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Suicide in the elderly is an underestimated and complex issue that has mainly been explored in sociological, clinical and psychological perspectives. Suicide in non-elderly adults has been associated with diverse neurobiological alterations that may shed light on future predictive markers and more efficient preventative interventions. The aim of this paper was to review studies specifically investigating the neurobiology of elderly suicidal behaviour. We performed a systematic English and French Medline and EMBASE search until 2013. Contrary to literature about the non-elderly, we found a paucity of studies investigating the biomarkers of suicidal risk in elderly adults. Main findings were found in the neurocognitive domain. Studies generally supported the existence of cognitive deficits, notably decision-making impairment and reduced cognitive inhibition, in patients with a history of suicidal act compared to patients without such history. However, replications are needed to confirm findings. Due to several limitations including the small number of available studies, frequent lack of replication and small sample size, no firm conclusions can be drawn. The authors encourage further investigations in this field as insight in the neurobiology of these complex behaviors may limit clichés about end of life and aging, as well as improve future prevention of suicide in the elderly. [ABSTRACT FROM AUTHOR]

BackgroundCognitive inhibition deficits have previously been found in suicide attempters. This study examined the neural basis for these deficits in depressed patients with and without a history of suicidal behavior.MethodFunctional magnetic resonance imaging was used to measure brain activation during the Go/No-Go response inhibition task in 25 unmedicated and depressed middle-aged suicide attempters, 22 unmedicated depressed patient controls with no personal or family history of suicidal behavior, and 27 healthy controls. Whole-brain analyses were conducted with SPM12.ResultsSuicide attempters exhibited an elevated number of commission errors relative to both control groups. However, suicide attempters did not differ from patient controls in terms of brain activation for any contrast. Analyses showed a significant association between depression and brain activation in the left inferior frontal gyrus and medial thalamus during Go v. No-Go, and in the bilateral parietal cortex and left orbitofrontal cortex during No-Go v. baseline. These regions were correlated with psychological pain, suicidal ideation and global functioning. There was no association between brain activation and personal histories of suicidal act.ConclusionsOur study suggests that deficits in cognitive inhibition, in relation to the inferior frontal gyrus, thalamus, orbitofrontal cortex and parietal cortex, are related to the depressive state and not specifically to suicide vulnerability. We hypothesize that state-related deficits may add to trait-like cognitive impairments to facilitate suicidal acts. These different types of cognitive impairments may necessitate different therapeutic strategies for the prevention of suicide. [ABSTRACT FROM PUBLISHER]

Highlights: [•] Childhood maltreatment is among the strongest predictors of psychiatric pathology. [•] DNA methylation mediates life-long neurobiological effects of childhood maltreatment. [•] Animal and human studies reveal conserved adaptations to early-life adversity. [ABSTRACT FROM AUTHOR]

Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[(11)C]methyl-L-tryptophan (11C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized 11C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH2). In all, 46 healthy controls had PET 11C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH2 gene and its 5′ upstream region. Several TPH2 SNPs were associated with lower normalized blood-to-brain clearance of 11C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5′ upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC. [ABSTRACT FROM AUTHOR]

Abstract: Despite strong evidence for a role of biological factors in the etiology and pathology of suicide, the study of traditional neurotransmitter systems has been able to explain only a small proportion of the neurobiology of what is now recognized as a complex genetic trait. The use of microarrays to simultaneously examine the expression levels of thousands of gene transcripts has vastly expanded our capacity to detect the involvement of additional genes and pathways in suicidality, and has opened many new avenues for the discovery of the biological underpinnings of suicide completion. This review examines microarray studies which have been used to identify genes displaying altered expression in suicide completers, and highlights some of the important methodological considerations and metabolic pathways which have emerged from these analyses. [Copyright &y& Elsevier]

The polyamine pathway has an essential role in many cellular functions and has been implicated in several pathological conditions. Accumulating evidence suggests that the polyamine system also plays a role in the etiology and pathology of mental disorders. Alterations in the expression and activity of polyamine metabolic enzymes, as well as changes in the levels of the individual polyamines, have been observed in multiple conditions, including schizophrenia, mood disorders, anxiety and suicidal behaviour. Additionally, these components have been found to be altered by various psychiatric treatments. Further, the polyamines and their precursors have demonstrated both antidepressant and anxiolytic effects. Overall, findings to date suggest that the polyamine pathway represents an important frontier for the development of neuropharmacological treatments. [ABSTRACT FROM AUTHOR]

Suicide ranks among the main causes of death in most Western countries and is, thus, an important public health problem. Over the last few years, it has been increasingly recognized that people who attempt or commit suicide have a certain individual predisposition, partly resulting from certain personality traits, in particular, impulsive-aggressive behaviors. The evidence suggests that impulsive-aggressive traits are part of a developmental cascade that increases suicide risk among a subset of suicides. These personality traits may also mediate familial transmission of suicidal behavior, defining a behavioral endophenotype that could be useful in molecular genetic studies of suicide. On the other hand, not all suicides are associated with impulsive-aggressive behaviors. There is a need to better understand the mechanisms mediating suicide among individuals with no history of impulsive-aggressive behaviors. [ABSTRACT FROM AUTHOR]

Evaluates the mapping susceptibility genes for bipolar disorder (BD) using a pharmacogenetic approach based on excellent response to lithium. Administration of a complete genome scan using markers; Evaluation of response to lithium with an average follow-up of 12 years; Role of the locus on chromosome 15q14 in the etiology of BD.

Investigates the link between tryptophan hydroxylase (TPH) and suicide completion. Association between the gene that codes TPH and suicidal behavior; Genotyping of a sample of suicide completers; Public-health problem of suicidal behavior; Evidence that subjects with suicidal behavior have reduced serotonergic neuro-transmission.

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stablize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a γ-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 ± 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (χ² = 8.09; empirical P=0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD=1.45; empirical P=0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is impli- cated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined. [ABSTRACT FROM AUTHOR]

The author discusses the sensitivity and specificity of suicide risk assessment of the patient wherein most individuals who commit suicide contact health care professionals. It examines the use of Convergent Functional Genomic in evaluating blood mitochondrial RNA biomarkers of suicidality. The author highlights the influence of polyamines into the neurotransmitter systems including glutamate, nitric oxide and agmatine.

Suicide and related behaviors are complex phenomena associated with different risk factors. While most individuals who display suicidal behavior do not have a history of early-life adversity, a significant minority does. In this symposium, Dr. Turecki will discuss results from his laboratory suggesting that early-life adversity increases risk of suicide by altering methylation patterns in discrete genetic loci. Stable gene expression resulting from these altered methylation patterns are likely to influence the development of stable emotional and behavioral phenotypes that, in turn, increase suicide risk. He will discuss recent data suggesting that these mechanisms are at play in the regulation of aggressive behavior. [ABSTRACT FROM AUTHOR]

Focuses on the role of polyglutamine in bipolar disorder. Response to lithium; Use of the repeat expansion detection technique.

Chronic stressors, during developmental sensitive periods and beyond, contribute to the risk of developing psychiatric conditions, including major depressive disorder (MDD). Epigenetic mechanisms including DNA methylation and histone modifications, at key stress response and neurotrophin genes, are increasingly implicated in mediating this risk. Although the exact mechanisms through which stressful environmental stimuli alter the epigenome are still unclear, research from the learning and memory fields indicates that epigenomic marks can be altered, at least in part, through calcium‐dependent signaling cascades in direct response to neuronal activity. In this review, we highlight key findings from the stress, MDD, and learning and memory fields to propose a model where stress regulates downstream cellular functioning through activity‐dependent epigenetic changes. Furthermore, we suggest that both typical and novel antidepressant treatments may exert positive influence through similar, activity‐dependent pathways. [ABSTRACT FROM AUTHOR]

It is unclear whether cognitive skill deficits during childhood carry risk for suicide attempt or mortality later in adulthood at the population level. We conducted a systematic review and meta-analysis of population-based studies examining the association between childhood cognitive skills and adult suicidal behavior, namely attempt and mortality. We systematically searched databases for articles then extracted study characteristics and estimates on the association between childhood cognitive skills (i.e., IQ or school performance at age ≤ 18 years) and later suicide attempt and mortality. Random-effect meta-analysis was used to quantify this association across all studies with available data. Twenty-three studies met the inclusion criteria and suggest an association between lower childhood cognitive skills and increased risk of suicidal behavior. Meta-analysis of the adjusted estimates from 11 studies (N = 2,830,191) found the association to be small but statistically significant. Heterogeneity was significant but moderate, and results were unlikely to be influenced by publication bias. In subgroup analyses, associations were significant only for males. No difference in effect size was found between suicide attempt and suicide mortality. Cognitive skills were measured with different cognitive subtests. Heterogeneity in the age of cognitive skills assessment. Meta-regression and subgroup analyses were based on a relatively low number of studies. Individuals with lower cognitive skills in childhood have a greater risk of suicidal behavior in adulthood, especially males. Although the association was small, interventions improving cognitive skills may yield large effects on suicide prevention at the population level if the association is causal. • Meta-analysis suggests an association between lower childhood cognitive skills and increased risk of suicidal behavior. • Meta-analysis of the adjusted estimates found that this association was small but statistically significant. • Found that heterogeneity was significant but moderate, and results were unlikely to be influenced by publication bias. • In subgroup analyses, associations were significant only for males. • No difference in effect size was found between suicide attempt and suicide mortality. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Little is known about differential suicide profiles across the life trajectory. This study introduces the life-course method in suicide research with the aim of refining the longitudinal and cumulative assessment of psychosocial factors by quantifying accumulation of burden over time in order to delineate distinctive pathways of completed suicide.MethodThe psychological autopsy method was used to obtain third-party information on consecutive suicides. Life-history calendar analysis served to arrive at an adversity score per 5-year segment that was then cluster-analysed and correlated to define victim profiles. RESULTS: Two distinct life trajectories emerged: (1) individuals who experienced childhood traumas, developmental adversity and little protection were more likely to present concurrent psychiatric and Axis II disorders; and (2) individuals who experienced less adversity but seemed more reactive to later major difficulties. CONCLUSIONS: The life calendar approach presented here in suicide research adds to the identification of life events, distal and recent, previously associated with suicide. It also quantifies the burden of adversity over the life course, defining two distinct profiles that could benefit from distinct targeted preventive intervention. [ABSTRACT FROM AUTHOR]

Objective: Involvement of personality traits in susceptibility to suicidality has been the subject of research since the 1950s. Because of the diversity of conceptual and methodological approaches, the extent of their independent contribution has been difficult to establish. Here, we review conceptual background and empirical evidence investigating roles of traits in suicidal behaviors. Method: We selected original studies published in English in MEDLINE and PsycINFO databases, focusing on suicidal ideation, suicide attempts, or suicide completions, and using standardized personality measures. Results: Most studies focused on investigating risk for suicide attempts. Hopelessness, neuroticism, and extroversion hold the most promise in relation to risk screening across all three suicidal behaviors. More research is needed regarding aggression, impulsivity, anger, irritability, hostility, and anxiety. Conclusion: Selected personality traits may be useful markers of suicide risk. Future research needs to establish their contributions in relation to environmental and genetic variation in different gender, age, and ethnocultural groups. [ABSTRACT FROM AUTHOR]

The different serotonin (5-HT) receptors, including the serotonin transporter (5-HTT), are excellent candidate genes for suicide and suicidal behavior, and thus, they have been investigated in a large number of allelic association studies. The individual results of these studies have been inconsistent and definite conclusions are difficult to establish. A reliable method for assessing individual studies and generating combined results is provided by systematic reviews using meta-analytical techniques. In this study, we carried out a systematic review of studies investigating 5-HT receptors and the 5-HTT in suicidal behavior. Studies were identified by means of MEDLINE database searches and by scanning reference lists. More than 190 articles were reviewed and 26 met the inclusion criteria. In all, 14 studies investigated six different 5-HT receptor loci and 12 studies investigated the 5-HTT promoter 44 bp insertion/ deletion polymorphism. Two specific meta-analyses were carried out, pooling studies investigating the 5-HT2A 102 T/C and the 5-HTT promoter loci that included, respectively, a total of 1599 and 2539 subjects. The combined evidence was significant for association with the 5-HTT locus (Mantel-Haenszel weighted odds ratio (M-H[sub w] OR) = 1.17 C1:1.04-1.32, P = 0.009), but not for the 5-HT2A 102 TlC variant (M-H[sub w] OR) = 1.09 CI: 0.93-1.27, P = 0.319). The 5-HTT result was robust and remained significant following sensitivity analysis, suggesting that 5-HTT may play a role in the predisposition to suicide. [ABSTRACT FROM AUTHOR]

The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR = 1.14, CI: 1.03-1.26, P = 0.015 for the promoter locus (N = 3467) and Mantel-Haenszel Weighted odds ratio OR = 1.18, CI: 1.05-1.32, P = 0.004 for the VNTR locus (N = 3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between... [ABSTRACT FROM AUTHOR]

This study examined mother-child interactions and DNA methylation of the oxytocin receptor (OXTR) gene in the child, in relation with controlling-attachment behaviors at early preschool age. Maternal interactive behaviors were coded using the Emotional Availability Scales, and child attachment behaviors were assessed with the Separation-Reunion procedure and coded with the Preschool Attachment Rating Scales. DNA methylation data were captured from exon 3 of the OXTR. Results indicated that lower maternal sensitivity was associated with more controlling-caregiving behaviors, and that less maternal structuring was associated with more controlling-punitive behaviors. Hypomethylation of the OXTR gene was associated with greater maternal structuring behaviors, and with more child controlling-caregiving behaviors. The moderating role of the OXTR gene was examined in the association between interactive behaviors and child controlling behaviors, but no interaction effect was found. These results suggest that maternal interactive behaviors and OXTR methylation are independently associated with child controlling attachment. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in relation to histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers.

• During pregnancy and postpartum, sleep is associated with vasopressin methylation. • Psychosocial stress may mediate the relationship between stress and vasopressin. • Sleep during perinatal period is worse in women with history of psychosocial stress. The relationship between disturbed sleep and stress is well-documented. Sleep disorders and stress are highly prevalent during the perinatal period, and both are known to contribute to a number of adverse maternal and foetal outcomes. Arginine vasopressin (AVP) is a hormone and a neuropeptide that is involved in stress response, social bonding and circadian regulation of the sleep-wake cycle. Whether the AVP system is involved in regulation of stress response and sleep quality in the context of the perinatal mental health is currently unknown. The objective of the present study was to assess the relationship between levels of cumulative and ongoing psychosocial risk, levels of disordered sleep and AVP methylation in a community sample of pregnant and postpartum women. A sample of 316 participants completed a battery of questionnaires during the second trimester of pregnancy (PN2, 12–14 weeks gestation), third trimester (PN3, 32–34 weeks gestation), and at 7–9 weeks postpartum (PP). Disordered sleep was measured using the Sleep Symptom Checklist at PN2, PN3 and PP; cumulative psychosocial risk was assessed with the Antenatal Risk Questionnaire (ANRQ) at PN2; salivary DNA was collected at the follow-up (FU, 2.9 years postpartum); and % methylation were calculated for AVP and for two of the three AVP receptor genes (AVPR1a and AVPR1b). Women were separated into high (HighPR) and low (LowPR) psychosocial risk groups, based on their scores on the ANRQ. Women in the HighPR group had significantly worse sleep disturbances during PN2 (p <.001) and PN3 (p <.001), but not at PP (p =.146) than women in the LowPR group. In HighPR participants only, methylation of AVP at intron 1 negatively correlated with sleep disturbances at PN2 (r s =-.390, p =.001), PN3 (r s =-.384, p =.002) and at PP (r s = -.269, p =.032). There was no association between sleep disturbances and AVPR1a or AVPR1b methylation, or between sleep disturbances and any of the AVP methylation for the LowPR group. Lastly, cumulative psychosocial stress was a moderator for the relationship between AVP intron 1 methylation and disordered sleep at PN2 (p <.001, adjusted R2 =.105), PN2 (p <.001, adjusted R2 =.088) and PP (p =.003, adjusted R2 =.064). Our results suggest that cumulative psychosocial stress exacerbates sleep disorders in pregnant women, and that salivary DNA methylation patterns of the AVP gene may be seen as a marker of biological predisposition to stress and sleep reactivity during the perinatal period. Further research is needed to establish causal links between AVP methylation, sleep and stress. [ABSTRACT FROM AUTHOR]

Background: Major depressive episode (MDE) has been associated with cognitive functioning alteration and hypovitaminosis D (hypoVD), but the relationship between hypoVD, depression, and cognition is not well understood. We aimed to compare patient with MDE with or without hypoVD in regard of cognitive functioning.Methods: 91 patients (38.5 years old, 65.9% female) with MDE were included in a cross-sectional study and were evaluated with a complete cognitive battery. None of the participants were medicated at the time of the inclusion. Serum 25-hydroxyvitamin D was measured using LC-MS/MS method, and hypovitaminosis was defined as 25OHD < 50nmol/L. Covariates were gender, season of dosage, first MDE onset, age, body mass index and depression severity RESULTS: Patients with hypoVD demonstrated a higher stroop intereference index time underscoring that means low cognitive inhibition ability. Mutiple logistic regression confirmed that hypoVD was significantly associated with high stroop interference time index after controlling by gender, season of dosage, first MDE onset, age, body mass index and depression severity.Conclusion: Our results suggest that patient with MDE having hypoVD may be more prone to cognitive impairment. [ABSTRACT FROM AUTHOR]

Background Suicidal behavior results from a complex interplay between stressful events and vulnerability factors, including neurocognitive alterations. Deficits in cognitive inhibition have previously been found in suicide attempters. Here, we examined the neural basis of these deficits in patients at-risk for suicide. Methods Functional magnetic resonance imaging was used to measure brain activation in 25 middle-aged depressed yet non-medicated suicide attempters (SA), 22 depressed patient controls with no personal or first-degree family history of suicidal behaviour (PC), and 27 healthy controls (HC) during the Go/No-Go response inhibition task. Results In whole brain exploration of No-Go versus Go inhibition contrast, SA show elevated activities in posterior cingulate gyrus compared to HC (Cluster FWE = 0.022). Further exploration of each individual condition against baseline (e.g. No-Go versus Baseline or Go versus Baseline) suggest this regional differences are mainly due to No-Go baseline comparison within each groups: namely, HC show a large reduced activities during No-Go blocks while PC and SA failed to show similar reductions comparing to baseline. Conclusion SA showed unique differentiated patterns of neural activity during Go-No-Go response inhibition differ from HC and PC mostly involving posterior cingulate gyrus. These findings indicate that suicide attempts during middle-aged are associated with abnormal activity in response inhibition neural circuitry. [ABSTRACT FROM AUTHOR]

Background The heritability of suicide is well established. Transmission of risk appears to follow traits more than disorders like depression. In the present project, we aimed at investigating the potential for transmission of cognitive deficits previously observed in suicide attempters, specifically impaired decision-making and cognitive control. Methods Seventeen healthy first-degree relatives of suicide completers with no personal history of suicidal act were compared to 18 first-degree relatives of individuals with major depressive disorder but no family history of suicidal act, and 19 healthy controls. Decision-making was assessed with the Iowa Gambling Task, and cognitive control with the Stroop Task, the Hayling Sentence Completion Test, and the Trail-Making Test. Results Both suicide and depressed relatives showed lower gambling task net scores than healthy controls. However, there were trends toward lower learning abilities in suicide than depressed relatives (interaction: p = 0.07), with more risky choices at the end of the test. Suicide relatives also showed a higher number of self-corrected errors relative to the total number of errors in the Stroop colour test compared to both control groups, with no difference in interference scores. There was no group-difference for any other cognitive tests. Conclusion Our findings suggest that decision-making impairment may be found in healthy relatives of suicides and represent a cognitive endophenotype of suicidal behaviour. Normal cognitive control (or self-corrected deficits) may protect relatives against suicidal acts. Impairments in value-based and control processes may, therefore, be part of the suicide vulnerability and represent potential targets of preventative interventions. [ABSTRACT FROM AUTHOR]

Astrocytes are glial cells specific to the central nervous system and involved in numerous brain functions, including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1 and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared with 17 matched controls using methylation binding domain-2 (MBD2) sequencing followed by validation with high-resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, those found in GRIK2 (glutamate receptor, ionotropic kainate 2) and BEGAIN (brain-enriched guanylate kinase-associated protein) were most significant and also showed significant correlations with gene expression. Cell-sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN. Functional cell assays revealed promoter and enhancer-like properties in this region that were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known Encyclopedia of DNA elements (ENCODE)-identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype. [ABSTRACT FROM AUTHOR]

Background. Suicidal behavior is frequently associated with a history of childhood abuse yet it remains unclear precisely how early life adversity may increase suicide risk later in life. As such, our aim was to examine whether lifetime trajectories of disruptiveness and anxiousness trait dysregulation explain the association between childhood adversity and suicidal behavior; and moreover, to test the potential modifying effects of mental disorders on these associations. Method. A sample of 1776 individuals from a prospective school-based cohort followed longitudinally for over 22 years was investigated. We tested the influence of disruptiveness and anxiousness trajectories from age 6 to 12 years on the association between childhood adversity (i.e. sexual and physical abuse) and history of suicide attempts (SA) using logistic regression models. Both adolescent externalizing and internalizing Axis I disorders and gender were tested as potential modifiers of these associations. Results. Four distinct longitudinal trajectories were identified for both disruptiveness and anxiousness. The high disruptiveness trajectory accounted for the association between childhood adversity and SA, but only for females. The high anxiousness trajectory also explained the association between adversity and SA; however, in this case it was not sex but mental disorders that influenced the potency of the mediating effect. More specifically, anxiousness fully explained the effect of adversity on SA in the presence of externalizing disorders, whereas in the absence of these disorders, this effect was significantly attenuated. Conclusions. This study provides evidence that both disruptiveness and anxiousness play an important role in explaining the relationship between childhood adversity and SA. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cognitive deficits, in relation to ventral and dorsal prefrontal cortex dysfunctions, have been associated with a higher risk of suicidal acts in young adult patients. Although a public health concern, much less is known about the neurocognitive basis of suicidal behavior in elderly. Here, we aimed at assessing alterations in cognitive inhibition, a suspected major mechanism of the suicidal vulnerability, in suicidal depressed elderly. Methods: We compared 20 currently depressed patients, aged 65 and older who recently attempted suicide to 20 elderly subjects with a current depression but no personal history of suicide attempt and 20 elderly controls. Using an extensive neuropsychological battery, we particularly examined different aspects of cognitive inhibition: access to relevant information (using the Reading with distraction task), suppression of no longer relevant information (Trail Making Test, Rule Shift Cards), and restraint of cognitive resources to relevant information (Stroop test, Hayling Sentence Completion test, Go/No-Go). Results: After adjustment for age, intensity of depression, Mini-Mental State Examination score and speed of information processing, suicidal depressed elderly showed significant impairments in all 3 domains of cognitive inhibition in comparison to both control groups. Limitations: Our results need replication in a larger sample size. Conclusions: Our study suggests that the inability to inhibit neutral information access to working memory, restrain and delete irrelevant information may impair the patient''s capacity to respond adequately to stressful situations subsequently leading to an increased risk of suicidal behavior during late-life depression. Interventions may be developed to specifically target cognitive impairment in the prevention of suicide in depressed elderly. [Copyright &y& Elsevier]

Abstract: Alzheimer′s Disease (AD) is the most common cause of dementia in elderly people. The presynaptic terminal is an important site of pathological changes in AD, leading to synaptic loss in specific brain regions, such as in the cortex and hippocampus. In this study, we investigated synaptosomal-associated protein, 25-kDa (SNAP25) mRNA levels and promoter DNA methylation in post mortem brain tissues (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood leukocytes of young, healthy elderly and AD patients. mRNA quantification was performed by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) using the ΔΔC T method and promoter DNA methylation was quantified by mass spectrometry using the Sequenom EpiTYPER platform. We observed a significant decrease in SNAP25 expression in AD across all the three brain regions in relation to the healthy elderly subjects, suggesting impairment in synaptic function. The changes in the auditory cortex reflected those observed in the hippocampus and entorhinal cortex, the primary areas affected in AD. However, no AD-associated differences in SNAP25 promoter DNA methylation were observed suggesting that other mechanisms may be involved in mediating the observed gene expression changes. [Copyright &y& Elsevier]

Suicide completion rates are significantly higher in males than females in most societies. Although gender differences in suicide rates have been partially explained by environmental and behavioral factors, it is possible that genetic factors, through differential expression between genders, may also help explain gender moderation of suicide risk. This study investigated X-linked genes in suicide completers using a two-step strategy. We first took advantage of the genetic structure of the French-Canadian population and genotyped 722 unrelated French-Canadian male subjects, of whom 333 were suicide completers and 389 were non-suicide controls, using a panel of 37 microsatellite markers spanning the entire X chromosome. Nine haplotype windows and several individual markers were associated with suicide. Significant results aggregated primarily in two regions, one in the long arm and another in the short arm of chromosome X, limited by markers DXS8051 and DXS8102, and DXS1001 and DXS8106, respectively. The second stage of the study investigated differential brain expression of genes mapping to associated regions in Brodmann areas 8/9, 11, 44 and 46, in an independent sample of suicide completers and controls. Six genes within these regions, Rho GTPase-activating protein 6, adaptor-related protein complex 1 sigma 2 subunit, glycoprotein M6B, ribosomal protein S6 kinase 90 kDa polypeptide 3, spermidine/spermine N(1)-acetyltransferase 1 and THO complex 2, were found to be differentially expressed in suicide completers. [ABSTRACT FROM AUTHOR]

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene–environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene–gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene–environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts and mood disorders may also have partially independent etiological pathways. To identify where these pathways diverge, we need to understand the differential, phenotype-specific gene–environment interactions such as the ones observed in the present study, using suitably powered samples. [ABSTRACT FROM AUTHOR]

Abstract: Several lines of evidence suggest that suicide may have, in part, a genetic predisposition. In this study, we identified a family with high rates of suicidal behavior and assessed brain gene expression levels in the proband. A neuronally-expressed solute carrier for glutamine (Sodium-coupled neutral amino acid transporter 1 (SNAT1), also known as solute carrier family 38, member 1 (SLC38A1)) was identified as severely decreased across all brain regions. Follow-up analysis by semi-quantitative polymerase chain reaction (qPCR) and Western blot confirmed the reduction of SNAT1. We categorized the SNAT1 gene in human brain, cloned the gene promoter and assessed in silico the expression pattern of SNAT1 in >25 tissues from human. Complete DNA sequencing of the SNAT1 gene was performed in the family and 276 controls. The family was homozygous for rare alleles which suggests a possible association between low expression of SNAT1 and suicidal behavior. [Copyright &y& Elsevier]

BACKGROUND: Suicide is the most serious consequence of major depressive disorder (MDD). Although the anterior cingulate cortex (ACC; Brodmann area [BA] 24) has been increasingly investigated for its role in the etiology of MDD, there is surprisingly very little information about the possible implication of this brain region in suicide. We hypothesized that changes in BA24 cell densities occur in depressed individuals who commit suicide, possibly reflecting an altered state of cortical plasticity that is thought to occur in depression. METHODS: We investigated cell densities and sizes in BA24 among suicide completers and matched sudden-death controls. We examined a 1-cm(3) tissue block from BA24a of the supracallosal ACC in 26 human postmortem brain specimens (13 depressed individuals who committed suicide and 13 controls). We assessed neuronal and glial cell densities as well as neuronal soma sizes in the upper and lower cortical layers using optical fractionator and nucleator 3-dimensional stereological probes. RESULTS: Glial densities, neuronal densities and soma sizes measured in BA24a did not differ significantly between controls and suicide completers. Secondary analyses showed a significant and robust increase in glial cell densities in BA24a of alcohol-dependent depressed suicide completers compared with depressed suicide completers who were not alcohol-dependent (38%) and, to a lesser extent, controls (30%). LIMITATIONS: Our study, conducted with tissue samples from men only, made use of a nonspecific stain that does not distinguish between neuronal or glial cell subtypes. Furthermore, the quantitative analysis concerned upper and lower cortical contours rather than individual cortical layers. CONCLUSION: Our results indicate that in BA24, glial density, neuronal density and soma size are not affected in MDD and suicide. They also suggest that alcohol dependence has an important influence on glial densities in this key limbic structure. [ABSTRACT FROM AUTHOR]

The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides=16, nondepressed suicides=8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.Molecular Psychiatry (2009) 14, 175–189; doi:10.1038/sj.mp.4002110; published online 16 October 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD. METHODS: Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein. RESULTS: BDNF levels were 36% lower in lymphoblasts from patients with BD (n = 12), compared with matched control participants (n = 13), and 55% lower when compared with their unaffected relatives (n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment. CONCLUSION: Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested. [ABSTRACT FROM AUTHOR]

BACKGROUND: It is unclear whether the association between impulsive-aggressive behaviours and suicide exists across different ages.MethodVia psychological autopsy, we examined a total of 645 subjects aged 11-87 years who died by suicide. Proxy-based interviews were conducted using the SCID-I & SCID-II or K-SADS interviews and a series of behavioural and personality-trait assessments. Secondarily, 246 living controls were similarly assessed. RESULTS: Higher levels of impulsivity, lifetime history of aggression, and novelty seeking were associated with younger age of death by suicide, while increasing levels of harm avoidance were associated with increasing age of suicide. This effect was observed after accounting for age-related psychopathology (current and lifetime depressive disorders, lifetime anxiety disorders, current and lifetime substance abuse disorders, psychotic disorders and cluster B personality disorders). Age effects were not due to the characteristics of informants, and such effects were not observed among living controls. When directly controlling for major psychopathology, the interaction between age, levels of impulsivity, aggression and novelty seeking predicted suicide status while controlling for the independent contributions of age and these traits. CONCLUSIONS: Higher levels of impulsive-aggressive traits play a greater role in suicide occurring among younger individuals, with decreasing importance with increasing age. [ABSTRACT FROM AUTHOR]

BackgroundIt is unclear whether the association between impulsive-aggressive behaviours and suicide exists across different ages.MethodVia psychological autopsy, we examined a total of 645 subjects aged 11?87 years who died by suicide. Proxy-based interviews were conducted using the SCID-I & SCID-II or K-SADS interviews and a series of behavioural and personality-trait assessments. Secondarily, 246 living controls were similarly assessed.ResultsHigher levels of impulsivity, lifetime history of aggression, and novelty seeking were associated with younger age of death by suicide, while increasing levels of harm avoidance were associated with increasing age of suicide. This effect was observed after accounting for age-related psychopathology (current and lifetime depressive disorders, lifetime anxiety disorders, current and lifetime substance abuse disorders, psychotic disorders and cluster B personality disorders). Age effects were not due to the characteristics of informants, and such effects were not observed among living controls. When directly controlling for major psychopathology, the interaction between age, levels of impulsivity, aggression and novelty seeking predicted suicide status while controlling for the independent contributions of age and these traits.ConclusionsHigher levels of impulsive-aggressive traits play a greater role in suicide occurring among younger individuals, with decreasing importance with increasing age. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Identification of factors that distinguish between ideators who act on their suicidal thoughts from those who do not is an important clinical and research objective.MethodWe examined correlates of suicide attempts in suicidal ideators, members of a French-Canadian, school-based cohort. Suicidal thoughts were evaluated in adolescence and early adulthood in the total sample of suicidal ideators, who were then stratified into subgroups consisting of persistent ideators, male ideators and female ideators. RESULTS: In addition to persistent suicidal ideas [odds ratios (ORs) 2.1-2.8], Axis I psychopathology, female gender and childhood sexual abuse (CSA) were the most consistent correlates of suicide attempts. Externalizing disorders were significant contributors in persistent ideators [drug misuse: OR 2.8, 95% confidence interval (CI) 1.1-6.9] and in male ideators in particular (disruptive disorders: OR 5.9, 95% CI 2.2-16.0). In women, psychiatric co-morbidity also had a significant effect (OR 1.6, 95% CI 1.1-2.1). CSA was of relevance in both women (OR 1.2, 95% CI 1.1-1.4) and persistent ideators (OR 1.3, 95% CI 1.1-1.5). Personality traits showed gender-specific contribution with affective instability (OR 1.1, 95% CI 1.01-1.1) and anxiousness (OR 1.3, 95% CI 1.1-1.7) contributing in men and disruptive aggression (OR 1.1, 95% CI 1.03-1.3) in women. CONCLUSIONS: Correlates of suicide attempts in suicidal ideators vary as a function of the persistence of suicidal ideas and gender. This heterogeneity across subgroups of suicidal ideators may be attributed, at least in part, to differences between the sexes, early environmental adversity, maladaptive personality, and psychiatric symptoms. Further exploration and continued prospective follow-up is necessary to examine these possibilities. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Suicidal behaviors in young individuals represent an important public health problem. Understanding their natural history and relationships would therefore be of clinical and research value. In this study, we examined the natural histories of several suicidal behaviors and investigated two conceptual models of suicidality (dimensional and categorical) in the context of adolescent and adult-onset suicide attempts.MethodParticipants were members of a prospectively studied, representative, population-based school cohort followed since age 6 (n=3017) through mid-adolescence (n=1715) to their early twenties (n=1684). Outcome measures included suicidal ideation, attempts and completions. RESULTS: Approximately one in 500 individuals died by suicide. About 33% had suicidal ideas and 9.3% made at least one suicide attempt. Over half (4.9%) of the self-reported attempters made their first attempt before age 18. With the exception of current suicidal ideas, non-fatal suicidal behaviors were more prevalent in females. In general, parental and cross-sectional self-reports underestimated suicidality rates. Aikaike (AIC) and Bayesian (BIC) information criteria suggested the ordinal model, and dimensional conceptualization of suicide attempts of different onset age, to be more optimal than its multinomial/categorical counterpart (ordinal: AIC 567.55, BIC 635.67; multinomial: AIC 616.59, BIC 723.83). Both models, nevertheless, identified five common factors of relevance to suicidal diathesis: gender, disruptive disorders, childhood anxiousness and abuse, and suicidal thoughts. CONCLUSIONS: Non-fatal suicidal behaviors in adolescents and young adults are more common than suggested by cross-sectional studies and parental reports. The dimensional model may be more useful in explaining the relationship of suicide attempts of different age of onset. [ABSTRACT FROM AUTHOR]

The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides=18, non depressed suicides=8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.Molecular Psychiatry (2007) 12, 640–655; doi:10.1038/sj.mp.4001969; published online 13 March 2007 [ABSTRACT FROM AUTHOR]

Objective: Despite an increased risk for suicide among individuals diagnosed with psychotic disorders, risk factors for completed suicide remain largely unexamined in this population. Using a case-control design, this study aimed to investigate clinical and behavioural risk factors for suicide completion in schizophrenia and other chronic psychotic disorders.Method: A total of 81 psychotic subjects were examined; of these, 45 died by suicide. Proxy-based interviews with, on average, 2 informants were conducted using the SCID I and II interviews and a series of personality trait assessments.Results: Psychotic individuals at risk for suicide are most readily identified by the presence of depressive disorders NOS, moderate to severe psychotic symptoms and a family history of suicidal behaviour. They also exhibited fewer negative symptoms, had more comorbid diagnoses and, contrary to findings in other populations, we found that cluster A and C personality trait symptoms seem to have protective effects against suicide in schizophrenics and other chronic psychotic suicides.Conclusions: Our study suggests that behavioural mediators of suicide risk, such as impulsive-aggressive behaviours, do not play a role in schizophrenic and chronic psychotic suicide. This is contrary to findings in other diagnostic groups, thus implying heterogeneity in predisposing mechanisms involved in suicide. [ABSTRACT FROM AUTHOR]

BACKGROUND: Adults in their twenties appear to be at high risk for suicidal behaviors (SBs) and there is substantial evidence suggesting that certain personality traits may increase individual vulnerability to suicide. METHOD: We investigated relationships of personality traits with two SBs in a cohort (n=1140) of 21- to 24-year-old adults, representative of the general population of Quebec. Subjects were assessed using a series of structured diagnostic and personality trait questionnaires. Multivariate logistic regression analyses were employed to identify personality trait correlates of suicide-attempt history and serious suicidal ideation in the context of other known risk factors, such as psychopathology and experiences of childhood sexual and physical abuse. RESULTS: Traits of conduct problems contributed to both suicide attempts [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06] and suicidal ideation (OR 1.04, 95% CI 1.02-1.07), while identity problems (OR 1.10, 95% CI 1.07-1.13) and gender-moderated impulsivity contributed exclusively to suicidal ideation. CONCLUSIONS: Personality traits may make independent contributions to current suicidal ideation and previous suicide attempts in certain subgroups of suicidal individuals. In order to further explore their utility as markers of suicide risk and targets of intervention further investigation in clinical samples and other cultural and age groups is necessary. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a major psychiatric condition that commonly requires prophylactic and episodic treatment. There is important variability in the therapeutic response and side-effect profiles to currently available pharmacological agents. Pharmacogenetics have provided new hopes to develop more efficient treatment strategies tailored to the individual patient's needs. This review assesses nonsystematically studies using pharmacogenetic strategies in BD. Most of these studies have focused on patients selected according to lithium response, and more recently, a growing number of studies have been investigating genetic factors in mixed samples of patients classified according to response to antidepressant treatment. Although previous clinical and family studies support the use of pharmacogenetic strategies both to increase phenotype homogeneity as well as to identify genetic factors that may mediate response to treatment, most molecular studies carried out to date are still preliminary and in need of external validation. A major problem has been comparability between studies, in part, because of differences in the criteria used to define response. More attention should be paid to standardize the criteria for drug response definition.The Pharmacogenomics Journal (2004) 4, 161-170. doi:10.1038/sj.tpj.6500245 Published online 13 April 2004 [ABSTRACT FROM AUTHOR]

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better longterm outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional5 and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome. [ABSTRACT FROM AUTHOR]

Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamineexpanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab lC2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]