Oxytocin receptor gene methylation as a molecular marker for severity of depressive symptoms in affective disorder patients.

BACKGROUND: Oxytocin (OXT) is a neuropeptide and hormone involved in emotional functioning and also seems to play a role in moderating the stress response. Both preclinical and clinical studies point to an increased methylation status of the Oxytocin receptor (OXTR) promoter region with concomitant deficits in social, cognitive and emotional functioning. We hypothesize that methylation levels (%) of the oxytocin receptor promoter region correlate with the severity of depression symptoms and/or with the severity of childhood trauma within this present sample of affective disorder patients. METHODOLOGY: Eight hundred forty six (846) affective disorder patients of Central European origin were recruited at the Department of Psychiatry and Psychotherapy of the Medical University Vienna, the Karl Landsteiner University for Health and Science and Zentren für seelische Gesundheit, BBRZ-Med Leopoldau. Psychiatric assessment included a semi-structured diagnostic interview (Schedules for Clinical Assessment in Neuropsychiatry), the Hamilton Depression Scale and the Childhood Trauma Questionnaire. Concomitantly DNA samples of peripheral blood cells were collected for Multiplexed and Sensitive DNA Methylation Testing. RESULTS: Our data suggests a positive but not significant association between OXTR promoter Exons 1-3 methylation levels and severity of depression symptoms as well as severity of emotional neglect in affective disorder patients and no association with childhood trauma. CONCLUSIONS: Our findings contribute to elucidate the role of OXTR in affective disorders, but further longitudinal studies in particular are necessary to broaden the current state of knowledge.

Monitoring neonatal abstinence syndrome in buprenorphine-exposed in vitro fertilization twins: A case study.

BACKGROUND: Prior studies have reported on the pregnancies and outcomes of in vitro fertilization (IVF) in special subpopulations; however, there is a lack of studies on opioid-exposed IVF-conceived neonates. CASE PRESENTATION: A young adult IVF-pregnant woman was maintained on buprenorphine throughout pregnancy and received follow-up from the addiction clinic from estimated gestational week 32. She delivered healthy dichorionic twins via cesarean section at 38 weeks gestational age (buprenorphine dose at time of delivery: 16 mg). All maternal supervised urinalysis taken as of gestational week 32 were negative for concomitant substances (prior to treatment initiation at the addiction clinic, only self-reports of abstinence from concomitant substances were available). Both healthy children (male birth weight: 3140 g, female birth weight: 2650 g) developed an unusual course of neonatal abstinence syndrome (NAS) requiring extensive treatment (total morphine dose male: 22 mg, and female: 26.75 mg; length of treatment: 33 and 34 days, respectively; duration of hospitalization: 40 days). DISCUSSION: The highly severe and long-lasting NAS in both neonates represents a very unusual course following an uneventful pregnancy, and influencing iatrogenic factors cannot be ruled out. Given the multiple variables influencing infant outcomes, this highlights the importance of high-quality, evidence-based standard operating procedures, which (1) are initiated as early as possible during pregnancy to minimize risk factors for adverse infant outcomes, such as concomitant substance use during pregnancy; (2) support the substance-dependent woman throughout the postpartum period, especially in cases of multiple and/or IVF-conceived pregnancies, where additional challenges may arise; and (3) consider the right of everyone to the enjoyment of the highest attainable standard of physical and mental health.

BDNF gene polymorphisms predicting treatment response to CBT-based rehabilitation of depression: to be submitted to: European Neuropsychopharmacology.

Genetic factors were shown to play a major role in both variation of treatment response and incidence of adverse effects to medication in affective disorders. Nevertheless, there is still a lack of therapygenetic studies, investigating the prediction of psychological therapy outcomes from genetic markers. Neuroplasticity and one of its mediators, brain-derived neurotrophic factor (BDNF), are potential research targets in this field. We aimed to investigate Tag SNP polymorphisms of the BDNF gene in depressed patients treated with cognitive behavioral therapy (CBT) in the context of a standardized 6-weeks outpatient rehabilitation program. Treatment response was assessed calculating the mean differences in BDI-II (Beck Depression Inventory) scores from admission to discharge. Six BDNF SNPs, including the Val66Met polymorphism (rs6265), were genotyped. Both genotypic data and BDI-II-scores at admission and discharge were available for 277 patients. Three SNPs, rs10501087 (p = 0.005, FDRp=0.015), rs11030104 (p = 0.006, FDRp=0.012), and the Val66Met polymorphism (rs6265, p<0.001, FDRp=0.006), were significantly associated with treatment response in depressed patients, even after multiple testing correction using the false discovery rate method (FDRp). We conclude that BDNF might serve as promising genetic marker for treatment response to psychological treatment in depression. However, due to our limited sample size, further studies are needed to disentangle the role of BDNF as potential therapygenetic marker.

Monoamino Oxidase A Gene Single-Nucleotide Polymorphisms and Methylation Status and the Risk of Violent Suicide Attempts in Affective Disorder Patients.

Background: When investigating the neurobiology of suicidal behavior, Monoamino Oxidase A (MAOA) is one of the prime suspects to consider. Interestingly, MAOA dysregulation has also been associated with violent behavior in previous publications. In the present study, we aimed to establish an association between polymorphisms of the MAOA gene and methylation status of the MAOA gene Exon I, and suicide attempts with violent methods in a sample of affective disorder patients. Methods: Eight hundred fourteen Caucasian affective disorder patients were assessed at the Department of Psychiatry and Psychotherapy of the Medical University Vienna, the Karl Landsteiner University for Health and Science and Zentren für seelische Gesundheit, BBRZ-Med Leopoldau. An assemblage of psychiatric interviews was performed (e.g., SCAN, HAMD, SBQ-R, CTQ) and DNA samples of peripheral blood cells were collected for Sequenom MassARRAY® iPLEX Gold genotyping and Multiplexed and Sensitive DNA Methylation Testing. Results: Female affective disorder patients with a history of violent suicide attempt were found to have a significantly increased frequency of the AA genotype in the rs5906957 single nucleotide polymorphism (p = 0.003). Furthermore, the MAOA gene exon I promoter region showed significantly decreased methylation in female violent suicide attempter(s) as opposed to female affective disorder patients who had no history of suicide attempt or no history of suicide attempt with violent method. Limitations: The small sample size hampers to reveal small genetic effects as to be expected in psychiatric disorders. Conclusions: This study offers promising findings about associations between the MAOA gene and violent suicide especially in women.

Austrian firearm legislation and its effects on suicide and homicide mortality: A natural quasi-experiment amidst the global economic crisis.

BACKGROUND: Restriction of access to suicide methods has been shown to effectively reduce suicide mortality rates. AIMS: To examine how the global economic crisis of 2008 and the firearm legislation reform of 1997 affected suicide and homicide mortality rate within Austria. METHODS: Official data for the years 1985-2016 for firearm certificates, suicide, homicide, unemployment rates and alcohol consumption were examined using auto regressive error and Poisson regression models. RESULTS: Firearm certificates, total suicide mortality rate, suicide and homicides by firearms, and the fraction of firearm suicides/homicides among all suicides/homicides decreased after the firearm legislation reform in 1997. However, significant trend changes can be observed after 2008. The availability of firearm certificates significantly increased and was accompanied by significant changes in trends of firearm suicide and homicide rates. Concurrently, the total suicide mortality rate in 2008, for the first time since 1985, stopped its decreasing trend. While the total homicide rate further decreased, the fraction of firearm homicides among all homicides significantly increased. CONCLUSION: The initially preventative effect of the firearm legislation reform in Austria in 1997 seems to have been counteracted by the global economic downturn of 2008. Increased firearm availability was associated with corresponding increases in both firearm suicide and firearm homicide mortality. Restrictive firearm legislation should be an imperative part of a country's suicide prevention programme. Although firearm legislation reform may have long-lasting effects, societal changes may facilitate compensatory firearm acquisitions and thus counteract preventive efforts, calling in turn again for adapted counter-measures.

Influence of CRHR1 Polymorphisms and Childhood Abuse on Suicide Attempts in Affective Disorders: A GxE Approach.

Background: Previous studies have shown that the hypothalamus-pituitary-adrenal-axis (HPA-axis) is closely involved in the development of affective disorders. Given that early life events are also linked to dysregulation of the same system, there might be an association between childhood adversities and suicidal behavior in affective disorders, moderated by HPA-axis genes. We aimed to investigate a potential association between childhood trauma and previous suicide attempts in affective disorder patients, moderated by variants of the corticotropin-releasing hormone receptor 1 (CRHR1) gene. Methods: The current pilot study is part of an ongoing study on suicidal behavior in affective disorders (VieSAD). Two hundred fifty eight Caucasian affective disorder patients were assessed at the Department of Psychiatry and Psychotherapy of the Medical University Vienna and the Karl Landsteiner University for Health and Science. An assemblage of psychiatric interviews was performed (e.g., SCAN, HAMD, SBQ-R, CTQ) and DNA samples of peripheral blood cells were genotyped with TaqMan® SNP Genotyping Assays (rs7209436, rs4792887, rs110402, rs242924, and rs242939). Results: Neither genetic, nor haplotypic associations between CRHR1 polymorphisms and previous suicide attempts could be established for the present sample. Using a binary logistic regression model, significant gene-environment-interactions were found for the single nucleotide polymorphisms (SNPs) rs7209436 and rs110402, reflecting the impact of childhood trauma and CRHR1 polymorphisms on previous suicide attempts. Limitations: A larger sample size will be required to ultimately elucidate the link between childhood trauma and the HPA axis in suicidal behavior. Conclusion: This pilot study presents promising gene-environment-interaction findings in affective disorder patients with a history of suicide attempts.

The Impact of COMT and Childhood Maltreatment on Suicidal Behaviour in Affective Disorders.

The inconsistent findings on the association between COMT (catecholamine-O-methyl-transferase) and suicidal behaviour gave reason to choose a clear phenotype description of suicidal behaviour and take childhood maltreatment as environmental factor into account. The aim of this candidate-gene-association study was to eliminate heterogeneity within the sample by only recruiting affective disorder patients and find associations between COMT polymorphisms and defined suicidal phenotypes. In a sample of 258 affective disorder patients a detailed clinical assessment (e.g. CTQ, SCAN, HAMD, SBQ-R, VI-SURIAS, LPC) was performed. DNA of peripheral blood samples was genotyped using TaqMan® SNP Genotyping Assays. We observed that the haplotype GAT of rs737865, rs6269, rs4633 is significantly associated with suicide attempt (p = 0.003 [pcorr = 0.021]), and that there is a tendency towards self-harming behaviour (p = 0.02 [pcorr = 0.08]) and also NSSI (p = 0.03 [pcorr = 0.08]), though the p values did not resist multiple testing correction. The same effect we observed with the 4-marker slide window haplotype, GATA of rs737865, rs6269, rs4633, rs4680 (p = 0.009 [pcorr = 0.045]). The findings support an association between the COMT gene and suicidal behaviour phenotypes with and without childhood maltreatment as environmental factor.

Influence of Sex on Suicidal Phenotypes in Affective Disorder Patients with Traumatic Childhood Experiences.

OBJECTIVES: In the current study, we aimed to investigate the impact of childhood trauma on suicidal behaviour phenotypes in a group of patients with diagnosed affective disorder (unipolar or bipolar affective disorder). PATIENTS AND METHODS: Patients with and without a history of childhood abuse, measured by Childhood Trauma Questionnaire (CTQ), were assessed to explore risks for suicidal behaviour (including suicide attempt, self-harm and non-suicidal self-injury). The tested sample consisted of 258 patients (111 males and 147 females, in-patients and out-patients at the Department of Psychiatry and Psychotherapy, Medical University of Vienna and University Hospital Tulln, Lower Austria). Psychiatric diagnoses were derived from the SCAN (Schedules for Clinical Assessment in Neuropsychiatry) interview. In addition, patients were administered the Lifetime Parasuicidal Count (LPC), Suicidal Behaviour Questionnaire (SBQ-R), and Viennese Suicide Risk Assessment Scale (VISURIAS) questionnaires. RESULTS: In contrast to male suicide attempters, female suicide attempters showed both significantly higher total CTQ scores (p<0.001), and higher CTQ subscores (emotional, physical and sexual abuse, as well as emotional and physical neglect) in comparison to the non-suicidal control group. Besides, females with a history of self-harming behaviour (including suicidal intention) and Non-Suicidal-Self Injury (NSSI) had significantly higher CTQ total scores (p<0.001) than the control group. CONCLUSION: These findings suggest gender differences in suicidal behaviour after being exposed to childhood trauma.