote or inhibit transcription. Other modifications such as SUMOylation are less well understood. Even less is known about the complex interplay that each of these modifications may have in conjunction with one another, though there importance is not disputed. The importance of histone regulation of DNA expression in the development of depression and other psychological disorders has been demonstrated more and more over the past few years, and this is an area of continued active research.

The observation of the importance of histone modification to depression was first described through histone deacetylase (HDAC) inhibition in rodent stress models. The administration of HDAC inhibitors such as sodium butyrate into brain regions associated with mood disorders had antidepressant effects, reverting the phenotype of social defeat stress model mice. . Histone methyltransferase action has also been implicated in affecting the development of depressive symptoms through transcription regulation. In recent rodent studies dividing mice into learned helplessness and resilient groups, it was found that the less resilient mice had lower BDNF expression than the resilient mice. This reduced expression was associated with the depressive phenotype, and was suspected to be the result of increased HDAC activity. Through Western Blotting analysis, researchers were able to demonstrate that the learned helplessness model mice had higher levels of HDAC5 binding to the promoter region of BDNF, thus inducing the depression-like phenotype in the mice. Administering a HDAC inhibiter eliminated the depression-like behavior and was able to restore the resilient phenotype in the learned helplessness mice (Su, et. al., 2016). From this very recent study, it can be concluded that there is a significant relationship between histone acetylation and depressive disorders, particularly in the case of chronic social stress as modeled in the learned-helplessness mice.

Since before 2009, HDAC inhibitors have been clearly shown to improve antidepressant responses in many animal models, suggesting that histone acetylation regulation is closely linked to the onset of depressive symptoms. Particularly in the nucleus accumbens, decreased levels of HDAC2 as a result of HDAC inhibitor use has been associated with an increase in H3 acetylation, leading to clear antidepressant effects in social defeat models of depression. These effects are often indistinguishable from those of other typical antidepressant treatments such as fluoxetine.

Chronic social defeat stress has also been shown to affect levels of histone methylation in the nucleus accumbens and other brain regions associated with depression. Histone H3 methylation in the nucleus accumbens has been linked to increased stress vulnerability associated with chronic cocaine use in rodent studies. The downregulation of G9a and GIp mRNA levels in the chronic cocaine using mice was also linked to transcriptional repression in the nucleus accumbens, which has been correlated with depressive symptoms. These results demonstrate that histone methylation in the nucleus accumbens when downregulated can activate further stress pathways that increase vulnerability to depression.

Little else has been clearly demonstrated about chromatin remodeling and histone modification, and their effects on the onset of depression, further inhibiting efforts to develop effective therapies. However, one study did analyze the effect of upregulation of BAZ1A (or ACF1), a chromatin-remodeler complex that associates with the ATPase SMARCA5 to form the ACF complex in the nucleus accumbens in mice models as another pathway through which chromatin is modified other than histone modification. The researchers simulated chronic social defeat in the rodents and found sustainably increased levels of ACF complex expression, as measured by co-immunoprecipitation of BAZ1A and SMARCA5. Further studies of upstream regulators of the ACF complex found that BDNF upregulated expression of the ACF complex, again strongly implicating BDNF as a driver of susceptibility to depression as a result of stress. Since ACF represses gene transcription, it is suspected that its overexpression alters susceptibility to stress through alteration of nucleosome structure of chromatin, repressing transcription in the nucleus accumbens of key antidepressant genes after repeated social defeat stress exposure (Sun et. al., 2015).

Future Direction for Research and Development
Arguably, a further elucidation and clarification of the exact mechanisms, both neurobiological and genetic, that underlie the development of depression is key for the development of more effective therapies. Epigenetic mechanisms have been clearly highlighted as areas of which new interventions can be developed to specifically target the biological drivers of depression. Monoamine oxidase inhibitors have been in use for an extensive period of time, but their side effects, such as nausea, dizziness, hypotension, sleep disturbances, and dry mouth, generally lead to counterindications for many patients (Mayo Clinic Staff, 2013). Many HDAC inhibitors have been developed for treatment of cancer, and could have many benefits to treating depression as well.

With sequencing technology and other genomic techniques rapidly improving each day, it may soon become possible to quickly and specifically determine the exact epigenetic alterations that an individual has that increase their vulnerability to depression. In this way, more targeted therapies can be chosen and new combination therapies that include pharmaceuticals targeting specific epigenetic alterations may be tailored to better treat each individual case of depression. More research can potentially be completed in investigating other epigenetic actors such as long non-coding RNAs and nuclear tethering of chromatin.