Epigenetic changes in the CYP2D6 gene are related to severity of suicide attempt: A cross-sectional study of suicide attempters.

BACKGROUND: The ability to accurately estimate risk of suicide deaths on an individual level remains elusive. METHODS: 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. RESULTS: 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). LIMITATIONS: Genotyping of CYP2D6 was not performed and CpG-site associations to gene expression were not explored. CONCLUSIONS: 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.

Increased Methylation of Brain-Derived Neurotrophic Factor (BDNF) Is Related to Emotionally Unstable Personality Disorder and Severity of Suicide Attempt in Women.

Brain-derived neurotrophic factor (BDNF) has previously been associated with the pathogenesis of both emotionally unstable personality disorder (EUPD) and suicidal behavior. No study has yet investigated BDNF-associated epigenetic alterations in a group of severely impaired EUPD and suicidal patients. The discovery cohort consisted of 97 women with emotionally unstable personality disorder (EUPD) with at least two serious suicide attempts (SAs) and 32 healthy female controls. The genome-wide methylation pattern was measured by the Illumina EPIC BeadChip and analyzed by robust linear regression models to investigate mean BDNF methylation levels in a targeted analysis conditioned upon severity of suicide attempt. The validation cohort encompassed 60 female suicide attempters, stratified into low- (n = 45) and high-risk groups (n = 15) based on degree of intent-to-die and lethality of SA method, and occurrence of death-by-suicide at follow-up. Mean BDNF methylation levels exhibited increased methylation in relation to EUPD (p = 0.0159, percentage mean group difference ~3.8%). Similarly, this locus was confirmed as higher-methylated in an independent cohort of females with severe suicidal behavior (p = 0.0300). Results were independent of age and BMI. This is the first study to reveal emerging evidence of epigenetic dysregulation of BDNF with dependence on features known to confer increased risk of suicide deaths (lethality of suicide-attempt method and presence of EUPD diagnosis with history of recent SAs). Further studies investigating epigenetic and genetic effects of BDNF on severe suicidal behavior and EUPD are needed to further elucidate the role of epigenetic regulatory mechanisms and neurotrophic factors in relation to suicide and EUPD, and hold potential to result in novel treatment methods.

Accelerated epigenetic aging in women with emotionally unstable personality disorder and a history of suicide attempts.

Emotional unstable personality disorder (EUPD; previously borderline personality disorder, BPD) is associated with excess natural-cause mortality, comorbid medical conditions, poor health habits and stress related epigenomic alterations. Previous studies demonstrated that GrimAge - a state-of-the-art epigenetic age (EA) estimator - strongly predicts mortality risk and physiological dysregulation. Herein, we utilize the GrimAge algorithm to investigate whether women with EUPD and a history of recent suicide attempts exhibit EA acceleration (EAA) in comparison to healthy controls. Genome-wide methylation patterns were measured using the Illumina Infinum Methylation Epic BeadChip in whole blood from 97 EUPD patients and 32 healthy controls. The control group was significantly older (p < 0.0001) and reported lesser exposure to violent behavior in both youth and adulthood (p < 0.0001). Groups were otherwise comparable regarding gender, BMI, or tobacco usage (p > 0.05). EA estimator DNAmGrimAge exceeded chronological age by 8.8 and 2.3 years in the EUPD and control group, respectively. Similarly, EAA marker AgeAccelGrim was substantially higher in EUPD subjects when compared to controls, in both univariate and multivariate analyzes (p < 0.00001). Tobacco usage conferred substantial within-group effects on the EA-chronological age difference, i.e., 10.74 years (SD = 4.19) compared to 6.00 years (SD = 3.10) in the non-user EUPD group (p < 0.00001). Notably, past alcohol and substance abuse, use of psychotropic medications, global assessment of functioning, self-reported exposure to violent behavior in youth and adulthood, later completed suicide (N = 8) and age at first suicide attempt did not predict EAA in the EUPD group (p > 0.05). These results underscore the importance of addressing medical health conditions along with low-cost preventative interventions aimed at improving somatic health outcomes in EUPD, such as efforts to support cessation of tobacco use. The independency of GrimAge to other EA algorithms in this group of severely impaired EUPD patients, suggest it may have unique characteristics to evaluate risk of adverse health outcomes in context of psychiatric disorders.

Psychometric validity of the Montgomery and Åsberg Depression Rating Scale for Youths (MADRS-Y).

BACKGROUND: Because of all the serious consequences of major depressive disorder (MDD), it is important to screen for MDD in adolescents. The aim of this study was to test the psychometric properties of the newly developed self-report depression scale MADRS-Y for adolescents in a normative Swedish sample. METHODS: The study included 620 adolescents in the age range of 12-20 years old. The normative sample was randomly split into two equal parts, to perform principal component analysis (PCA) on sample one and confirmatory factor analysis (CFA) on sample two. We investigated the psychometrics. RESULTS: The result from the PCA suggested that all 12 potential items should be used, and the items loaded on the same construct of depression. The CFA supported the one-factor structure with good fit indices. Measurement invariance was confirmed, allowing interpretation regardless of gender or age differences. Reliability was good, α .89, for both samples separately. Test-retest reliability was good to excellent (intraclass correlation coefficients = .87 and .91). Evidence of convergent and discriminant validity was shown. CONCLUSIONS: The results in the current study suggest that the MADRS-Y is a brief, reliable, and valid self-report questionnaire of depressive symptoms for adolescents in the general population.

Accelerated epigenetic aging in suicide attempters uninfluenced by high intent-to-die and choice of lethal methods.

Suicide attempts (SA) are associated with excess non-suicidal mortality, putatively mediated in part by premature cellular senescence. Epigenetic age (EA) estimators of biological age have been previously demonstrated to strongly predict physiological dysregulation and mortality risk. Herein, we investigate if violent SA with high intent-to-die is predictive of epigenetics-derived estimates of biological aging. The genome-wide methylation pattern was measured using the Illumina Infinium Methylation EPIC BeadChip in whole blood of 88 suicide attempters. Subjects were stratified into two groups based on the putative risk of later committed suicide (low- [n = 58] and high-risk [n = 30]) in dependency of SA method (violent or non-violent) and/or intent-to-die (high/low). Estimators of intrinsic and extrinsic EA acceleration, one marker optimized to predict physiological dysregulation (DNAmPhenoAge/AgeAccelPheno) and one optimized to predict lifespan (DNAmGrimAge/AgeAccelGrim) were investigated for associations to severity of SA, by univariate and multivariate analyses. The study was adequately powered to detect differences of 2.2 years in AgeAccelGrim in relation to SA severity. Baseline DNAmGrimAge exceeded chronological age by 7.3 years on average across all samples, conferring a mean 24.6% increase in relation to actual age. No individual EA acceleration marker was differentiated by suicidal risk group (p > 0.1). Thus, SA per se but not severity of SA is related to EA, implicating that excess non-suicidal mortality in SA is unrelated to risk of committed suicide. Preventative healthcare efforts aimed at curtailing excess mortality after SA may benefit from acting equally powerful to recognize somatic comorbidities irrespective of the severity inherent in the act itself.

Plasma levels of S100B and neurofilament light chain protein in stress-related mental disorders.

The pathophysiological changes underlying stress-related mental disorders remain unclear. However, research suggests that alterations in astrocytes and neurons may be involved. This study examined potential peripheral markers of such alterations, including S100B and neurofilament light chain (NF-L). We compared plasma levels of S100B and NF-L in patients with chronic stress-induced exhaustion disorder (SED), patients with major depressive disorder (MDD), and healthy controls. We also investigated whether levels of S100B and NF-L correlated with levels of astrocyte-derived extracellular vesicles (EVs that indicate astrocyte activation or apoptosis) and with symptom severity. Only women had measurable levels of S100B. Women with SED had higher plasma levels of S100B than women with MDD (P < 0.001) and healthy controls (P < 0.001). Self-rated symptoms of cognitive failures were positively correlated with levels of S100B (rs = 0.434, P = 0.005) as were depressive symptoms (rs = 0.319, P < 0.001). Plasma levels of astrocyte-derived EVs were correlated with levels of S100B (rs = 0.464, P < 0.001). Plasma levels of NF-L did not differ between the groups and were not correlated with symptom severity or EV levels. Thus, long-term stress without sufficient recovery and SED may be associated with raised plasma levels of S100B, which may be evidence of pathophysiological changes in astrocytes. The findings also support the hypothesis that plasma levels of S100B are associated with cognitive dysfunction.

Impaired cognitive functioning in stress-induced exhaustion disorder: a new tablet-based assessment.

BACKGROUND: The adverse health effects of stress induced exhaustion disorder (SED) cause increasing concern in Western societies. This disorder is characterized by severe fatigue, decreased tolerance to further stress, and attention and memory lapses. Despite subjective complaints, individual cognitive deficits are not always detected in a clinical setting, which calls for the validation of more sensitive instruments. AIM: The objective of this study was to investigate if a short, tablet-based serial naming task, MapCog Spectra (MCS) could be used as a marker for cognitive problems in SED. PARTICIPANTS: The study comprised of 39 subjects (35 females, four males) with SED. Their mean age was 46,8 years (SD 10.1; range 30-60 yrs.). All participants were healthcare professionals, with a college or university degree, doctors, registered nurses, and psychologists. METHODS: The MCS was used to assess the number of aberrant pauses during serial naming of coloured geometrical shapes. The Coding, Matrix Reasoning, Digit Span, Symbol Search of the WAIS-IV, and RUFF 2&7 tests, were administered together with a short interview. RESULTS: Mean values were within normal reference limits for all tests, except for the MCS, which showed a significantly higher number of aberrant pauses (p < 0,001) in the SED group, compared to normal reference values. Although subjects performed within normal limits on the RUFF 2&7, a significant difference between individuals was found in the performance strategy of the participants. CONCLUSION: Here we report that subjects with SED have performance deficits on the MCS, in terms of aberrant pause times, despite average performance on WAIS-IV tests measuring inductive reasoning, processing speed, working memory, and attention. We also demonstrate that subjects use different strategies to overcome their problems. These findings add to the growing evidence of cognitive deficits in SED and that the MCS might aid neuropsychologists in disentangling cognitive markers, important to substantiate the subjective complaints of affected individuals.

Isoforms of soluble vascular endothelial growth factor in stress-related mental disorders: a cross-sectional study.

Vascular endothelial growth factor (VEGF) has been implicated in the pathophysiology of stress-related mental disorders. However, VEGF levels have seldom been compared across mental disorders and never by isoforms. Pathophysiological processes involving leakage of astrocyte-derived extracellular vesicles (EVs) across the blood-brain barrier could be associated with VEGF levels in patients with stress-related mental disorders. This cross-sectional study compared plasma levels of VEGF121, VEGF165, and VEGF121 + VEGF165 (VEGFtotal) in patients with stress-induced exhaustion disorder (SED) (n = 31), patients with major depressive disorder (MDD) (n = 31), and healthy controls (n = 61). It also analyzed the correlation between VEGF and astrocyte-derived EVs in plasma. An enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF121 and VEGF165 in citrate plasma, and flow cytometry was used to measure astrocyte-derived EVs in plasma. The mean concentration of soluble VEGF121 (sVEGF121) was significantly higher in patients with SED than healthy controls (P = 0.043). Mean sVEGF165 was significantly lower in patients with MDD than patients with SED (P = 0.004) or healthy controls (P = 0.037). Mean sVEGFtotal was significantly higher in patients with SED than in patients with MDD (P = 0.021) and also higher in patients with SED than healthy controls (P = 0.040). Levels of sVEGF121 were positively correlated with levels of astrocyte-derived EVs only in patients with SED (P = 0.0128). The same was true of levels of sVEGFtotal and astrocyte-derived EVs (P = 0.0046). Differing levels of VEGF isoforms may reflect different pathophysiological mechanisms in SED and MDD. Further research is needed to better understand the potential roles of VEGF isoforms and astrocyte-derived EVs in mental disorders.

Leakage of astrocyte-derived extracellular vesicles in stress-induced exhaustion disorder: a cross-sectional study.

Patients with stress-induced exhaustion disorder (SED) demonstrate cognitive dysfunction similar to patients with minor traumatic brain injury (TBI). We have previously detected elevated concentrations of astrocyte-derived extracellular vesicles (EVs) in patients with TBI. As such, we hypothesized that astrocyte-derived EVs could be higher in patients with SED than in patients with major depressive disorder (MDD) and healthy controls. Patients with SED (n = 31), MDD (n = 31), and healthy matched controls (n = 61) were included. Astrocyte-derived EVs (previously known as microparticles) were measured in plasma with flow cytometry and labeled against glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4). In addition, platelet EVs and their CD40 ligand expression were measured. Patients with SED had significantly higher concentrations of AQP4 and GFAP-positive EVs and EVs co-expressing AQP4/GFAP than patients with MDD and healthy controls. Patients with MDD had significantly higher concentrations of GFAP-positive EVs and EVs co-expressing AQP4/GFAP than healthy controls. Platelet EVs did not differ between groups. CD40 ligand expression was significantly higher in patients with SED and MDD than in controls. In conclusion, the present study suggests that patients with SED, and to some extent, patients with MDD, have increased leakage of astrocyte-derived EVs through the blood-brain barrier.

Exposure to Early Life Adversity and Interpersonal Functioning in Attempted Suicide.

BACKGROUND: Early life adversity (ELA) may lead to an increased risk for mental health problems including suicidal behavior. ELA alters biological stress systems that affect behavior and control within the individual that in turn will affect interpersonal behavior. Strained relations and interpersonal conflicts leading to rejection and isolation have been shown to be factors for suicidal behavior. Difficulties in interpersonal relationships are a common reason for seeking help in psychiatric care. In the present study, we examined relationship between different types of interpersonal problems and adverse childhood experiences in patients with a recent suicide attempt. METHOD: The study included 181 recent suicide attempters. We assessed early life adversity and specific interpersonal problems by using the Karolinska Interpersonal Violence Scale and the Inventory of Interpersonal problems respectively. RESULTS: Suicide attempters with high levels of early life adversity expressed a more socially avoidant, non-assertive, and exploitable personal style even after adjustment for comorbidities with personality disorder and substance use disorder. CONCLUSIONS: Patients with a recent suicide attempt with high levels of early life adversity tend to isolate themselves, of being introvert, and having difficulties to open up and confide in others. They report low self-confidence and self-esteem and problems with feeling and expressing anger. These behaviors complicate interaction with others and make establishment of solid relationships more difficult. In regards to detection of suicidal communication and treatment of suicidal patients, this may lead to misinterpretations and difficulties to fully benefit from treatment given or for professionals to provide the appropriate treatment. Clinicians should closely investigate the presence of early life adversity in suicidal patients and pay attention to their personal style and their difficulties in interpersonal exchange.

Comparison of exhaustion symptoms in patients with stress-related and other psychiatric and somatic diagnoses.

BACKGROUND: Several rating scales assessing stress-related symptoms of exhaustion have emerged in recent years. However, more knowledge is needed about the performance of these rating scales in patients with stress-related disorders as well as in other patient groups. With the recently developed Karolinska Exhaustion Disorder Scale (KEDS), we compared symptoms of exhaustion in different patient groups that were sorted according to diagnosis. METHODS: Patients were sampled consecutively from departments of occupational medicine (DOM) at three Danish hospitals. The total study group comprised 698 care-seeking patients (487 women). Patients with stress-related diagnoses (n = 217; the International Classification of Diseases [ICD]-10 code F43: reaction to severe stress and adjustment disorder) were compared to a diverse group of patients with a range of somatic diagnoses (n = 338) and to patients with other psychiatric diagnoses (n = 143), including subgroups with major depression disorder (n = 34; F32 and F33) and problems related to employment and unemployment (n = 99; Z56). The data were analysed using linear mixed models with the SPSS statistical program. RESULTS: The mean KEDS sum score in patients with stress-related diagnoses (29.3; SD = 8.0) was significantly higher than in patients with other psychiatric diagnoses (25.9; SD = 9.5) and in patients with somatic diagnoses (17.6; SD = 10.8). The subgroup with a major depression disorder had high mean KEDS sum scores (31.4, SD = 8.1), similar to patients with stress-related diagnoses, while the mean KEDS sum score in patients with problems related to employment and unemployment (Z56) was 23.5 (SD = 9.0). Young and old patients scored similarly on KEDS, but in patients with somatic diagnoses, female patients scored significantly higher than male patients. CONCLUSION: The symptoms of exhaustion measured with KEDS were higher in patients with stress-related diagnoses and major depression disorder than in patients with somatic diagnoses. The intermediate level of the symptoms of exhaustion that were associated with problems related to employment and unemployment, (Z56) compared to the lower level of the symptoms with somatic diagnoses, suggests that KEDS might be useful in detecting mild, prodromal states of exhaustion. This needs further investigation.

Role of rehabilitation in chronic stress-induced exhaustion disorder: A narrative review.

OBJECTIVE: An increase in numbers of cases of sick leave due to stress have been reported from several European countries during recent decades. Chronic stress-induced exhaustion disorder is associated with physiological and neurobiological perturbations that may contribute to cognitive problems and long-term exhaustion. Rehabilitation of patients with chronic stress-induced exhaustion disorder is therefore challenging. This narrative review summarizes the evidence regarding the effectiveness of different interventions for the rehabilitation of patients with chronic stress-induced exhaustion disorder. METHODS: Both structured and unstructured searches of research studies and reports were performed in order to find knowledge sources. The structured search had 2 predefined inclusion criteria: (i) chronic stress-induced exhaustion/clinical burnout/severe burnout/stress-induced exhaustion; and (ii) rehabil-itation with improvement of symptoms and/or return to work as outcomes. RESULTS: Cognitive behavioural interventions and multimodal interventions seem to reduce symptoms. Workplace interventions, either work-focused cognitive behavioural or workplace dialogue, seem to improve return to work. Sleep is important for both symptom improvement and return to work, and interventions for improving sleep might therefore be important. For improvement of cognitive function, which is a main complaint among patients with chronic stress-induced exhaustion disorder, aerobic and cognitive training may have some effect. CONCLUSION: In summary, the few studies of high-quality that examine interventions for rehabilitation of chronic stress-induced exhaustion disorder show only marginal effects. Thus, it is important to prevent the onset of chronic stress-induced exhaustion disorder.

As good as it gets: an empirical study on mentally-ill patients and their stay at a general hospital in Sweden, 1896-1905.

General hospital care and treatment of mentally ill patients in a Swedish town was studied in records for 503 patients, 1896-1905. Restraint was extremely rare; 65% left the hospital as healthy or improved. Non-psychotic and alcoholic patients spent fewer days in hospital than patients with psychosis or dementia. There was no evidence of a social status bias. For 36% of the patients a certificate for mental hospital care was issued, with additional information. The cause of illness was stated as unknown for 42% of these patients; adverse circumstances were recorded for 18%. Heredity for mental illness was found in 50% of the patients, particularly in those with mania. Patients with a higher social status were underrepresented.

Exposure to interpersonal violence and risk of post-traumatic stress disorder among women with borderline personality disorder.

BACKGROUND: This study aims to determine the validity of the Karolinska Interpersonal Violence Scale (KIVS), as a screening tool for PTSD, among women with borderline personality disorder (BPD) and severe suicidal behavior. METHOD: 106 women with BPD and at least two suicide attempts were assessed with the KIVS for exposure to interpersonal violence as a child and as an adult. The screening ability of the KIVS for the diagnosis of PTSD was analyzed using receiver operating characteristic curve analysis. RESULTS: PTSD diagnosis was valid for 61 (58%) women with BPD. The KIVS - exposure of lifetime interpersonal violence, displayed fair accuracy of predicting diagnosis of PTSD (area under the curve 0.79, confidence interval [0.71, 0.88]) and performed well (sensitivity 0.90 and specificity 0.62), with a cut-off score of 4 (range 0-10). Poly-traumatization was not significantly related to PTSD diagnosis as compared to single traumatization, whereas sexual victimization was significantly more prevalent in women with PTSD diagnosis, as compared to other types of traumatic events. CONCLUSION: A score of 4 or more on the KIVS - exposure to interpersonal lifetime violence presents well as a screening instrument for risk of PTSD, among women with BPD.

Mental illness in Sweden (1896-1905) reflected through case records from a local general hospital.

Mental illness in a hospital in a medium-sized town in Sweden was studied. Consecutive case records from 1896 to 1905, and also from 2011, were selected. In the historical sample, neurasthenia was the most common diagnosis, followed by affective disorders and alcohol abuse. ICD-10 diagnoses corresponded well with the historical diagnoses. Melancholia resembled modern criteria for depression. Mania, insania simplex and paranoia indicated more severe illness. Abuse was more common among men and hysteria among women. Those with a medical certificate for mental hospital care were very ill and showed no gender difference. There were no diagnoses for abuse, but 17% had a high level of alcohol consumption. The pattern of signs and symptoms displayed by patients does not appear to change with time.

Platelet monoamine oxidase activity and interpersonal violence in male suicide attempters.

Low platelet monoamine oxidase B (MAO-B) activity, proxy of low central serotonergic functions, has been shown to correlate with criminal behavior in adolescents that come from an unfavorable psychosocial environment but not in adolescents from good conditions, indicating a link between environment, MAO-B activity and aggressive behavior. The purpose of this study was to examine the association between MAO-B activity and lifetime interpersonal violence in suicide attempters. The study included a total of 28 suicide attempters (18 men and 10 women). Assessments of childhood exposure to and expressed interpersonal violence during childhood and as an adult were carried out with the Karolinska Interpersonal Violence Scale (KIVS). Platelet MAO-B activity was measured with 2-phenylethylamine (b-PEA) as substrate. Broken down by gender, the correlations between platelet MAO-B activity and both exposure scores to interpersonal violence as a child and expressed lifetime interpersonal violence were significant in male suicide attempters (r = -0.61, p = 0.035; r = -0.84, p = 0.0005), but not in women. Our finding of significant associations between interpersonal violence and low MAO-B activity need to be replicated in other cohorts of suicide attempters.

Clinical severity as a moderator of outcome in psychodynamic and dialectical behavior therapies for borderline personality disorder.

The aim of the present study was to assess the effect of initial level of psychiatric severity on treatment outcome in psychodynamic therapy and dialectical behavior therapy (DBT) for borderline personality disorder (BPD). It was hypothesized that DBT would lead to better outcome for patients with high psychiatric severity, whereas dynamic treatment would lead to better outcome for patients with lower psychiatric severity. Data from the 5th-year follow-up of the Stockholm City Council's and the Karolinska Institute's Psychotherapy Project were used in the present study. A total of 106 female patients diagnosed with BPD with at least 2 past suicide attempts were randomized into object-relational psychotherapy (ORP; based on transference-focused psychotherapy), DBT, and treatment as usual. Patients' baseline global severity index was used as a moderator. Global Assessment of Functioning (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [American Psychiatric Association, 1994]) was used to examine outcome. There was a significant 3-way interaction of Time × Treatment × Severity. Post hoc analyses suggested that patients with lower levels of severity had significantly better outcomes in object-relational psychotherapy. For patients with higher severity, the 3 treatments resulted in similar outcomes in terms of level of functioning. Outcome of treatment for BPD might differ significantly for patients depending on their initial levels of overall psychiatric severity. If our findings are replicated for patients with low severity and supported for a high-severity sample, psychiatric severity can be used as a low-cost and effective tool to match patients with BPD to optimal treatments. (PsycINFO Database Record