Associations have been seen between suicidal behavior and differential DNA methylation of certain genes, with one study showing significant hypomethylation of ARHGEF38 in postmortem brain samples from individuals with bipolar disorder who died by suicide. Our objective was to explore ARHGEF38 methylation in individuals with bipolar disorder and a history of suicide attempt.

With pyrosequencing, we looked at the previously identified region of interest in ARHGEF38. We investigated the methylation levels of 3 CpG sites in 47 individuals with bipolar disorder and a history of suicide attempt, 47 individuals with bipolar disorder without a history of suicide attempt, and 47 non-bipolar disorder controls.

None of the CpG sites measured had an association between groups, although there were distinct clusters of differential methylation in each group. Applying genotypes of SNPs found in the region of interest, rs2121558 and rs1447093, these clusters showed stepwise methylation at each CpG site, regardless of phenotype.

In this relatively small sample size study, differential methylation in ARHGEF38 was not associated with history of suicide attempt, failing to replicate findings from a related outcome, suicide death. However, we did provide evidence of SNP and DNA methylation interplay in this region. This highlights the potential relevance of considering genetics when interrogating epigenetic mechanisms.

ARHGEF38 methylation is not associated with bipolar disorder and suicide attempt Methylation of ARHGEF38 is heavily influenced by the presence of SNPs Suicide phenotype, genetics, and sample type impact DNA methylation.

Major depressive disorder (MDD) is a debilitating disorder. Suicide attempts are 5-times higher in MDD patients than in the general population. Interestingly, not all MDD patients develop suicidal thoughts or complete suicide. Thus, it is important to study the risk factors that can distinguish suicidality among MDD patients. The present study examined if DNA methylation changes can distinguish suicidal behavior among depressed subjects. Genome-wide DNA methylation was examined in the dorsolateral prefrontal cortex of depressed suicide (MDD+S; n = 15), depressed non-suicide (MDD-S; n = 17), and nonpsychiatric control (C; n = 16) subjects using 850 K Infinium Methylation EPIC BeadChip. The significantly differentially methylated genes were used to determine the functional enrichment of genes for ontological clustering and pathway analysis. Based on the number of CpG content and their relative distribution from specific landmark regions of genes, 32,958 methylation sites were identified across 12,574 genes in C vs. MDD+/-S subjects, 30,852 methylation sites across 12,019 genes in C vs. MDD-S, 41,648 methylation sites across 13,941 genes in C vs. MDD+S, and 49,848 methylation sites across 15,015 genes in MDD-S vs. MDD+S groups. A comparison of methylation sites showed 33,129 unique methylation sites and 5451 genes in the MDD-S group compared to the MDD+S group. Functional analysis suggested oxytocin, GABA, VGFA, TNFA, and mTOR pathways associated with suicide in the MDD group. Altogether, our data show a distinct pattern of DNA methylation, the genomic distribution of differentially methylated sites, gene enrichment, and pathways in MDD suicide compared to non-suicide MDD subjects.

Suicide is a manner of death resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk.

We have identified the hippocampal tissue transcriptomes, gene ontology, cell type proportions, and dendritic spine morphology in controls (n = 28) and suicide decedents (n = 22). In addition, the transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons were also investigated in controls (n = 2) and suicide decedents (n = 2).

The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA, and MLXIPL gene expressions were upregulated in hippocampal tissue of suicide decedents. The gene ontology identified 29 significant pathways including NPAS4-associated gene ontology terms "excitatory post-synaptic potential", "regulation of postsynaptic membrane potential" and "long-term memory" indicating alteration of glutamatergic synapses in the hippocampus of suicide decedents. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide decedents. In addition, suicide decedents had increased dendric spine density in the hippocampus, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide decedents.

Our findings will provide new insights into the hippocampal neuropathology of suicide.

Background: Environmental factors make an important contribution to suicide. Histone tails are prone to different modifications, leading to changes of chromatin (de)condensation and consequently gene expression. Materials & methods: Level of H3K14ac was studied with chromatin immunoprecipitation followed by high-throughput DNA sequencing. Genes were further validated with RT-qPCR; using hippocampal tissue. Results: We showed lowered H3K14ac levels in individuals who died by suicide. The genes ADORA2A, B4GALT2 and MMP14 showed differential expression in individuals who died by suicide. Identified genetic and protein interactions among genes show interactions with suicide-related genes. Conclusion: Further investigations of histone modifications in association with DNA methylation and miRNA are needed to expand our knowledge of the genes that could significantly contribute to suicide.

Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual's vulnerability to suicide. These factors include various potential causes, from psychiatric disorders to genetic and epigenetic alterations. These changes can induce dysfunctions in crucial systems such as the serotonergic, cannabinoid, and hypothalamic-pituitary-adrenal axes. In addition, early life experiences of abuse can profoundly impact an individual's ability to cope with stress, ultimately leading to changes in the inflammatory system, which is a significant risk factor for suicidal behavior. Thus, it is clear that suicidal behavior may result from a confluence of multiple factors. This review examines the primary risk factors associated with suicidal behavior, including psychiatric disorders, early life adversities, and epigenetic modifications. Our goal is to elucidate the molecular changes at the genetic, epigenetic, and molecular levels in the brains of individuals who have taken their own lives and in the plasma and peripheral mononuclear cells of suicide attempters and how these changes may serve as predisposing factors for suicidal tendencies.

Around the world, more the 700,000 individuals die by suicide every year. It is necessary to understand the mechanisms associated with suicidal behavior. Recently, an increase in gene expression studies has been in development. Through a systematic review, we aimed to find a candidate gene in gene expression studies on postmortem brains of suicide completers. Databases were systematically searched for published studies. We performed an online search using PubMed, Scopus and Web of Science databases to search studies up until May 2023. The terms included were "gene expression", "expressed genes", "microarray", "qRT-PCR", "brain samples" and "suicide". Our systematic review included 59 studies covering the analysis of 1450 brain tissues from individuals who died by suicide. The majority of gene expression profiles were obtained of the prefrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, ventral prefrontal cortex and orbital frontal cortex area. The most studied mRNAs came of genes in glutamate, γ-amino-butyric acid and polyamine systems. mRNAs of genes in the brain-derived neurotrophic factor, tropomyosin-related kinase B (TrkB), HPA axis and chemokine family were also studied. On the other hand, psychiatric comorbidities indicate that suicide by violent death can alter the profile of mRNA expression.

Stress is associated with various epigenetic changes. Some stress-induced epigenetic changes are highly dynamic, whereas others are associated with lasting marks on the epigenome. In our study, a comprehensive narrative review of the literature was performed by investigating the epigenetic changes that occur with acute stress, chronic stress, early childhood stress, and traumatic stress exposures, along with examining those observed in post-mortem brains or blood samples of suicide completers and attempters. In addition, the transgenerational effects of these changes are reported. For all types of stress studies examined, the genes Nr3c1, OXTR, SLC6A4, and BDNF reproducibly showed epigenetic changes, with some modifications observed to be passed down to subsequent generations following stress exposures. The aforementioned genes are known to be involved in neuronal development and hormonal regulation and are all associated with susceptibility to mental health disorders including depression, anxiety, personality disorders, and PTSD (post-traumatic stress disorder). Further research is warranted in order to determine the scope of epigenetic actionable targets in individuals suffering from the long-lasting effects of stressful experiences.

The ability to accurately estimate risk of suicide deaths on an individual level remains elusive.

This study reports on a case-control study set-up from a well-characterized cohort of 88 predominantly female suicide attempters (SA), stratified into low- (n = 57) and high-risk groups (n = 31) based on reports of later death by suicide, as well as degree of intent-to-die and lethality of SA method. We perform an unbiased analysis of 12,930 whole-blood derived CpG-sites (Illumina Infinium EPIC BeadChip) previously demonstrated to be more conciliable with brain-derived variations. The candidate site was validated by pyrosequencing. External replication was performed in (1) relation to age at index suicide attempt in 97 women with emotionally unstable personality disorder (whole-blood) and (2) death by suicide in a mixed group of 183 prefrontal-cortex (PFC) derived samples who died by suicide or from non-psychiatric etiologies.

CYP2D6-coupled CpG-site cg07016288 was hypomethylated in severe suicidal behavior (p < 10E-06). Results were validated by pyrosequencing (p < 0.01). Replication analyses demonstrate hypomethylation of cg07016288 in relation to age at index SA in females (p < 0.05) and hypermethylation in PFC of male suicide completers (p < 0.05).

Genotyping of CYP2D6 was not performed and CpG-site associations to gene expression were not explored.

CYP2D6-coupled epigenetic markers are hypomethylated in females in dependency of features known to confer increased risk of suicide deaths and hypermethylated in PFC of male suicide completers. Further elucidating the role of CYP2D6 in severe suicidality or suicide deaths hold promise to deduce clinically meaningful results.

Schizophrenia is a debilitating disease that is associated with higher rates of death by unnatural causes including suicide. Exposure to stressful events is an important risk factor for suicidal ideation (SI); however, the mechanisms that link stress, SI, and suicide remain unclear. Epigenetic processes are involved in both vulnerability to suicidal behavior and stress. Therefore, we sought to study the relationship between epigenetic modifications and suicidal behavior and stress.

This pilot study was conducted on 39 patients diagnosed with schizophrenia (54% men and age 45.5 ± 12.7). We analyzed the effects of (a) stress exposure and (b) the mediation of DNA methylation [via an epigenetic wide association study (EWAS) of more than 450 000 CpG sites across the genome] on SI severity.

The top CpG site mediating the effect of global stress exposure on SI was cg27660192 located in an intergenic region on chromosome 11, exerting a facilitating effect on worsening SI through DNA hypomethylation.

These preliminary results indicate that DNA methylation in peripheral tissues can shed light on the complex relationship between stress and SI in schizophrenia.

Suicide is a condition resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk. Here, we have identified the hippocampal transcriptomes, gene ontology, cell type proportions, dendritic spine morphology, and transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons in postmortem brain tissue from suicide deaths. The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA, and MLXIPL gene expressions were upregulated in tissue from suicide deaths. The gene ontology identified 29 significant pathways including NPAS4-associated gene ontology terms "excitatory post-synaptic potential", "regulation of postsynaptic membrane potential" and "long-term memory" indicating alteration of glutamatergic synapses in the hippocampus of suicide deaths. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide deaths. In addition, suicide deaths had increased dendric spine density, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide deaths. The suicide-associated differentially expressed genes in NPCs were RELN, CRH, EMX2, OXTR, PARM1 and IFITM2 which overlapped with previously published results. The previously-known suicide-associated differentially expressed genes in differentiated neurons were COL1A1, THBS1, IFITM2, AQP1, and NLRP2. Together, these findings would help better understand the hippocampal neurobiology of suicide for identifying therapeutic targets to prevent suicide.

Epigenetic mechanisms are involved in regulation of many pathologies, including suicidal behaviour. However, the factors through which epigenetics affect suicidal behaviour are not fully understood.

We analysed DNA methylation of eight neuropsychiatric genes (NR3C1, SLC6A4, HTR1A, TPH2, SKA2, MAOA, GABRA1, and NRIP3) in brain regions (hippocampus, insula, amygdala, Brodmann area 46) and blood of 25 male suicide victims and 28 male control subjects, using bisulphite next-generation sequencing.

Comparing mean methylation values, notable changes were observed in NR3C1 (insula p-value = 0.05), HTR1A (insula p-value < 0.001, blood p-value = 0.001), SKA2 (insula p-value = 0.03, blood p-value = 0.016), MAOA (blood p-value < 0.001), GABRA1 (insula p-value = 0.05, blood p-value = 0.024) and NRIP3 (hippocampus p-value = 0.001, insula p-value = 0.002, amygdala p-value = 0.014). Comparing methylation pattern between blood and brain, similarity was observed between blood and insula for HTR1A. Gene expression analysis in hippocampus revealed changes in expression of NR3C1 (p-value = 0.049), SLC6A4 (p-value = 0.017) and HTR1A (p-value = 0.053).

Results provide an insight into the altered state of DNA methylation in suicidal behaviour. Epigenetic differences could therefore affect suicidal behaviour in both previously known and in novel neuropsychiatric candidate genes.

Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.

Suicide is multifactorial and polygenic phenotype, affected by environmental and genetic factors. Among epigenetic mechanisms, miRNAs have been studied, but so far no very concise results exist. To overcome limitations of candidate miRNA and whole genome sequencing approaches, we created an in silico analysis algorithm that would help select the best suitable miRNAs that target the most interesting genes associated with suicidality. We used databases/web algorithms DIANA microT, miRDB, miRmap, miRWalk, and TargetScan and candidate genes SLC6A4, HTR1A, BDNF, NR3C1, ZNF714, and NRIP3. Based on a prediction algorithm, we have chosen miRNAs that are targeting regulation of the genes listed, and are at the same time being expressed in the brain. The highest ranking scores were obtained for hsa-miR-4516, hsa-miR-3135b, hsa-miR-124-3p, hsa-miR-129-5p, hsa-miR-27b-3p, hsa-miR-381-3p, hsa-miR-4286. Expression of these miRNAs was tested in the brain tissue of 40 suicide completers and controls, and hsa-miR-4516 and hsa-miR-381-3p showed a trend for statistical significance. We also checked the expression of the target genes of these miRNAs, and for NR3C1 expression was lower in suicide completers compared to controls, which is in accordance with the available literature results. To determine the miRNAs that are most suitable for further suicidality research, more studies, combining in silico analysis and wet lab experiments, should be performed.

Suicide is a major public health problem. Worldwide, around 800000 people die by suicide every year. Suicide is a multifactorial disorder, with numerous environmental and genetic risk factors involved. Among the candidate genes, changes in the BDNF locus at the gene, epigenetic, mRNA, and protein expression levels have been implicated in psychiatric disorders, including suicidal behavior and completed suicides.

To investigate changes in BDNF methylation and expression of four alternative BDNF transcripts for association with completed suicide.

This case-control study included 42 unrelated male Caucasian subjects, where 20 were control subjects who died following acute cardiac arrest, and 22 were suicide victims who died by hanging. DNA and RNA were extracted from brain tissue (Brodmann area 9 and hippocampus) and from blood. DNA methylation and mRNA expression levels were determined by targeted bisulfite next-generation sequencing and reverse-transcription quantitative PCR. Statistical analysis was done by use of two-tailed Student's t tests for two independent samples, and the Benjamini-Hochberg procedure was implemented for correction for multiple comparisons.

In DNA from brain tissue, there were no significant differences in BDNF methylation between the study groups. However, data showed significantly reduced DNA methylation of the BDNF region upstream of exon I in blood samples of suicide victims compared to the controls (5.67 ± 0.57 vs 6.83 ± 0.64, P corr = 0.01). In Brodmann area 9 of the brain of the suicide victims but not in their hippocampus, there was higher expression of BDNF transcript I-IX (NM_170731.4) compared to the controls (0.077 ± 0.024 vs 0.05 ± 0.013, P = 0.042). In blood, expression analysis for the BDNF transcripts was not feasible due to extensive RNA degradation.

Despite the limitations of the study, the obtained data further support a role for BDNF in suicidality. However, it should be noted that suicidal behavior is a multifactorial disorder with numerous environmental and genetic risk factors involved.

Suicide is a major global hazard. There is a need for increasing suicide awareness and effective and evidence-based interventions, targeting both suicidal ideation and conduct. However, anti-suicide pharmacological effects are unsatisfactory. The human hippocampus is vulnerable to neuropsychiatric damages and subsequently releases psychobiological signals. Human hippocampal studies of suicide completers have shown mechanistic changes in neurobiology, which, however, could not reflect the neuropathological 'fingerprints' of fatal suicide ideations and suicide attempts. In this review, we provide several leading theories of suicide, including the serotoninergic system, Wnt pathway and brain-derived neurotrophic factor/tropomyosin receptor kinase B signalling, and discuss the evidence for their roles in suicide and treatment. Moreover, the cognitive dysfunctions associated with suicide risk are discussed, as well as the novel evidence on cognitive therapies that decrease suicidal ideation. We highlight the need to apply multi-omics techniques (including single-nucleus RNA sequencing and mass spectrometry histochemistry) on hippocampal samples from donors who died by suicide or legal euthanasia, to clarify the aetiology of suicide and propose novel therapeutic strategies.

Most psychiatric disorders are associated with an elevated risk of suicide. Suicidal behavior is the product of the interaction of many risk factors, such as genetics and environmental factors. Hence, epigenetics research may help to understand the mechanisms leading to suicidal ideation and behavior. This review will discuss epigenetic studies in both suicidal ideation and behavior. Epigenetic modifications are likely to be important in both suicidal ideation and behavior. Most of the reviewed studies found significant epigenetic modifications linked with suicidal behavior rather than ideation. Although sizable research has been carried out on this topic, most studies have been done on small-scale samples, and future research is required in larger samples with better clinical characterization of suicide phenotypes to investigate these epigenetic modifications further.

Psychiatric disorders, including suicide, are complex disorders that are affected by many different risk factors. It has been estimated that genetic factors contribute up to 50% to suicide risk. As the candidate gene approach has not identified a gene or set of genes that can be defined as biomarkers for suicidal behaviour, much is expected from cutting edge technological approaches that can interrogate several hundred, or even millions, of biomarkers at a time. These include the '-omic' approaches, such as genomics, transcriptomics, epigenomics, proteomics and metabolomics. Indeed, these have revealed new candidate biomarkers associated with suicidal behaviour. The most interesting of these have been implicated in inflammation and immune responses, which have been revealed through different study approaches, from genome-wide single nucleotide studies and the micro-RNA transcriptome, to the proteome and metabolome. However, the massive amounts of data that are generated by the '-omic' technologies demand the use of powerful computational analysis, and also specifically trained personnel. In this regard, machine learning approaches are beginning to pave the way towards personalized psychiatry.

Suicide represents a major health concern, especially in developing countries. While many demographic risk factors have been proposed, the underlying molecular pathology of suicide remains poorly understood. A body of evidence suggests that aberrant DNA methylation and expression is involved. In this study, we examined DNA methylation profiles and concordant gene expression changes in the prefrontal cortex of Mexicans who died by suicide.

In collaboration with the coroner's office in Mexico City, brain samples of males who died by suicide (n = 35) and age-matched sudden death controls (n = 13) were collected. DNA and RNA were extracted from prefrontal cortex tissue and analyzed with the Infinium Methylation480k and the HumanHT-12 v4 Expression Beadchips, respectively.

We report evidence of altered DNA methylation profiles at 4430 genomic regions together with 622 genes characterized by differential expression in cases vs controls. Seventy genes were found to have concordant methylation and expression changes. Metacore-enriched analysis identified 10 genes with biological relevance to psychiatric phenotypes and suicide (ADCY9, CRH, NFATC4, ABCC8, HMGA1, KAT2A, EPHA2, TRRAP, CD22, and CBLN1) and highlighted the association that ADCY9 has with various pathways, including signal transduction regulated by the cAMP-responsive element modulator, neurophysiological process regulated by the corticotrophin-releasing hormone, and synaptic plasticity. We therefore went on to validate the observed hypomethylation of ADCY9 in cases vs control through targeted bisulfite sequencing.

Our study represents the first, to our knowledge, analysis of DNA methylation and gene expression associated with suicide in a Mexican population using postmortem brain, providing novel insights for convergent molecular alterations associated with suicide.

Suicidal behavior is influenced by many risk factors such as childhood trauma, stressful life events, genetic factors, and severe mental illnesses. Suicidal ideation is present in 50% of schizophrenia patients and is associated with an elevated risk of suicide attempt. Studies have shown that epigenetic mechanisms are associated with suicidal behavior in schizophrenia. Although several studies have suggested the importance of epigenetic factors in suicidal ideation and behavior, no studies have investigated global methylation in association with these two phenotypes. This study investigated global methylation level/change in association with current and emergent suicidal ideation and also with suicide attempt. Forty-seven schizophrenia patients were assessed for the association between global methylation and suicide attempt, and a subsample of these patients (n = 27) was assessed for current suicidal ideation. Afterwards, we performed a longitudinal analysis in which global methylation changes during a 3-month follow-up were compared between patients with and without emergent suicidal ideation. This methylation analysis did not find evidence for a significant association between global methylation and suicidal ideation or suicide attempt. To date, there are no robust biomarkers predicting suicidal ideation or behavior in psychotic patients. This study is the first to investigate global methylation in predicting suicidal ideation and behavior. Although we did not find evidence for an association between global methylation and these phenotypes, our findings may offer novel insights into the molecular mechanisms linked to suicide. Future investigation may measure global methylation in association with suicidal ideation or behavior in larger samples.

In this study, we investigate the epigenetic mechanisms associated with current suicidal ideation. Gene expression changes have been found in post-mortem brain of suicide victims. However, it is not clear how in-vivo gene expression change confers risk for suicide. DNA methylation is a form of epigenetic modification that regulates gene expression. Our primary aim is to investigate genome-wide methylation in conferring risk for current suicidal ideation (SI) in schizophrenia. The presence of current SI and genome-wide methylation patterns were assessed in 107 patients with schizophrenia. DNA methylation has been measured in white blood cells as a possible peripheral biomarker of SI. SI was the primary outcome variable in a model including methylation status of white blood cells using the Illumina 450 array. We have tested the association with genome-wide methylation levels in 19 subjects with current SI and 88 subjects without current SI and we found that higher methylation level in the CpG cg06121808 located in the gene SLC20A1 on chromosome 2 was associated with current SI (p = 0.000003; beta difference = 0.06). Furthermore, the distal promoter analysis showed that the gene SMPD2 was hypermethylated in suicide ideators (p = 0.0001; beta difference = 0.02). Thus, molecular biomarkers could advance our understanding of the molecular mechanisms of stress-related SI. Furthermore, the methylation sites that we have identified should be replicated in other suicide related phenotypes to generate robust biomarkers with high translational value for proof of concept interventions aiming at reducing SI.

Suicidal behaviors have been associated with both heritable genetic variables and environmental risk factors. Epigenetic processes, such as DNA methylation, have important roles in mediating the effects of the environment on behavior. Dysregulation of these processes has been observed in many psychiatric disorders, and evidence suggests that they may also be involved in suicidal behaviors. Herein, we have summarized candidate gene and epigenome-wide studies which have investigated DNA methylation in relation to suicidal behaviors, as well as discussed some of the limitations of the field to date.

Clozapine is an atypical antipsychotic used in treatment-resistant bipolar disorder. There is evidence for its anti-suicidal, anti-aggressive properties and efficacy in substance use comorbidities. Despite guidelines, the drug is used in 1.5% of bipolar patients only. Considering its effectiveness in treatment-resistant cases as well as its epigenetic effects it may become transformative treatment in bipolar disorder impacting the clinical course and psychosocial burden of the disease.