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Brain targets to lower the high risk of suicide in Bipolar Disorder (BD) are needed. Neuroimaging studies employing analyses dependent on regional assumptions could miss hubs of dysfunction critical to the pathophysiology of suicide behaviors and their prevention. This study applied intrinsic connectivity distribution (ICD), a whole brain graph‐theoretical approach, to identify hubs of functional connectivity (FC) disturbances associated with suicide attempts in BD. ICD, from functional magnetic resonance imaging data acquired while performing a task involving implicit emotion regulation processes important in BD and suicide behaviors, was compared across 40 adults with BD with prior suicide attempts (SAs), 49 with BD with no prior attempts (NSAs) and 51 healthy volunteers (HVs). Areas of significant group differences were used as seeds to identify regional FC differences and explore associations with suicide risk-related measures. ICD was significantly lower in SAs than in NSAs and HVs in bilateral ventromedial prefrontal cortex (vmPFC) and right anterior insula (RaIns). Seed connectivity revealed altered FC from vmPFC to bilateral anteromedial orbitofrontal cortex, left ventrolateral PFC (vlPFC) and cerebellum, and from RaIns to right vlPFC and temporopolar cortices. VmPFC and RaIns ICD were negatively associated with suicidal ideation severity, and vmPFC ICD with hopelessness and attempt lethality severity. The findings suggest that SAs with BD have vmPFC and RaIns hubs of dysfunction associated with altered FC to other ventral frontal, temporopolar and cerebellar cortices, and with suicidal ideation, hopelessness, and attempt lethality. These hubs may be targets for novel therapeutics to reduce suicide risk in BD.

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

Background This study assessed the prevalence of suicidal behavior and associated risk factors in public primary health care in Mozambique. Methods The Mini International Neuropsychiatric Interview was used to evaluate suicidal behavior among 502 adults attending three Primary Health Care (PHC) settings. Results In the past month, 13% (n = 63) of PHC attendees expressed suicidal ideation, 8% (n = 40) had made a suicide plan, 4% (n = 20) had made a suicide attempt, and 5% (n = 25) reported a lifetime suicide attempt. Females had 2.8-fold increased odds of suicide plan (95% CI: 1.5, 5.5) and 3.3-fold increased odds of suicide attempt in the past month (95% CI: 1.2, 9.1). Each 10-year increase in age was associated with 0.61-fold the odds of suicide plan (95% CI: 0.38, 0.98) and 0.09-fold the odds of suicide attempt (95% CI: 0.01, 0.69) in the past month. People living with HIV (PLWHA) had 2.2-fold increased adjusted odds of past month suicide attempt (CI: 1.1, 4.1). Conclusion Suicidal behaviors are common among adults attending PHC clinics in Mozambique. Screening and linkage to effective preventive interventions are urgently needed in PHC settings. Females, younger individuals, and PLWHA are at elevated risk for suicidal behavior in PHC.

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.

IntroductionDepression is the most common mental disorder among people living with HIV/AIDS and has a negative impact on HIV treatment outcomes. Training lay HIV counselors to identify and manage depression may contribute to improved patient access and adherence to treatment, and reduce stigma and discrimination among lay health workers toward both HIV and depression. The purpose of this study was to assess the current knowledge and attitudes of lay HIV counselors toward managing depression in primary care in Mozambique.MethodsWe conducted a mixed-methods cross-sectional study to assess depression-related knowledge and attitudes among lay HIV counselors in 13 primary healthcare facilities in Mozambique. We used the quantitative Depression Attitude Questionnaire (DAQ) scale, followed by open-ended questions to further explore three key DAQ domains: the nature of depression, treatment preferences, and professional attitudes or reactions.ResultsThe sample included 107 participants (77.6% female, mean age: 32.3 years, sd = 7.4). Most (82.2%) had less than a high/technical school education. Findings suggested that some HIV counselors had knowledge of depression and described it as a cluster of psychological symptoms (e.g., deep sadness, anguish, apathy, isolation, and low self-esteem) sometimes leading to suicidal thoughts, or as a consequence of life stressors such as loss of a loved one, abuse, unemployment or physical illness, including being diagnosed with HIV infection. HIV counselors identified talking to trusted people about their problems, including family and/or counseling with a psychotherapist, as the best way for patients to deal with depression. While acknowledging challenges, counselors found working with patients with depression to be rewarding.ConclusionLay health counselors identified HIV and psychosocial issues as key risk factors for depression. They believed that the treatment approach should focus on social support and psychotherapy.

BACKGROUND: Elevated aggression and impulsivity are implicated in Bipolar Disorder (BD); however, relationships between these behavioral constructs have not been clarified, which can lead to misconceptions with negative consequences including stigma and adverse outcomes including suicide. The study aimed to clarify brain-based distinctions between the two constructs and their associations to risk factors, symptoms and suicide thoughts and behaviors. METHODS: Self-rated Brown-Goodwin Aggression (BGA) and Barratt Impulsiveness Scale (BIS) scores were compared between adults with BD (n=38, 74% female) and healthy controls (HC, n=29, 64% female). Relationships were examined between BGA and BIS with childhood trauma questionnaire (CTQ), mood, comorbidities, and magnetic resonance imaging gray matter volume (GMV) assessments. RESULTS: In BD, BGA and BIS total scores were both elevated and associated with childhood maltreatment (CM), particularly emotional CM, depression, substance use disorders (SUDs) and suicide attempts (SAs). BGA scores were increased by items corresponding to dysregulation of emotional and social behavior and associated with elevated mood states and suicide ideation and GMV decreases in bilateral orbitofrontal cortex and left posterior insula brain regions, previously associated with these behaviors and clinical features. BIS motor impulsiveness scores were associated with GMV decreases in anterior cingulate cortex implicated in mood and behavioral dyscontrol. LIMITATIONS: modest sample size, self-reports CONCLUSIONS: The findings suggest separable brain-based domains of dysfunction in BD of motor impulsiveness versus emotionally dysregulated feelings that are primarily self-directed. Both domains are associated with suicide behavior and modifiable risk factors of CM, depression and SUDs that could be targeted for prevention.

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

BACKGROUND 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.

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.

Delivery of effective antidepressant treatment has been hampered by a lack of objective tools for predicting or monitoring treatment response. This study aimed to address this gap by testing novel dynamic resting-state functional network markers of antidepressant response.The Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study randomized adults with major depressive disorder to 8 weeks of either sertraline or placebo, and depression severity was evaluated longitudinally. Participants completed resting-state neuroimaging pretreatment and again after 1 week of treatment (n = 259 eligible for analyses). Coactivation pattern analyses identified recurrent whole-brain states of spatial coactivation, and computed time spent in each state for each participant was the main dynamic measure. Multilevel modeling estimated the associations between pretreatment network dynamics and sertraline response and between early (pretreatment to 1 week) changes in network dynamics and sertraline response.Dynamic network markers of early sertraline response included increased time in network states consistent with canonical default and salience networks, together with decreased time in network states characterized by coactivation of cingulate and ventral limbic or temporal regions. The effect of sertraline on depression recovery was mediated by these dynamic network changes. In contrast, early changes in dynamic functioning of corticolimbic and frontoinsular-default networks were related to patterns of symptom recovery common across treatment groups.Dynamic resting-state markers of early antidepressant response or general recovery may assist development of clinical tools for monitoring and predicting effective intervention.

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.

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.

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/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.

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

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

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

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.

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

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.

To date, there are no biomarkers for major depressive disorder (MDD) treatment response in clinical use. Such biomarkers could allow for individualized treatment selection, reducing time spent on ineffective treatments and the burden of MDD. In search of such a biomarker, multisite pretreatment and early-treatment (1 week into treatment) structural magnetic resonance (MR) images were acquired from 184 patients with MDD randomized to an 8-week trial of the selective serotonin reuptake inhibitor (SSRI) sertraline or placebo. This study represents a large, multisite, placebo-controlled effort to examine the association between pretreatment differences or early-treatment changes in cortical thickness and treatment-specific outcomes. For standardization, a novel, robust site harmonization procedure was applied to structural measures in a priori regions (rostral and caudal anterior cingulate, lateral orbitofrontal, rostral middle frontal, and hippocampus), chosen based on previously published reports. Pretreatment cortical thickness or volume did not significantly associate with SSRI response. Thickening of the rostral anterior cingulate cortex in the first week of treatment was associated with better 8-week responses to SSRI (p = 0.010). These findings indicate that frontal lobe structural alterations in the first week of treatment may be associated with long-term treatment efficacy. While these associational findings may help to elucidate the specific neural targets of SSRIs, the predictive accuracy of pretreatment or early-treatment structural alterations in classifying treatment remitters from nonremitters was limited to 63.9%. Therefore, in this large sample of adults with MDD, structural MR imaging measures were not found to be clinically translatable biomarkers of treatment response to SSRI or placebo.

Objective Neurocognitive dysfunction in patients with residual or emergent symptoms after treatment for Lyme Disease is often attributed to comorbid depression. In this study, patients with Post-Treatment Lyme Disease Syndrome (PTLDS) were compared to patients with Major Depressive Disorder (MDD), as well as healthy comparison subjects (HC), on neurocognitive measures administered through the same laboratory, to determine if patterns of performance were similar. Methods Two analyses were conducted. First, performance on the Wechsler Adult Intelligence Scale (WAIS-III) and on subtests from the Wechsler Memory Scale (WMS-III) was compared among the groups. Second, comparable subgroups of PTLDS and MDD patients with at least one low WMS-III score were compared on an additional set of measures assessing motor function, psychomotor performance, attention, memory, working memory, and language fluency, to determine if the overall profile of performance was similar in the two subgroups. Results In the first analysis, PTLDS patients performed more poorly than both MDD and HC on tasks assessing verbal abilities, working memory, and paragraph learning. Processing speed in the two patient groups, however, was equally reduced. In the second analysis, MDD patients with low WMS-III exhibited concomitantly greater difficulties in psychomotor speed and attention, while low-WMS-III PTLDS patients exhibited greater difficulties in language fluency. Conclusions MDD and PTLDS can be confused neuropsychologically because both exhibit similar levels of psychomotor slowing. However, problems on memory-related tasks, though mild, are more pronounced in PTLDS. PTLDS patients with poorer memory also exhibit poorer language fluency, and less deficit in processing speed and attention compared to MDD.

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

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.

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

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.

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.

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.

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.

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

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.