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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

Abnormalities in brain structural measures, such as cortical thickness and subcortical volumes, are observed in patients with major depressive disorder (MDD) who also often show heterogeneous clinical features. This study seeks to identify the multivariate associations between structural phenotypes and specific clinical symptoms, a novel area of investigation. T1-weighted magnetic resonance imaging measures were obtained using 3 T scanners for 178 unmedicated depressed patients at four academic medical centres. Cortical thickness and subcortical volumes were determined for the depressed patients and patients' clinical presentation was characterized by 213 item-level clinical measures, which were grouped into several large, homogeneous categories by K-means clustering. The multivariate correlations between structural and cluster-level clinical-feature measures were examined using canonical correlation analysis (CCA) and confirmed with both 5-fold and leave-one-site-out cross-validation. Four broad types of clinical measures were detected based on clustering: an anxious misery composite (composed of item-level depression, anxiety, anhedonia, neuroticism and suicidality scores); positive personality traits (extraversion, openness, agreeableness and conscientiousness); reported history of physical/emotional trauma; and a reported history of sexual abuse. Responses on the item-level anxious misery measures were negatively associated with cortical thickness/subcortical volumes in the limbic system and frontal lobe; reported childhood history of physical/emotional trauma and sexual abuse measures were negatively correlated with entorhinal thickness and left hippocampal volume, respectively. In contrast, the positive traits measures were positively associated with hippocampal and amygdala volumes and cortical thickness of the highly-connected precuneus and cingulate cortex. Our findings suggest that structural brain measures may reflect neurobiological mechanisms underlying MDD features.

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].

The risk for major depression is common 30 days after treatment for early pregnancy loss, especially among Black women., OBJECTIVE: To explore the relationship between race and depression symptoms among participants in an early pregnancy loss clinical trial. METHODS: We performed a planned secondary analysis of a randomized trial by comparing treatments for medical management of early pregnancy loss. We hypothesized that Black participants would have higher odds of risk for major depression (measured with the CES-D [Center for Epidemiological Studies-Depression] scale) 30 days after early pregnancy loss treatment when compared with non-Black participants. We analyzed the data as a cohort, with the primary exposure being race and secondary exposure being high adverse childhood experience scores (measured with the Adverse Childhood Experience scale). Our primary outcome was risk for major depression (score of 21 or higher on the CES-D scale) 30 days after early pregnancy loss treatment. RESULTS: Three hundred participants diagnosed with a nonviable intrauterine pregnancy from 5 to 12 weeks of gestation were randomized as part of the original trial from May 2014 to April 2017. Of 275 respondents included in this analysis, 120 [44%] self-identified as Black and 155 [56%] self-identified as non-Black. After early pregnancy loss treatment, 65 [24%] participants were at risk for major depression. Black participants had an increased risk for major depression (57%) after early pregnancy loss treatment compared with non-Black participants (43%; odds ratio [OR] 2.02; 95% CI 1.15–3.55). After adjustment for risk for baseline depression, adverse childhood experience score, and parity, the odds of risk for major depression 30 days after pregnancy loss treatment remained higher for Black participants when compared with non-Black participants (OR 2.02; 95% CI 1.15–3.55; adjusted OR 2.48; 95% CI 1.28–4.81). CONCLUSION: Overall, approximately one quarter of women who experience an early pregnancy loss are at an increased risk for major depression 30 days after treatment. This risk is about twice as high for Black women compared with non-Black women. There is a need for appropriate mental health resources for women undergoing early pregnancy loss care. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02012491.

BackgroundTreatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner.MethodsIn the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16.ResultsGreater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline.ConclusionThese exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

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.

Suicidal behavior (SB) can be impulsive or methodical; violent or not; follow a stressor or no obvious precipitant. This study tested whether childhood trauma, affective lability, and aggressive and impulsive traits predicted greater SI variability. We also assessed whether affective lability, aggressive or impulsive traits explain childhood trauma’s effects on SI variability and whether those with highly variable SI respond to stressful events with increases in SI. Finally, we assessed variable SI’s trajectory over 2 years. Depressed participants (n = 51) had ecological momentary assessments (EMA) over 7 days at baseline, 3, 6, 12, 18, and 24 months. SI variability was assessed using the square Root of the Mean Square of Successive Deviations. Mixed Effects Models were fit as appropriate. Childhood trauma was associated with subsequent aggression. Physical abuse predicted both aggression and affective lability as well as SI variability, but not impulsivity. In two-predictor models, physical abuse’s effect on SI variability was no longer significant, when controlling for the effect of higher aggression and impulsivity. Those with high SI variability exhibited greater increases in SI after stressors compared with those with less variability. We did not find that SI variability changed over time, suggesting it might be trait-like, at least over 2 years. Variable SI predisposes to marked SI increases after stressful events and may be a trait increasing risk for impulsive SB, at least over 2 years.

BACKGROUND Researchers and clinicians have typically relied on retrospective reports to monitor suicidal thoughts and behaviors. Smartphone technology has made real-time monitoring of suicidal thoughts possible via mobile ecological momentary assessment (EMA). However, little is known about how information gleaned from EMA compares with that obtained by retrospective reports. The authors sought to compare suicidal ideation (SI) assessed over 1 week using EMA with a retrospective gold-standard interviewer-administered measure covering the same period. METHODS Fifty-one adults with major depressive disorder completed 1 week of EMA (6×/day) assessing SI. Following completion of EMA, participants completed an interviewer-administered Scale for Suicide Ideation (SSI) retrospectively assessing the same week. RESULTS SI severity assessed through EMA was positively correlated with scores on the retrospective SSI. However, 58% of participants reporting ideation with EMA denied any past-week ideation on the SSI. Participants who endorsed SI during EMA but not on the SSI were no less likely to have a history of suicidal behavior than those who reported SI in both formats. CONCLUSION EMA captures instances of suicidal thinking that go undetected through retrospective report and thereby may help us to identify an at-risk subgroup otherwise missed.

Serotonergic dysfunction is implicated in major depressive disorder (MDD), but the mechanisms of this relationship remain elusive. Serotonin 1A (5-HT1A) autoreceptors regulate brain-wide serotonin neuron firing and are positioned to assert large-scale effects on negative emotion. Here we investigated the relationship between raphe 5-HT1A binding and brain-wide network dynamics of negative emotion. 22 healthy-volunteers (HV) and 27 medication-free participants with MDD underwent positron emission tomography (PET) using [11C]CUMI-101 (CUMI) to quantify 5-HT1A binding in midbrain raphe nuclei and functional magnetic resonance imaging (fMRI) scanning during emotionally negative picture viewing. Causal connectivity across regions responsive to negative emotion was estimated in the fMRI data using a multivariate dynamical systems model. During negative picture viewing, MDD subjects demonstrated significant hippocampal inhibition of amygdala, basal-ganglia, thalamus, orbital frontal cortex, inferior frontal gyrus and dorsomedial prefrontal cortex (IFG, dmPFC). MDD-related connectivity was not associated with raphe 5-HT1A binding. However, greater hippocampal inhibition of amygdala, thalamus, IFG and dmPFC correlated with hippocampal 5-HT1A binding. Correlation between hippocampal 5-HT1A binding and the hippocampal inhibition network was specific to MDD but not HV. MDD and HV groups also differed with respect to the correlation between raphe and hippocampal 5-HT1A binding which was more pronounced in HV. These findings suggest that increased hippocampal network inhibition in MDD is linked to hippocampal serotonergic dysfunction which may in turn arise from disrupted linkage in raphe to hippocampus serotonergic circuitry.

Prior research suggests that sleep disturbances are associated with increased risk of suicide. However, sleep disturbances are associated with a wide range of psychiatric disorders, and it is unknown whether this association is independent of psychopathology. In a large nationally representative prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we used structural equation modeling to examine the shared and specific effects of three sleep complaints (i.e., trouble falling asleep, early morning awakening, and hypersomnia) on the 3-year occurrence of attempting suicide. Because psychiatric disorders increase the risk of suicide attempt almost exclusively through a general psychopathology factor representing their shared effect, covariates included that factor, prior history of suicide attempt, and a wide range of sociodemographic and clinical characteristics. The 3-year prevalence rate of suicide attempt was 0.6% (n = 241). Compared with participants who did not attempt suicide between the two waves, those who did reported significantly more frequently having trouble falling asleep (44.6% vs. 16.6%), early morning awakening (38.9% vs. 12.7%), and hypersomnia (35.0% vs. 10.7%). Following adjustments, effects of sleep complaints on this risk were significant and exerted almost exclusively through a general sleep complaints factor representing the shared effect across all sleep complaints. There were no residual associations of any individual sleep complaint with attempting suicide above that association. Sleep complaints are associated with an increased risk of attempting suicide independently of psychopathology, and should be included in suicide risk assessments as these symptoms may provide targets for reducing the risks of suicidal behaviors.

Despite increased access to mental health care for the previously uninsured and expanding evidence-based treatments for mood, anxiety, psychotic, and substance use disorders, suicide is on the rise in the United States. Since 1999, the age-adjusted suicide rate in the United States has increased 33%, from 10.5 per 100,000 standard population to 14.0. As of yet, there are no clinically available biomarkers, laboratory tests, or imaging to assist in diagnosis or the identification of the suicidal individual. Suicide risk assessment remains a high-stakes component of the psychiatric evaluation and can lead to overly restrictive management in the name of prevention or to inadequate intervention because of poor appreciation of the severity of risk. This article focuses primarily on suicide risk assessment and management as a critical first step to prevention, given the fact that more research is needed to identify precision treatments and effective suicide prevention strategies. Suicide risk assessment provides the clinical psychiatrist with an opportunity for therapeutic engagement with the ultimate goals of relieving suffering and preventing suicide.

Objective To compare white matter integrity (WMI) in bipolar disorder (BD) relative to healthy volunteers (HVs) and major depressive disorder (MDD). To determine the relationship of bipolar-specific differences in WMI to cerebral perfusion, body mass index (BMI), and blood pressure as indices of cardiovascular function. Methods Thirty-two participants with BD, 44 with MDD, and 41 HV were recruited. All BD and MDD participants were in a major depressive episode, and all but 12 BD participants were medication-free. 64-direction diffusion tensor imaging (DTI) and arterial spin labeling (ASL) sequences were obtained. Tract-based spatial statistics (TBSS) on four DTI indices were employed to distinguish patterns of DTI in BD relative to HV and MDD groups. BMI, blood pressure, and medical histories were also obtained for the BD participants. Results A cluster of lower axial diffusivity (AD) was found in BD participants in comparison to the HVs in the left posterior thalamic radiation, superior longitudinal fasciculus, inferior longitudinal fasciculus, fronto-occipital fasciculus, and internal capsule. Mean AD in the significant cluster was not associated with cerebral blood flow (CBF) in the region as measured by ASL, and was not associated with BMI or blood pressure. A cluster of lower AD was also found in the BD group when compared to MDD that had spatial overlap with the HV comparison. Conclusions The results indicate a deficit of AD in BD when compared to MDD and HV groups. No association between AD values and either cerebral perfusion, BMI, or blood pressure was found in BD.

Preclinical studies have implicated kappa opioid receptors (KORs) in stress responses and depression-related behaviors, but evidence from human studies is limited. Here we present results of a secondary analysis of data acquired using positron emission tomography (PET) with the KOR radiotracer [11C]GR103545 in 10 unmedicated, currently depressed individuals with major depressive disorder (MDD; 32.6 ± 6.5 years, 5 women) and 13 healthy volunteers (34.8 ± 10 years, 6 women). Independent component analysis was performed to identify spatial patterns of coherent variance in KOR binding (tracer volume of distribution, VT) across all subjects. Expression of each component was compared between groups and relationships to symptoms were explored using the 17-item Hamilton Depression Rating Scale (HDRS). Three components of variation in KOR availability across ROIs were identified, spatially characterized by [11C]GR103545 VT in (1) bilateral frontal lobe; (2) occipital and parietal cortices, right hippocampus, and putamen; and (3) right anterior cingulate, right superior frontal gyrus and insula, coupled to negative loading in left middle cingulate. In MDD patients, component 3 was negatively associated with symptom severity on the HDRS (r = −0.85, p = 0.0021). There were no group-wise differences in expression of any component between patients and controls. These preliminary findings suggest that KOR signaling in cortical regions relevant to depression, particularly right anterior cingulate, could reflect MDD pathophysiology.

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.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Objective: To estimate the prevalence of major depressive episode (MDE) in patients with presumptive pulmonary tuberculosis (pre-PTB, defined by cough lasting ≥ 3 weeks) and compare it between patients with pulmonary tuberculosis (PTB) and without PTB. Methods: Patients with pre-PTB (n=260) were screened for depression using the Patient Health Questionnaire (PHQ-9). Those individuals with scores ≥ 10 were subsequently assessed with the depression module of the Mini International Neuropsychiatric Interview (MINI-Plus) to confirm diagnosis. Associations of categorical variables with PTB and MDE were calculated using the chi-square test and OR. Results: PTB was confirmed in 98 patients (37.7%). A high proportion of both groups (active PTB and no PTB) screened positive for depression (60.2 vs. 62.1%, respectively). Among 159 patients who screened positive for depression, a subset of 97 (61.0%) were further evaluated with the MINI-Plus; current MDE was confirmed in 54.6% (53/97). On univariate and multivariate analysis, female sex was the only factor associated with the diagnosis of current MDE (p = 0.04). Conclusion: The prevalence of MDE was high among individuals with prolonged respiratory symptoms, independent of PTB diagnosis. This is consistent with other studies of depression in primary care in Brazil.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. 222 unmedicated adults with MDD randomized to receive sertraline (n=110) or placebo (n=112) in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study completed demographic and clinical assessments, and pre-treatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on Week-8 depression levels (Fs≥9.67,ps≤0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower Week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pre-treatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pre-treatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment. Trial Registration: NCT01407094; http://clinicaltrials.gov/show/NCT01407094

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 Abnormalities in the hypothalamic-pituitary-adrenal axis, serotonergic system, and stress response have been linked to the pathogenesis of major depressive disorder. State-dependent hyper-reactivity of the hypothalamic-pituitary-adrenal axis is seen in major depressive disorder, and higher binding to the serotonin 1A receptor is observed as a trait in both currently depressed and remitted untreated major depressive disorder. Here, we sought to examine whether a relationship exists between cortisol secretion in response to a stressor and serotonin 1A receptor binding throughout the brain, both in healthy controls and participants with major depressive disorder. Methods Research participants included 42 medication-free, depressed subjects and 31 healthy volunteers. Participants were exposed to either an acute, physical stressor (radial artery catheter insertion) or a psychological stressor (Trier Social Stress Test). Levels of serotonin 1A receptor binding on positron emission tomography with [11C]WAY-100635 were also obtained from all participants. The relationship between [11C]WAY-100635 binding and cortisol was examined using mixed linear effects models with group (major depressive disorder vs control), cortisol, brain region, and their interactions as fixed effects and subject as a random effect. Results We found a positive correlation between post-stress cortisol measures and serotonin 1A receptor ligand binding levels across multiple cortical and subcortical regions, independent of diagnosis and with both types of stress. The relationship between [11C]WAY-100635 binding and cortisol was homogenous across all a priori brain regions. In contrast, resting cortisol levels were negatively correlated with serotonin 1A receptor ligand binding levels independently of diagnosis, except in the RN. There was no significant difference in cortisol between major depressive disorder participants and healthy volunteers with either stressor. Similarly, there was no correlation between cortisol and depression severity in either stressor group. Conclusions This study suggests that there may be a common underlying mechanism that links abnormalities in the serotonin system and hypothalamic-pituitary-adrenal axis hyper-reactivity to stress. Future studies need to determine how hypothalamic-pituitary-adrenal axis dysfunction affects mood to increase the risk of suicide in major depression.

BackgroundAlthough there are extensive data on clinical psychopathology in youth with suicidal ideation, data are lacking regarding their neurocognitive function.AimsTo characterise the cognitive profile of youth with suicidal ideation in a community sample and evaluate gender differences and pubertal status effects.MethodParticipants (N = 6151, age 11–21 years, 54.9% females) from the Philadelphia Neurodevelopmental Cohort, a non-help-seeking community sample, underwent detailed clinical evaluation. Cognitive phenotyping included executive functioning, episodic memory, complex reasoning and social cognitive functioning. We compared participants with suicidal ideation (N = 672) and without suicidal ideation (N = 5479). Regression models were employed to evaluate differences in cognitive performance and functional level, with gender and pubertal status as independent variables. Models controlled for lifetime depression or general psychopathology, and for covariates including age and socioeconomic status.ResultsYouth with suicidal ideation showed greater psychopathology, poorer level of function but better overall neurocognitive performance. Greater functional impairment was observed in females with suicidal ideation (suicidal ideation × gender interaction, t = 3.091, P = 0.002). Greater neurocognition was associated with suicidal ideation post-puberty (suicidal ideation × puberty interaction, t = 3.057, P = 0.002). Exploratory analyses of specific neurocognitive domains showed that suicidal ideation-associated cognitive superiority was more prominent in post-pubertal males compared with females (Cohen's d = 0.32 and d = 0.11, respectively) across all cognitive domains.ConclusionsSuicidal ideation was associated with poorer functioning yet better cognitive performance, especially in post-pubertal males, as measured by a comprehensive cognitive battery. Findings point to gender and pubertal-status specificity in the relationship between suicidal ideation, cognition and function in youth.Declaration of interestR.B. serves on the scientific board and reports stock ownership in ‘Taliaz Health’, with no conflict of interest relevant to this work. M.A.O. receives royalties for the commercial use of the Columbia-Suicide Severity Rating Scale from the Research Foundation for Mental Hygiene. Her family owns stock in Bristol-Myers Squibb. All other authors declare no potential conflict of interest.

Background Identifying brain activity patterns that are associated with suicidal ideation (SI) may help to elucidate its pathogenesis and etiology. Suicide poses a significant public health problem, and SI is a risk factor for suicidal behavior. Methods Forty-one unmedicated adult participants in a major depressive episode (MDE), 26 with SI on the Beck Scale for Suicidal Ideation and 15 without SI, underwent resting-state functional magnetic resonance imaging scanning. Twenty-one healthy volunteers (HVs) were scanned for secondary analyses. Whole brain analysis of both amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF was performed in MDE subjects to identify regions where activity was associated with SI. Results Subjects with SI had greater ALFF than those without SI in two clusters: one in the right hippocampus and one in the thalamus and caudate, bilaterally. Multi-voxel pattern analysis distinguished between those with and without SI. Post hoc analysis of the mean ALFF in the hippocampus cluster found it to be associated with a delayed recall on the Buschke memory task. Mean ALFF from the significant clusters was not associated with depression severity and did not differ between MDE and HV groups. Discussion These results indicate that SI is associated with altered resting-state brain activity. The pattern of elevated activity in the hippocampus may be related to how memories are processed.

BackgroundCognitive behavioral therapy (CBT) is an effective treatment for many patients suffering from major depressive disorder (MDD), but predictors of treatment outcome are lacking, and little is known about its neural mechanisms. We recently identified longitudinal changes in neural correlates of conscious emotion regulation that scaled with clinical responses to CBT for MDD, using a negative autobiographical memory-based task.MethodsWe now examine the neural correlates of emotional reactivity and emotion regulation during viewing of emotionally salient images as predictors of treatment outcome with CBT for MDD, and the relationship between longitudinal change in functional magnetic resonance imaging (fMRI) responses and clinical outcomes. Thirty-two participants with current MDD underwent baseline MRI scanning followed by 14 sessions of CBT. The fMRI task measured emotional reactivity and emotion regulation on separate trials using standardized images from the International Affective Pictures System. Twenty-one participants completed post-treatment scanning. Last observation carried forward was used to estimate clinical outcome for non-completers.ResultsPre-treatment emotional reactivity Blood Oxygen Level-Dependent (BOLD) signal within hippocampus including CA1 predicted worse treatment outcome. In contrast, better treatment outcome was associated with increased down-regulation of BOLD activity during emotion regulation from time 1 to time 2 in precuneus, occipital cortex, and middle frontal gyrus.ConclusionsCBT may modulate the neural circuitry of emotion regulation. The neural correlates of emotional reactivity may be more strongly predictive of CBT outcome. The finding that treatment outcome was predicted by BOLD signal in CA1 may suggest overgeneralized memory as a negative prognostic factor in CBT outcome.

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

Background/aims: While substantial prior research has evaluated the psychometric properties of the 12-item Concise Health Risk Tracking-Self Report (CHRT-SR12), a measure of suicide propensity and suicidal thoughts, no prior research has investigated its factor structure, sensitivity to change over time, and other psychometric properties in a placebo-controlled trial of antidepressant medication, nor determined whether symptoms change throughout treatment. Methods: Participants in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study ( n=278) provided data to evaluate the factor structure and sensitivity to change over time of the CHRT-SR12 through eight weeks of a clinical trial in which participants received either placebo or antidepressant medication (sertraline). Results/Outcomes: Factor analysis confirmed two factors: propensity (comprised of first-order factors including pessimism, helplessness, social support, and despair) and suicidal thoughts. Internal consistency (α’s ranged from 0.69–0.92) and external validity were both acceptable, with the total score and propensity factor scores significantly correlated with total scores and single-item suicidal-thoughts scores on the self-report Quick Inventory of Depressive Symptoms and the clinician-rated 17-item Hamilton Rating Scale for Depression. Through analyzing CHRT-SR12 changes over eight treatment weeks, the total score and both the factors decreased regardless of baseline suicidal thoughts. Change in clinician-rated suicidal thoughts was reflected by change in both the total score and propensity factor score. Conclusions/interpretation: These results confirm the reliability, validity, and applicability of the CHRT-SR12 to a placebo-controlled clinical trial of depressed outpatients receiving antidepressant medication.

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.

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.

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.

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.

BackgroundPatients with bipolar disorder have a high lifetime risk of suicide. Predicting, preventing and managing suicidal behavior are major goals in clinical practice. Changes in suicidal thoughts and behavior are common in the course of treatment of bipolar disorder.MethodsUsing a dataset from a randomized clinical trial of bipolar disorder treatment (N=98), we tested predictors of future suicidal behavior identified through a review of literature and applied marginal variable selection and machine learning methods. The performance of the models was assessed using the optimism-adjusted C statistic.ResultsNumber of prior hospitalizations, number of prior suicide attempts, current employment status and Hamilton Depression Scale were identified as predictors and a simple logistic regression model was constructed. This model was compared with a model incorporating interactions with treatment group assignment, and more complex variable selection methods (LASSO and Survival Trees). The best performing models had average optimism-adjusted C-statistics of 0.67 (main effects only) and 0.69 (Survival Trees). Incorporating medication group did not improve prediction performance of the models.ConclusionsThese results suggest that models with a few predictors may yield a clinically meaningful way to stratify risk of emerging suicide events in patients who are undergoing pharmacologic treatment for bipolar disorder.Significance StatementThis study aims to find out whether suicide events that occur during the pharmacological treatment of bipolar disorder, a severe psychiatric disorder that is highly associated with suicide behavior, can be predicted. Using existing methods, we developed and compared several predictive models. We showed that these models performed similarly to predictive models of other outcomes, such as treatment efficacy, in unipolar and bipolar depression. This suggests that suicide events during bipolar disorder may be a feasible target for individualized interventions in the future.

Despite substantial suicide prevention efforts, US suicide rates continue to climb, currently reaching about 14 per 100,000 individuals. Suicidal behavior has been linked to neurobiological, neurocognitive and behavioral factors; however, integrative, multi-modal studies are rare. Furthermore, prospective studies, crucial to understanding future risk factors, have focused on a single predictor and a single outcome, implying that suicidal behavior is homogeneous. But recent research shows suicidal behavior is complex and heterogeneous, with the possible existence of subtypes. The present report describes a project testing a model that posits two putative subtypes, using a prospective, multi-model design. The subtypes differ in regard to the patterns of suicidal ideation and underlying mechanisms. One hundred subjects diagnosed with a Major Depressive episode, half of whom have attempted suicide in the past, are enrolled and followed for two years, notably the highest risk period for suicidal behavior. Baseline assessments include a clinical assessment, neurocognitive and behavioral tasks, Ecological Momentary Assessments (EMA), PET imaging, and a cognitive emotion regulation task in the MRI scanner. The follow-up assessment includes a clinical assessment and EMA. The study findings have the potential to pave the way for a clearer understanding of suicidal ideation and behaviors and to improve our ability to treat those at risk for suicide by developing tailored approaches that will allow for more accurate pharmacological and psychosocial interventions.

The association of aggression and impulsivity with suicidal behavior (SB) in depression may vary across countries. This study aimed (i) to compare aggression and impulsivity levels, measured with the Brown-Goodwin Scale (BGS) and the Barratt Impulsivity Scale (BIS), respectively, between New York City (NYC) (US), Madrid (Spain) and Florence (Italy) (ANOVA); and (ii) to investigate between-site differences in the association of aggression and impulsivity with previous SB (binary logistic regression). Aggression scores were higher in NYC, followed by Florence and Madrid. Impulsivity levels were higher in Florence than in Madrid or NYC. Aggression and impulsivity scores were higher in suicide attempters than in non-attempters in NYC and in Madrid. SB was associated with aggression in NYC (OR 1.12, 95% CI 1.07–1.16; p < 0.001) and in Florence (OR 1.11, 95% CI 1.01–1.22; p = 0.032). Impulsivity was linked with SB in NYC (OR 1.01, 95% CI 1.00–1.02; p < 0.001) and in Madrid (OR 1.03, 95% CI 1.02–1.05; p < 0.001). The higher suicide rates in NYC, compared to Madrid or Florence, may be, in part, explained by these cross-cultural differences in the contribution of aggression-impulsivity to SB, which should be considered by future research on SB prevention.

International audience; Background: It remains unclear whether the dopaminergic and noradrenergic systems may be implied in suicide attempt risk. In addition, although the serotonergic system has been extensively studied, no formal meta-analysis has been performed to examine its association with suicide attempt.Methods: Using PRISMA methodology, we performed a systematic literature review and random-effects meta-analyses of the differences in cerebrospinal fluid (CSF) levels of 5-HIAA, HVA and MHPG between suicide attempters and individuals who never attempted suicide.Results: We identified 30 studies including 937 suicide attempters and 1128 non-attempters; 29 of them measured CSF levels of 5-HIAA, 22 measured CSF levels of HVA and 14 measured CSF levels of MHPG. CSF levels of 5-HIAA and HVA were significantly lower in suicide attempters than in non-attempters [SMD = -0.43 (95% CI: -0.71 to -0.15; p < 0.01) and SMD = -0.45 (95% CI: -0.72 to -0.19; p < 0.01), respectively]. We did not find a significant association between CSF MHPG levels and suicide attempt.Limitations: Our analyses relied on a limited number of studies of good quality and most studies included small sample sizes.Conclusion: Both serotonin and dopamine systems may play a role in suicide attempt risk. Our findings suggest that a silo approach to biomarkers should be phased out in favor of the study of multiple systems in parallel and in the same populations to progress in the identification of the biological components independently associated with suicide risk, with the goal of identifying new treatment targets and improving suicide risk prediction.

PURPOSE We developed and implemented a new model of collaborative care that includes a triage and referral management system. We present initial implementation metrics using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework. METHODS Primary care clinicians in 8 practices referred patients with any unmet mental health needs to the Penn Integrated Care program. Assessments were conducted using validated measures. Patients were primarily triaged to collaborative care (26%) or specialty mental health care with active referral management (70%). We conducted 50 qualitative interviews to understand the implementation process and inform program refinement. Our primary outcomes were reach and implementation metrics, including referral and encounter rates derived from the electronic health record. RESULTS In 12 months, 6,124 unique patients were referred. Assessed patients reported symptoms consistent with a range of conditions from mild to moderate depression and anxiety to serious mental illnesses including psychosis and acute suicidal ideation. Among patients enrolled in collaborative care, treatment entailed a mean of 7.2 (SD 5.1) encounters over 78.1 (SD 51.3) days. Remission of symptoms was achieved by 32.6% of patients with depression and 39.5% of patients with anxiety. Stakeholders viewed the program favorably and had concrete suggestions to ensure sustainability. CONCLUSIONS The Penn Integrated Care program demonstrated broad reach. Implementation was consistent with collaborative care as delivered in seminal studies of the model. Our results provide insight into a model for launching and implementing collaborative care to meet the needs of a diverse group of patients with the full range of mental health conditions seen in primary care.

Background Smartphone monitoring could contribute to the elucidation of the correlates of suicidal thoughts and behaviors (STB). In this study, we employ smartphone monitoring and machine learning techniques to explore the association of wish to die (passive suicidal ideation) with disturbed sleep, altered appetite and negative feelings. Methods This is a prospective cohort study carried out among adult psychiatric outpatients with a history of STB. A daily questionnaire was administered through the MEmind smartphone application. Participants were followed-up for a median of 89.8 days, resulting in 9,878 person-days. Data analysis employed a machine learning technique called Indian Buffet Process. Results 165 patients were recruited, 139 had the MEmind mobile application installed on their smartphone, and 110 answered questions regularly enough to be included in the final analysis. We found that the combination of wish to die and sleep problems was one of the most relevant latent features found across the sample, showing that these variables tend to be present during the same time frame (96 hours). Conclusions Disturbed sleep emerges as a potential clinical marker for passive suicidal ideation. Our findings stress the importance of evaluating sleep as part of the screening for suicidal behavior. Compared to previous smartphone monitoring studies on suicidal behavior, this study includes a long follow-up period and a large sample.

Environment (E) is pivotal in explaining variability in brain and behavior development, including suicidal ideation (SI) and behavior. It is therefore critical to systematically study relationships among environmental exposures (i.e., exposome) and suicidal phenotypes. Here, we evaluated the role of individual-level adversity and neighborhood environment and their interaction (E x E) in association with youth SI. Sample included youth (N = 7,054, ages 11–21) from the Philadelphia Neurodevelopmental Cohort, which investigated clinical phenotypes in a diverse US community population. We examined cross-sectional associations of environmental exposures with lifetime history of SI (n = 671), focusing on interactions between individual-level exposures to assaultive trauma (n = 917) and neighborhood-level socioeconomic status (SES) quantified using geocoded Census data. Models included potential confounds and overall psychopathology. Results showed that assaultive trauma was strongly associated with SI (OR = 3.3, 95%CI 2.7–4, p, Graphical abstract Image 1, Highlights • Environment (E) is key in shaping development of suicidal ideation (SI). • We integrated individual-level trauma exposure and neighborhood-level data on socioeconomic status (SES) in N=7,054 youths. • Trauma was robustly associated with youth SI in our cohort, while SES had no association with SI. • Only in youth with history of assaultive trauma, low SES was associated with lower SI rates (trauma by SES interaction). • Results suggest a stress inoculation effect that was shown in animal models, but has not been shown in human suicide research.

International audience; To analyze the relationship between suicide in men and stratified measures of religiosity.Methods: We studied 192 suicides and 81 controls (nonsuicide, sudden, or accidental death). We employed the psychological autopsy method to compile diagnoses based on DSM-IV criteria. Overall, religiosity and participation in religious associations were determined using a Likert-type scale. Given the limited participation of women in the religious associations of southern Spain, only male subjects were included.Results: Religious participants had decreased risk of suicide compared to nonparticipants (OR = 0.148, 95% CI = 0.049-0.447). This lower risk was further associated with the degree of involvement in religious activity. Suicides accounted for 73.47% of subjects with no religious participation, 61.17% of those with some participation, and 56.52% of frequent participants (linear trend test Z = -2.0329, p = .042). Membership in a religious association was also associated with a lower rate of suicide compared to nonmembers (OR = 0.356, 95% CI = 0.172-0.736). This effect was similarly associated with the degree of involvement in the association. Suicides accounted for 74.67% of subjects who never participated in the activities of a religious association, 69.23% of those who sometimes participated, and 42.86% of frequent participants (linear trend test Z = -3.4082, p < .001).Conclusions: Religiosity, either as general participation or through a religious association, was associated with protection against suicide proportional to the degree of involvement in religious activities.

Objective To examine factors differentiating individuals whose first suicide attempt was during childhood (ages 5–12 yrs) from those who first attempted suicide during adolescence (13–19 yrs) and during adulthood (≥20 yrs). Method A sample of 418 participants (ages 18–64 yrs) with a mood disorder and ≥1 lifetime suicide attempt was divided into three groups according to age of first suicide attempt (childhood: N = 43, adolescent: N = 149, adulthood: N = 226) and compared on demographics, childhood adversity, parental psychopathology, comorbid lifetime axis I diagnoses, self-harm and characteristics of first attempt. Results Participants in the Childhood Attempt group were more likely to report childhood adversity, parental alcohol use disorder and subsequent suicide attempts than the two other groups. They were also more likely to have a depressed mother, non-suicidal self-injury (NSSI) during childhood and adolescence, lifetime PTSD and aggressive behavior than the Adulthood Attempt group. The Adolescent Attempt group had more childhood adversity, parental suicidal behavior, lifetime PTSD and NSSI during adolescence than the Adulthood Attempt group. The groups differed on methods of first attempt, and its lethality was related to age of attempt. Conclusions Early adversity and parental psychopathology are particularly prominent in those who make childhood suicide attempts, suggesting that this group may represent a suicidal behavior subtype.

Objective The cognitive theory of suicide postulates that hopelessness is an essential precondition for suicidal ideation in patients with depressive disorder . However, the explanatory power and predictive value of hopelessness for suicidal ideation remain uncertain. Methods From 1997 to 2007, patients with depressive disorder who were cohorts from the Vantaa Depression Studies (n = 406) completed the Scale for Suicide Ideation (SSI), Beck Hopelessness Scale (BHS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Perceived Social Support Scale-Revised (PSSS-R), and Eysenck Personality Inventory-Q (EPI-Q) at baseline, 6 and 18 months, and 5 years. We conducted a mixed-effects generalized linear regression and clustered receiver-operating characteristics analysis to test how well BDI and BHS predict severe suicidal ideation within and between patients. Results BHS predicted clinically significant suicidal ideation (odds ratio [OR] = 2.8), explaining 13.1% of between-patient and and 3.5% of within-patient variance of SSI. Adjusting for the fixed effect of BDI removed a substantial part of the effect of BHS on SSI (adjusted OR = 1.38, P = .018). BAI moderated the effect of BHS on SSI, whereas EPI-Q and PSSS-R did not. BDI detected suicidal ideation more accurately (area under the receiver-operating characteristics curve [AUC] = 0.846) than BHS (AUC = 0.754). Conclusions In patients with depressive disorder, hopelessness explains suicidal ideation, but largely because it covaries with depressive symptoms. The role of hopelessness as a central determinant of suicidal ideation in depression may have been overestimated. Symptoms of anxiety moderate the association between hopelessness and suicidal ideation. Severity of depressive symptoms may predict suicidal ideation more accurately than hopelessness.

Background. Aberrant activity of the subcallosal cingulate (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses (rsFC) on resting-state functional magnetic resonance imaging (fMRI) data, collected before and after a course of cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), using seeds from three SCC subdivisions. Methods. Resting-state data were collected from unmedicated patients with current MDD (Hamilton Depression Rating Scale-17 > 16) before and after 14-sessions of CBT monotherapy. Treatment outcome was assessed using the Beck Depression Inventory (BDI). Rostral anterior cingulate (rACC), anterior subcallosal cingulate (aSCC), and Brodmann’s area 25 (BA25) masks were used as seeds in connectivity analyses that assessed baseline rsFC and symptom severity, changes in connectivity related to symptom improvement after CBT, and prediction of treatment outcomes using whole-brain baseline connectivity. Results. Pretreatment BDI negatively correlated with pretreatment rACC ~ dorsolateral prefrontal cortex and aSCC ~ lateral prefrontal cortex rsFC. In a region-of-interest longitudinal analysis, rsFC between these regions increased post-treatment (p FDR). In whole-brain analyses, BA25 ~ paracentral lobule and rACC ~ paracentral lobule connectivities decreased post-treatment. Whole-brain baseline rsFC with SCC did not predict clinical improvement. Conclusions. rsFC features of rACC and aSCC, but not BA25, correlated inversely with baseline depression severity, and increased following CBT. Subdivisions of SCC involved in top-down emotion regulation may be more involved in cognitive interventions, while BA25 may be more informative for interventions targeting bottom-up processing. Results emphasize the importance of subdividing the SCC in connectivity analyses.

Efforts in research, prevention, and treatment of suicidal behavior have produced mixed results. One of the main barriers to combating suicidal behavior lies in the very conceptualization of suicide, a phenomenon that is at once sociological, psychiatric, and even philosophical, and one that has not always been included in the field of health care. There are also many barriers at the social level, ranging from stigma against people with suicidal behavior to stigma towards psychiatric care, as well as the controversial role of the media. The media plays an important role in society and depending on its attitude it can be either beneficial or harmful in our fight against suicidal behavior. Differences between countries - in the provision of resources, in the way of understanding the phenomenon or in the manner of providing official figures - pose an additional challenge to suicide prevention on a global level. In the field of research, predicting suicidal behavior by identifying effective risk markers is severely hampered by the low occurrence of suicide in the population, which limits the statistical power of studies. The authors recommend combining various risk factors to build predictive models. This, in addition to employing increasingly precise machine learning techniques, is a step in the right direction, although there is still a long way to go before the expected results can be obtained. Finally, adequate training of health professionals, both specialized and non-specialized, as well as gatekeeper training, is crucial for implementing suicide prevention strategies in the population.

It is unclear whether anxiety increases or decreases suicidal risk. This may contribute to the lack of guidance on which antidepressant medications are best for suicidal depressed patients who present with high anxiety. This study explored whether anxiety predicts suicidal ideation in depressed individuals treated with paroxetine or bupropion. An 8-week double-blind trial comparing controlled-release paroxetine (N=36) versus extended-release bupropion (N=38) for effect on suicidal ideation and behavior in depressed patients with suicidal ideation, past attempt, or both found an advantage for paroxetine, but anxiety effects were not investigated. This secondary analysis explored the relationship, measured at baseline and weekly, of anxiety with suicidal ideation. Anxiety severity measured weekly correlated with suicidal ideation severity irrespective of treatment (P=0.012). Patients with high baseline anxiety showed a trend toward faster reduction of suicidal ideation with paroxetine compared with bupropion treatment (standard P=0.047; bootstrap P=0.077). The latter finding, if confirmed in larger samples, could enhance choice of antidepressant medication for suicidal, depressed patients presenting with high levels of anxiety.

BackgroundMajor depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.MethodsWithin an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.ResultsFive pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).ConclusionsA subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.