Psychopathological and neuropsychological outcomes of deep brain stimulation for severe- treatment-resistant obsessive-compulsive disorder: An open-label case series.

OBJECTIVE: Deep brain stimulation (DBS) is considered a promising intervention for treatment-resistant obsessive-compulsive disorder (OCD). The present study describes the outcomes of the first DBS procedures for OCD in Iran. METHODS: Four women patients (age range, 25-35 years) with severe OCD meeting stringent criteria for refractoriness to treatment were selected by Psychosurgery Review Board. DBS electrodes were bilaterally implanted in the internal capsule and nucleus accumbens (NAc). Clinical and neuropsychological assessments were undertaken before and after implantation. The outcomes included Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Hamilton Anxiety Rating Scale (HAM-A), neuropsychological assessments including the Wisconsin Card Sorting Test, Wechsler Memory Scale, and adverse events. RESULTS: The baseline mean score of the Y-BOCS and HAM-A was 32 ± 6 and 23 ± 14 respectively and decreased to 26 ± 8 and 17 ± 9 after one-year implantation, showing a 19% improvement. Two patients were responders and showed a notable improvement. One patient's score declined 28%, who was not satisfied with DBS results, and one patient worsened under-stimulation. Improvements in the severity of anxiety and cognitive performance were consistent with OCD improvement, and the successfully treated patients showed improvement in anxiety and cognitive performance. No significant cognitive declines were seen. Two patients' suicidal ideation appeared after DBS as an important adverse event. CONCLUSION: Bilateral DBS of the internal capsule/NAc may be an effective and safe treatment for treatment-refractory OCD. However, there is a need to consider accessibility, high cost, cost-effectiveness, and standardized methodology in future research.

A Novel Link between the Oxytocin Receptor Gene and Impulsivity.

Impulsivity includes hasty actions, social intrusiveness or premature decision-making. Neuropeptides like oxytocin alleviate haste and anxiety, and affect fear conditioning. However, no investigations have been done via gene-network based approach with cognitive and interventional genetic association studies to scrutinize the link between impulsive behavior and oxytocin. Here, interactive gene network and pathways associated with impulsivity were reconstructed, and serotonin transporter gene (SLC6A4) and serotoninergic synaptic transmission were identified as the most central gene and pathway related to impulsivity. Young healthy males received intranasal oxytocin or placebo, and impulsivity was evaluated via go/no-go test. Test performance scores then were analyzed based on commission and omission errors, response inhibition and reaction time. Blood DNA was extracted and a 761 bp intronic region in oxytocin receptor (OXTR) gene was amplified and sequenced using PCR-pyrosequencing. Employing Haploview, haplotypes and linkage disequilibrium (LD) pattern among all SNPs in the target sequence were determined based on D' and LOD values, and rs2254298 with the highest LD was indicated as the tag SNP. Oxytocin group and participants with GG genotype showed a significantly decreased commission error and increased inhibition. This means that oxytocin alleviated impulsive behavior, and subjects with GG genotype had lower rate of impulsivity than those with GA and AA genotypes. rs2254298 may modulate the function or expression of the OXTR gene, implying that G allele may increase the expression of OXTR gene compared to A allele. We suggest that intranasal oxytocin may notably moderate impulsive behavior and tendency to make hasty or premature decisions.

The experience of patients with bipolar disorder from diagnosis disclosure: A qualitative study.

Background: Disclosure of the diagnosis is an essential part of the treatment process and an important part of patient rights. However, it can be a very stressful experience, especially in mental health disorders. Patients with bipolar disorder have a unique experience of receiving and managing their diagnosis. The objective of the current study was to explore the experience of patients with bipolar disorder of diagnosis disclosure. Methods: This was a qualitative study. Participants were recruited from patients who knew their disorder's name using purposive sampling method. The inclusion criteria were being diagnosed by a psychiatrist as having bipolar disorder and the disclosure was conducted by a psychiatrist. Sixteen semi-structured, in-depth interviews were conducted with twelve patients. Data were analyzed using thematic content analysis. Results: Patients received their diagnosis name in three steps including Wandering in Unknowns, Limited Brightness and Reaching to a Relative Insight. Patients believed that disclosure of the diagnosis was not accompanied by enough information. Conclusion: The disclosure of diagnosis in patients with bipolar disorder without providing enough information is stressful and is not helpful in empowering these patients. Based on our results, disclosure of diagnosis to patients with bipolar disorder was not conducted with enough information and patients had problems for understanding their symptoms and treatments.

Oxytocin moderates risky decision-making during the Iowa Gambling Task: A new insight based on the role of oxytocin receptor gene polymorphisms and interventional cognitive study.

The oxytocinergic system influences attentional bias towards emotional cues and feedback-based learning. Considering a tag single-nucleotide polymorphism (SNP) found through analysis of an intronic haplotype in the oxytocin receptor (OXTR) gene, we investigated the effect of oxytocin on risky decision-making via the Iowa Gambling Task (IGT). Young healthy males received intranasal oxytocin or placebo, and the IGT was performed where raw scores, net scores and total time were recorded, and ratio of advantageous to disadvantageous choices was calculated. Using PCR-pyrosequencing, a 761 bp target sequence in the OXTR gene was amplified and sequenced after the extraction of whole blood DNA. Employing Haploview, haplotypes and linkage disequilibrium (LD) pattern among all 14 SNPs in the intronic region were determined based on D' and LOD values, and rs2254295 with the highest LD was indicated as the tag SNP. GTT was shown to have the highest frequency among the found haplotypes. Oxytocin group and participants with the TT genotype demonstrated a significantly increased raw score, net score and advantageous choices, whereas the total time was not influenced remarkably. This means that oxytocin significantly reduced the risk taking in decision-making, and participants with the TT genotype had less premature or risky decisions than those with the CT and CC genotypes. rs2254295 may modulate the function or expression of the OXTR gene, implying that T allele may increase the expression of the OXTR gene compared to C allele. We suggest that oxytocin may remarkably moderate the risk attitude and its consequences during uncertain decision-making.

Integrated analysis of the genetic basis of suicidal behavior: what has been shown by structural genetic studies so far.

OBJECTIVE: In recent decades, the role of genetic factors in the predisposition to suicidal behavior has attracted considerable attention. Although each genetic investigation appears to be valuable, no one study on its own can comprehensively explain the etiology of suicidal behavior. METHODS: In this study, using a broad literature review, we found the suicide-associated gene coexpression network. In addition, cytoband, molecular function, biological process, cellular component, tissue-based expression, and disease/disorder enrichment analyses were carried out to determine the most central cellular and molecular infrastructures involved in suicidal behavior. RESULTS: The reconstructed network consisted of 104 genes, including 91 previously known genes and 13 novel genes, and 354 interactions. Topological analysis showed that in total, CCK, INPP1, DDC, and NPY genes are the most fundamental hubs in the network. We found that suicide genes are significantly concentrated within chromosomes 11 and 6. Further analysis showed that monoaminergic signal transduction, especially through GPCRs, in the cingulate gyrus, superior prefrontal gyrus, dorsal striatum, and the cerebellum are the main, deficient routes in suicide. Moreover, it turned out that genetically, suicidal behavior is more likely in patients with mood and affective disorders. CONCLUSION: Like other behavioral disorders, suicide has a complex and multifactorial basis and at present, the only approaches to the integrated study of such disorders are computer-based methods. The results of such studies, although subject to a degree of uncertainty, however, can pave the way for future basic and clinical studies.

What do the genetic association data say about the high risk of suicide in people with depression? A novel network-based approach to find common molecular basis for depression and suicidal behavior and related therapeutic targets.

BACKGROUND: Available sources indicate that the risk of suicide in people with major depression is higher than other psychiatric disorders. Although it seems that these two conditions may have a shared cause in some cases, no studies have been conducted to identify a common basis for them. METHODS: In this study, following an extensive review of literature, we found almost all the genes that are involved in major depression and suicidal behavior, and we isolated genes shared between the two conditions. Then, we found all physical or functional interactions within three mentioned gene sets and reconstructed three genetic interactive networks. All networks were analyzed topologically and enriched functionally. Finally, using a drug repurposing approach, we found the main available drugs that interacted with the most central genes shared between suicidal behavior and depression. RESULTS: The results demonstrated that BDNF, SLC6A4, CREB1, and TNF are the most fundamental shared genes; and generally, disordered dopaminergic, serotonergic, and immunologic pathways in neuronal projections are the main shared deficient pathways. In addition, we found two genes, SLC6A4 and SLC6A2, to be the main therapeutic targets, and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) and Tricyclic Antidepressants (TCA) to be the most effective drugs for individuals with depression at risk for suicide. CONCLUSIONS: Our results, in addition to shedding light on the integrated molecular basis of depression-suicide, offer new therapeutic targets for individuals with depression at high risk for suicide and could pave the way for future preclinical and clinical studies. However, integrative systems biology-based studies highly depend on existing data and related databases, as well as the arrival of new experimental data sources in the future, possibly affecting the current results.

Obsessive-compulsive disorder, which genes? Which functions? Which pathways? An integrated holistic view regarding OCD and its complex genetic etiology.

Obsessive-compulsive disorder (OCD) is characterized by recurrent obtrusive and repetitive acts typically occurred following anxiety. In the last two decades, studies done on the gene sequences, large-scale and point mutations and gene-gene, gene-environment and gene-drug interactions have led to the discovery of hundreds of genes associated with OCD. Although each gene in turn is a part of the etiology of this disorder; however, OCD, like other mental disorders is complex and a comprehensive and integrated view is necessary to understand its genetic basis. In this study, through an extensive review of existing published studies, all genes associated with OCD were found. Then, in order to integrate the results, all the interactions between these genes were explored and the achievement was represented as an interactive genetic network. Furthermore, the reconstructed network was analyzed. It was found that GRIN2A, GRIN2B and GRIA2 are the most central nodes in the network. Functional and pathway enrichment analysis showed that glutamate-related pathways are the main deficient systems in patients with OCD. By studying genes shared between OCD and other diseases, it was cleared that OCD, epilepsy and some types of cancer have the most number of shared genes. The results of this study, in addition to reviewing the available results as a comprehensive and integrated manner, provide new hypotheses for future studies.

Methamphetamine-induced psychosis is associated with DNA hypomethylation and increased expression of AKT1 and key dopaminergic genes.

Methamphetamine, one of the most frequently used illicit drugs worldwide, can induce psychosis in a large fraction of abusers and it is becoming a major problem for the health care institutions. There is some evidence that genetic and epigenetic factors may play roles in methamphetamine psychosis. In this study, we examined methamphetamine-induced epigenetic and expression changes of several key genes involved in psychosis. RNA and DNA extracted from the saliva samples of patients with methamphetamine dependency with and without psychosis as well as control subjects (each group 25) were analyzed for expression and promoter DNA methylation status of DRD1, DRD2, DRD3, DRD4, MB-COMT, GAD1, and AKT1 using qRT-PCR and q-MSP, respectively. We found statistically significant DNA hypomethylation of the promoter regions of DRD3 (P = 0.032), DRD4 (P = 0.05), MB-COMT (P = 0.009), and AKT1 (P = 0.0008) associated with increased expression of the corresponding genes in patients with methamphetamine psychosis (P = 0.022, P = 0.034, P = 0.035, P = 0.038, respectively), and to a lesser degree in some of the candidate genes in non-psychotic patients versus the control subjects. In general, methamphetamine dependency is associated with reduced DNA methylation and corresponding increase in expression of several key genes involved in the pathogenesis of psychotic disorders. While these epigenetic changes can be useful diagnostic biomarkers for psychosis in methamphetamine abusers, it is also consistent with the use of methyl rich diet for prevention or suppression of psychosis in these patients. However, this needs to be confirmed in future studies. © 2016 Wiley Periodicals, Inc.

DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.

INTRODUCTION: Dysfunctional serotonin signaling has been linked to the pathogenesis of autism, obsessive compulsive disorder, mood disorders and schizophrenia. While the hypo-activity of serotonin signaling is involved in the pathogenesis of depression, anxiety and obsessive compulsive disorder; LSD, an agonist of serotonin type 2 receptor (5-HTR2A) induces psychosis. Therefore, anxiety and depressive disorders are treated by SSRIs which inhibit serotonin transporter (5-HTT) while psychotic disorders are controlled by drugs that block serotonin and/or dopamine receptors. Since genetic polymorphisms and epigenetic dysregulation of 5-HTT are involved in the pathogenesis of mental diseases, we analyzed DNA methylation of 5-HTT promoter in post-mortem brains and saliva samples of patients with schizophrenia (SCZ) and bipolar disorder (BD) to evaluate its potential application as a diagnostic and/or therapeutic biomarker in SCZ and BD. METHODS: Whole genome DNA methylation profiling was performed for a total of 24 samples (including two saliva samples) using the Illumina 27K (for 12 samples) and 450K DNA methylation array platform (for another 12 samples), followed by bisulfite sequencing to identify candidate CpGs for further analysis. Quantitative methylation specific PCR (qMSP) was used to assess the degree of CpG methylation of 5-HTT promoter in 105 post-mortem brains (35 controls, 35 SCZ and 35 BD) and 100 saliva samples (30 controls, 30 SCZ, 20 BD and 20 first degree relatives of SCZ or BD). The U133 2.0 Plus Human Transcriptome array for a total of 30 post-mortem brain samples (each group 10) followed by quantitative real-time PCR was used to study 5-HTT expression in 105 post-mortem brain samples. RESULTS: The qMSP analysis for 5-HTT promoter region showed DNA hypermethylation in post-mortem brain samples of SCZ patients (~30%), particularly in drug free patients (~60%, p=0.04). Similarly, there was a trend for DNA hypermethylation in antipsychotic free BD patients (~50%, p=0.066). qMSP analysis of DNA extracted from the saliva samples also exhibited hypermethylation of 5-HTT promoter in patients with SCZ (~30%, p=0.039), which was more significant in drug naïve SCZ patients (>50%, p=0.0025). However, the difference was not significant between the controls and unaffected first degree relatives of patients with SCZ (p=0.37) and versus patients using antipsychotic drugs (p=0.2). The whole genome transcriptome analysis of post-mortem brain samples showed reduced expression of 5-HTT in SCZ compared to the control subjects (~50%, p=0.008), confirmed by quantitative real-time PCR analysis (~40%, p=0.035) which was more significant in drug free SCZ patients (~70%, p=0.022). CONCLUSION: A correlation between reduction in 5-HTT expression and DNA hypermethylation of the 5-HTT promoter in drug naïve SCZ patients suggests that an epigenetically defined hypo-activity of 5-HTT may be linked to SCZ pathogenesis. Furthermore, this epigenetic mark in DNA extracted from saliva can be considered as one of the key determinants in a panel of diagnostic and/or therapeutic biomarkers for SCZ.

DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder.

The failure in the discovery of etiology of psychiatric diseases, despite extensive genetic studies, has directed the attention of neuroscientists to the contribution of epigenetic modulations, which play important roles in fine-tuning of gene expression in response to environmental factors. Previously, we analyzed 115 human post-mortem brain samples from the frontal lobe and reported DNA hypo methylation of the membrane-bound catechol-O-methyltransferase (MB-COMT) gene promoter, associated with an increased gene expression, as a risk factor for schizophrenia (SCZ) and bipolar disorder (BD). Since most epigenetic modifications are tissue specific and the availability of brain tissue to identify epigenetic aberrations in living subjects is limited, detection of epigenetic abnormalities in other tissues that represent the brain epigenetic marks is one of the critical steps to develop diagnostic and therapeutic biomarkers for mental diseases. Here, hypothesizing that; those factors that lead to the brain MB-COMT promoter DNA hypo-methylation may also cause concurrent epigenetic aberrations in peripheral tissues, we analyzed MB-COMT promoter methylation in DNA derived from the saliva in SCZ, BD and their first-degree relatives (20 cases each) as well as 25 control subjects. Using bisulfite DNA sequencing and quantitative methylation specific PCR (qMSP), we found that similar to the brain, MB-COMT promoter was hypo-methylated (∼50%) in DNA derived from the saliva in SCZ and BD compared to the control subjects (p = 0.02 and 0.037, respectively). These studies suggest that DNA methylation analysis of MB-COMT promoter in saliva can potentially be used as an available epigenetic biomarker for disease state in SCZ and BD.

Hypomethylation of the serotonin receptor type-2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder.

Several lines of evidence indicate that dysfunction of serotonin signaling and HTR2A receptor are involved in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BD). DNA methylation of HTR2A at T102C polymorphic site influences HTR2A expression and aberrant DNA methylation of HTR2A promoter was reported in postmortem brain of patients with SCZ and BD. Hypothesizing that the brain's epigenetic alteration of HTR2A may also exist in peripheral tissues that can be used as a diagnostic/therapeutic biomarker, we analyzed HTR2A promoter DNA methylation in DNA extracted from the saliva of patients with SCZ and BD, and their first degree relatives versus normal controls. Bisulfite sequencing was used to screen DNA methylation status of the HTR2A promoter CpGs and qMSP was used to quantify the degree of cytosine methylation at differentially methylated sites. Most of the cytosines of the HTR2A promoter were unmethylated. However, CpGs of the -1438A/G polymorphism site, -1420 and -1223 were >95% methylated. The CpG at T102C polymorphic site and neighboring CpGs were ∼70% methylated both in the patients and controls. qMSP analysis revealed that the cytosine of the T102C polymorphic site was significantly hypo-methylated in SCZ, BD, and their first degree relatives compared to the controls. Cytosine methylation of HTR2A at T102C polymorphic site in DNA derived from the saliva can potentially be used as a diagnostic, prognostic, and/or therapeutic biomarker in SCZ and BD. However, these preliminary observations need to be replicated in other populations with a larger sample size to be considered for clinical applications.