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During adolescence, suicide risk increases; effective treatments are needed to reduce risk.Databases were searched (1995-2020) for randomized controlled trials (RCTs) concerning psychosocial treatments for suicide prevention in adolescents (10-18 yrs). Data were extracted from the timepoint closest to 6 months. Cohen's ds were estimated for reducing suicidal ideation (SI), self-harming behaviors (SHB) excluding strictly non-suicidal self-injury, and suicide attempts (SA) and analyzed using generalized least square regression. Meta-analytic innovations included within-person correlations to reflect trait suicidality; annualization to control for exposure; estimated lifetime risk based on ages; and modeling inclusion/exclusion criteria. Alternate approaches included relative risk and comparison of intervention and control treatments to baseline.Of 30 RCTs, 6 assessing SHB (4 measuring SA), and 7 assessing SI demonstrated treatment effectiveness. Overall, interventions decreased SI (n = 25) with low effect size (d = 0.08, p = 0.01), non-significant after controlling for publication bias (d = 0.05, p = 0.1); interventions were non-significant for SHB (n = 25, d = 0.001, p = 0.97) or SA (n = 18, d = 0.03, p = 0.52). To prevent one SHB, the number needed to treat (NNT) was 45[26,156]; for SA, NNT=42[24,149]. Non-superiority may relate to effectiveness of control treatments. Thus, experimental and control treatments also were compared to baseline: both reduced SI (p 0.0001), and effectiveness improved for SHB (NNT=12) and SA (NNT=11).Study heterogeneity and inconsistent statistical reporting limited meta-analysis.Psychosocial interventions for suicide risk in adolescents showed little effectiveness compared with control treatments; suicide outcomes improved in both groups compared to baseline. Different approaches may be needed, including precision medicine methodologies and standardized statistical reporting criteria.

OBJECTIVE: To identify risk factors for preadolescent onset suicidal behavior compared with adolescent/young adult onset suicidal behavior in a longitudinal sample of youth with parental history of mood disorders. METHODS: The sample includes 545 youth who were age 21 years or less at the time of their baseline assessment. Participants underwent baseline and yearly study assessments. Observations were censored at the time point closest to the first episode of suicidal behavior for youth with suicidal behavior and at the time of last observation for youth without suicidal behavior. Youth were categorized into 3 groups: first onset of suicidal behavior before the age of 13 (n=32), first onset of suicidal behavior between the ages of 13–21 (n=51) and those without suicide related behaviors (n=462). ANOVA, Chi-square, Fisher’s exact test and multinomial regression were used to test the hypotheses. RESULTS: Significant predictors of preadolescent onset suicidal behavior were diagnosis of depressive disorder (RRR=11.41, p

It has been argued that unipolar major depressive disorder (MDD) and bipolar disorder (BD) exist on a continuous spectrum, given their overlapping symptomatology and genetic diatheses. The Bipolarity Index (BI) is a scale that considers bipolarity as a continuous construct and was developed to assess confidence in bipolar diagnosis. Here we investigated whether BI scores correlate with gray matter volume (GMV) in a sample of unmedicated unipolar and bipolar depressed individuals.158 subjects (139 with MDD, 19 with BD) in a major depressive episode at time of scan were assigned BI scores. T1-weighted Magnetic Resonance Imaging scans were obtained and processed with Voxel-Based Morphometry using SPM12 (CAT12 toolbox) to assess GMV. Regression was performed at the voxel level to identify clusters of voxels whose GMV was associated with BI score, (p0.001, family-wise error-corrected cluster-level p0.05), with age, sex and total intracranial volume as covariates.GMV was inversely correlated with BI score in four clusters located in left lateral occipital cortex, bilateral angular gyri and right frontal pole. Clusters were no longer significant after controlling for diagnosis. GMV was not correlated with BI score within the MDD cohort alone.Incomplete clinical data required use of a modified BI scale.BI scores were inversely correlated with GMV in unmedicated subjects with MDD and BD, but these correlations appeared driven by categorical diagnosis. Future work will examine other imaging modalities and focus on elements of the BI scale most likely to be related to brain structure and function.

© 2020 Elsevier Ltd. All rights reserved., Pro-inflammatory status has been implicated in depression and suicidal behaviors. Polyunsaturated fatty acids (PUFAs) and cytokines, two types of inflammatory biomarkers, have been associated with suicide, independent of depression severity. How these biomarkers relate to each other is less clear. We measured plasma phospholipid levels of arachidonic acid (AA%), docosahexaenoic acid (DHA%), and eicosapentaenoic acid (EPA%) as a percentage of total phospholipids, as well as serum interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α), in 80 patients with major depressive disorder (MDD) and 24 healthy controls (HC). Individual PUFA and cytokine species were compared using ANOVA across four suicide risk-stratified groups: 1) highest-risk, recent (within 5 years) suicide attempters (n = 20); 2) high-risk, severe current suicidal ideators (having intent or plan) with no recent attempt history (n = 22); 3) low-risk, current non-ideators who were also lifetime non-attempters (n = 38); and 4) HC (n = 24). None of the participants were enrolled following an acute suicide attempt. Of biomarkers studied, only DHA% (p = 0.012) and IL-1β (p = 0.002) differed between groups. In post-hoc testing, DHA% was lower in attempters than ideators (p = 0.018) or MDD non-ideators (trend level, p = 0.073). IL-1β was lowest in attempters, differentiating them from ideators (p = 0.009) and HC (p = 0.004). Recent suicide attempt, one of the most powerful predictors of suicide risk, was also most closely tied to inflammatory indices in this study. Low DHA% as an indicator of suicide risk is consistent with previous reports; however, lower IL-1β was unexpected and may relate to acuity/chronicity of inflammation. There is a need for prospective studies of immune status with respect to suicidal behaviors., This work was supported by the American Foundation for Suicide Prevention (AFSP) [(PI: Sublette) 10/1/13 – 9/30/15], the Association for Research and Development of the School of Medicine, University of Lisbon (Ganança), and by the National Institutes of Health [5 R01 MH48514-20 (PI: Oquendo) 12/01/08-11/30/14] and [1 P50 MH090964-01A1 (PI: Mann) 7/19/13 – 6/30/18].

Background Smaller hippocampal volumes are reported in adults with major depressive disorder (MDD) and in reported childhood abuse. The hippocampus is a complex structure with distinct functional subfields. We sought to examine the effect of MDD diagnosis and childhood abuse on hippocampal subfields. Methods Forty-one MDD participants (17 reported abuse and 24 did not) and 46 healthy volunteers (HV) (2 reported abuse) underwent T1- weighted structural magnetic resonance imaging (MRI) and clinical characterization in a retrospective design. A subfield segmentation program was used to measure the whole and subfield hippocampal volumes. Linear mixed-effects models were fitted for group comparisons. Results No main effect of diagnosis interaction effect between diagnosis and subfield region was observed. However, a comparison of abused MDD vs. HVs showed a group by region interaction. A significant interaction between childhood abuse and region was observed. Effects were confined to the left side of the brain, and post hoc, exploratory region-specific tests indicated smaller left CA1 volume in abused MDD compared with non-abused MDD. In addition, smaller amygdala volume was found in all MDD compared with HVs. Limitations We did not have a sample of healthy volunteers with reported childhood abuse. Conclusions The diagnosis of pure MDD may not be sufficient to exert effects on hippocampal volumes, indicating the importance of taking into account childhood trauma in studies on psychopathological mechanisms. Left CA1 might be the hippocampal subfield most relevant to reported childhood abuse. Smaller amygdala volume may be related to MDD diagnosis independent of childhood abuse.

Background Our lab has previously found that structural integrity in tracts from the raphe nucleus (RN) to the amygdala, measured by fractional anisotropy (FA), predicts remission to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). This could potentially serve as a biomarker for remission that can guide clinical decision-making. To enhance repeatability and reproducibility, we replicated our study in a larger, more representative multi-site sample. Methods 64 direction DTI was collected in 144 medication-free patients with MDD from the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. We performed probabilistic tractography between the RN and bilateral amygdala and hippocampus and calculated weighted FA in these tracts. Patients were treated with either sertraline or placebo, and their change in Hamilton Depression Rating Scale (HDRS) score reported. Pretreatment weighted FA was compared between remitters and nonremitters, and correlation between FA and percent change in HDRS score was assessed. Exploratory moderator and voxel analyses were also performed. Results Contrary to our hypotheses, FA was greater in nonremitters than in remitters in RN-left and right amygdala tracts (p = 0.02 and 0.01, respectively). Pretreatment FA between the raphe and left amygdala correlated with greater, not reduced, HDRS (r = 0.18, p = 0.04). This finding was found to be greater in the placebo group. Moderator and voxel analyses yielded no significant findings. Conclusions We found greater FA in nonremitters between the RN and amygdala than in remitters, and a correlation between FA and symptom worsening, particularly with placebo. These findings may help reveal more about the nature of MDD, as well as guide research methods involving placebo response.

Background Baseline rostral anterior cingulate cortex (rACC) activity is a well-replicated nonspecific predictor of depression improvement. The rACC is a key hub of the default mode network, which prior studies indicate is hyperactive in major depressive disorder. Because default mode network downregulation is reliant on input from the salience network and frontoparietal network, an important question is whether rACC connectivity with these systems contributes to depression improvement. Methods Our study evaluated this hypothesis in outpatients (N = 238; 151 female) enrolled in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) 8-week randomized clinical trial of sertraline versus placebo for major depressive disorder. Depression severity was measured using the Hamilton Rating Scale for Depression, and electroencephalography was recorded at baseline and week 1. Exact low-resolution electromagnetic tomography was used to compute activity from the rACC, and key regions within the default mode network (posterior cingulate cortex), frontoparietal network (left dorsolateral prefrontal cortex), and salience network (right anterior insula [rAI]). Connectivity in the theta band (4.5–7 Hz) and beta band (12.5–21 Hz) was computed using lagged phase synchronization. Results Stronger baseline theta-band rACC–rAI (salience network hub) connectivity predicted greater depression improvement across 8 weeks of treatment for both treatment arms (B = −0.57, 95% confidence interval = −1.07, −0.08, p = .03). Early increases in theta-band rACC–rAI connectivity predicted greater likelihood of achieving remission at week 8 (odds ratio = 2.90, p = .03). Conclusions Among patients undergoing treatment, theta-band rACC–rAI connectivity is a prognostic, albeit treatment-nonspecific, indicator of depression improvement, and early connectivity changes may predict clinically meaningful outcomes.

Background Findings regarding brain circuitry abnormalities in suicide attempters (SAs) converge across bipolar disorder (BD) and major depressive disorder (MDD), the most common disorders observed in suicides. These abnormalities appear to be present during adolescence/young adulthood when suicide rates increase steeply, and suicide is a leading cause of death in this age group. Identification of brain circuitry common to adolescent/young adult SAs with BD and MDD is important for generating widely effective early prevention strategies. We examined brain circuitry in SAs in adolescents/young adults across these two disorders. Methods Eighty-three participants (ages 14–25 years), 46 with BD (21 SAs) and 37 with MDD (19 SAs), underwent structural and diffusion-weighted magnetic resonance scanning. Whole-brain analyses compared gray matter (GM) volume and white matter (WM) fractional anisotropy (FA) between SAs and non-suicide attempters (NSAs) across and within BD and MDD (p Results Across and within BD and MDD, SAs showed differences compared to NSAs in ventral prefrontal cortex (PFC) GM volume and fronto-limbic (including uncinate fasciculus (UF)) WM FA. Exploratory analyses showed additional within-disorder differences for BD SAs in dorsolateral PFC (dlPFC) and hippocampus GM volume and UF FA, and for MDD SAs dorsomedial and dlPFC GM and dorsal frontal WM. However, there was no significant interaction between suicide attempt status and diagnosis. Limitations Modest sample size. Conclusions Common fronto-limbic gray and white matter alterations in adolescent/young adult SAs are potential targets for suicide prevention strategies across mood disorders. Preliminary findings of disorder-specific regional findings could suggest diagnostic-specific optimal targets may exist.

BACKGROUND: Mood disorders are major risk factors for suicidal behavior. While cross-sectional studies implicate frontal systems, data to aid prediction of suicide-related behavior in mood disorders are limited. Longitudinal research on neuroanatomical mechanisms underlying suicide risk may assist in developing targeted interventions. Therefore, we conducted a preliminary study investigating baseline gray and white matter structure and longitudinal structural changes associated with future suicide attempts. METHODS: High-resolution structural magnetic resonance imaging, diffusion tensor imaging, and suicide-related behavioral assessment data for 46 adolescents and young adults with mood disorders [baseline age(mean)=18 years; 61% female] were collected at baseline and at follow-up (interval(mean)=3 years). Differences in baseline and longitudinal changes in gray matter volume and white matter fractional anisotropy in frontal systems that distinguished the participants who made future attempts from those who did not were investigated. RESULTS: Seventeen (37%) of participants attempted suicide within the follow-up period. Future attempters (those attempting suicide between their baseline and follow-up assessment), compared to those who did not, showed lower baseline ventral and rostral prefrontal gray matter volume and dorsomedial frontal, anterior limb of the internal capsule, and dorsal cingulum fractional anisotropy, as well as greater decreases over time in ventral and dorsal frontal fractional anisotropy (p

Memory deficits are reported in major depressive disorder (MDD). Prefrontal cortical and mesiotemporal cortical (MTC)/subcortical regions are involved in the Buschke Selective Reminding Task (SRT), a verbal list-learning task. To determine whether depression-related changes in resting brain metabolism explain (in part) the deficits in SRT performance found in MDD, statistical correlation maps were calculated between SRT total recall score (TR) and relative regional cerebral metabolic rate for glucose (rCMRglu), measured by [18F]-flourodeoxyglucose (FDG) positron emission tomography (PET), in unmedicated, depressed MDD patients (N = 29). Subsequently, to explore hypothesized loss of top-down control in MDD, we compared the correlations between rCMRglu of SRT-relevant regions of the dorsolateral prefrontal cortex (dlPFC) and amygdala in a larger cohort of MDD (N = 60; 29 inclusive) versus healthy controls (HC) (N = 43). SRT performance of patients is on average 0.5 standard deviation below published normative mean. TR and rCMRglu positively correlate in bilateral dorsomedial PFC, dlPFC, dorsal anterior cingulate; negatively correlate in bilateral MTC/subcortical regions, and cerebellum. rCMRglu in dlPFC correlates negatively with that in amygdala in HC but not in MDD. Depression-related changes present in FDG-PET measured resting brain activity may be in part responsible for memory deficit found in MDD.

Globally, suicide is the second leading cause of death for youth ages 10-24 years, and more than 75% of all deaths by suicide occur in low- and middle-income countries (LMIC).

Background Neurocognitive deficits are common in depression, but most prior studies have not found strong associations between standard measures of symptom severity and the extent of these neurocognitive deficits. Diagnostic heterogeneity, or the lack of specific questions about neurocognition in these measures, may be undermining these associations. Method Neuropsychological performance was assessed via 10 tasks in a sample of 262 unmedicated patients with Major Depressive Disorder (MDD) and compared to that in healthy volunteers (n = 140), then correlated with (1) standard measures of depression severity including the Hamilton Depression Rating Scale and Beck Depression Inventory, (2) previously established, factor-analytically derived symptom factors that characterize the heterogeneity of these scales, and (3) a separate measure of cognitive complaint (Cognitive Failures Questionnaire) that was included to address the absence of specific questions about cognition in standard rating scales. Results Neurocognitive performance in these unmedicated MDD patients was not significantly associated with either total scores on the depression severity measures, any of their derived symptom factors, or the degree of subjective cognitive complaint – which itself was most strongly associated with mood disturbance. Limitations Depressed patients with the most prominent neurovegetative symptoms may be underrepresented in this sample. Conclusions Neurocognitive deficits were only weakly associated with standard depression symptom ratings, and not captured by self-report ratings of cognitive complaint. Neurocognitive deficits appear to be a separate symptom dimension that cannot be inferred from overall depression severity and require their own assessment, given that they have prognostic value for functional outcomes, suicide risk, and differential therapeutics.

The current study examined the contribution of baseline neuropsychological functioning to the prediction of antidepressant outcome with cognitive behavioral therapy (CBT) for Major Depressive Disorder (MDD). We hypothesized that depressed participants who were more neurocognitively intact and had less rigid, negative thinking would respond better to CBT. Thirty-one MDD patients completed a comprehensive neuropsychological battery before initiation of CBT. A subgroup also completed a probabilistic reversal learning task. Depression severity was assessed with the Beck Depression Inventory (BDI); rigid, negative thinking was assessed with the Dysfunctional Attitudes Scale (DAS) and the Automatic Thoughts Questionnaire (ATQ) throughout treatment. Remitters were compared to non-remitters. Paradoxically, eventual remitters performed generally worse across the neuropsychological battery considered as a whole. Univariate testing showed a significant difference on only a single measure, the Continuous Performance Test d', when corrected for multiple comparisons. Baseline rigid, negative thinking did not predict treatment outcome. Results suggest that the structure of CBT may particularly benefit individuals with mild depression-related neurocognitive difficulties during a depressive episode. Further research is needed to examine these patient characteristics and their potential contribution to the mechanisms of CBT efficacy.

Suicide is the second leading cause of death among undergraduate students, with an annual rate of 7.5 per 100,000. Suicidal behavior (SB) is complex and heterogeneous, which might be explained by there being multiple etiologies of SB. Data-driven identification of distinct at-risk subgroups among undergraduates would bolster this argument. We conducted a latent class analysis (LCA) on survey data from a large convenience sample of undergraduates to identify subgroups, and validated the resulting latent class model on a sample of graduate students. Data were collected through the Interactive Screening Program deployed by the American Foundation for Suicide Prevention. LCA identified 6 subgroups from the undergraduate sample (N = 5654). In the group with the most students reporting current suicidal thoughts (N = 623, 66% suicidal), 22.5% reported a prior suicide attempt, and 97.6% endorsed moderately severe or worse depressive symptoms. Notably, LCA identified a second at-risk group (N = 662, 27% suicidal), in which only 1.5% of respondents noted moderately severe or worse depressive symptoms. When graduate students (N = 1138) were classified using the model, a similar frequency distribution of groups was found. Finding multiple replicable groups at-risk for suicidal behavior, each with a distinct prevalence of risk factors, including a group of students who would not be classified as high risk with depression-based screening, is consistent with previous studies that identified multiple potential etiologies of SB.

Background Major depressive disorder (MDD) is associated with impaired attention control and alterations in frontal-subcortical connectivity. We hypothesized that attention control as assessed by Stroop task interference depends on white matter integrity in fronto-cingulate regions and assessed this relationship using diffusion tensor imaging (DTI) in MDD and healthy volunteers (HV). Methods DTI images and Stroop task were acquired in 29 unmedicated MDD patients and 16 HVs, aged 18–65 years. The relationship between Stroop interference and fractional anisotropy (FA) was examined using region-of-interest (ROI) and tract-based spatial statistics (TBSS) analyses. Results ROI analysis revealed that Stroop interference correlated positively with FA in left caudal anterior cingulate cortex (cACC) in HVs (r = 0.62, p = 0.01), but not in MDD (r = −0.05, p= 0.79) even after controlling for depression severity. The left cACC was among 4 ROIs in fronto-cingulate network where FA was lower in MDD relative to HVs (F(1,41) = 8.87, p = 0.005). Additionally, TBSS showed the same group interaction of differences and correlations, although only at a statistical trend level. Limitations The modest sample size limits the generalizability of the findings. Conclusions Structural connectivity of white matter network of cACC correlated with magnitude of Stroop interference in HVs, but not MDD. The cACC-frontal network, sub-serving attention control, may be disrupted in MDD. Less cognitive control may include enhanced effects of salience in HVs, or less effective response inhibition in MDD. Further studies of salience and inhibition components of executive function may better elucidate the relationship between brain white matter changes and executive dysfunction in MDD.

Lipid microdomains (‘lipid rafts’) are plasma membrane subregions, enriched in cholesterol and glycosphingolipids, which participate dynamically in cell signaling and molecular trafficking operations. One strategy for the study of the physicochemical properties of lipid rafts in model membrane systems has been the use of nuclear magnetic resonance (NMR), but until now this spectroscopic method has not been considered a clinically relevant tool. We performed a proof-of-concept study to test the feasibility of using NMR to study lipid rafts in human tissues. Platelets were selected as a cost-effective and minimally invasive model system in which lipid rafts have previously been studied using other approaches. Platelets were isolated from plasma of medication-free adult research participants (n=13) and lysed with homogenization and sonication. Lipid-enriched fractions were obtained using a discontinuous sucrose gradient. Association of lipid fractions with GM1 ganglioside was tested using HRP-conjugated cholera toxin B subunit dot blot assays. 1H high resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) spectra obtained with single-pulse Bloch decay experiments yielded spectral linewidths and intensities as a function of temperature. Rates of lipid lateral diffusion that reported on raft size were measured with a two-dimensional stimulated echo longitudinal encode-decode NMR experiment. We found that lipid fractions at 10–35% sucrose density associated with GM1 ganglioside, a marker for lipid rafts. NMR spectra of the membrane phospholipids featured a prominent ‘centerband’ peak associated with the hydrocarbon chain methylene resonance at 1.3 ppm; the linewidth (full width at half-maximum intensity) of this ‘centerband’ peak, together with the ratio of intensities between the centerband and ‘spinning sideband’ peaks, agreed well with values reported previously for lipid rafts in model membranes. Decreasing temperature produced decreases in the 1.3 ppm peak intensity and a discontinuity at ~18 °C, for which the simplest explanation is a phase transition from Ld to Lo phases indicative of raft formation. Rates of lateral diffusion of the acyl chain lipid signal at 1.3 ppm, a quantitative measure of microdomain size, were consistent with lipid molecules organized in rafts. These results show that HRMAS NMR can characterize lipid microdomains in human platelets, a methodological advance that could be extended to other tissues in which membrane biochemistry may have physiological and pathophysiological relevance., Graphical abstract fx1, Highlights • Lipid raft properties have been studied mainly in model membranes or cell cultures. • We report a novel 1H NMR approach to lipid raft characterization in human platelets. • We find spectroscopy, diffusion, and phase transitions consistent with lipid rafts. • NMR plus bioassays may be used to study raft-mediated cell function in human tissues.

Aims To determine (1) the prevalence of SubD states among adults with diabetes, and (2) whether evidence exists of an independent association between diabetes status and SubD, controlling for selected confounders. Methods Data from the 2007–2012 National Health and Nutrition Examination Surveys were combined to estimates of depressive states by diabetes status among the noninstitutionalized U.S. adult population, and to assess the association of diabetes status and depressive states using a polytomous logistic regression model. Results An estimated 17%, or 3.7 million, of U.S. adults with diabetes (diagnosed and undiagnosed) met criteria for either mD or ssD. The majority of SubD cases with diabetes were found to be ssD (10.1%) compared with mD (6.9%). After controlling for the effects of age, sex, race and ethnicity, education, body mass index, and poverty as covariates, an independent association persists between diagnosed diabetes and each SubD grouping (ssD: OR=1.82, CIs 1.33, 2.47; mD: OR=1.95, CIs 1.39, 2.74) compared with respondents having no diabetes. No association was found between depression and undiagnosed diabetes or prediabetes compared with those having no diabetes. Conclusion Milder forms of depression such as ssD and mD are more extant than major depressive episodes among adults with diabetes. The odds that an adult with diagnosed diabetes meets the criteria for ssD or mD are higher by 80% and 95%, respectively, after controlling for age, sex, race and ethnicity, education, body mass index, and poverty factors when compared against adults with no diabetes.

Background Personality dysfunction represents one of the only predictors of differential response between active treatments for depression to have replicated. We examine whether depressed patients with higher neuroticism scores, a marker of personality dysfunction, show differences compared with depressed patients with lower scores in the functioning of two brain regions associated with treatment response, the anterior cingulate and anterior insula cortices. Methods Functional magnetic resonance imaging data during an emotional Stroop task were collected from 135 adults with major depressive disorder at four academic medical centers participating in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) study. Secondary analyses were conducted including a sample of 28 healthy subjects. Results In whole-brain analyses, higher neuroticism among adults with depression was associated with increased activity in and connectivity with the right anterior insula cortex to incongruent compared with congruent emotional stimuli (all k ≥ 281, all p p Conclusions This study provides convergent evidence for the importance of the right anterior insula cortex as a brain-based marker of clinically meaningful individual differences in neuroticism among adults with depression. This is a critical next step in linking personality dysfunction, a replicated clinical predictor of differential antidepressant treatment response, with differences in underlying brain function.

Resumen Objetivo Examinar las propiedades psicometricas de la version en espanol de la escala C-SSRS (Sp-CSSRS). Metodo Estudio de validacion naturalista, transversal y multicentrico. Muestra: 467 pacientes psiquiatricos ambulatorios (242 con tentativa de suicidio previa). Instrumentos: C-SSRS; Escala de Hamilton para la Depresion (HDRS); Escala de Intencionalidad Suicida de Beck; Escala de Gravedad Medica de la Tentativa (MDS). Resultados Validez del constructo: el coeficiente de Pearson entre la subescala de gravedad (C-Grave) y la de intensidad (C-Int) de la Sp-C-SSRS fue 0,44 (p Conclusion La Sp-C-SSRS es un instrumento fiable y valido para evaluar la ideacion y la conducta suicidas en la practica clinica y en contextos de investigacion.

Summary 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.

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.

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.

Objective To develop a brief and reliable psychometric scale to identify individuals at risk for suicidal behaviour. Method 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 the 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.

Resumen Objetivo Desarrollar una escala breve y fiable para identificar a las personas en riesgo de conducta suicida. Metodo Diseno: estudio de caso-control. Muestra y centro: 182 individuos (61 personas que intentaron suicidarse, 57 controles psiquiatricos y 64 controles sanos) con una edad de 18 anos o mas, admitidos en la Unidad de Urgencias del Hospital Universitario Puerta de Hierro de Madrid, Espana. Mediciones: todos los participantes rellenaron un formulario que incluia sus caracteristicas sociodemograficas y clinicas, y la Escala de Personalidad y Acontecimientos Vitales (27 cuestiones). Para evaluar los diagnosticos del Eje I, a todos los pacientes psiquiatricos (incluyendo a las personas que intentaron suicidarse) se les realizo la Entrevista Neuropsiquiatrica Internacional. Analisis estadistico: se aplico estadistica descriptiva para los factores sociodemograficos. Ademas, se aplicaron las pruebas de independencia de χ2 para evaluar las diferencias de las variables sociodemograficas y clinicas, y de la Escala de Personalidad y Acontecimientos Vitales entre grupos. Se llevo a cabo una regresion lineal escalonada con seleccion de variable retrospectiva para elaborar la escala abreviada de Personalidad y Acontecimientos Vitales (S-PLE). A fin de evaluar la precision se realizo un analisis de ROC. Se evaluo la fiabilidad interna utilizando la α de Cronbach, y la fiabilidad externa mediante un procedimiento de prueba-reprueba. Resultados La escala S-PLE, que se compone unicamente de 6 cuestiones, reflejo un buen desempeno al discriminar los controles sanos, los controles psiquiatricos y los intentos de suicidio en una muestra independiente. Por ejemplo, la escala S-PLE discrimino a las personas que intentaron suicidarse y a las que no lo hicieron en el pasado, con una sensibilidad del 80% y una especificidad del 75%. El area bajo la curva ROC fue del 88%. Un analisis factorial extrajo solamente un factor, lo que revela la dimension unica de la escala S-PLE. Ademas, la escala S-PLE aporta valores de fiabilidad interna y externa que se incluyen dentro de los rangos debil (prueba-reprueba: 0,55) y aceptable (α de Cronbach: 0,65). El tiempo de realizacion es de alrededor de un minuto. Conclusiones La escala S-PLE es un instrumento util y preciso para calcular el riesgo de conducta suicida en centros asistenciales donde escasea el tiempo.

Neuropsychological dysfunction is associated with risk for suicidal behavior, but it is unknown if antidepressant medication treatment is effective in reducing this dysfunction, or if specific medications might be more beneficial. A comprehensive neuropsychological battery was administered at baseline and after eight weeks of treatment within a randomized, double-blind clinical trial comparing paroxetine and bupropion in study of patients with DSM-IV major depressive disorder and either past suicide attempt or current suicidal thoughts. Change in neurocognitive performance was compared between assessments and between medication groups. Treatment effects on Hamilton Depression Rating Scale and Scale for Suicidal Ideation were compared with neurocognitive improvement. Neurocognitive functioning improved after treatment in all patients, without clear advantage for either medication. Improvement in memory performance was associated with a reduction in suicidal ideation independent of the improvement of depression severity. Overall, antidepressant medication improved neurocognitive performance in patients with major depression and suicide risk. Reduced suicidal ideation was best predicted by a combination of the independent improvements in both depression symptomatology and verbal memory. Targeted treatment of neurocognitive dysfunction in these patients may augment standard medication treatment for reducing suicidal behavior risk.

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.

Considerable evidence suggests that testosterone may play a role in the pathophysiology of mood disorders in females. This is the first prospective study to examine whether blood testosterone levels predict suicide attempts in females with bipolar disorder.Females with a DSM-IV diagnosis of a bipolar disorder in a depressive or mixed episode with at least one past suicide attempt were enrolled. Demographic and clinical parameters were assessed and recorded. Plasma testosterone was assayed using a double antibody radioimmunoassay procedure. Patients were followed up prospectively for up to 2.5 years.At baseline, testosterone levels positively correlated with the number of previous major depressive episodes and suicide attempts. Cox proportional hazards regression analysis found that higher baseline testosterone levels predicted suicide attempts during the follow-up period.A limitation of the study is that the sample size is modest. Another limitation is that we did not have a bipolar nonattempter or healthy volunteer control group for comparison.Testosterone levels may predict suicidal behavior in women with bipolar disorder.

Brain Derived Neurotrophic Factor (BDNF) regulates brain synaptic plasticity. BDNF affects serotonin signaling, increases serotonin levels in brain tissue and prevents degeneration of serotonin neurons. These effects have hardly been studied in human brain. We examined the relationship of the functional val66met polymorphism of the BDNF gene to serotonin 1A (5-HT(1A)) receptor binding in vivo. 50 healthy volunteers (HV) and 50 acutely depressed, unmedicated patients with major depressive disorder (MDD) underwent PET scanning with the 5-HT(1A) receptor ligand, [(11)C]WAY-100635 and a metabolite corrected arterial input function. A linear mixed effects model compared 5-HT(1A) receptor binding potential (BP(F), proportional to the number of available receptors) in 13 brain regions of interest between met allele carriers (met/met and val/met) and noncarriers (val/val) using sex and C-1019G genotype of the 5-HT(1A) receptor promoter functional polymorphism as covariates. There was an interaction between diagnosis and allele (F=4.23, df=1, 94, p=0.042), such that met allele carriers had 17.4% lower BP(F) than non-met carriers in the HV group (t=2.6, df=96, p=0.010), but not in the MDD group (t=-0.4, df=96, p=0.58). These data are consistent with a model where the met allele of the val66met polymorphism causes less proliferation of serotonin synapses, and consequently fewer 5-HT(1A) receptors. In MDD, however, the effect of the val66met polymorphism is not detectable, possibly due to a ceiling effect of over-expression of 5-HT(1A) receptors in mood disorders.

Few studies have examined white matter abnormalities in suicide attempters using diffusion tensor imaging (DTI). This study sought to identify white matter regions altered in individuals with a prior suicide attempt.DTI scans were acquired in 13 suicide attempters with major depressive disorder (MDD), 39 non-attempters with MDD, and 46 healthy participants (HP). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were determined in the brain using two methods: region of interest (ROI) and tract-based spatial statistics (TBSS). ROIs were limited a priori to white matter adjacent to the caudal anterior cingulate cortex, rostral anterior cingulate cortex, dorsomedial prefrontal cortex, and medial orbitofrontal cortex.Using the ROI approach, suicide attempters had lower FA than MDD non-attempters and HP in the dorsomedial prefrontal cortex. Uncorrected TBSS results confirmed a significant cluster within the right dorsomedial prefrontal cortex indicating lower FA in suicide attempters compared to non-attempters. There were no differences in ADC when comparing suicide attempters, non-attempters and HP groups using ROI or TBSS methods.Low FA in the dorsomedial prefrontal cortex was associated with a suicide attempt history. Converging findings from other imaging modalities support this finding, making this region of potential interest in determining the diathesis for suicidal behavior.

While prominent models of suicidal behavior emphasize the hypothalamic- pituitary-adrenal (HPA) axis dysregulation, studies examining its role have yielded contradictory results. One possible explanation is that suicide attempters are a heterogeneous group and HPA axis dysregulation plays a more important role only in a subset of suicidal individuals. HPA axis dysregulation also plays a role in impulsivity and aggression. We hypothesize subgroups of attempters, based on levels of impulsivity and aggression, will differ in HPA axis dysregulation. We examined baseline cortisol, total cortisol output, and cortisol reactivity in mood disordered suicide attempters (N = 35) and non-attempters (N = 37) during the Trier Social Stress Test. Suicide attempters were divided into four subgroups: low aggression/low impulsivity, high aggression/low impulsivity, low aggression/high impulsivity, and high aggression/high impulsivity. As hypothesized, attempters and non-attempters did not differ in any cortisol measures while stress response differed based on impulsivity/aggression levels in suicide attempters, and when compared to non-attempters. Specifically, attempters with high impulsive aggression had a more pronounced cortisol response compared with other groups. This is the first study to examine the relationship between cortisol response and suicidal behavior in impulsive aggressive subgroups of attempters. These findings may help to identify a stress responsive suicidal subtype of individuals.