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Hispanic immigration in the USA and its effect on many areas of US society are of great relevance to health care, public health, mental health, and medical and social sciences. In this report, we review and discuss pertinent literature on causes, procedures, and eventual outcomes of Hispanic migration waves throughout the last four decades. Hispanic immigrants do not constitute a monolithic group, despite the clear predominance of Mexican and Mexican-American segments. Common features of Hispanic immigrants include a younger average age, higher presence of married households, and lower educational levels than the overall US population. Differences within the Hispanic immigrant population are present in naturalisation figures, English language fluency, occupational and income status, health insurance coverage, and sense of accomplishment in the host society. We examine most of these aspects in the context of the so-called Hispanic paradox, presented as both a cause and a result of a heavily discussed acculturative process. We investigate prevalence and other data on depression, anxiety, substance abuse, and psychotic syndromes, with emphasis on the need to do further neurobiological, epigenetic, and sociocultural research in the Hispanic population., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Self-rated depression and hopelessness severity are predictors of suicide attempt in major depression. This study evaluated whether: (1) greater self-rated distress relative to severity of clinician-rated depression is a trait; (2) that trait is familial; and (3) that trait is linked to familial transmission of suicidal behavior. A total of 285 mood disorder probands and 457 offspring were assessed twice, at least 1 year apart. Family and subject intra-class correlations for self-report depression and hopelessness, controlling for clinician-rated depression severity, were computed. Mixed general linear models determined offspring-proband correlations. Within-individual intra-class correlation (ICC) for depression-hopelessness was 37.8% (bootstrap 95% CI: 31.0-46.3%). Parent-offspring ICC was 10.7% (bootstrap 95% CI: 3.5-17.8%). Suicide attempt concordant parent-offspring correlation for subjective depression was positive, but negative for attempter parent and nonattempter offspring (p = .0213 for slope interaction). Pessimism was greater in proband or offspring attempters than proband or offspring nonattempters (p < .05). Self-reported hopelessness is partly trait-dependent, and there is modest familial transmission of self-reported depression linked to suicidal behavior that may partly explain familial transmission of suicidal behavior.

Objective: To examine the psychometric properties of a Spanish version of the C-SSRS (Sp-CSSRS)., Method: Data are from a naturalistic, cross-sectional, multicentre, validation study, including 467 psychiatric outpatients, 242 of whom had a history of suicide attempt. The study measures were: C-SSRS; the Hamilton Depression Rating Scale (HDRS); the Beck Suicide Intent Scale; the Medical Damage Scale., Results: Construct validity: Pearson coefficient between the C-SSRS severity (C-Sev) and intensity (C-Int) of ideation subscale scores was 0.44 (P<.000) for the total sample. Likewise, Pearson coefficient between C-Sev score and HDRS item 3 was 0.56 (P<.000). For the sub-sample of patients with suicide attempt, significant Pearson correlations were found between the C-Sev and the Beck Suicide Intent Scale scores (r=0.22; P=.001). Discriminant validity: Significant differences were found in C-Sev and C-Int scores between patients with and without suicide attempt (P<.000). The C-Sev score discriminated between patients based on HDRS item 3 (P<.009). Sensitivity to change: Linear regression showed that a one-unit decrease in HDRS item 3 corresponded to a decrease of 5.08 units in the C-Sev score (P=.141). A one-unit change in HDRS item 3 corresponded to a change of 13.51 on the C-Int assessments (P=.007). Cronbach's alpha was 0.53 for C-Int. The principal component analysis identified 2 components that explain 55.66% of the total variance (C-Int)., Conclusion: The data support that the Sp-C-SSRS is a reliable and valid instrument for assessing suicidal ideation and behaviour in daily clinical practice and research settings., (Copyright © 2016 SEP y SEPB. Published by Elsevier España. All rights reserved.)

Unlabelled: Remission rates for Major Depressive Disorder (MDD) are low and unpredictable for any given antidepressant. No biological or clinical marker has demonstrated sufficient ability to match individuals to efficacious treatment. Biosignatures developed from the systematic exploration of multiple biological markers, which optimize treatment selection for individuals (moderators) and provide early indication of ultimate treatment response (mediators) are needed. The rationale and design of a multi-site, placebo-controlled randomized clinical trial of sertraline examining moderators and mediators of treatment response is described. The target sample is 300 participants with early onset (≤30 years) recurrent MDD. Non-responders to an 8-week trial are switched double blind to either bupropion (for sertraline non-responders) or sertraline (for placebo non-responders) for an additional 8 weeks. Clinical moderators include anxious depression, early trauma, gender, melancholic and atypical depression, anger attacks, Axis II disorder, hypersomnia/fatigue, and chronicity of depression. Biological moderator and mediators include cerebral cortical thickness, task-based fMRI (reward and emotion conflict), resting connectivity, diffusion tensor imaging (DTI), arterial spin labeling (ASL), electroencephalograpy (EEG), cortical evoked potentials, and behavioral/cognitive tasks evaluated at baseline and week 1, except DTI, assessed only at baseline. The study is designed to standardize assessment of biomarkers across multiple sites as well as institute replicable quality control methods, and to use advanced data analytic methods to integrate these markers. A Differential Depression Treatment Response Index (DTRI) will be developed. The data, including biological samples (DNA, RNA, and plasma collected before and during treatment), will become available in a public scientific repository., Clinical Trial Registration: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC). Identifier: NCT01407094. URL: http://clinicaltrials.gov/show/NCT01407094., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Psychosocial and behavioural interventions that address suicidal thoughts and behaviour during treatment (direct interventions) might be more effective in preventing suicide and suicide attempts than indirect interventions that address symptoms associated with suicidal behaviour only (eg, hopelessness, depression, anxiety, quality of life). To test this hypothesis, we did a systematic review and meta-analysis of psychosocial and behavioural interventions aimed at preventing suicide and suicide attempts., Methods: For this systematic review and meta-analysis, we searched MEDLINE and PsycINFO from inception to Dec 25, 2015, for randomised controlled trials that reported suicides or suicide attempts as an outcome, irrespective of participants' diagnoses or the publication language. We excluded studies with pharmacological or device-based interventions, those that targeted communities or clinicians, primary prevention trials, and trials that reported events of non-suicidal self-injury as suicide attempts. Trials that had no suicides or suicide attempts in both groups were also excluded. Data were extracted by one investigator and independently verified by a second investigator. We used random-effects models of the odds ratio (OR) based on a pooled measure of suicides and the number of individuals who attempted suicide, immediately post-treatment and at longer-term follow-up., Findings: Of 2024 unique abstracts screened, 53 articles met eligibility criteria and reported on 44 studies; 31 studies provided post-treatment data with 6658 intervention group participants and 6711 control group participants at baseline, and 29 studies provided follow-up data. The post-treatment difference between direct interventions and indirect interventions did not reach statistical significance at the 0·05 level (OR 0·62 [95% CI 0·45-0·87] vs 0·93 [0·77-1·12], p=0·06) and represented a large effect size (Cohen's d=0·77). At longer-term follow-up, the difference was not significant (OR 0·65 [0·46-0·91] vs 0·82 [0·70-0·96], p=0·25) but still represented a medium effect size (Cohen's d=0·47). These effect sizes emphasise the clinical importance of direct interventions. Post-hoc subgroup and sensitivity analyses showed that our results are robust and unlikely to be notably affected by between-study heterogeneity or publication bias., Interpretation: Psychosocial and behavioural interventions that directly address suicidal thoughts and behaviour are effective immediately post-treatment and long term, whereas treatments indirectly addressing these components are only effective long term. Moreover, although the differences shown between direct and indirect strategies were non-significant, the difference in favour of direct interventions represented a large post-treatment improvement and medium improvement at longer-term follow-up. On the basis of these findings, clinicians working with patients at risk of suicide should address suicidal thoughts and behaviours with the patient directly. Although direct interventions are effective, they are not sufficient, and additional efforts are needed to further reduce death by suicide and suicide attempts. Continued patient contact might be necessary to retain long-term effectiveness., Funding: National Institute of Nursing Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: We tested the relationship between genotype, gene expression and suicidal behavior and major depressive disorder (MDD) in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior, and MDD; FK506-binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2), and Glucocorticoid Receptor (NR3C1)., Materials and Methods: Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N = 277) and a postmortem sample (N = 209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9; N = 59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium)., Results: We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, which was associated with increased risk of suicide attempt (OR = 1.58, t = 6.03, P = .014). Six SNPs on this gene, three SNPs on SKA2, and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex (pFCTX). One NR3C1 transcript had lower expression in suicide relative to nonsuicide sudden death cases (b = -0.48, SE = 0.12, t = -4.02, adjusted P = .004)., Conclusion: We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the pFCTX. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior., (© 2016 Wiley Periodicals, Inc.)

Studies looking at the relationship of the hypothalamic-pituitary-adrenal (HPA) axis to suicidal behavior and its risk factors, such as depression, childhood abuse, and impulsive aggression, report inconsistent results. These studies also do not always differentiate between subjects who go on to attempt suicide, suicidal subjects who never attempted suicide, and non-suicidal subjects with psychiatric disorders. In this study, we examined cortisol responses to an experimental stressor, the Trier Social Stress Test (TSST), in 208 offspring of parents with mood disorder. Offspring suicide attempters showed lower total cortisol output (β=-0.47, 95% CI (-0.83, -0.11), p=0.01) compared with offspring with suicide-related behavior (SRB) but never attempted, non-suicidal offspring, and a healthy control group. The result remained significant even after controlling for sex, age, race, ethnicity, site, socio-economic status, and hour of the day when the TSST was conducted. Suicide attempters also showed lower baseline cortisol before the TSST (β=-0.45, 95% CI (-0.74, -0.17), p=0.002). However, there were no significant differences between the groups on cortisol reactivity to stress (β=4.5, 95% CI (-12.9, 22), p=0.61). Although subjects with suicide attempt and SRB have similar clinical and psychosocial characteristics, this is the first study to differentiate them biologically on HPA axis indices. Blunted HPA axis activity may increase risk for suicide attempt among individuals with psychopathology by reducing their ability to respond adaptively to ongoing stressors. These results may help better identify subjects at high risk for suicidal behavior for targeted prevention and intervention efforts.

Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples., (© 2016 Wiley Periodicals, Inc.)

Fatty acid desaturase genes (FADS1-FADS2) encode desaturases participating in the biosynthesis of long-chain polyunsaturated fatty acids. As long-chain polyunsaturated fatty acids are implicated in major depressive disorder (MDD) and suicide risk, and as both are partly heritable, we studied the association of FADS1-FADS2 polymorphisms with MDD (635 cases, 480 controls) and suicide attempt status (291 attempters, 344 MDD nonattempters). Eighteen FADS-related single-nucleotide polymorphisms were genotyped from Caucasians enrolled in Madrid (n=791) or New York City (n=324) and entered as predictors into logistic regression analyses with diagnostic group or suicide attempt history as outcomes and location and sex as covariates. No associations were observed between any single-nucleotide polymorphisms and diagnosis or attempt status. As statistical power was adequate, we conclude that FADS1-FADS2 genetic variants may not be a common determinant of MDD.

Objective: Our aim was to analyse sociodemographic and clinical differences between non-suicidal (NS) bipolar patients (BP), BP reporting only suicidal ideation (SI) and BP suicide attempters according to Columbia-Suicide Severity Rating Scale (C-SRSS) criteria. Secondarily, we also investigated whether the C-SRSS Intensity Scale was associated with emergence of suicidal behaviour (SB)., Method: A total of 215 euthymic bipolar out-patients were recruited. Semistructured interviews including the C-SRSS were used to assess sociodemographic and clinical data. Patients were grouped according to C-SRSS criteria: patients who scored ≤1 on the Severity Scale were classified as NS. The remaining patients were grouped into two groups: 'patients with history of SI' and 'patients with history of SI and SB' according to whether they did or did not have a past actual suicide attempt respectively., Results: Patients from the three groups differed in illness onset, diagnosis, number of episodes and admissions, family history, comorbidities, rapid cycling and medication, as well as level of education, functioning, impulsivity and temperamental profile., Conclusion: Our results suggest that increased impulsivity, higher rates of psychiatric admissions and a reported poor controllability of SI significantly increased the risk for suicidal acts among patients presenting SI., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

White matter abnormalities are implicated in major depressive disorder (MDD). As omega-3 polyunsaturated fatty acids (PUFAs) are low in MDD and affect myelination, we hypothesized that PUFA supplementation may alleviate depression through improving white matter integrity. Acutely depressed MDD patients (n = 16) and healthy volunteers (HV, n = 12) had 25-direction diffusion tensor imaging before and after 6 weeks of fish oil supplementation. Plasma phospholipid omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 PUFA arachidonic acid (AA) levels were determined before and after supplementation using high-throughput extraction and gas chromatography and expressed as a percentage of total phospholipids (PUFA%). Fractional anisotropy (FA) was computed using a least-squares-fit diffusion tensor with non-linear optimization. Regression analyses were performed with changes in PUFA levels or Hamilton Depression Rating Scale scores as predictors, voxel-wise difference maps of FA as outcome, covariates age and sex, with family-wise correction for multiple comparisons. Increases in plasma phospholipid DHA% (but not EPA% or AA%) after fish oil predicted increases in FA in MDD but not HV, in a cluster including genu and body of the corpus callosum, and anterior corona radiata and cingulum (cluster-level p < 0.001, peak t-score = 8.10, p = 0.002). There was a trend for greater change in FA in MDD responders over nonresponders (t = -1.874, df = 13.56, p = 0.08). Decreased depression severity predicted increased FA in left corticospinal tract and superior longitudinal fasciculus (cluster-level p < 0.001, peak t-score = 5.04, p = 0.0001). Increased FA correlated with increased DHA% and decreased depression severity after fish oil supplementation suggests therapeutic effects of omega-3 PUFAs may be related to improvements in white matter integrity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine's antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg(-1) intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r=-0.78, P=0.023), but no other measures.

Objective: Personality features may indicate risk for both mood disorders and suicidal acts. How dimensions of temperament and character predispose to suicide attempts remains unclear., Method: Patients (n = 597) from 3 prospective cohort studies (Vantaa Depression Study [VDS], Jorvi Bipolar Study [JoBS], and Vantaa Primary Care Depression Study [PC-VDS]) were interviewed at baseline, at 18 months, and, in VDS and PC-VDS, at 5 years (1997-2003). Personality was measured with the Temperament and Character Inventory-Revised (TCI-R), and follow-up time spent in major depressive episodes (MDEs) as well as lifetime (total) and prospectively ascertained suicide attempts during the follow-up were documented., Results: Overall, 219 patients had 718 lifetime suicide attempts; 88 patients had 242 suicide attempts during the prospective follow-up. The numbers of both the total and prospective suicide attempts were associated with low self-directedness (β = -0.266, P = .004, and β = -0.294, P < .001, respectively) and high self-transcendence (β = 0.287, P = .002, and β = 0.233, P = .002, respectively). Total suicide attempts were linked to high novelty seeking (β = 0.195, P = .05). Prospective, but not total, suicide attempts were associated with high harm avoidance (β = 0.322, P < .001, and β = 0.184, P = .062, respectively) and low reward dependence (β = -0.274, P < .001, and β = -0.134, P = .196, respectively), cooperativeness (β = -0.181, P = .005, and β = -0.096, P = .326, respectively), and novelty seeking (β = -0.137, P = .047). No association remained significant when only prospective suicide attempts during MDEs were included. After adjustment was made for total time spent in MDEs, only high persistence predicted suicide attempts (β = 0.190, P < .05). Formal mediation analyses of harm avoidance and self-directedness on prospectively ascertained suicide attempts indicated significant mediated effect through time at risk in MDEs, but no significant direct effect., Conclusions: Among mood disorder patients, suicide attempt risk is associated with temperament and character dimensions. However, their influence on predisposition to suicide attempts is likely to be mainly indirect, mediated by more time spent in depressive episodes., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Background: Many, but not all studies of suicide attempters' cortisol response to stress-either social stress or pharmacological challenge-report an exaggerated response. Recent studies of resting baseline cortisol in past suicide attempters, however, have found lower baseline levels., Methods: In this study, baseline salivary cortisols were obtained prior to a stress procedure from adults with lifetime diagnoses of a mood disorder (N=69), 31.9% of whom had made a prior suicide attempt. Data were collected during the piloting of this stress procedure, at various times of day and with/without an additional confederate in the room., Results: Adjusting for procedural, demographic and clinical variables that affect salivary cortisol levels-including time of day of sampling, order of procedure with respect to other assessments, past alcohol abuse, current medication use, and bipolar diagnosis-past suicide attempters had lower baseline cortisol levels compared to non-attempters., Limitations: This is a pilot study with modest sample sizes using statistical, rather than experimental control of numerous variables affecting salivary cortisol levels., Conclusions: Results confirm previous studies. Low baseline cortisol levels have been associated with childhood adversity and externalizing disorders, suggesting a potential role in reducing inhibitions for risky and dangerous behaviors. Further research is needed to more fully characterize these associations and their role in suicidal behavior risk., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The lower-expressing (S') alleles of the serotonin transporter (5-HTT) gene promoter polymorphism (5-HTTLPR) are linked to mood and anxiety related psychopathology. However, the specific neural mechanism through which these alleles may influence emotional and cognitive processing remains unknown. We examined the relationship between both 5-HTTLPR genotype and in vivo 5-HTT binding quantified via PET with amygdala reactivity to emotionally negative stimuli. We hypothesized that 5-HTT binding in both raphe nuclei (RN) and amygdala would be inversely correlated with amygdala reactivity, and that number of S' alleles would correlate positively with amygdala reactivity., Methods: In medication-free patients with current major depressive disorder (MDD; N=21), we determined 5-HTTLPR genotype, employed functional magnetic resonance imaging (fMRI) to examine amygdala responses to negative emotional stimuli, and used positron emission tomography with [(11)C]DASB to examine 5-HTT binding., Results: [(11)C]DASB binding in RN and amygdala was inversely correlated with amygdala response to negative stimuli. 5-HTTLPR S' alleles were not associated with amygdala response to negative emotional stimuli., Limitations: Primary limitations are small sample size and lack of control group., Conclusions: Consistent with findings in healthy volunteers, 5-HTT binding is associated with amygdala reactivity to emotional stimuli in MDD. 5-HTT binding may be a stronger predictor of emotional processing in MDD as compared with 5-HTTLPR genotype., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Comorbid personality disorders may predispose patients with mood disorders to suicide attempts (SAs), but factors mediating this effect are not well known., Methods: Altogether 597 patients from three prospective cohort studies (Vantaa Depression Study, Jorvi Bipolar Study, and Vantaa Primary Care Depression Study) were interviewed at baseline, at 18 months, and in VDS and PC-VDS at 5 years. Personality disorders (PDs) at baseline, number of previous SAs, life-charted time spent in major depressive episodes (MDEs), and precise timing of SAs during follow-up were determined and investigated., Results: Overall, 219 (36.7%) patients had a total of 718 lifetime SAs; 88 (14.7%) patients had 242 SAs during the prospective follow-up. Having any PD diagnosis increased the SA rate, both lifetime and prospectively evaluated, by 90% and 102%, respectively. All PD clusters increased the rate of new SAs, although cluster C PDs more than the others. After adjusting for time spent in MDEs, only cluster C further increased the SA rate (by 52%). Mediation analyses of PD effects on prospectively ascertained SAs indicated significant mediated effects through time at risk in MDEs, but also some direct effects., Limitations: Findings generalizable only to patients with mood disorders., Conclusions: Among mood disorder patients, comorbid PDs increase the risk of SAs to approximately two-fold. The excess risk is mostly due to patients with comorbid PDs spending more time in depressive episodes than those without. Consequently, risk appears highest for PDs that most predispose to chronicity and recurrences. However, also direct risk-modifying effects of PDs exist., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Immune dysregulation has been implicated in depression and other psychiatric disorders. What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the scientific literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects of inflammation on suicide risk., Methods: We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980 through February, 2015. Papers were included if they were written in English and focused on cytokine measurements in patients with suicidal behaviors., Results: The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion. The most consistent finding was elevated interleukin (IL)-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, IL-4, and soluble Il-2 receptors., Conclusions: Given the complexity suggested by the heterogenous cytokine findings, putative mediators and moderators of inflammation on suicidal behavior merit further study. Elevated IL-6 was the most robust cytokine finding, associated with suicidal ideation and both nonfatal suicide attempts and suicides. Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function to impact suicidal behavior, and explore the potential beneficial effects of reducing IL-6 on suicide risk., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although religion is reported to be protective against suicide, the empirical evidence is inconsistent. Research is complicated by the fact that there are many dimensions to religion (affiliation, participation, doctrine) and suicide (ideation, attempt, completion). We systematically reviewed the literature on religion and suicide over the last 10 years (89 articles) with a goal of identifying what specific dimensions of religion are associated with specific aspects of suicide. We found that religious affiliation does not necessarily protect against suicidal ideation, but does protect against suicide attempts. Whether religious affiliation protects against suicide attempts may depend on the culture-specific implications of affiliating with a particular religion, since minority religious groups can feel socially isolated. After adjusting for social support measures, religious service attendance is not especially protective against suicidal ideation, but does protect against suicide attempts, and possibly protects against suicide. Future qualitative studies might further clarify these associations.

Objectives: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5-HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [(11)C]DASB, we compared 5-HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs)., Experimental Design: 5-HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of VT/fP (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt., Principal Observations: 5-HTT binding (VT/fP ) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BPF*, BPP*, and BPND*) indicated lower binding in BD compared with HV across these six regions of interest (BPF*: P = 0.047; BPP*: P = 0.032; BPND*: P = 0.031). 5-HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder., Conclusions: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [(11)C]DASB. We do not find evidence of abnormal 5-HTT binding in bipolar depression using our primary outcome measure, VT /fP . However, we did observe lower 5-HTT binding in BD with alternative outcome measures that are frequently used with [(11)C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted., (© 2015 Wiley Periodicals, Inc.)

This issue of Focus on Suicide brings us new data about risk assessment, with 2 articles examining the utility of rating scales for assessment of suicidal behavior. Youngstrom et al conduct a careful comparison of 3 suicide rating scales: the Columbia Suicide Severity Rating Scale (C-SSRS), the Suicide Tracking Scale (STS), and the Sheehan Suicidality Tracking Scale (S-STS). While the scales did comparably in 2 broad categories, suicidal ideation and suicide attempts, the study suggests that some subtypes of suicidal behavior/ideation are not captured as well by the S-STS., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Objective: To develop a brief and reliable psychometric scale to identify individuals at risk for suicidal behaviour., Design: Case-control study., Sample and Setting: 182 individuals (61 suicide attempters, 57 psychiatric controls, and 64 psychiatrically healthy controls) aged 18 or older, admitted to the Emergency Department at Puerta de Hierro University Hospital in Madrid, Spain., Measures: All participants completed a form including their socio-demographic and clinical characteristics, and the Personality and Life Events scale (27 items). To assess Axis I diagnoses, all psychiatric patients (including suicide attempters) were administered the Mini International Neuropsychiatric Interview., Statistical Analysis: Descriptive statistics were computed for the socio-demographic factors. Additionally, χ(2) independence tests were applied to evaluate differences in socio-demographic and clinical variables, and the Personality and Life Events scale between groups. A stepwise linear regression with backward variable selection was conducted to build the Short Personality Life Event (S-PLE) scale. In order to evaluate the accuracy, a ROC analysis was conducted. The internal reliability was assessed using Cronbach's α, and the external reliability was evaluated using a test-retest procedure., Results: The S-PLE scale, composed of just 6 items, showed good performance in discriminating between medical controls, psychiatric controls and suicide attempters in an independent sample. For instance, the S-PLE scale discriminated between past suicide and past non-suicide attempters with sensitivity of 80% and specificity of 75%. The area under the ROC curve was 88%. A factor analysis extracted only one factor, revealing a single dimension of the S-PLE scale. Furthermore, the S-PLE scale provides values of internal and external reliability between poor (test-retest: 0.55) and acceptable (Cronbach's α: 0.65) ranges. Administration time is about one minute., Conclusions: The S-PLE scale is a useful and accurate instrument for estimating the risk of suicidal behaviour in settings where the time is scarce., (Copyright © 2015 SEP y SEPB. Published by Elsevier España. All rights reserved.)

Genome wide array studies have reported limited success in identifying genetic markers conferring risk for suicidal behavior (SB). This may be attributable to study designs with primary outcome other than SB. We performed a GWAS on suicides and cases with a history of nonfatal suicide attempts compared with psychiatric controls and healthy volunteers. A consortium of USA, Canadian and German teams assembled two groups of cases (suicide attempters and suicides, N = 577) and non-attempter psychiatric and healthy controls (N = 1,233). Logistic regression was used to test genotype-suicidal behavior association. The test was repeated separating suicide attempt and completed suicide as outcomes. No SNP reached genome-wide significance, but several SNPs within STK3, ADAMTS14, PSME2, and TBX20 genes reached P < 1 × 10(-5) . The top SNPs for the suicide attempt analysis included two from DPP10, one from CTNNA3 and one from STK32B. In the suicide analysis we found seven SNPs from the TBX20 gene in the top hits. Pathway analysis identified the following pathways: "Cellular Assembly and Organization," "Nervous System Development and Function," "Cell Death and Survival," "Immunological Disease," "Infectious Disease," and "Inflammatory Response." The top genes in the SB analysis did not overlap with those in the ideation analysis. No genome wide significant results suggest that susceptibility to SB has genetic risk factors with smaller effect sizes. The strongest candidate genes, ADAMTS14, and PSME2 (both linked to inflammatory response), STK3 (neuronal cell death), and TBX20 (brainstem motor neuron development), have not been previously reported in association with suicide and warrant further study., (© 2015 Wiley Periodicals, Inc.)

In the last decade, many studies have used automated processes to analyze magnetic resonance imaging (MRI) data such as cortical thickness, which is one indicator of neuronal health. Due to the convenience of image processing software (e.g., FreeSurfer), standard practice is to rely on automated results without performing visual inspection of intermediate processing. In this work, structural MRIs of 40 healthy controls who were scanned twice were used to determine the test-retest reliability of FreeSurfer-derived cortical measures in four groups of subjects-those 25 that passed visual inspection (approved), those 15 that failed visual inspection (disapproved), a combined group, and a subset of 10 subjects (Travel) whose test and retest scans occurred at different sites. Test-retest correlation (TRC), intraclass correlation coefficient (ICC), and percent difference (PD) were used to measure the reliability in the Destrieux and Desikan-Killiany (DK) atlases. In the approved subjects, reliability of cortical thickness/surface area/volume (DK atlas only) were: TRC (0.82/0.88/0.88), ICC (0.81/0.87/0.88), PD (0.86/1.19/1.39), which represent a significant improvement over these measures when disapproved subjects are included. Travel subjects' results show that cortical thickness reliability is more sensitive to site differences than the cortical surface area and volume. To determine the effect of visual inspection on sample size required for studies of MRI-derived cortical thickness, the number of subjects required to show group differences was calculated. Significant differences observed across imaging sites, between visually approved/disapproved subjects, and across regions with different sizes suggest that these measures should be used with caution., (© 2015 Wiley Periodicals, Inc.)

Objective: Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error- (discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures., Method: A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals., Results: Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms., Conclusions: The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.

Background: Depression is characterized by poor executive function, but - counterintuitively - in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study., Method: One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials)., Results: Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007)., Conclusions: Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.

Background: Previous research suggests that various types of childhood maltreatment frequently co-occur and confer risk for attempting suicide. However, it is unknown whether the effect of childhood maltreatment on this risk occurs through diverse, specific mechanisms or through a generalized liability, independently of psychopathology. Although these competing explanations have different implications for intervention, they have never been evaluated empirically., Method: Structural equation modeling was used to examine the effect of different types of childhood maltreatment (ie, sexual abuse, physical and emotional abuse and neglect) on suicide attempt risk, and on age at first suicide attempt and repeated suicide attempts among attempters. Analyses controlled for demographic characteristics and DSM-IV Axis I and Axis II disorders. Data were drawn from a nationally representative survey of US adults, the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions (N = 34,653)., Results: Childhood maltreatment was associated with an increased risk for attempting suicide and an earlier age at first suicide attempt among attempters, independently of psychopathology (P < .005). These associations operated mainly through the latent variable representing effects shared by the different types of childhood maltreatment, although sexual abuse had an additional, direct effect on the risk of suicide attempt. Childhood maltreatment types were not significantly associated with a history of multiple suicide attempts (all P values > .05)., Conclusions: The association between childhood maltreatment and suicide attempt operates mainly through a single broad liability, suggesting that the mechanisms underlying this dimension should be considered as an important therapeutic target for suicide prevention., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Most mental disorders, when examined independently, are associated with an elevated risk for suicide attempt. However, mental disorders often co-occur, and that co-occurrence is well explained by models where specific mental disorders are understood as manifestations of latent dimensions of psychopathology. To date, it remains unclear whether the risk of suicide attempt is due to specific mental disorders, to specific dimensions of psychopathology (that is, internalizing and externalizing dimensions), to a general psychopathology factor or to a combination of these explanations. In a large nationally representative prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we used structural equation modeling to examine the shared and specific effects of Axis I and Axis II disorders on the occurrence of suicide attempts in the general population and among individuals with a lifetime history of suicidal ideation. Effects of mental disorders on the risk of suicide attempt were exerted almost exclusively through a general psychopathology factor representing the shared effect across all mental disorders. Effects of remitted psychiatric disorders on the risk of suicide attempt were fully mediated by current mental disorders. Similar patterns of associations were found in individuals with suicidal ideation. These results held when using different approaches to modeling psychiatric comorbidity. Our findings underscore the importance of adopting dimensional approaches to comorbidity in the study of suicidal behavior. Because mental disorders increase the risk of suicide attempt through a general psychopathology liability, this dimension should be considered as an important therapeutic target to substantially advance suicide prevention.

Multiple lines of research have implicated the serotonin 1A (5-HT1A) receptor in major depressive disorder (MDD). Despite this, quantification of 5-HT1A is yet to yield a clinically relevant MDD biomarker. One reason may be that reported sex differences in the serotonergic system confound the comparison between diagnostic groups. Therefore, this study sought to determine whether differences in 5-HT1A binding between depressed and control subjects are affected by sex. Using positron emission tomography (PET), serotonin 1A binding was quantified in 50 patients with MDD (34 female, 16 male) and 57 healthy controls (32 female, 25 male). The subjects' 5-HT1A density (BPF, equal to the product of the density of available receptors and tracer affinity), was determined by using the PET tracer [carbonyl-C-11]-WAY-100635, a selective 5-HT1A antagonist. Results indicated that male MDD subjects had a 67.0% higher BPF across 13 brain regions compared with male controls (df=103, p<0.0001). The greatest difference between MDD subjects and controls was in the raphe (132%, p=0.000). Furthermore, by using a threshold, male controls can be distinguished from depressed males with high sensitivity and specificity (both >80%). In females, the separation between diagnostic groups yields much lower sensitivity and specificity. This data therefore suggests a specific biosignature for MDD in males. Identification of such a biosignature could provide a deeper understanding of depression pathology, help identify those at highest risk, and aid in the development of new therapies. Further, these findings suggest that combining male and female cohorts may not be optimal for some MDD studies.

Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.

Longitudinal investigation of the neural correlates of reward processing in depression may represent an important step in defining effective biomarkers for antidepressant treatment outcome prediction, but the reliability of reward-related activation is not well understood. Thirty-seven healthy control participants were scanned using fMRI while performing a reward-related guessing task on two occasions, approximately one week apart. Two main contrasts were examined: right ventral striatum (VS) activation fMRI BOLD signal related to signed prediction errors (PE) and reward expectancy (RE). We also examined bilateral visual cortex activation coupled to outcome anticipation. Significant VS PE-related activity was observed at the first testing session, but at the second testing session, VS PE-related activation was significantly reduced. Conversely, significant VS RE-related activity was observed at time 2 but not time 1. Increases in VS RE-related activity from time 1 to time 2 were significantly associated with decreases in VS PE-related activity from time 1 to time 2 across participants. Intraclass correlations (ICCs) in VS were very low. By contrast, visual cortex activation had much larger ICCs, particularly in individuals with high quality data. Dynamic changes in brain activation are widely predicted, and failure to account for these changes could lead to inaccurate evaluations of the reliability of functional MRI signals. Conventional measures of reliability cannot distinguish between changes specified by algorithmic models of neural function and noisy signal. Here, we provide evidence for the former possibility: reward-related VS activations follow the pattern predicted by temporal difference models of reward learning but have low ICCs.

Polyunsaturated fatty acid (PUFA) status has been associated with neuropsychiatric disorders, including depression and risk of suicide. Long-chain PUFAs (LC-PUFAs) are obtained in the diet or produced by sequential desaturation and elongation of shorter-chain precursor fatty acids linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3). We compared DNA methylation patterns in genes involved in LC-PUFA biosynthesis in major depressive disorder (MDD) with (n = 22) and without (n = 39) history of suicide attempt, and age- and sex-matched healthy volunteers (n = 59). Plasma levels of selected PUFAs along the LC-PUFA biosynthesis pathway were determined by transesterification and gas chromatography. CpG methylation levels for the main human LC-PUFA biosynthetic genes, fatty acid desaturases 1 (Fads1) and 2 (Fads2), and elongation of very long-chain fatty acids protein 5 (Elovl5), were assayed by bisulfite pyrosequencing. Associations between PUFA levels and diagnosis or suicide attempt status did not survive correction for multiple testing. However, MDD diagnosis and suicide attempts were significantly associated with DNA methylation in Elovl5 gene regulatory regions. Also the relative roles of PUFA levels and DNA methylation with respect to diagnostic and suicide attempt status were determined by least absolute shrinkage and selection operator logistic regression analyses. We found that PUFA associations with suicide attempt status were explained by effects of Elovl5 DNA methylation within the regulatory regions. The observed link between plasma PUFA levels, DNA methylation, and suicide risk may have implications for modulation of disease-associated epigenetic marks by nutritional intervention.

Importance: Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin(1A) autoreceptor in the brainstem raphe of individuals who die by suicide., Objectives: To determine the relationships between brain serotonin(1A) binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin(1A) antagonist radiotracer carbon C 11 [11C]-labeled WAY-100635., Design, Setting, and Participants: Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin(1A) binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality., Main Outcomes and Measures: The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation., Results: Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin(1A) BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin(1A) BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin(1A )BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin(1A) BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12)., Conclusions and Relevance: Higher brainstem raphe serotonin(1A)BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin(1A) BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin(1A) BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts.

Current methodologies employed in collecting data for suicide research present several limitations. In this article, we describe a novel method and tool to prospectively study suicidal behavior and its related risk and protective factors in different countries. This tool is a web-based database, which will initially be developed and piloted by suicide research groups from Austria, Brazil, Chile, France, Italy, Mexico, Spain, Sweden, and the US. The database will develop and integrate research tools key to collaboration, permit exploration of ethical considerations, and provide a universal interface in English, Spanish, French, Portuguese, Italian, and German that will make it possible to incorporate new groups from different countries to the network. The common database resulting of this cross-national effort will allow researchers to share and compare data across countries in a large sample of patients. Using anonymous electronic records of patients, we will: 1) determine the impact of risk and protective factors (viz. aggression and religious affiliation) in different socio-cultural environments; 2) develop a clinical model of suicidal behavior that integrates the multiple dimensions implicated; 3) try differentiating the effects of biological, environmental, and cultural factors on suicidal behavior, and 4) offer the global psychiatric research community a tool that will standardize assessment across nations, allowing for better generalization.

Objective: To investigate distinguishing features between bipolar I, II and unipolar depression, and impulsivity/aggression traits in particular., Methods: Six hundred and eighty-five (n=685) patients in a major depressive episode with lifetime Unipolar (UP) depression (n=455), Bipolar I (BP-I) disorder (n=151), and Bipolar II (BP-II) (n=79) disorder were compared in terms of their socio-demographic and clinical characteristics., Results: Compared to unipolar patients, BP-I and BP-II depressed patients were significantly younger at onset of their first depressive episode, and were more likely to experience their first depressive episode before/at age of 15. They also had more previous affective episodes, more first- and second-degree relatives with history of mania, more current psychotic and subsyndromal manic symptoms, and received psychopharmacological and psychotherapy treatment at an earlier age. Furthermore, BP-I and BP-II depressed patients had higher lifetime impulsivity, aggression, and hostility scores. With regard to bipolar subtypes, BP-I patients had more trait-impulsivity and lifetime aggression than BP-II patients whereas the latter had more hostility than BP-I patients. As for co-morbid disorders, Cluster A and B Personality Disorders, alcohol and substance abuse/dependence and anxiety disorders were more prevalent in BP-I and BP-II than in unipolar patients. Whereas the three groups did not differ on other socio-demographic variables, BP-I patients were significantly more often unemployed that UP patients., Conclusion: Our findings comport with major previous findings on differences between bipolar and unipolar depression. As for trait characteristics, bipolar I and II depressed patients had more life-time impulsivity and aggression/hostility than unipolar patients. In addition, bipolar I and II patients also differed on these trait characteristics., (Copyright © 2014. Published by Elsevier Masson SAS.)

Objective: Suicide, a major cause of death worldwide, has distinct biological underpinnings. The authors review and synthesize the research literature on biomarkers of suicide, with the aim of using the findings of these studies to develop a coherent model for the biological diathesis for suicide., Method: The authors examined studies covering a large range of neurobiological systems implicated in suicide. They provide succinct descriptions of each system to provide a context for interpreting the meaning of findings in suicide., Results: Several lines of evidence implicate dysregulation in stress response systems, especially the hypothalamic-pituitary-adrenal axis, as a diathesis for suicide. Additional findings related to neuroinflammatory indices, glutamatergic function, and neuronal plasticity at the cellular and circuitry level may reflect downstream effects of such dysregulation. Whether serotonergic abnormalities observed in individuals who have died by suicide are independent of stress response abnormalities is an unresolved question., Conclusions: The most compelling biomarkers for suicide are linked to altered stress responses and their downstream effects, and to abnormalities in the serotonergic system. Studying these systems in parallel and in the same populations may elucidate the role of each and their interplay, possibly leading to identification of new treatment targets and biological predictors.

Background: Neuropeptide Y (NPY) may enhance resilience to chronic stress. Low brain NPY reported in major depression may normalize in response to antidepressants., Methods: In this study, we examined the relationship of reported childhood trauma to cerebrospinal fluid (CSF) NPY-like immunoreactivity (NPY-LI) in 61 medication-free major depressive disorder (MDD) patients and 20 matched healthy volunteers., Results: Higher CSF NPY-LI was found in MDD compared to the healthy volunteer group (p = 0.01). A positive correlation of CSF NPY-LI with more adverse childhood trauma (p = 0.001) may be indicative of an intact but insufficient NPY-related stress response., Conclusions: We hypothesize that differences in published results may be explained by the existence of two groups of MDD in terms of CSF NPY levels: MDD with low CSF NPY prior to stress or in response to stress, and those with robust NPY responses to stress. Future studies should confirm the two groups and seek the molecular mechanism for their differences., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems., Methods and Materials: Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale., Results: Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA., Conclusions: Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients., (© 2014 Wiley Periodicals, Inc.)

Background: Our previous work identified deficits in interference processing and learning/memory in past suicide attempters who were currently depressed and medication-free. In this study, we extend this work to an independent sample studied at various stages of illness and treatment (mild symptoms, on average) to determine if these deficits in past suicide attempters are evident during a less severe clinical state., Method: A total of 80 individuals with a past history of major depression and suicide attempt were compared with 81 individuals with a history of major depression and no lifetime suicide attempts on a battery of neurocognitive measures assessing attention, memory, abstract/contingent learning, working memory, language fluency and impulse control., Results: Past attempters performed more poorly in attention, memory and working memory domains, but also in an estimate of pre-morbid intelligence. After correction for this estimate, tests that had previously distinguished past attempters - a computerized Stroop task and the Buschke Selective Reminding Test - remained significantly worse in attempters. In a secondary analysis, similar differences were found among those with the lowest levels of depression (Hamilton Depression Rating Scale score <10), suggesting that these deficits may be trait markers independent of current symptomatology., Conclusions: Deficits in interference processing and learning/memory constitute an enduring defect in information processing that may contribute to poor adaptation, other higher-order cognitive impairments and risk for suicidal behavior.

Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n = 48) and healthy volunteers (HV, n = 35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n = 39; HV, n = 33) completed the Barratt Impulsiveness Scale. Plasma PUFAs eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6) were quantified and ln-transformed to mitigate distributional skew. Ln-transformed PUFA (lnPUFA) levels were predictors in regression models, with aggression or impulsivity scores as outcomes, and cofactors of sex and diagnostic status (MDD with or without a history of substance use disorder [SUD], or HV). Interactions were tested between relevant PUFAs and diagnostic status. Additional analyses explored possible confounds of depression severity, self-reported childhood abuse history, and, in MDD patients, suicide attempt history. Among PUFA, lnEPA but not lnDHA predicted aggression (F1,76 = 12.493, p = 0.001), and impulsivity (F1,65 = 5.598, p = 0.021), with interactions between lnEPA and history of SUD for both aggression (F1,76 = 7.941, p = 0.001) and impulsivity (F1,65 = 3.485, p = 0.037). Results remained significant when adjusted for childhood abuse, depression severity, or history of suicide attempt. In conclusion, low EPA levels were associated with aggression and impulsivity only in patients with MDD and comorbid SUD, even though in most cases SUD was in full sustained remission., (Copyright © 2014 Elsevier Ltd. All rights reserved.)