Epigenetics and Psychiatry

Abstract

Psychiatric disorders including major depressive disorder, drug addiction, and schizophrenia are debilitating illnesses with a multitude of complex symptoms underlying each of these disorders. In recent years, it has become appreciated that the onset and development of these disorders goes beyond the one gene–one disease approach. Rather, the involvement of many genes is likely linked to these illnesses, and regulating the activation or silencing of gene function may play a crucial role in contributing to their pathophysiology. Epigenetic modifications such as histone acetylation and deacetylation, as well as DNA methylation can induce lasting and stable changes in gene expression, and have therefore been implicated in promoting the adaptive behavioral and neuronal changes that accompany each of these illnesses. In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment.

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Introduction

Psychiatric disorders such as depression, drug addiction, and schizophrenia are complex and heterogeneous diseases with a multitude of factors that contribute to their pathophysiology, making it difficult to link any one specific gene to the underlying cause of the disorder or the treatment. While data from twin studies have provided compelling evidence for the contribution of genetics as a predisposition to the development of these psychiatric diseases [1], environmental factors such as stress are also known to play significant roles in the manifestation of mental illness [2–4]. These external stimuli are often chronic in nature and extend over significant periods of time, leading to long-term behavioral changes as those observed in patients suffering from psychiatric disorders. Mounting evidence suggests that epigenetic mechanisms, which induce stable and lasting changes in gene expression in response to environmental events and behavioral experiences, may play a role in processes that contribute to the pathophysiology of psychiatric disorders.

Epigenetics is a dynamic process that can change gene expression without alterations in the DNA sequence, and promote stable changes in the chromatin structure allowing for regulation of gene transcriptional states [5–7]. Chromatin is comprised of DNA that is wrapped around the histone octamer to make up the core nucleosome that contains two copies each of the core histones H2A, H2B, H3, and H4 [8, 9]. A variety of chromatin remodeling enzymes, including histone acetyltransferases (HATs) and histone deacetylases (HDACs), can influence gene activity by inducing either an active or inactive chromatin state, respectively. Histone acetyltransferases add acetyl groups to lysine residues of the histone tail, causing the chromatin to be in a relaxed state and therefore favoring gene transcription. Histone deacetylases work by promoting transcriptional repression through the removal of acetyl groups from histone tails. Together, HDACs and HATs function to tightly regulate the chromatin state by regulating histone acetylation and impacting gene expression. There are many other posttranslational modifications that can occur on histone residues to impact gene expression including but not limited to phosphorylation, sumoylation, methylation and ubiquitination. These epigenetic mechanisms occur in postmitotic neurons, suggesting alterations in these processes may impact adult brain function. Another epigenetic mechanism targets DNA directly. DNA can be methylated via DNA methyltransferases (DNMTs), typically occuring at CpG sites and repressing gene activity [10–12]. While the importance of DNA methylation during development is well established, the role of DNA methylation-demethylation in the adult brain has only recently become an active area of investigation. Currently there is little known about DNA demethylation in postmitotic neurons and there remains much speculation about how this process may occur. Nevertheless, epigenetic mechanisms, through their impact on gene expression, can contribute to functional changes within cells that impact circuit level changes in brain and ultimately behavior. Studies of epigenetic mechanisms in psychiatric disorders have primarily focused on acetylation on specific histone residues and DNA methylation, thus this review will provide an overview of these processes in the field.

Epigenetic Mechanisms of Antidepressant Action and Depression

Major depressive disorder (MDD) is the second leading cause of disability worldwide, and current estimates reported by the National Institute of Mental Health (NIMH) show the 12-month prevalence of MDD is approximately 6.7 % of the U.S. adult population with 30.4 % of these affected individuals classified as severe cases [13]. Persons suffering from MDD can experience a wide range of symptoms including anhedonia, sleep disturbances, anxiety, and loss of appetite, and these symptoms are often of such severity that it interferes with the patient’s daily activities [14, 15].

A major obstacle in the treatment of MDD is the lack of fast acting efficacious drugs. Traditional antidepressants such as serotonin selective reuptake inhibitors (SSRIs) typically take several weeks to exert a therapeutic effect with a significant number of patients failing to respond, making it critical to better delineate the mechanisms of antidepressant action. Several lines of evidence have linked brain-derived-neurotrophic factor (BDNF) as a potential therapeutic target in antidepressant action as well as in mediating depressive-like behaviors (for review [16]). Chronic antidepressant treatment that mirrors the time necessary to elicit an antidepressant response increases BDNF expression in the hippocampus [17, 18]; an infusion of BDNF into the midbrain [19] and hippocampus [20] is sufficient to trigger an antidepressant response in rodents, and the loss of BDNF in the hippocampus attenuates antidepressant efficacy in animal models [21–23], providing evidence of a role for BDNF in antidepressant efficacy. Conversely, it is known that there is a high degree of co-morbidity between stress and depression, and decreased BDNF expression is observed in the hippocampus in response to different forms of stress [24] that correlate with depression-related behavior. Previous studies have indicated that stress can alter circuitry in limbic brain regions, specifically in the hippocampus where neurotrophic factors are known to exert effects [25]. Interestingly, BDNF, which is highly expressed in limbic structures, is indeed decreased in the hippocampus of rodents following exposure to chronic stress paradigms such as immobilization [26], unpredictable stress [27], and swim stress [28]. In many of these studies the changes in BDNF expression were sustained, indicating that stress can leave lasting marks on the genome, which has led to the suggestion that epigenetic mechanisms may be involved in mediating these effects.

Recent work has started to investigate whether alterations in BDNF related to depression and antidepressant responses are driven by epigenetics. A role for chromatin remodeling in mediating long-lasting adaptations in the brain and contributing to the development of depressive-like behaviors was recently investigated in rodents [29]. Chronic social defeat stress (CSDS), which induces depression-like behavior in mice, resulted in decreased mRNA levels of two Bdnf splice variants with increased histone methylation at their respective promoters in the hippocampus. This downregulation of Bdnf was reversed with chronic administration of the tricylic antidepressant imipramine, which also increased histone acetylation at the respective promoters. A later study used perinatal exposure to methylmercury in mice to induce a depressive-like phenotype and found a similar decrease in Bdnf expression in the hippocampus; it was shown to be mediated through hypermethylation on histone 3 lysine 27 (H3K27), a site correlated with transcriptional repression, thus providing a link between chromatin modifications and depressive-like behavior [30]. A separate study established that decreased BDNF expression observed in the mesolimbic pathway following CSDS (which persisted for 4 weeks after the paradigm) is required for the avoidance behavior seen in mice following CSDS, and that deletion of BDNF in the ventral tegmental area (VTA) exerted an antidepressant like effect and rescued the avoidance behavior [31]. In all these studies, the changes in BDNF expression were reversed by chronic, but not acute administration of imipramine or fluoxetine respectively, suggesting that sustained changes in gene expression may underlie the chronic changes in behaviors related to depression and stress. These putative links between depressive-like behaviors, antidepressant efficacy, and BDNF expression in rodent models have put forth the hypothesis that epigenetic mechanisms may underlie the involvement of BDNF in the etiology of MDD, specifically in cases of chronic stress, as well as in its treatment.

Epigenetic regulation of additional genes have started to be examined in the context of depression-like behavior or antidepressant responses. A recent study investigated the epigenetic regulation of the small Rho-GTPase, RAS-related C3 botulinum toxin substrate 1 (Rac1) in relation to depressive like behaviors [32]. Rac1 has previously been characterized as a crucial regulator of synaptic stability, and postmortem studies from patients with MDD have identified decreases in synapse number in cortical regions of the brain [33] although the precise mechanism behind these changes is unknown. To further explore this in rodents, mice were subjected to CSDS and showed social avoidance behavior suggestive of depression-related behavior. Moreover, there was a significant reduction in Rac1 expression selectively in a subcortical reward region, the nucleus accumbens (NAc), for 35 days following CSDS with these effects partially reversed following chronic administration of the tricyclic antidepressant imipramine. Such long-lasting decreases in gene expression led the authors to examine whether this was the result of epigenetic regulation of Rac1. Quantitative ChIP (qChIP) analysis revealed a reduction in histone H3 acetylation (pan-acH3) as well as enhanced methylation at the lysine 27 residue of H3 (H3K27) site of the Rac1 promoter region in CSDS mice, which helped bring about a repressive chromatin state and the subsequent decrease in Rac1 gene expression. Interestingly, overexpression of Rac1 in the NAc was sufficient to rescue the social deficits observed following CSDS, suggesting an important role for Rac1 in modulating depressive-like behaviors. Postmortem tissue from patients diagnosed with MDD yielded similar results as the animal studies. In MDD subjects who were not on antidepressant treatment at the time of death, Rac1 levels in the NAc were significantly decreased. In MDD patients on antidepressant treatment at their time of death, the results were less conclusive with ~50 % of the subjects having normalized Rac1 levels compared to control patients. Future studies are needed to more closely examine the potential involvement of epigenetic mechanisms contributing to the alterations in Rac1 expression in MDD patients as suggested by the animal studies.

Epigenetic regulation of type-2 metabotropic glutamate (mGluR2) receptors have recently been linked to antidepressant efficacy [34]. Previous work has demonstrated that L-acetylcarnitine (LAC), a pharmacological compound which promotes acetylation of histones as well as non-histone proteins, can induce mGlu2 receptor expression by increasing acetylation of the p65 subunit of NF-kappaB (NF-κB) in dorsal root ganglion (DSR) neurons, thus controlling its transcriptional activity and providing an analgesic effect [35]. Following 3 days of intraperitoneal injections, LAC was found to have a rapid and enduring antidepressant effect (up to 2 weeks) in Flinders Sensitive Line (FSL) rats, which have been previously characterized as an animal model of depressive-like behaviors and have reduced expression and function of mGlu2/3receptors in the hippocampus [36, 37]. The 3 days of LAC injections also rescued the decrease in mGlu2 receptor levels in the prefrontal cortex and hippocampus observed in rats treated with saline via increased levels of acetylated H3K27 at the Grm2 promoter. Furthermore, LAC treatment increased acetylation of the p65 subunit of NF-κB thereby promoting transcription of the mGlu2 receptor (Grm2) gene in the hippocampus and prefrontal cortex of the FSL rats. Taken together, these data suggest a link between epigenetic regulation of mGlu2 receptors and antidepressant action. Rather intriguingly, clinical studies have shown LAC to be well tolerated in humans leaving open the possibility of examining whether LAC is effective in producing an antidepressant response in depressed patients.

In addition to the histone modifications detailed above, there are other forms of epigenetic processes, including DNA methylation, that have been implicated in depressive-like behaviors. DNMTs are believed to play important roles in regulating learning and memory [38–40], and recent work has explored a possible link to depressive-like behaviors. Following CSDS, the expression of the de novo DNMT enzyme, DNMT3a, was significantly increased in the NAc of mice, and this change persisted for 10 days [41]. This same study also showed that overexpression of DNMT3a in rat in the NAc resulted in social avoidance behavior and less latency to immobility time in the Forced Swim Test paradigms, both indicative of depressive-like phenotypes. This effect was specific to DNMT3a and no changes in expression of the other DNMT family members, DNMT1 or DNMT3b, were detected following CSDS, suggesting a possible role for DNMT3a in behaviors related to depression (Table 1).

Table 1.

Epigenetic modifications and MDD

Treatment	Modification	Effect	Reference
CSDS	↑ Histone methylation at Bdnf promoter	↓ Bdnf mRNA in HC	Tsankova et al., 2006 [19]
Perinatal methylmecury exposure	↑ Histone methylation at H3K27	↓ Bdnf mRNA in HC	Onischenko et al. 2008 [30]
CSDS	↓ pan-acH3 acetylation and ↑ methylation at H3K27 site of Rac1 promoter	↓ Rac 1 in NAc	Golden et al., 2013 [32]
LAC	↑ Acetylation of NF-кB	↑ mGlu2 receptor in PFC and HC	Nasca et al. 2013 [34]
CSDS	↑ DNA methylation	↑ DNMT3a mRNA in NAc	LaPlant et al. 2010 [41]

MDD is a disease encompassed by the development of multiple symptoms that often manifest slowly over time and cause long-term changes in behavior. Recent data from rodent studies as well as postmortem tissue has suggested that epigenetic processes, known to cause stable and enduring changes in gene function, may be involved in the disease process. Future studies will be necessary to extend these findings into human depression as well as investigate whether specific epigenetic mechanisms can be targeted as more effective treatments for depression.

Epigenetics and Addiction

Drug addiction is a chronic and debilitating psychiatric illness characterized by uncontrollable and compulsive drug seeking behavior despite the mental and physical consequences associated with being addicted to drugs of abuse [42]. The path to addiction can begin with an individual’s voluntary use of drugs, however, repeated exposure can induce lasting changes in brain reward areas, causing individuals to compulsively use and seek drugs. It has previously been shown that chronic exposure to drugs of abuse can alter gene expression in key brain reward areas including the ventral tegmental area (VTA), NAc, and PFC [43]. Acute or chronic cocaine administration has been shown to increase overall histone H3 and H4 acetylation in the NAc suggesting that stimulants can influence epigenetic processes [48]. An active area of research is whether epigenetic mechanisms may be involved in the long-term changes in brain circuitry induced by drug exposure.

BDNF, aside from its putative involvement in MDD, has been implicated to play a role in addiction. Acute self-administration of cocaine causes an increase in BDNF protein in the NAc [44], and infusions of BDNF into the NAc [44] and VTA [45] cause an increase in cocaine self-administration in rats, suggesting a role for BDNF in the facilitation of reward related behaviors such as that seen in drug abuse and drug seeking. Following cocaine exposure, there is a persistent release of BDNF in the VTA and NAc [46] as well as the striatum [47] during withdrawal. In 2005, Kumar et al. reported that histone modifications play a role in cocaine’s effect on BDNF in an animal model of addiction. Chronic cocaine exposure induced acetylation of histone H3 at the BDNF promoter region in the striatum, an effect that lasted for 24 hours after the last cocaine injection [48], suggesting that epigenetic mechanisms may play a role in cocaine’s regulation of BDNF.

In yet another study, it was established that an acute injection of cocaine increases expression of the immediate early genes c-fos and fosB in the NAc by inducing histone H4 acetylation on their respective proximal promoter sites [48, 49]. A similar study followed up on this work and demonstrated that the mechanism through which this induction of fosB occurs is via the histone acetyltransferase CREB-binding protein (CBP) [50]. Following acute exposure to cocaine, CBP is recruited to the fosB promoter region and acetylates histone H4 resulting in an overall increase in fosB expression. The results of this study demonstrate a role for histone acetylation in regulating changes in gene expression that underlie addiction behaviors.

As previously mentioned, histone deacetylases play a crucial role in regulating gene activity by inducing modifications of the chromatin structure. There are 11 mammalian HDACs classified into four distinct HDAC families, class I, IIa, IIb, and IV, which are grouped according to sequence homology, subcellular localization, and expression patterns [51]. In a recent study, it was shown that the loss of the class II HDAC, HDAC5, results in an increased response to cocaine reward following conditioned place preference (CPP), and this effect was specific to HDAC5 with no changes seen in HDAC9 knockout mice [52]. Interestingly, this effect was normalized with a partial rescue of HDAC5, specifically in the NAc. The authors concluded that HDAC5 regulates the cocaine response via acetylation of target genes within the NAc, including RapGEF6, Gnb4, Suv39H1, and the NK1 receptor, highlighting an important example of how histone decacetylases can function to regulate gene activity in response to drugs of abuse.

HDAC inhibitors have received notable attention in recent literature as regulators of cocaine-induced addiction behaviors in rodents [53–55]. Interestingly, in the study from Kumar et al. described above, the authors were able to demonstrate that histone acetylation is an important process in the regulation of addiction behaviors through the use of a pan-HDAC inhibitor, sodium butyrate, which has been previously shown to provide therapeutic effects in neurodegenerative disease [56]. Co-administration of sodium butyrate and cocaine resulted in a synergistic effect, leading to increased cFos expression as well as increased histone H3 acetylation at the cFos promoter [48]. Additional data from a more recent publication demonstrated that the chronic infusion of a more specific class I HDAC inhibitor, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]benzamide (MS-275), into the NAc blocks cocaine-induced locomotor sensitization, and this occurs through an induction in global histone H3 acetylation [57]. This work suggests a role for class I HDACs in epigenetic mechanisms that contribute to addiction behaviors. Further work will be necessary to delineate which specific HDAC may be involved in this process (Table 2).

Table 2.

Epigenetic modifications and addiction

Treatment	Modification	Effect	Reference
Chronic cocaine exposure	↑ H3 acetylation	↑ Induction of BDNF at promoter region	Kumar et al. 2005 [48]
Acute cocaine exposure	↑ H4 acetyation	↓ fosB	Levine et al. 2005 [50]
Co-administration of sodium butyrate and cocaine	↑ H3 acetylation	↑ cFos mRNA in striatum	Kumar et al. 2005 [48]
Chronic infusion of MS-275	↑ global H3 acetylation	Blocks cocaine induced locomotor sensitization	Kennedy et al. 2013 [57]

Chronic exposure to drugs of abuse leads to long-term changes in brain function suggesting that alterations in gene activity may contribute to the phenotypes seen in addicted individuals. There has been much work over the past several years outlining the important role of transcription and downstream targets in the action of drugs of abuse. More recent work has started to examine whether epigenetic modifications in response to administration of drugs of abuse contribute to the development and maintenance of addiction. The studies outlined above illustrate a few examples of how epigenetic regulation of genes related to drug addiction may underlie the lasting changes in neuronal and behavioral adaptations that result from the addicted state. However, more work is needed to better delineate how epigenetic changes may influence specific downstream targets implicated in mediating long-term aspects of addiction following drug exposure.

Epigenetics and Schizophrenia

Schizophrenia is a chronic and severe mental disorder that affects approximately 1 % of the population [58] and is characterized by deficits in thought processes and social behaviors, paranoia, hallucinations, and inappropriate emotional responses [59, 60]. Linkage and association studies suggest a contribution of genetics to the development of schizophrenia [61], however no single gene has been isolated to its etiology. Recent studies have started to examine whether epigenetic processes may underlie the pathophysiology of this disease.

An early hypothesis that emerged regarding schizophrenia was that epigenetic control of gene expression, specifically DNA methylation, at promoters within γ-aminobutyric acid (GABA) containing neurons, is a key factor in the development of this illness [62]. Studies done in postmortem tissue have reported a downregulation of several genes expressed within GABAergic neurons, including reelin and GAD1, in individuals with a history of schizophrenia, suggesting that a disruption in inhibitory neuronal circuitry contributes to the deficits observed in these patients [63, 64]. Interestingly, the reelin promoter contains a prominent CpG island suggesting it may be vulnerable to epigenetic modifications via DNA methylation [65]. Indeed, recent studies reported an increase in methylation at the promoter region of reelin in postmortem brain tissue of patients diagnosed with schizophrenia [66, 67]. Moreover, in vitro experiments utilizing human cell lines showed that treatment with the DNMT1 inhibitor aza-2′-deoxycytidine significantly increases reelin mRNA expression [65]. In a mouse model of schizophrenia, reelin mice treated with L-methionine, a compound previously shown to exacerbate the symptoms of schizophrenia in human subjects, had decreased reelin expression levels associated with hypermethylation of the reelin promoter following chronic administration of L-methionine [68]. These data suggest a possible role for alterations in DNA methylation in regulating reelin expression levels and potentially the etiology of schizophrenia; however, much work is needed to delineate which DNMTs (DNMT1, 3a, or 3b) may be involved in carrying out these modifications and how important these specific genes are in mediating the pathophysiology of schizophrenia.

Likewise, the GAD67 promoter is rich in GC cites and it is hypothesized that changes in methylation may regulate GAD67 activity in a similar fashion to reelin, which may underlie the functional deficits of these genes as seen in patients with schizophrenia. More recent work has demonstrated a correlation in vitro between increased GAD67 expression and decreases in methylation at key regions within the promoter following the administration of MS-275, an inhibitor of histone methylation, providing some evidence that GAD67 is prone to hypermethylation [69]. However, this work was done using pharmacological agents that offer less target specificity, and additional studies are necessary to understand the mechanisms that drive the changes in methylation to regulate the function of GAD67.

Several recent studies have reported changes in DNMT1 and DNMT3a in postmortem tissue of individuals with schizophrenia, further suggesting the potential involvement of aberrant DNA methylation with the disease process. In a group of patients where some individuals were on antipsychotic medication, there was a significant increase in DNMT1 mRNA expression in cortical GABAergic neurons of schizophrenic patients compared to non-psychiatric patient controls [65, 70]. Likewise, DNMT3a (but not DNMT3b) expression was significantly upregulated in GABA expressing neurons in the cortex of patients with schizophrenia, and this increase was independent of any antipsychotic medication the patients were taking at the time of death [71]. This abundant overexpression of DNMTs in postmortem brains of schizophrenia patients suggests they may be responsible for the hypermethylation of genes within GABAergic neurons including reelin and GAD67. These data provide further support for the prevailing view that changes in DNA methylation of key genes within GABA expressing neurons may have a significant role in the etiology of schizophrenia.

It is also plausible that HDACs may be involved in regulating epigenetic mechanisms that underlie schizophrenia. In the study described above, it was demonstrated that administration of valproate, a mood stabilizer with HDAC inhibition activity, normalizes the decrease in reelin expression following administration of L-methionine and promotes acetylation of global histone H3 in the mouse brain [68]. It has also been reported that valproate can facilitate demethylation at the reelin promoter following withdrawal of L-methionine treatment as well as increase acetylation levels of histone H3 at the reelin promoter by approximately 50 % [72]. Taken together, these studies suggest a crosstalk between histone acetylation and DNA methylation at key promoters of GABA containing neurons, which may underlie the pathophysiology of schizophrenia.

In accordance with a possible role in the development of schizophrenia, histone acetylation/deacetylation may be involved in mediating antipsychotic treatment. A recent paper showed that chronic treatment with the atypical antipsychotic, clozapine, in mice and humans leads to a downregulation of mGlu2 receptor expression via a decrease in acetylation at its promoter site, and that it is specifically an increase of HDAC2 binding to the mGlu2 promoter that mediates this effect [73]. Additionally, chronic infusion of the class I and II HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in mice blocked the repressive histone modifications and augmented the beneficial behavioral effects induced by clozapine treatment. These findings suggest a novel role for HDAC2 as a therapeutic target in the treatment of schizophrenia, and encourage a need for the development of selective inhibitors that can distinguish between the individual HDACs (Table 3).

Table 3.

Epigenetic modifications and schizophrenia

Tissue/Species	Treatment	Effect	Reference
Postmortem brain tissue	Patients diagnosed with SZ	↑ Methylation at reelin promoter	Abdolmaleky et al. 2005 [66]
			Grayson et al. 2005 [67]
Human cell line	aza-2′-deoxycytidine	↑ Reelin MRNA	Chen et al. 2002 [65]
Reelin mice	Chronic L-methionine administration	↓ Reelin via hypermethylation of reelin promoter	Tremolizzo et al. 2002 [68]
N2T cells	MS-275	↓ Methylation at GAD67 promoter and ↑ GAD67 expression	Chen et al. 2011 [69]
Postmortem brain tissue	Patients diagnosed with SZ (some on antipsychotics)	↑ DNMT1, 3a mRNA in cortical GABA neurons	Chen et al. 2002 [65]
			Veldic et al. 2005 [70]
			Zhubi et al. 2009 [71]
Mice	Chronic treatment with clozapine	↓ mGlu2 receptor expression via acetylation at the promoter site	Kurita et al. 2012 [73]
Mice	Chronic treatment with SAHA in PFC	↑ mGlu2, mGlu3 mRNA in PFC via H3 acetylation at respective promoters	Kurita et al. 2012 [73]

Altogether, the studies in this section detail the strong correlation between epigenetic modifications of genes implicated in schizophrenia and the disorder. While much of this evidence comes from postmortem studies, complementary approaches with mouse models have also tried to implicate epigenetic mechanisms with the disease process as well as the mechanism for antipsychotic action. An active area of investigation is whether these epigenetic alterations that have been identified contribute to the development of schizophrenia or whether they occur as part of the disease process. The generation of better animal models for schizophrenia will hopefully provide a better understanding of critical factors that are involved in this disorder and treatment options. In the meantime, further investigation of epigenetic mechanisms that may contribute to alterations of specific genes implicated in schizophrenia remains an active area of research.

Conclusions and Future Studies

A growing body of work suggests that epigenetics may play a role in the pathophysiologies that contribute to psychiatric illness such as major depressive disorder, drug addiction, and schizophrenia. These modifications, which often occur in response to environmental stimuli such as chronic stress and drugs of abuse, can drive changes in epigenetic mechanisms such as histone modifications and DNA methylation at global levels as well as at promoter regions of key target proteins to produce long-lasting and stable changes in gene expression. With a better understanding of how epigenetic mechanisms underlie psychiatric disorders, the hope is to better characterize how these modifications impact specific genes that may contribute to these disorders.

Much emphasis has been placed on histone modifications and DNA methylation and there has been data in support of using pharmacological HDAC and DNMT inhibitors as therapeutic tools in treating the psychiatric disorders mentioned in this review. However, most of these drugs are pan inhibitors with multiple targets, offering little specificity towards an individual gene or specific drug target. This could prove to be problematic in treating psychiatric illnesses as chronic administration of these drugs may cause deleterious effects that are not yet clearly understood. Furthermore, different HDAC and DNMT subtypes have distinct roles in psychiatric disorders and there is little known about how they impact specific downstream genes. These concerns could potentially be addressed in the future through more extensive delineation of the distinct mechanisms that underlie the epigenetic action of the different subtypes within the HDAC and DNMT family. Overall, through a better understanding of how epigenetic mechanisms carry out long-lasting and adaptive changes in gene function and expression, researchers will uncover new avenues of treatment therapies to address the needs of individuals suffering from psychiatric illness.