Parent of origin effect and allelic expression imbalance of the serotonin transporter in bipolar disorder and suicidal behaviour

Suicide and suicidal behaviour are a major health concern worldwide particularly in patients with mood disorders. Family, adoption and twin studies show that genetics influences suicidal behaviour. The serotonin transporter (5HTT) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since 5HTT binding is decreased in the brain of suicide completers. Because the effect of genomic imprinting in the 5HTT gene on suicidal behaviour has not been investigated, we analysed the parent-of-origin effect (POE) of four 5HTT markers and the differential expression of the 5HTT G2651T (rs1042173) alleles in suicide attempters affected by bipolar disorder. We performed a family based association study and ETDT/QTDT analyses of the rs25531, HTTLPR, VNTR-2 and G2651T polymorphisms in 312 nuclear families with at least one subject affected by bipolar disorder. The main outcomes investigated in this study are bipolar disorder diagnosis, suicide attempts, suicidal behaviour severity and age at onset of bipolar disorder. We also compared the allele-specific mRNA levels in lymphoblastoid cells from 13 bipolar suicide attempters and 8 bipolar non-suicide attempters. Allele 2651T was transmitted significantly more often to bipolar patients (P = 0.042). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of T/G-specific mRNA expression between bipolar attempters and non-attempters. These data do not support a role for differential allelic expression of 5HTT for suicidal behaviour in bipolar disorder. Small sample size and the fact that RNA was obtained from lymphoblastoid cell lines were some of the limitations of this study.     

Suicide attempters with Borderline Personality Disorder show differential orbitofrontal and parietal recruitment when reflecting on aversive memories

Suicidal behavior and difficulty regulating emotions are hallmarks of Borderline Personality Disorder (BPD). This study examined neural links between emotion regulation and suicide risk in BPD. 60 individuals with BPD (all female, mean age = 28.9 years), 46 of whom had attempted suicide, completed a fMRI task involving recalling aversive personal memories. Distance trials assessed the ability to regulate emotion by recalling memories from a third-person, objective viewpoint. Immerse trials assessed emotional reactivity and involved recalling memories from a first-person perspective. Behaviorally, both groups reported less negative affect on Distance as compared to Immerse trials. Neurally, two sets of findings were obtained. The first reflected differences between attempters and non-attempters. When immersing and distancing, attempters showed elevated recruitment of lateral orbitofrontal cortex, a brain region implicated in using negative cues to guide behavior. When distancing, attempters showed diminished recruitment of the precuneus, a region implicated in memory recall and perspective taking. The second set of findings related to individual differences in regulation success – the degree to which individuals used distancing to reduce negative affect. Here, we observed that attempters who successfully regulated exhibited precuneus recruitment that was more similar to non-attempters. These data provide insight into mechanisms underlying suicide attempts in BPD. Future work may examine if these findings generalize to other diagnoses and also whether prior findings in BPD differ across attempters and non-attempters.     

Cross-sectional assessment of diet quality in individuals with a lifetime history of attempted suicide

Increased evidence indicates an association between psychiatric disorders and dietary pattern. The objective of this study is to describe the differences in food consumption between suicide attempters and non-attempters. We analyzed the dietary information retrospectively collected from 6803 adults, aged 17 to 39 years, who also completed a mental disorder diagnostic interview as a part of the Third National Health and Nutrition Examination Survey, 1988–1994. The Healthy Eating Index score was used to measure the degree of compliance with the national diet guidelines. In men, attempters (n = 92) had a high odds of low consumption of vegetables (OR = 2.47, 95%CI = 1.19, 5.15). In women, attempters (n = 275) had a high odds of insufficient fruit consumption (OR = 2.36, 95%CI = 1.15, 4.85). For both men and women, the component scores for meat were lower in non-attempters compared with attempters. On a scale of zero (no serving) to 10 (meeting the serving recommendations), the scores were 6.74 (SE: 0.39) and 7.76 (0.10), respectively, for attempters and non-attempters among men, and 5.81 (0.33) and 6.43 (0.07), respectively, for attempters and non-attempters among women. It was further observed that female attempters ate significantly less fish and seafood. These results were obtained after adjustment for various factors, including the history of medical and psychiatric illnesses. The data suggest that fruits, vegetables and meat were significantly under-consumed in adults who had ever attempted suicide. The deleterious contribution of insufficient consumption of these foods to physical and psychiatric status in attempters merits investigation. In clinical practice, psychiatrists should pay more attention to what patients eat.     

ABCB1 gene polymorphisms and violent suicide attempt among survivors

IntroductionThose suicide attempters that choose violent methods dramatically diminish the possibility of survival. Completed suicide using violent means, which is common among first-time suicide attempters, was recently found to be more likely among T allele carriers in the three most common ABCB1 SNPs, encoding for P-gp. Thus, this study examined, for the first time, whether these ABCB1 SNPs were associated with the use of violent means among survivors of a suicide attempt.Material and methodsSuicide attempters (n = 578, 87.4% women; of whom 16.6% committed a violent intent) were genotyped for exonic SNPs in the ABCB1 (C1236T, G2677T/A, C3435T). The relations of the three genotypes and of the TTT haplotype with the use of a violent suicide method were evaluated separately. The impact of confounds on these variables was controlled.ResultsA higher frequency (p = 0.02) of suicide attempters using violent methods was found among those carrying the ABCB1 haplotype (1236TT-2677TT-3435TT). Since gender and number of previous suicide attempts were identified as confounds, the relation was tested in the subset of women who were first-time attempters or second- and more-time attempters. The ABCB1 haplotype increased the risk more than three times in those women attempting a violent suicide for the first time (OR = 3.6; CI95%: 1.08–12.09; p = 0.04).DiscussionThe ABCB1 haplotype (1236TT-2677TT-3435TT) was related to the use of a violent suicide attempt method. Genotyping for these three ABCB1 SNPs may be helpful to detect people at risk of first suicide intents using violent methods.     

Temperament and character of suicide attempters

Temperamental features are strongly associated with suicidal behaviors both in general population and clinical samples. In the present study we considered the association between personality traits, measured by Temperament and Character Inventory (TCI), and suicidal behavior. We analyzed five samples: a German control sample of 1148 healthy individuals; 144 German suicide attempters affected by Mood (n=101), Schizophrenia spectrum (n=20) and Borderline Personality (n=23) Disorders; 46 Italian suicide attempters affected by Mood Disorders (UP=15; BP=31); 76 German non-suicide Mood Disorder patients; 147 Italian non-suicide Mood Disorder patients. Suicide attempters showed higher scores in Harm Avoidance (HA) and lower scores in Self-Directedness (SD) and Cooperativeness (C), when compared to controls. Nevertheless, comparing the German and the Italian suicide attempter groups with the non-suicide Mood Disorder patient groups, no differences were detected. This could be due to the effect of Mood Disorder on personality. In conclusion, the present study reveals the difficulty to disentangle the personality profile of suicide attempters from their psychopathology. Those findings may be useful for cautions in further dissecting this complex phenotype.     

Adolescent self-injurers: Comparing non-ideators,suicide ideators,and suicide attempters

Adolescent non-suicidal self-injury (NSSI) and suicidality are serious health concerns; however, factors that contribute to the transition from NSSI to suicide ideation and suicide attempts are unclear. To address this gap, we investigated whether demographic characteristics, child maltreatment, and psychiatric factors are associated with the level suicidality among adolescents with a history of self-injury. Participants were three groups of adolescent inpatient self-injurers (n = 397, 317 female), aged 13–18 years (M = 15.44, SD = 1.36): (a) non-ideators (n = 96; no current suicide ideation and no lifetime suicide attempts), (b) suicide ideators (n = 149; current ideation and no lifetime attempts), and (c) suicide attempters (n = 152; current ideation and at least one lifetime attempt). Participants completed interviews assessing psychiatric diagnoses, suicidality, and NSSI characteristics, as well as questionnaires on childhood trauma, psychiatric symptoms, and risky behavior engagement. Depression severity was associated with greater odds being a suicide ideator (p < 0.001, OR = 1.04) and an attempter (p < 0.001, OR = 1.05) compared to a non-ideator. Suicide attempters used more NSSI methods and reported greater risky behavior engagement than non-ideators (p = 0.03, OR = 1.29 and p = 0.03, OR = 1.06, respectively) and ideators (p = 0.015, OR = 1.25 and p = 0.04, OR = 1.05, respectively); attempters used more severe NSSI methods (e.g., burning). Our results identify a wide range of risk markers for increasing lethality in a sample at high risk for suicide mortality; future research is needed to refine risk assessments for adolescent self-injurers and determine the clinical utility of using risk markers for screening and intervention.     

Are structural brain abnormalities associated with suicidal behavior in patients with psychotic disorders?

Suicide represents a major health problem world-wide. Nevertheless, the understanding of the neurobiological underpinnings of suicidal behavior remains far from complete. We compared suicide attempters to non-attempters, and high vs. low lethality attempters, to identify brain regions associated with suicidal behavior in patients with psychotic disorders. 489 individuals with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder I and 262 healthy controls enrolled in the B-SNIP study were studied. Groups were compared by attempt history and the highest medical lethality of previous suicide attempts. 97 patients had a history of a high lethality attempt, 51 of a low lethality attempt and 341 had no attempt history. Gray matter volumes were obtained from 3T structural MRI scans using FreeSurfer. ANCOVAs were used to examine differences between groups, followed by Hochberg multiple comparison correction. Compared to non-attempters, attempters had significantly less gray matter volume in bilateral inferior temporal and superior temporal cortices, left superior parietal, thalamus and supramarginal regions, right insula, superior frontal and rostral middle frontal regions. Among attempters, a history of high lethality attempts was associated with significantly smaller volumes in the left lingual gyrus and right cuneus. Compared to non-attempters, low lethality attempters had significant decreases in the left supramarginal gyrus, thalamus and the right insula. Structural brain abnormalities may distinguish suicide attempters from non-attempters and high from low lethality attempters among individuals with psychotic disorders. Regions in which differences were observed are part of neural circuitries that mediate inhibition, impulsivity and emotion, visceral, visual and auditory perception.     

Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder

Background

Inflammation has been linked to depression and suicide risk. One inflammatory process that has been minimally investigated in this regard is cytokine-stimulated production of kynurenine (KYN) from tryptophan (TRP). Recent data suggest that KYN increases in cerebrospinal fluid (CSF) are associated with depressive symptoms secondary to immune activation. KYN may alter dopaminergic and glutamatergic tone, thereby contributing to increased arousal, agitation and impulsivity - important risk factors in suicide. We hypothesized that patients with major depressive disorder (MDD) and a history of suicide attempt would have higher levels of KYN than depressed nonattempters, who in turn would have higher levels than healthy volunteers.

Methods

Plasma KYN, TRP, and neopterin were assayed by high performance liquid chromatography in three groups: healthy volunteers (n = 31) and patients with MDD with (n = 14) and without (n = 16) history of suicide attempt. Analysis of variance tested for group differences in KYN levels.

Results

KYN levels differed across groups (F = 4.03, df = (2,58), and p = 0.023): a priori planned contrasts showed that KYN was higher in the MDD suicide attempter subgroup compared with MDD non-attempters (t = 2.105, df = 58, and p = 0.040), who did not differ from healthy volunteers (t = 0.418, df = 58, and p = 0.677). In post hoc testing, KYN but not TRP was associated with attempt status, and only suicide attempters exhibited a positive correlation of the cytokine activation marker neopterin with the KYN:TRP ratio, suggesting that KYN production may be influenced by inflammatory processes among suicide attempters.

Conclusion

These preliminary results suggest that KYN and related molecular pathways may be implicated in the pathophysiology of suicidal behavior.     

Risk factors of future suicide in suicide attempters – A comparison between suicides and matched survivors

The objective of this study was to find risk factors for suicide by looking for clinical and care/treatment consumption differences between 15 hospitalized suicide attempters, who later committed suicide (“completers”), and 15 suicide attempters who did not (“non-completers”), matched according to sex, age and principal diagnosis. Completers had significantly more often attempted suicide after the index admission. After index, completers had received more psychiatric care and treatment than non-completers. Comorbidity was common in both groups of patients. Personality disorders according to the DSM III-R, axis II, Cluster B, however, tended to be more common in the completer group. Increased comorbidity over time could also be seen to a larger extent in completers. In spite of the matching of principal diagnosis, completers tended to have higher Montgomery–Åsberg Depression Rating Scale ratings than non-completers. They also had significantly higher Suicide Assessment Scale (SUAS) scores. From this study, it is apparent that suicide attempters at risk of future suicide have major and multiple psychiatric problems, which cause difficulties in the care and treatment.     

Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: analysis of suicidality in major psychosis

Suicide is an act deliberately initiated and performed by a person with full knowledge that a fatal outcome is probable. The serotonin 2A (5-HT2A) receptor gene has been implicated in the pathogenesis of suicidal behaviour by a genetic association between the 5-HT2A T102C silent polymorphism and suicidality in patients with mood disorders and schizophrenia. However, a recent meta-analysis failed to confirm this association. We developed an improved quantitative assay for the measurement of allele-specific methylation of the 5-HT2A gene, and found that the methylation of the C allele in the pre-frontal cortex of heterozygous suicide victims (n = 10) was not significantly different in comparison with the non-suicide group (n = 10) (p = 0.084). We also analyzed methylation of the C allele in white blood cell DNA from bipolar and schizophrenic attempters and found a significant difference in the schizophrenic attempters (p = 0.00013) but not in the bipolar attempters (p = 0.616).Because the 5-HT2A gene is subject to imprinting, the parent-of-origin may affect inheritance of suicidal behaviour. Thus, we examined the parental origin of specific alleles for genetic association in a genetic family-based sample of major psychoses in which information on suicidal behaviour was available. This result suggests that methylation of the 102C allele does not influence completed suicide.     

Attempted suicide predicts suicide risk in schizophrenia spectrum psychosis

Background: People with schizophrenia have an increased risk of suicide and attempted suicide is suggested to be an important risk factor. Aim: Our objective was to assess the cumulative survival, predictive values and odds ratios of attempted suicide for suicide in a long-term cohort of patients with schizophrenia spectrum psychosis with and without previous attempted suicide. Method: Inpatients (n=224) hospitalized with schizophrenia spectrum psychosis were followed for a mean of 25 years. All patients were followed up for causes of death. Information on suicide attempt before the end of the observation period was retrieved from medical records. Results: Eight percent died by suicide during the follow-up. Eighteen percent of suicide attempters died by suicide. Two percent of non-attempters died by suicide. There was a strong association between previous suicide attempt and suicide in men and women. Odds ratio for attempters vs. non-attempters was 10. Suicide risk was almost three times higher in male than female suicide attempters. Conclusion: Previous attempted suicide is an important risk factor for suicide in both men and women with schizophrenia spectrum psychosis, particularly in male suicide attempters. The suicide risk remains high over a long period. Continuous assessment of risk factors and appropriate treatment are crucial for this patient group to prevent suicide.     

Suicide risk among individuals with sleep disturbances in Japan: a case–control psychological autopsy study

ObjectiveThis case–control psychological autopsy study aimed to explore a relationship between sleep disturbances and suicide among Japanese, as well as determine the importance and usability of screening for sleep disturbances in suicide prevention.MethodsA semi-structured interview was conducted with the close family members of 49 adult suicide completers and 145 gender-, age-, and residential municipality-matched living controls. The survey included sections on demographics, sleep disturbances, and mental disorders. Conditional logistic regression analyses were performed to compare sleep disturbance prevalence between the two groups.ResultsA significantly higher prevalence of sleep disturbances was found among the suicide group (75.5%) compared to the controls (11.0%) (odds ratio [OR]=21.6, p < 0.001). The association remained significant after adjusting for mental disorders (OR = 12.7, p < 0.001). The population attributable risk percent of suicide associated with sleep disturbances and mental disorders was estimated to be 56.4% and 35.3%, respectively.ConclusionsThe study confirmed that sleep disturbances are an important risk factor of suicide, independent of mental disorders. Sleep disturbances accounted for a greater proportion of suicide cases than did mental disorders in the Japanese population given the higher prevalence, and could thus be considered an important target in suicide prevention in Japan.     

Association between C-reactive protein and suicidal behavior in an adult inpatient population

ObjectivesTo examine the relationship of inflammation and suicidal behavior in hospitalized adult psychiatric patients.MethodWe retrospectively examined serum high sensitivity C-reactive protein (hsCRP) levels in inpatients at a tertiary-level university hospital (N = 184). The inpatients comprised three cohorts: 1) patients admitted following a suicide attempt, 2) patients with suicidal ideation, and 3) inpatient psychiatric controls. Additionally, we gathered demographic data, clinical data, smoking status, white blood cell count, and fasting lipid panel.ResultsAs CRP level increased, the probability of patients belonging to the suicide attempt group increased as compared to both the probabilities of being in inpatient psychiatric control and or suicide ideation groups [OR = 2.09, CI = (1.29, 3.38) and OR = 1.75, CI = (1.15, 2.66) respectively]. We also observed a significant effect of depression in that depressed patients were more likely to have a suicide attempt when compared to patients with no depression or with mania [OR = 10.38, CI = (1.97, 54.70)].ConclusionsThere seems to be an inflammation gradient, measured by CRP levels, from recent suicide attempters, suicidal ideators and psychiatric controls. We replicated the association between a pro-inflammatory state and suicidal behavior in a sample of “real world” severely ill psychiatric inpatients.     

Differences in cholesterol and metabolic syndrome between bipolar disorder men with and without suicide attempts

Patient with mental illnesses such as schizophrenia and bipolar disorder have an increased prevalence of metabolic syndrome (MetS) and its components compared to general population. Among psychiatric disorders, bipolar disorder ranks highest in suicidality with a relative risk ratio of completed suicide of about 25 compared to the general population. Regarding the biological hypotheses of suicidality, low blood cholesterol level has been extensively explored, although results are still conflicting. The aim of this study was to investigate whether there were differences in the serum cholesterol levels in hospitalized bipolar disorder men patients with history of suicide attempts (N = 20) and without suicide attempts (N = 20). Additionally, we investigated if there were differences in the prevalence of MetS according to NCEP ATP-III criteria in these two groups of patients. Results of the study indicated significantly lower serum cholesterol levels (p = 0.013) and triglyceride levels (p = 0.047), in the bipolar disorder men with suicide attempts in comparison to bipolar disorder men without suicide attempts. The overall prevalence of MetS was 11/40 (27.5%). On this particular sample it was higher in the non-attempters 8/20 (40.0%) than in attempters 3/20 (15.0%) bipolar men group, but without statistical significance. Lower concentrations of serum cholesterol might be useful biological markers of suicidality in men with bipolar disorder.     

Regional Brain Glucose Uptake Distinguishes Suicide Attempters from Non-Attempters in Major Depression

This study compared regional cerebral metabolic rates of glucose (rCMRglu) determined by [¹⁸F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in suicide attempters and non-attempters. Medication-free patients with major depression (n = 29) had FDG-PET after single-blind administration of placebo (day 1) and fenfluramine (day 2). Suicide attempt history was obtained before scanning and at assessments over 2 subsequent years. Statistical parametric mapping evaluated associations between attempt status and rCMRglu, controlling for age. The study included 13 patients with and 16 without a history of suicide attempt within 2 years before or after scanning. After placebo, rCMRglu in attempters was lower in right dorsolateral prefrontal regions and higher in ventromedial regions than in non-attempters. After fenfluramine, relatively hypometabolic areas enlarged, and no hypermetabolic areas were detected. Distinct rCMRglu patterns may be serotonin-sensitive biomarkers of suicide risk.     

Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide

There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neuronal/glial glutamate transporters was determined by qPCR in postmortem prefrontal cortex. The anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) were selected from young MDD patients who had committed suicide (MDD-S; n = 17), from MDD patients who died of non-suicide related causes (MDD-NS; n = 7) and from matched control subjects (n = 12). We also compared elderly depressed patients who had not committed suicide (n = 14) with matched control subjects (n = 22). We found that neuronal located components (EAAT3, EAAT4, ASCT1, SNAT1, SNAT2) of the glutamate-glutamine cycle were increased in the ACC while the astroglia located components (EAAT1, EAAT2, GLUL) were decreased in the DLPFC of MDD-S patients. In contrast, most of the components in the cycle were increased in the DLPFC of MDD-NS patients. In conclusion, the glutamate-glutamine cycle - and thus glutamine transmission - is differentially affected in depressed suicide patients and depressed non-suicide patients in an area specific way.     

Proteomic analysis of the CSF in unmedicated patients with major depressive disorder reveals alterations in suicide attempters

Abstract This is the first report on proteomic analysis of the cerebrospinal fluid (CSF) in unmedicated suicide attempters and non-attempters with major depressive disorder.Two-dimensional (2D) gel electrophoresis revealed that suicide attempters differed from non-attempters in one protein with an approximate molecular weight of 33 kD and an isoelectric point of 5.2. Proteomic analysis of the CSF is a promising non hypothesis-driven screening method for the detection of new candidate genes in neurobiological suicide research.