Epigenetic Aspects of Posttraumatic Stress Disorder

Disease Markers 30 (2011) 77–87 77 DOI 10.3233/DMA-2011-0749 IOS Press

Epigenetic aspects of posttraumatic stress disorder

Ulrike Schmidt, Florian Holsboer∗ and Theo Rein Max Planck Institute of Psychiatry, Munich, Germany and Neuro Novag GmbH, Munich, Germany

Abstract. Development of psychiatric diseases such as posttraumatic stress disorder (PTSD) invokes, as with most complex diseases, both genetic and environmental factors. The era of genome-wide high throughput technologies has sparked the initiation of genotype screenings in large cohorts of diseased and control individuals, but had limited success in identification of disease causing genetic variants. It has become evident that these efforts at the genomic level need to be complemented with endeavours in elucidating the proteome, transcriptome and epigenetic profiles. Epigenetics is attractive in particular because there is accumulating evidence that the lasting impact of adverse life events is reflected in certain covalent modifications of the chromatin. In this review, we outline the characteristics of PTSD as a stress-related disease and survey recent developments revealing epigenetic aspects of stress-related disorders in general. There is also increasing direct evidence for gene programming and epigenetic components in PTSD. Finally, we discuss treatment options in the light of recent discoveries of epigenetic mechanisms of psychotropic drugs.

1. Introduction that psychiatric disorders can be traced back to one single epigenetic modification, inasmuch as many differ- The term epigenome refers to the entirety of all ent genetic variants are conveying disease susceptibili- molecular control elements programming the genome ty. These diseases present with highly variable clinical respectively regulating gene activities. Like any molec- signs and symptoms but these diverse features cannot ular action,also epigenetic programming can go wrong. be linked to specific genetic and epigenetic variations. Accordingly, distinct epigenetic defects are reported In fact it is likely that they derive from a complex web for a variety of diseases and some of them are already of connected but different causes. known to constitute a main pathogenetic mechanism, Only a small proportion of individuals develops post- e.g. in patients suffering from Rett syndrome. traumatic PTSD after having been exposed to a trau- One of the major environmental factors established matic event [13]. PTSD only occurs if a (yet still un- as inducer of epigenetic changes is stress. Stress is known) biological predisposition coincides with a trau- known to contribute to the pathogenesis of a variety of matic stressor. This instantly forces the supposition disorders, including the majority of psychiatric disor- that the epigenome, especially in regard to its capacity ders like major depression and posttraumatic stress dis- to mediate communication between environment and order (PTSD). There is robust evidence for epigenetic genome, might grossly contribute to PTSD pathogene- contribution to the development of PTSD-like symp- sis. toms in rodents while so far there are only few studies In this review the most important molecular epige- demonstrating the connection between trauma-induced netic programming mechanisms are illustrated to allow epigenetic changes and the onset and perpetuation of for a better understanding of the following paragraphs PTSD symptoms in humans. Generally, it is unlikely where the dynamic principle of the epigenome including its reagibility to environmental factors and final- ∗Corresponding author: Dr. Florian Holsboer, E-mail: holsboer@ ly the current state of knowledge regarding epigenet- mpipsykl.mpg.de. ic modifications in stress-related diseases, in particular

PTSD-animalmodels and PTSD patients, are discussed which in turn elicits the release of glucocorticoidsfrom on the basis of the most recent publications. the adrenalcortex. Then, cortisol as the final peripheral molecule exerts its actions on metabolism, immunity and brain functions. Increased and prolonged produc- 2. PTSD as stress-related disease tion of CRH and cortisol explain many of the behavioral, circulatory, metabolic and immune manifesta- The term stress was first employed in a biological tionsof syndromesassociated with acuteand especially contextby the endocrinologistHans Selye in the 1930s. with chronic stress, such as PTSD. He later broadened and popularized his concept to in- Transient HPA-system shifts were found in a variety clude inappropriate physiological response to any de- of psychiatric diseases, e.g. it is an established find- mand. In his usage “stress” refers to the condition ing that many patients suffering from major depression and “stressor” to the stimulus triggering the unphysio- (MD) display a hyperactivity of their stress hormone logical response. It covers a wide range of phenome- system [40]. In contrast to patients with MD, many au- na, from mild irritation to drastic dysfunction that may thorsfoundan HPA-axis hypoactivity in PTSD-patients cause severe health breakdown mostly occurring in re- reflected for instance by lowered serum cortisol lev- sponse to maximal stressors. els [11,107] and an enhanced suppression of cortisol These maximal stressors are also termed traumata; in the DEX/CRH-test [101,107]. However, a recent the term trauma derives from the greek word τραµα meta-analysis of 37 studies [57] found no differences meaning wound. A traumatic event involves a single, in plasma cortisol levels between adult individuals with enduring or repeating experience that seriously threat- PTSD and controls. But interestingly, sub-group anal- ens the physical or psychic integrity of the concerned yses revealed some remarkable results: both the patient person. According to DSM-IV also witnessing a seri- cluster havingexperiencedphysicalor sexualabuse and ous threat or the death of another person can be clas- the female patient cluster exhibited significantly lower sified as a traumatic event, but in any case a horrible cortisol levels in comparison to their respective con- experience can be categorized as a traumatic incident trol subgroups. Despite the limitation of differences only if the individuals exposed in the course of the in data collection and assessment, that meta-analysis event experienced feelings of helplessness and massive clearly reveals the complexity and heterogeneity of the horror. The disability to cope or integrate the ideas neuroendocrine concomitants of PTSD [71]. and emotions involved with that experience leads to the Besides the HPA-axis, also the sympathetic nervous sense of being overwhelmed. Symptoms usually arise weeks or months, in rare system (SNS) is a key circuit in PTSD pathophysiolo- cases even decades after traumatic experiences. More- gy. Its major neurotransmitter norepinephrine (NE) is over, diagnosing PTSD includes the assumption that an importantplayer in the central as well as in the auto- without a traumatic event this psychiatric disease would nomicstressresponse. NEisproducedinneuronsofthe not have been appeared. Thus, the stressor precipitat- locus coeruleus and interacts in concert with CRH and ed the onset of PTSD which is characterized mainly vasopressin to increase fear conditioning and memory by recurrent and intrusive distressing recollections of encoding. In theperiphery,stress leadsto releaseof NE the event (e.g. flashbacks), nervous hyperarousal and and epinephrine from the adrenal medulla, resulting in trauma-stimuli associated avoidance anxiety each last- an organismic alarm reaction. Thus, NE is involved in ing more than one month, thus causing significant im- the development of two main clusters of PTSD symp- pairment in social, occupational, or other important ar- toms, namely re-experiencing symptoms and hyper- eas of functioning. arousal which is expressed inter alia with an exaggerat- Like other stress-related psychiatric diseases PTSD ed startle responseand increased heart rate [85]. Hence comesalong with a variety of neuroendocrinologicalal- it is not surprising that the most consistent findings in terations. The hypothalamus-pituitary-adrenal (HPA) PTSD neuroendocrinestudies are increased central and axis has been the main focus of neuroendocrine re- peripheral noradrenergic activities [32,104]. search in PTSD [104]. Taken together, PTSD is a stress-related disease not Perception of stress leads to synthesis and release only because PTSD symptoms are precipitated by a of corticotropin-releasing hormone (CRH) and vaso- traumatic stressor but also because this severe psychi- pressin by hypothalamic nuclei which stimulate the se- atric condition is accompanied by drastic alterations in cretion of adrenocorticotropin (ACTH) at the pituitary the two major stress hormone systems. U. Schmidt et al. / Epigenetic aspects of posttraumatic stress disorder 79

3. The epigenome lated DNA is recognised and bound by a family of methylated DNA binding proteins of which methyl- The term epigenetics has been coined even long be- CpG-binding protein2 (MeCP2) has attracted particu- fore the structure of genes has been discovered [36, lar attention. MeCP2 recruits the histone deacetylase 95]. In today’s biomedical research, epigenetics ex- (HDAC) complex mSin3A, thereby attracting HDAC-1 plores the regulatory functions of covalent chromatin and HDAC-2, thus ultimately abolishing histone acety- modificationsas well as of microRNAs in gene activity. lation and inactivating chromatin [44]. DNA methyla- These chromatin modifications do not alter the genet- tion can, in addition, impede DNA bindingof transcrip- ic information per se, but govern access to it and can tion factors [89,93]. However, DNA methylation could be maintained and stably inherited through mitosis and also be associated with increased gene transcription if meiosis. The modifications comprise in mammals pre- it interferes with DNA binding of a repressor. dominantly the post-replicative attachment of a methyl A wealth of enzymes executing the addition and re- groupatcarbonposition 5 of the nucleobasecytosine as moval of covalent chromatin modifications has been well as acetylation, methylation and phosphorylation found, albeit the exact mechanism of active cytosine of histone proteinsat defined aminoacid positions[45]. demethylation has not been elucidated yet. As key ex- More rare modificationsare sumoylation [81], ubiquiti- ecutors of diverse regulatory signals these enzymes are nation [82], ADP-ribosylation [37], biotinylation [16], target of intense drug development efforts. carbonylation [100], deimination [23], proline isomer- ization [66], and glycosylation [43] of histones. Inextensionofamodelthatwasbasedonthelinkbe- 4. Epigenetic aspects of stress-related psychiatric tween histone acetylation and gene transcription [92], diseases Strahl and Allis proposed a general “histone code” model for the combinatorial function of specific post- While epigenetic mechanisms have been under in- translational histone modifications in gene transcrip- vestigation in cancer and developmental research for tion [87]. According to this concept, the combinatorial decades [10], they recently attracted intensified atten- arrangement of distinct histone modifications forms a tion by neuroscientists as a potential mediator of gene code that is read and interpreted by nonhistone chro- environment interactions. Environmental insults im- matin associating proteins that signal the encoded in- pacting on the epigenome may represent the molecu- formation to downstream functions such as gene tran- lar programming of stable long-term effects on gene scription. Since a nucleosome comprises several his- expression in the brain, and thus on cerebral function. tones, this combination results also in a “nucleosome Mostof the experimentalevidencefor the role of epi- code”, allowing a plethora of epigenetic states. genetic mechanisms in stress-related psychiatric dis- The histone modification status, in particular his- eases originates from animal models. Psychiatric dis- tone acetylation, is intimately linked to the degree of eases pose a particular challenge for researchersaiming DNA methylation [64]. DNA can be methylated in at modelling diseases in animals [46,60]. Nevertheless, mammals at cytosines residing in CpG dinucleotides. several models have been established, based on the re- 60–80% of these dinucleotides are methylated in hu- alisation of stress as central risk factor for the develop- mans [75]. In general, CpG dinucleotides are grossly ment of psychiatric diseases. Common to the diverse underrepresented in the genome. This has been ex- animal models is the exposure of the animal to stress plained by the impossibility for the cellular repair ma- during a sensitive period in life, i.e. in the prenatal, chinery to specifically correct a deaminated methylated postnatal and adolescent phase. This is in congruence cytosine, which leads to the legitimate DNA nucleo- with the observation in humans that adults who suf- side thymine, while deamination of unmethylated cy- fered from severe early life stress such as parental loss tosine produces uracile, which can easily be recognised or neglect presented with higher basal levels of stress as a non-DNA nucleoside. CpGs are enriched in so hormone and were at greater risk of developing mood called “CpG-islands” [30], which are usually found in disorders [65]. the 5’ regulatory regions of most genes. DNA methy- Already more than half a century ago, disturbances lation usually leads to gene silencing through effects of the mother-neonate interaction in rodents have been on chromatin structure. This can involve more gener- demonstrated to alter adult phenotypes that include al mechanisms leading to hypoacetylation of histones neuroendocrine function, behaviour, metabolism and and formation of condensed chromatin [8,9]. Methy- cognition, e.g. [49]. For example, rats experiencing 80 U. Schmidt et al. / Epigenetic aspects of posttraumatic stress disorder maternal separation in the first weeks of life develop patients with depression, Moreover, individuals hav- increased anxiety and cognitive deficits later in life [72, ing experienced early life trauma have elevated corti- 73]. Programming of HPA axis (re)activity has been sol [38] secretion following the Dex/CRH test, indirect- extensively investigated as a critical juncture between ly reflecting elevation of hypothalamic vasopressin. In early life environmentand health in the adult [24,29,67, fact in mice where HPA hyperactivity and depression- 86]. These alterations of HPA axis settings frequently and anxiety-like behaviour was permanently induced go along with changes in GR expression [28,50,96], by early life trauma, a vasopressin receptor antagonist whose activation is pivotal for balancing HPA activity modulated neuroendocrine and behavioural sequelae through negative feed-back loops at the level of CRH, from stress-exposure. vasopressin, and ACTH [24]. Importantly, blunting Another common way to model the pathogenesis of the early life experience-induced differences in hip- depression-like states is chronic stress exposure of ro- pocampal GR expression blocks the effects on HPA dents [46]. Social defeat of an experimental mouse by activity in adulthood [55,56]. Moreover, loss of GR serial confrontation with aggressive mice over 10 days expression in the hippocampus leads to dysfunctional induces depression-like syndromes such as anxiety- HPA axis regulation and enhanced anxiety-related be- related symptoms, anhedonia and loss of interest in so- haviour [12], further corroborating the notion of pro- cial interaction. The aptitude of this model for investi- gramming hippocampal GR levels as the underlying gating depression-like states is further substantiated by mechanism translating early life experience into dif- the observations that antidepressants can reverse most ferential HPA reactivity and differences in the HPA- of the stress-induced symptoms [7,91]. Brain derived associated behavioural spectrum. neurotrophic factor (BDNF) was found to be stably Theearly life-induced programming of GRlevelshas downregulated after chronic social defeat along with been directly linked to epigenetic alterations of the GR methylation of lysine 27 of histone H3 (H3K27) [91], gene. More specifically, in animals experiencing dif- which constitutes a repressive epigenetic mark. Chron- ferent maternal care, disparate DNA methylation pat- ic treatment with antidepressants restored bdnf RNA terns and chromatin acetylation levels (acetylation at expressiontogetherwith reversalof the behaviouralim- lysine 9 of histone 3) were identified in the exon 17 pairments. However,H3K27 methylation remained un- promoter of GR [96], which is the relevant regulato- changed, which was suggested to represent a “molecu- ry region determining GR expression in the hippocam- lar scar” that may contribute to the risk of reappearance pus [52]. The change in DNA methylation was linked of symptoms in depressed patients after discontinuing to impaired binding of the transcription factor nerve antidepressant treatment [76]. growth factor-inducible protein A, whose response ele- Even though in humans obvious limitations prevent ment harbored differentially methylated cytosines [96]. insight to the same depth as in animal studies, sig- This example provides intriguing molecular insight in- nificant evidence has accumulated for the importance to the epigenetic mechanisms underlying experience- of epigenetic mechanisms in psychiatric diseases. For induced programming of neuroendocrine circuits and example, a recent study examining post mortem brain behaviour. tissue from suicide subjects with a history of early In a more recent study, early life stress was found childhood neglect and/or abuse revealed a significant to cause a persistent increase of vasopressin, accompa- promoter-wide hypermethylation of rRNA genes [53]. nied by sustained DNA hypomethylation of a relevant In schizophrenia, alterations in GABAergic mRNA regulatory region [62]. This hypomethylation affected expression have been identified as a key feature. Ex- CpG dinucleotides that are recognised by MeCP2. In- pression of glutamate decarboxylate 1 (GAD1) has triguingly, the ability of MeCP2 to bind to these sites is been found to be decreased in schizophrenia, in con- controlledbyneuronalactivity. Thus, in this modelear- junction with a risk haplotype, along with reduced lev- ly life stress inducesepigenetic markingof an HPA reg- elsof (tri)methylationat lysine4 ofhistone H3 (H3K4), ulatory gene via neuronal activity-directed regulation astimulatory epigeneticmark [42]. Moreover,theatyp- of protein DNA interaction of MeCP2 as the molecular ical antipsychotic clozapine increased H3K4 methyla- underpinnings of neuroendocrine and behavioral alter- tion at GAD1 and promoteroccupancywith the respec- ations that are frequent features in stress-related dis- tive methyltransferase [42]. In another study, DNA hy- eases. This finding is remarkable insofar as increased permethylation of the reelin gene promoter has been vasopressin secretion from the hypothalamic nuclei is observed in post mortem brains from schizophrenic known to induce anxiety in rodents and is elevated in patients [1]. This could explain the significantly re- U. Schmidt et al. / Epigenetic aspects of posttraumatic stress disorder 81 duced expression of this important neuronal protein in In contrast to these findings in suicide victims, dif- schizophrenia [19,27]. Although reelin promoter hy- ferential methylation of GR was not found in a very re- permethylation was not found in another study [90], centstudy focussingon majordepression [3]. Levels of the role of DNA methylation at this promoter is cor- total GR were found to be unchanged in samples orig- roborated by studies reporting its demethylation by the inating from individuals who had suffered from major antipsychotic drugs clozapine and sulpiride [25]. depression, while the transcripts derived from differ- DNA methylation changes related to schizophrenia ent transcriptional start sites displayed some variation. and bipolar disorder have recently been discovered in a GR exon 1F transcripts were downregulated in major genome-wide methylation analysis using post-mortem depression, accompanied by reduced levels of the ex- braintissue [59]. The studyidentified prominentlociof on 1F transcription factor NGFI-A [3]. However, pro- methylation changes that are involved in glutamatergic moter 1F was found unmethylated throughout in ma- and GABAergic neurotransmission, brain development jor depression and controls. Therefore, changes in GR and other processes connected to disease. In addition, expression from promoter 1F are not due to direct epi- DNA methylation at the BDNF gene has been found to genetic programming at this promoter, but more likely correlate with polymorphisms that previously had been caused by diminished NGFI-A activity [3]. Assum- associated with major psychosis [59]. A study examining that the individuals tested in this study did not ex- ing the DNA methylation pattern at the X chromosome perience abuse, and in comparison with the observed in peripheral cells of female monozygotic twin pairs methylation changes in abuse victims [54], this implies that were either concordant or discordant for bipolar importantdifferencesin the pathomechanismsof major disease or schizophrenia provided further evidence for depression and abuse victims. epigenetic mechanisms operating in disease etiology of Finally, a pilot study aimed at evaluating the associa- bipolar disorder [77]. Moreover, another comparison tionof DNA methylationin buccal cells and risk for de- of twin pairs concordantor discordantfor bipolardisor- pression [68]. Themethylation analysisfocussedonthe der identified differentially methylatedgenes that could serotonin transporter gene (5HTT) in a sample drawn contribute to the pathophysiology of this disease [48]. froma longitudinalstudy of adolescenthealth. In carri- MeCP2, an essential interpreter protein of the epi- ers of the 5HTTLPR short-allele depressive symptoms genetic mark DNA methylation, has been linked to a were more abundant among those with increased buc- variety of mental dysfunctions and diseases. Rett syn- cal 5HTT methylation [68]. Larger studies are under- drome is a neurodevelopmental disorder that is most way in several laboratories to explore the possibility to frequently (95%) caused by spontaneous mutations in develop peripheral epigenetic markers in depression. the MeCP2 gene located at the X-chromosome [5,74] and is the most frequent cause of mental retardation in females [35]. Moreover, mutations in MeCP2 have 5. Evidences for epigenetic modulation in PTSD been associated with X-linked autism [74] and the An- gelman Syndrome. The animal models for psychiatric diseases as well In an effort to translate the observations of early life as the human cohorts outlined above exhibit some phe- stress-induced epigenetic programming of GR expres- notypic overlap with PTSD, and therefore, these find- sion to the situation in humans, the neuron-specific GR ings also have shaped concepts for PTSD research [79, promoter was examined for epigenetic differences be- 102]. There are also examples for specific PTSD an- tween post-mortem hippocampi from suicide subjects imal models. In a mouse model that uses inescapable with a known history of early life abuse and hippocampi electric foot shock to induce PTSD-like symptoms [83], from either suicide subjects without early life abuse or maternal inexperience was identified as a risk factor controls [54]. In suicide victims with early life abuse, for PTSD [84]. This points at the relevance of epige- the mRNA levels of GR were found to be downregulat- netic factors in PTSD-like behavior. In another PTSD ed concomitantly with elevated promoter methylation. model in rats, predator scent stress was used [17], Moreover,promoter constructsmimicking theobserved and the differences in hippocampal DNA methylation methylation pattern exhibited reduced binding of the were assessed on a genome-wide scale between ani- transcription factor nerve growth factor–inducible pro- mals not responding and responding with PTSD-like tein A [54]. These findings closely resemble the situ- symptoms [15]. The findings not only suggest changes ation observed with reduced parental care as early life in global methylation pattern involved in PTSD devel- stressor in rodents [96,97]. opment, but also present the differentially methylat- 82 U. Schmidt et al. / Epigenetic aspects of posttraumatic stress disorder ed gene Disks Large-Associated Protein (DLGP2) as a induces downstream alterations in immune function by possible target in PTSD. reducing methylation levels of immune-related genes, There is also persuasive evidence for crucial epige- although – as with many association studies of that netic processes in PTSD from clinical studies. In a type – it remains unclear to what extent the leukocyte post mortem study of patients that committed suicide epigenome represents the cerebral epigenome. mRNA levels of GR were found to be downregulated Taken together, these examples from clinical and an- in those suicide victims that had been exposed to early imal studies lead to the conclusion that during vulner- life trauma. This was associated with elevated promot- able ontogenetic episodes of different species a variety er methylation [54]. Moreover, it is known from a va- of stressors can induce epigenetic modifications with riety of studies that victims of early life stress or trau- consecutive behavioral modifications which at least to matic events like abuse or neglect exhibit significantly some extent can be transmitted transgenerationally. higher morbidity rates for a variety of disorders, especially for cardiovascular and affective diseases in their later adulthood [98]. A clinical study with pregnant 6. Perspectives women revealed that massive stress during pregnancy induces changes in epigenetic HPA axis programming Considerable research efforts are underway world- in utero associated with an increased vulnerability for wide to developdrugsthat target the epigenome. These psychiatric disorders possibly transmissible to follow- may also change the treatment regimes in PTSD. To ing generations [79]. Yehuda and colleagues studied betterassess the usefulnessof“epigeneticdrugs”, a bet- mothers who were pregnant while they were exposed ter understanding of the exact epigenetic mechanisms to the terror attack on September 11, 2001: Mothers in PTSD is needed, and particular attention needs to suffering from PTSD as well as their babies exhibited significantly lower salivary cortisol levels in compari- be directed towards the specificity and mechanisms of son to the exposed but PTSD-free control group [106]. drug action, and towards the time window of opportu- Moreover, the observation that a cohort of individu- nity for treatment. als that all developed PTSD after having been exposed While it is still not proven yet that the observed epi- to the same terror attack exhibited markedly changed genetic alterations are actually causal for the observed gene expression patterns that included genes involved phenotypicalterations after stress, epigenetic actions of in HPA regulation, again points to epigenetic modula- psycho-active drugs as well as psychoactivity of drugs tion of gene activity [103]. Another clinical study ex- impacting on the epigenome have been observed. For amining the offspring of Holocaust victims also points example, psychopharmaceuticalshave also been shown to a trauma-induced, inheritable epigenetic modulation to impact on DNA methylation, as demonstrated for of the stress hormone system since serum cortisol lev- specific promoters or for broader effects through inhi- els were found to be significantly lower in healthy off- bition of DNA methyltransferases (DNMTs) [25,70]. spring of victims suffering from PTSD in comparison A large body of evidence points to the potential use to those with PTSD-free ancestors [106]. of HDAC inhibitors in psychiatric diseases. Exposure A recent clinical study on epigenetics and the patho- to chronic social stress leads, after an initial decrease, genesis of PTSD applied methylation microarrays to to a persistent increase in acetylation of histone H3 assay CpG sites in leukocyte DNA from more than in the nucleus accumbens and to a decreased level of 14,000 genes among 23 PTSD-affected and 77 PTSD- HDAC2 [21]. The changes in H3 acetylation were re- unaffected individuals [108]. This association study verted by the application of HDAC inhibitors, which revealed that immune system functions are significant- also exerted robust antidepressant-like effects. More- ly overrepresented among the annotations associated over, the alterations of the transcriptome induced by with genes uniquely unmethylated among PTSD pa- an HDAC inhibitor were very similar to those induced tients. Epigenetic variability in immune function by by the antidepressant fluoxetine [21]. A related study PTSD was corroborated using an independent biolog- investigated promoter chromatin regulation by chro- ical marker of immune response to infection, namely matin immunoprecipitation-chip assays in the nucle- the typically latent herpesvirus CMV-a, whose activity us accumbens of chronically stressed mice. Many of was significantly higher among those with PTSD. Thus, the stress-induced changes were reversed by treatment this report suggests a biologic model of PTSD etiolo- with imipramine, and the resultant pattern exhibited a gy in which an externally experienced traumatic event surprising similarity to that of stress-resilient mice [99]. U. Schmidt et al. / Epigenetic aspects of posttraumatic stress disorder 83

Fig. 1. One carbon cycle linking to epigenetic modiﬁcations of DNA and histones. Methylation of DNA, histones and other molecules in the cell is orchestrated by an array of enzymes controlling the turnover of the involved metabolites. Options for (auxiliary) epigenetic treatment focus on manipulation of the enzymatic activity of DNA- and histone-methylatransferases, as well as of the levels of folate, SAM and vitamin B12. The remethylation of homocysteine via betaine occurs in live and kidney, but not in the central nervous system (dashed arrow). THF, tetrahydrofolate; SAM, S-adenosylmethionine.

HDACIs have also been shown to impact on DNA is only short-term. It is conceivable that an immedi- methylation at schizophrenia-relevant promoters, via ate posttraumatic pharmacological intervention, some- decreasing the activity of DNMTs, very similar to the times referred to as secondary prevention, might pre- effects of direct DNMT inhibitors [47]. Yet other re- vent the onset of PTSD symptoms. In the majority of search directions explore the possibility of manipulat- patients, PTSD symptoms appear weeks after the trau- ing the available pool of methyl donors. For exam- matic experience, and early intervention prior to emer- ple, S-adenosyl-methionine (SAM, Fig. 1), an impor- gence of clinical symptoms may be an opportunity also tant methyl donor in cellular processes, has been evalu- for treatment with epigenetic drugs that interfere with ated for potential antidepressant effects with promising programming of PTSD symptoms. results [58]. In addition, folate and vitamin B12 status, There is a limited number of studies exploring the two other important components of the one carbon cy- possibility of secondary treatment in PTSD: Adrenore- cle, have been linked to the incidenceof depression and ceptor antagonists like the conventionally used anti- to the success of antidepressant treatment [18,63,69]. hypertensive propranolol have been found to prevent Moreover, genetic variants of the enzyme that cataly- or at least to mitigate the onset of PTSD-typical re- ses the conversion of 5,10 methylene tetrahydrofolate experiencing symptoms like flashbacks and intrusions to 5-methyl-tetrahydrofolate (Fig. 1) have been linked if applied in the immediate aftermath of a traumat- to depression [18,69]. Thus, genetic variation of the ic event [33,94]. Many authors have suggested that respective enzymes will have to be considered when propranolol and other anti-adrenergic drugs to impede assessing the impact of treatment regimes that target the one carbon pathway [14]. memory formation thereby preventing the onset of tan- While all these developments are encouraging, it talizing flashbacks in predisposed individuals. This no- needsto be consideredthatmostof the epigenetic drugs tion however is not unanimously accepted and some exert pleiotropic effects and are thus prone to exhibit authors have questioned the therapeutic and/or preven- severe side effects [22,34]. For psychiatric diseases in tive effectsof adrenoreceptorantagonistsin PTSD [61]. general, it will be necessary to develop and test drugs Furthermore, low dosed glucocorticoid administration directed towards more specific epigenetic mechanisms. has been reported to reduce the risk of developing PTSD Together with advances in understanding the specific after a traumatic event [78]. In addition, morphine is and probably individual epigenetic processes in dis- reported to reduce the risk of subsequent development ease, this may allow formulation of personalized epige- of PTSD after serious injury [39]. Finally, there is also netic treatment, possibly as co-medication, optimizing evidence from a mouse model that post stress preven- efficacy and minimizing side effects. tive treatment with the SSRI sertraline reduces the de- InPTSDinparticular,sideeffectsmaybetolerableor velopmentof PTSD-like behavior[51]. 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