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In most positron emission tomography (PET) molecular brain imaging studies, regions of interest have been defined anatomically and examined in isolation. However, by defining regions based on physiology and examining relationships between them, we may derive more sensitive measures of receptor abnormalities in conditions such as major depressive disorder (MDD). Using an average of 52 normalized binding potential maps, acquired using radiotracer [11C]-WAY100635 and full arterial input analysis, we identified two molecular volumes of interest (VOIs) with contiguously high serotonin 1A receptor (5-HT1A) binding sites: the olfactory sulcus (OLFS) and a band of tissue including piriform, olfactory, and entorhinal cortex (PRF). We applied these VOIs to a separate cohort of 25 healthy control males and 16 males with MDD who received [11C]-WAY100635 imaging. Patients with MDD had significantly higher binding than controls in both VOIs, ( p 1A autoreceptors and post-synaptic receptors in molecular VOIs. Molecular connectivity was significant in healthy controls ( p

Kious and Battin (2019) describe a pressing and profound ethical dilemma in psychiatry. This dilemma is rooted in conceptual parity—the view that psychiatric illness and somatic illnesses exist wit...

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.

Serotonin 1A (5-HT1A ) receptors play a direct role in neuronal development, cell proliferation, and dendritic branching. We hypothesized that variability in 5-HT1A binding can affect cortical thickness, and may account for a subtype of major depressive disorder (MDD) in which both are altered. To evaluate this, we measured cortical thickness from structural magnetic resonance imaging (MRI) and 5-HT1A binding by positron emission tomography (PET) in an exploratory study. To examine a range of 5-HT1A binding and cortical thickness values, we recruited 25 healthy controls and 19 patients with MDD. We hypothesized increased 5-HT1A binding in the raphe nucleus (RN) would be negatively associated with cortical thickness due to reduced serotonergic transmission. Contrary to our hypothesis, raphe 5-HT1A binding was positively correlated with cortical thickness in right posterior cingulate cortex (PCC), a region implicated in the default mode network. Cortical thickness was also positively correlated with 5-HT1A in each cortical region. We further hypothesized that the strength of 5-HT1A -cortical thickness correlation depends on the number of axons between the raphe nucleus and each region. To explore this we related 5-HT1A -cortical thickness correlation coefficients to the number of tracts connecting that region and the raphe, as measured by diffusion tensor imaging (DTI) in an independent sample. The 5-HT1A -cortical thickness association correlated significantly with the number of tracts to each region, supporting our hypothesis. We posit a defect in the raphe may affect the PCC within the default mode network in MDD through serotonergic fibers, resulting in increased ruminative processing.

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.

OBJECTIVE To examine whether bipolar disorder and borderline personality disorder represent 2 different disorders or alternative manifestations of the same disorder. METHODS The data were collected between January 1, 2004, and December 31, 2005. The analyses were conducted between December 21 and December 27, 2010. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed on 25 symptoms assessing depression, mania, and borderline personality disorder from the National Epidemiologic Survey on Alcohol and Related Conditions, a large nationally representative sample of the US adult population (N = 34,653). DSM-IV criteria were used for diagnosis of bipolar disorder and borderline personality disorder. RESULTS A 3-factor solution provided an excellent fit in both the EFA (root mean square error of approximation [RMSEA] = 0.017, comparative fix index [CFI] = 0.997) and the CFA (RMSEA = 0.024, CFI = 0.993). Factor 1 (Borderline Personality Disorder) loaded on all 9 borderline personality disorder symptoms, factor 2 (Depression) loaded on 8 symptoms of depression, and factor 3 (Mania) loaded on 7 symptoms of mania plus the psychomotor agitation item of the depression section. The correlations between the Borderline Personality Disorder and Depression factors (r = 0.328) and between the Borderline Personality Disorder and Mania factors (r = 0.394) were lower than the correlation between Depression and Mania factors (r = 0.538). CONCLUSIONS A model with 3 positively correlated factors provided an excellent fit for the latent structure of borderline personality disorder and bipolar disorder symptoms. The pattern of pairwise correlations between the 3 factors is consistent with the clinical presentation of 2 syndromes (depression and mania) that can be characterized as a unitary psychiatric entity (bipolar disorder) and a third syndrome (borderline personality disorder) that is often comorbid with bipolar disorder. The findings converge in suggesting that bipolar disorder and borderline personality disorder are overlapping but different pathologies. These findings may serve to inform ongoing efforts to refine the existing psychiatric nosology and to suggest new avenues for etiologic and treatment research.

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.

Objective:Bipolar disorder is associated with high risk for suicidal behavior that often develops in adolescence and young adulthood. Elucidation of involved neural systems is critical for prevention. This study of adolescents and young adults with bipolar disorder with and without a history of suicide attempts combines structural, diffusion tensor, and functional MR imaging methods to investigate implicated abnormalities in the morphology and structural and functional connectivity within frontolimbic systems.Method:The study had 26 participants with bipolar disorder who had a prior suicide attempt (the attempter group) and 42 participants with bipolar disorder without a suicide attempt (the nonattempter group). Regional gray matter volume, white matter integrity, and functional connectivity during processing of emotional stimuli were compared between groups, and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors.Results:Comp...

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.

Objectives To evaluate feasibility and effects of a sub-anesthetic infusion dose of ketamine versus midazolam on suicidal ideation in bipolar depression. Neurocognitive, blood and saliva biomarkers were explored. Methods Sixteen participants with bipolar depression and a Scale for Suicidal Ideation (SSI) score of ≥4 were randomized to ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg). Current pharmacotherapy was maintained excluding benzodiazepines within 24 hours. The primary clinical outcome was SSI score on day 1 post-infusion. Results Results supported feasibility. Mean reduction of SSI after ketamine infusion was almost 6 points greater than after midazolam, although this was not statistically significant (estimate=5.84, SE=3.01, t=1.94, P=.074, 95% confidence interval ([CI)]=−0.65 to 12.31). The number needed to treat for response (SSI

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.

We aimed to examine the relationship between religion and suicide attempt and ideation. Three hundred twenty-one depressed patients were recruited from mood-disorder research studies at the New York State Psychiatric Institute. Participants were interviewed using the Structured Clinical Interview for DSM Disorders, Columbia University Suicide History form, Scale for Suicide Ideation, and Reasons for Living Inventory. Participants were asked about their religious affiliation, importance of religion, and religious service attendance. We found that past suicide attempts were more common among depressed patients with a religious affiliation (odds ratio, 2.25; p = 0.007). Suicide ideation was greater among depressed patients who considered religion more important (coefficient, 1.18; p = 0.026) and those who attended services more frequently (coefficient, 1.99; p = 0.001). We conclude that the relationship between religion and suicide risk factors is complex and can vary among different patient populations. Physicians should seek deeper understanding of the role of religion in an individual patient's life in order to understand the person's suicide risk factors more fully.

A Silent Contributor to Opioid-Overdose Deaths Most strategies for reducing opioid-overdose deaths don’t include screening for suicide risk or address tailoring of interventions for suicidal persons. And the inaccuracy of data on the proportion of opioid deaths that are suicides hinders appropriate prevention.

Although recent years have seen large decreases in the overall global rate of suicide fatalities, this trend is not reflected everywhere. Suicide and suicidal behaviour continue to present key challenges for public policy and health services, with increasing suicide deaths in some countries such as the USA. The development of suicide risk is complex, involving contributions from biological (including genetics), psychological (such as certain personality traits), clinical (such as comorbid psychiatric illness), social and environmental factors. The involvement of multiple risk factors in conveying risk of suicide means that determining an individual’s risk of suicide is challenging. Improving risk assessment, for example, by using computer testing and genetic screening, is an area of ongoing research. Prevention is key to reduce the number of suicide deaths and prevention efforts include universal, selective and indicated interventions, although these interventions are often delivered in combination. These interventions, combined with psychological (such as cognitive behavioural therapy, caring contacts and safety planning) and pharmacological treatments (for example, clozapine and ketamine) along with coordinated social and public health initiatives, should continue to improve the management of individuals who are suicidal and decrease suicide-associated morbidity. Suicide and suicidal behaviour continue to present key challenges for public policy and health services. This Primer discusses the global burden of suicide and suicidal behaviours, and provides an overview of our current understanding of the mechanisms of suicide, including risk factors for suicidal ideation and the transition from ideation to suicide attempt.

Objective: Suicidal ideation (SI) is heterogeneous with different patterns and risk factors. SI can be persistent with stable severity, but may also fluctuate rapidly over a short period of time. The latter pattern is likely associated with affective instability and may consist of activation of SI at times of stress, that then subside. Although affective instability is a hallmark of borderline personality disorder (BPD), little is known about SI variability in BPD. We hypothesized that SI variability would be associated with affective instability in BPD suicide attempters. Method: Sample included 38 females with BPD and history of suicidal behavior. SI was assessed over 1 week using ecological momentary assessment (EMA) at six epochs daily. The relationship between SI variability (i.e., change of SI from one epoch to another) and SI severity (i.e., average scores across epochs), and affective instability, assessed using the Affective Lability Scale (ALS), were examined. Possible confounding effects of depression severity and impulsiveness were tested. Results: Participants demonstrated high ALS scores and wide range of SI variability. ALS scores predicted SI variability, even after controlling for depression severity. Although ALS also predicted SI severity, this association was driven by depression severity. ALS did not correlate with impulsiveness score. Conclusions: Affective instability may predict SI variability in BPD suicide attempters independent of depression severity. This supports our model of suicidal subgroups with different constellations of clinical aspects and risk factors. Future studies could examine these associations in larger samples and different populations to determine implications for suicide prevention.

Growing evidence suggests that the glutamatergic modulator ketamine has rapid antidepressant effects in treatment-resistant depressed subjects. The anticholinergic agent scopolamine has also shown promise as a rapid-acting antidepressant. This study applied genome-wide markers to investigate the role of genetic variants in predicting acute antidepressant response to both agents. The ketamine-treated sample included 157 unrelated European subjects with major depressive disorder (MDD) or bipolar disorder (BD). The scopolamine-treated sample comprised 37 unrelated European subjects diagnosed with either MDD or BD who had a current Major Depressive Episode (MDE), and had failed at least two adequate treatment trials for depression. Change in Montgomery-Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) scale scores at day 1 (24 h post-treatment) was considered the primary outcome. Here, we conduct pilot genome-wide association study (GWAS) analyses to identify potential markers of ketamine response and dissociative side effects. Polygenic risk score analysis of SNPs ranked by the strength of their association with ketamine response was then calculated in order to assess whether common genetic markers from the ketamine study could predict response to scopolamine. Findings require replication in larger samples in light of low power of analyses of these small samples. Neverthless, these data provide a promising illustration of our future potential to identify genetic variants underlying rapid treatment response in mood disorders and may ultimately guide individual patient treatment selection in the future.

Patients with major depressive disorder (MDD) present with heterogeneous symptom profiles, while neurobiological mechanisms are still largely unknown. Brain network studies consistently report disruptions of resting-state networks (RSNs) in patients with MDD, including hypoconnectivity in the frontoparietal network (FPN), hyperconnectivity in the default mode network (DMN), and increased connection between the DMN and FPN. Using a large, multisite fMRI dataset (n = 189 patients with MDD, n = 39 controls), we investigated network connectivity differences within and between RSNs in patients with MDD and healthy controls. We found that MDD could be characterized by a network model with the following abnormalities relative to controls: (i) lower within-network connectivity in three task-positive RSNs [FPN, dorsal attention network (DAN), and cingulo-opercular network (CON)], (ii) higher within-network connectivity in two intrinsic networks [DMN and salience network (SAN)], and (iii) higher within-network connectivity in two sensory networks [sensorimotor network (SMN) and visual network (VIS)]. Furthermore, we found significant alterations in connectivity between a number of these networks. Among patients with MDD, a history of childhood trauma and current symptoms quantified by clinical assessments were associated with a multivariate pattern of seven different within- and between-network connectivities involving the DAN, FPN, CON, subcortical regions, ventral attention network (VAN), auditory network (AUD), VIS, and SMN. Overall, our study showed that traumatic childhood experiences and dimensional symptoms are linked to abnormal network architecture in MDD. Our results suggest that RSN connectivity may explain underlying neurobiological mechanisms of MDD symptoms and has the potential to serve as an effective diagnostic biomarker.

BACKGROUND Serotonin transporter (5-HTT) binding and polyunsaturated fatty acids (PUFAs) are implicated in major depressive disorder (MDD). Links between the two systems in animal models have not been investigated in humans. METHODS Using positron emission tomography (PET) and [ 11 C]DASB, we studied relationships between 5-HTT binding potential and plasma levels of PUFAs docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) in medication-free MDD patients ( n =21). PUFAs were quantified using transesterification and gas chromatography. Binding potential BP P , and alternative outcome measures BP F and BP ND , were determined for [ 11 C]DASB in six a priori brain regions of interest (ROIs) using likelihood estimation in graphical analysis (LEGA) to calculate radioligand total distribution volume (V T ), and a validated hybrid deconvolution approach (HYDECA) that estimates radioligand non-displaceable distribution volume (V ND ) without a reference region. Linear mixed models used PUFA levels as predictors and binding potential measures as outcomes across the specified ROIs; age and sex as fixed effects; and subject as random effect to account for across-region binding correlations. As nonlinear relationships were observed, a quadratic term was added to final models. RESULTS AA predicted both 5-HTT BP P and depression severity nonlinearly, described by an inverted U-shaped curve. 5-HTT binding potential mediated the relationship between AA and depression severity. LIMITATIONS Given the small sample and multiple comparisons, results require replication. CONCLUSIONS Our findings suggest that AA status may impact depression pathophysiology through effects on serotonin transport. Future studies should examine whether these relationships explain therapeutic effects of PUFAs in the treatment of MDD.

Background: In sub-Saharan Africa, mental and substance-related disorders account for 19% of all years lived with disability, yet the intersection between poverty and mental distress is poorly understood since most psychiatric research is conducted in high-income countries. Aims: To examine the prevalence of and associations between food insecurity, mental distress and suicidal ideation in three rural village clusters in sub-Saharan Africa. Method: Cross-sectional multivariate analysis of sociodemographic variables associated with mental distress and suicidal ideation in three countries. The sample included 1,142 individuals from three rural village clusters in Nigeria ( n = 380), Uganda ( n = 380) and Ghana ( n = 382). Food insecurity was measured based on the number of months in the previous year that the respondent’s family reported being ‘unable to eat two square meals per day’. Mental distress was assessed using the Kessler non-specific psychological distress scale (K6) and suicidal ideation was measured using an item from PRIME-MD. Other sociodemographic variables included gender, age, literacy and occupation. Results: The prevalence of individuals with moderate or severe mental distress in Nigeria, Uganda and Ghana were higher than previously reported in the literature: 35.5%, 30.8% and 30.4%, respectively, and suicidal ideation rates were 29.7%, 21.3% and 10.9%. No differences were observed in mental distress between men and women in any of the sites. Being a farmer (vs student or other) was protective for mental distress in two sites (Uganda and Ghana) but no other social indicators, such as age, gender, literacy and food insecurity, were significantly associated with mental distress. Risk for suicidal ideation differed across sites: it was associated with food insecurity in Nigeria, female gender in Uganda, and older age in Uganda. Conclusions: Mental distress and suicidal ideation were highly prevalent in three settings of extreme poverty across all groups, in ways that were not always consistent with the global literature. These findings suggest that more research is needed in to better understand the social etiology of mental distress in sub-Saharan Africa.

Structural brain deficits are linked to risk for suicidal behavior. However, there is disagreement about the nature of these deficits, probably due to the heterogeneity of suicidal behavior in terms of the suicidal act's lethality. We hypothesized that individuals with major depressive disorder (MDD) and history of more lethal suicide attempts would have lower gray matter volume (GMV) of the prefrontal regions and insula compared with MDD lower-lethality attempters and MDD non-attempters. We collected structural MRI scans on 91 individuals with MDD; 11 with history of higher-lethality suicide attempts, 14 with lower-lethality attempts, and 66 were non-attempters. Differences in GMV between these three groups were examined using both regions-of-interest (ROI) and brain-wide voxel-based morphometry (VBM) analyses. Both ROI and VBM analyses showed that higher-lethality suicide attempters have greater GMV of the prefrontal cortical regions and insula, compared with the other two groups. Although this contrasts with our hypothesis, the observed larger prefrontal cortex GMV in higher-lethality suicide attempters may underlie the set of attributes observed previously in this suicidal subgroup, including enhanced suicide attempt planning, greater response inhibition, and delayed reward capabilities. Future studies should further examine the role of these brain regions in relation to suicidal intent and planning.

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.

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. Language: en

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.

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.

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.

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.

This study aimed to identify biomarkers of major depressive disorder (MDD), by relating neuroimage-derived measures to binary (MDD/control), ordinal (severe MDD/mild MDD/control), or continuous (depression severity) outcomes. To address MDD heterogeneity, factors (severity of psychic depression, motivation, anxiety, psychosis and sleep disturbance) were also used as outcomes. A multi-site, multimodal imaging (diffusion MRI, dMRI, and structural MRI, sMRI) cohort (52 controls and 147 MDD patients) and several modeling techniques- penalized logistic regression (PLR), random forest (RF) and support vector machine (SVM)- were used. An additional cohort (25 controls and 83 MDD patients) was used for validation. The optimally performing classifier (SVM) had a 26.0% misclassification rate (binary), 52.2±1.69% accuracy (ordinal) and r =0.36 correlation coefficient (p-value

OBJECTIVE: Based on previous findings that suicidal ideation (SI) and behavior (SB) arose in depressed preschoolers and showed stability into school age, we sought to investigate whether unique clinical and psychosocial correlates of SI/SB and non-suicidal self-injurious behaviors (NSSI) could be identified in young children recuited into a depression treatment study and healthy controls. METHOD: Data from n=288 3.0-6.11 year-old children recruited for participation in a psychotherapy treatment study of depression and n=26 healthy control subjects (total N=314) were used. At baseline, subjects received a comprehensive assessment of psychopathology and suicidal ideation/suicidal behavior. Multinominal logistic regressions were conducted comparing those with no SI/SB/NSSI to those with SI/SB or NSSI. Those with SI/SB who also had NSSI were placed in the SI/SB group. RESULTS: In this sample of young children, the rates of NSSI, SI, and SB were 21.3%, 19.1% and 3.5% respectively. Children with SI/SB or NSSI experienced a greater frequency of violent life events than children with no SI/SB/NSSI. Children with SI/SB had significantly more preoccupation with death compared to subjects with NSSI and subjects with no SI/SB/NSSI. Children with SI/SB had more vegetative signs of depression and greater depression severity and those with NSSI were more irritable with higher depression severity than those with no SI/SB/NSSI. CONCLUSION: Distinct characteristics of SI/SB and NSSI in early childhood were identified, informing high risk sub-groups. Findings suggest that clinicians should be aware of the potential for SI/SB and/or NSSI in young children and should directly address these symptoms in clinical interviews. CLINICAL TRIAL REGISTRATION INFORMATION: A Randomized Controlled Trial of PCIT-ED for Preschool Depression. https://clinicaltrials.gov/; NCT02076425.

Endogenous kappa opioids mediate pathological responses to stress in animal models. However, the relationship of the kappa opioid receptor (KOR) to life stress and to psychopathology in humans is not well described. This pilot study sought, for the first time, to quantify KOR in major depressive disorder (MDD) in vivo in humans using positron emission tomography (PET). KOR binding was quantified in vivo by PET imaging with the [11 C]GR103545 radiotracer in 13 healthy volunteers and 10 participants with current MDD. We examined the relationship between regional [11 C]GR103545 total volume of distribution (VT ) and diagnosis, childhood trauma, recent life stress, and, in a subsample, salivary cortisol levels during a modified Trier Social Stress Test (mTSST), amygdala, hippocampus, ventral striatum and raphe nuclei. Whole-brain voxel-wise analyses were also performed. [11 C]GR103545 VT did not differ significantly between MDD participants and healthy volunteers in the four a priori ROIs (p = 0.50). [11 C]GR103545 VT was unrelated to reported childhood adversity (p = 0.17) or recent life stress (p = 0.56). A trend-level inverse correlation was observed between [11 C]GR103545 VT and cortisol area-under-the curve with respect to ground during the mTSST (p = 0.081). No whole-brain voxel-wise contrasts were significant. Regional [11 C]GR103545 VT , a measure of in vivo KOR binding, does not differentiate MDD from healthy volunteers in this pilot sample. Future studies may examine KOR binding in subgroups of depressed individuals at increased risk for KOR abnormalities, including co-occurring mood and substance use disorders, as well as depression with psychotic features.

Summary Although psychiatric disorders are classified as non-communicable diseases, we believe this classification is too rigid and limiting. We present evidence of the communicability of psychiatric disorders through three major pathways: infectious and ecological, familial, and sociocultural communicability. Successful strategies developed to control the spread of communicable infectious diseases are relevant to curtailing the communicability of psychiatric disorders, thereby reducing their burden. Current interventions and policies that conceptualise psychiatric illnesses as non-communicable mostly focus on the individual. By applying strategies from infectious disease and chronic illness prevention models within a socioecological framework, we posit a broad communicable chronic disease psychiatric illness control plan for effectively treating the patient with the psychiatric disorder (host) as early as possible, providing benefits to their family and the community, and preventing transmission to others.

Smoking is frequently associated with suicidal behavior, but also with confounding other risk factors. We investigated whether smoking independently predicts suicidal ideation, attempts (SAs), or modifies risk of SAs during major depressive episodes (MDEs). In the Vantaa Depression Study (VDS), a 5-year prospective study of psychiatric patients (N = 269) with major depressive disorder (MDD), we investigated the association of suicidal ideation and smoking, and smoking as an independent risk factor for SAs in 2-level analyses of risk during MDEs. Smoking was not significantly associated with suicidal ideation, nor SAs after controlling for confounding factors, and no evidence of a significant effect during MDEs was found. Smoking was neither significantly associated with suicidal ideation, nor predicted suicide attempts.

Cognitive reserve may mitigate the degree of cognitive deficit observed in Major Depressive Disorder (MDD), confounding attempts to fully characterize the nature of these deficits. In this study, cognitive reserve was examined as a potential moderator of neurocognitive deficits in MDD. Unmedicated, currently depressed patients with MDD (n = 269), and healthy volunteers (n = 143) were compared on measures assessing psychomotor speed, interference processing, verbal memory, visual memory, and executive functioning. Moderating effects of education level and estimated intelligence level were examined as interactions, along with age, in a regression model for each test. Differences between patients and non-patients were found with most measures, and sustained in regression models as main effects. However, the interaction of estimated intelligence and patient status was significant for processing speed, verbal memory, visual memory, and executive functioning, with patient/non-patient differences diminishing with higher estimated intelligence. Neither estimated intelligence nor education level impacted interference processing differences, which were reduced with increasing age. Better intellectual ability moderates the effect of MDD on neurocognitive test performance. This effect may confound attempts to characterize these deficits in higher functioning samples. More challenging tasks may be needed, given the potential predictive value of neurocognition for differential therapeutic and clinical outcomes.