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Resilience represents coping abilities to overcome exposure to psychopathological risk. In the context of risk factors for suicidal behavior, it is unknown if this attribute is deficient in suicide attempters, how it relates to other measures of risk, and where it may overlap with other risk factors associated with suicidal behavior.The present study examined the performance on the Connor-Davidson Resilience Scale (CD-RISC) in three groups of individuals with familial risk for both mood disorder and suicidal behavior, as well as a healthy comparison group. Other risk factors for suicidal behavior, such as depression severity, hopelessness, and lifetime impulsiveness were examined as well to determine if these mediated group differences in CD-RISC scores.CD-RISC scores differed between groups, with lowest scores in the past attempter group. However, CD-RISC scores were strongly correlated with other common risk factors for suicide attempt, including hopelessness, subjective depression, and reasons for living, which together explained 68 % of the CD-RISC variance. Group differences in CD-RISC scores were eliminated when the model included these covariates.Sample sizes were modest, and depression severity was low overall and significantly higher in the past suicide attempter group.The CD-RISC has demonstrated utility for predicting risk for depression, but appears to overlap with other known risk factors for suicidal behavior, especially hopelessness and subjective depression. Though it encapsulates variance from multiple risk factors in a single scale, it may not provide additional predictive power above and beyond these other risk factors for suicidal behavior.

OBJECTIVE: Studies demonstrate rapid antidepressant and anti-suicidal ideation effects of subanesthetic ketamine. The specific subcomponents of depression that are most closely tied to reduction of suicidal ideation with ketamine treatment are less explored. METHODS: Exploratory, post hoc analysis of data from a randomized clinical trial of ketamine vs midazolam in patients with major depressive disorder (MDD) and clinically significant suicidal ideation examined changes in factor analysis-derived symptom clusters from standard measures of depression (Hamilton Depression Rating Scale, HDRS; Beck Depression Inventory, BDI) and mood disturbance (Profile of Mood States, POMS), and their relationship to severity of suicidal ideation (Beck Scale for Suicidal Ideation; SSI). Ratings obtained before and one day after blinded intravenous infusion were decomposed into component factors or published subscales. Treatment effects on factors/subscales were compared between drugs, correlations with changes in suicidal ideation were tested, and stepwise regression was used to derive predictors of change in SSI. RESULTS: Factor scores for HDRS Psychic Depression, HDRS Anxiety, BDI Subjective Depression, POMS Depression and POMS Fatigue improved more with ketamine than midazolam. Stepwise regression showed across both drugs that improvement in HDRS Psychic Depression, POMS Depression, and HDRS Anxiety predicted 51.6% of the variance in reduction of suicidal ideation. LIMITATIONS: Secondary analysis of clinical trial data. CONCLUSIONS: Ketamine’s rapid effects on suicidal ideation appear to be mostly a function of its effects on core mood and anxiety symptoms of MDD, with comparatively little contribution from neurovegetative symptoms with the potential exception of vigor/fatigue. TRIAL REGISTRATION: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT01700829.

BackgroundThe serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters with depression. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to familial risk and resilience for suicidal behavior.Methods[11C]CUMI-101 positron emission tomography imaging to quantify regional brain 5-HT1A receptor binding was conducted in individuals considered to be at high risk for mood disorder or suicidal behavior on the basis of having a first- or second-degree relative(s) with an early onset mood disorder and history of suicidal behavior. These high-risk individuals were subdivided into the following groups: high risk resilient having no mood disorder or suicidal behavior (n = 29); high risk with mood disorder and no suicidal behavior history (n = 31); and high risk with mood disorder and suicidal behavior (n = 25). Groups were compared with healthy volunteers without a family history of mood disorder or suicidal behavior (n = 34). Participants underwent the Trier Social Stress Task (TSST). All participants were free from psychotropic medications at the time of the TSST and PET scanning.ResultsWe observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND for all participants and BPp in a subset of the sample) and definitions of regions of interest (ROIs; standard or serotonin system-specific ROIs). We also found no group differences on TSST outcomes. Within the high risk with mood disorder and suicidal behavior group, lower BPp binding (β = −0.084, SE = 0.038, P = .048) and higher cortisol reactivity to stress (β = 9.25, 95% CI [3.27,15.23], P = .004) were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes.Conclusions5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how hypothalamic-pituitary-adrenal axis function influences such risk.

Objective Recent neurocognitive studies of patients with post-treatment Lyme disease syndrome (PTLDS) find consistent deficits in memory and processing speed. Language fluency deficits are observed as well but may be secondary to poor memory and slowing rather than an independent deficit. Method This study performed a secondary analysis of data presented previously, including individuals with PTLDS and comparison samples of healthy volunteers (HC) and patients with major depressive disorder (MDD), to determine if language fluency deficits could be accounted for by poor performance in these other neurocognitive domains. Results Basic verbal abilities, memory, and processing speed were all significantly associated with fluency performance. MDD patients’ fluency deficits relative to HC were accounted for by these covariates. However, PTLDS patients’ poorer fluency performance relative to both other groups was not. Conclusions Language fluency appears to be an independent area of neurocognitive deficit within the constellation of PTLDS symptoms.

Suicidal behavior is associated with deficits in cognitive control; however, suicidal ideation (SI), a key precursor to suicidal behavior, has been less consistently linked to neuropsychological functioning. Additionally, no study to date has examined attentional control capacities in relation to variability in suicidal ideation, defined as fluctuation in SI intensity and duration across short periods of time. Prior research suggests that suicidal individuals with highly variable SI experience greater stress-responsive increases in SI and cortisol, potentially raising risk for suicidal behavior. Here, we examined attentional control capacities associated with SI variability and severity in ninety-five subjects with major depressive disorder. Variability and severity of SI and depressive affect were quantified using Ecological Momentary Assessment (EMA) over a 7-day period. Participants completed the Continuous Performance Task (CPT) and a computerized Stroop task for assessment of attentional control. EMA SI variability was associated with greater attentional interference on the Stroop task, and this was not accounted for by severity of SI, concurrently assessed depressive affect, or baseline depression. CPT performance was not related to SI variability or intensity. Findings highlight the utility of EMA methods in characterizing patterned experiences of SI and suggest that attentional control deficits may contribute to these characteristic patterns.

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 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: Suicidal individuals are a heterogeneous population and may differ in systematic ways in their responsiveness to stress. The primary aim of the present study was to identify whether a different pattern of physiological stress response exists among adult suicide attempters with a history of behavioral problems during childhood and adolescence, which earlier studies have related to both decreased activity of the HPA axis and to suicidal behaviors. METHOD: Seventy-eight participants with Borderline Personality Disorder were assessed using the SCID-II, and completed self-report measures assessing their history of suicide attempts, history of aggressive behaviors, depressive symptoms, history of lifetime abuse and demographics. Participants’ cortisol reactivity was assessed using the Trier Social Stress Test. RESULTS: Analyses indicated that suicide attempters with a history of behavioral problems in youth (n=30) had a significantly lower response to stress than both suicide attempters without such a history (n=26) and non-attempters (n=22), when controlling for lifetime history of abuse. The groups did not differ in basal cortisol. CONCLUSIONS: These findings suggest a unique subtype of suicide attempter among those with Borderline Personality Disorder, characterized by a blunted physiological stress response.

Prior studies sought to explain the predisposition to suicidal behavior in terms of myopic preference for immediate versus delayed reward, generating mixed evidence. Data from gambling and bandit tasks, however, suggest that suboptimal decisions in suicidal individuals are explained by inconsistent valuation rather than myopic preferences. We tested these two alternative hypotheses using a delay discounting task in 622 adults (suicide attempters with depression, suicide ideators with depression, nonsuicidal participants with depression, and healthy controls) recruited across three sites through inpatient psychiatric units, mood disorders clinics, primary care, and advertisements. Multilevel models revealed group differences in valuation consistencies in all three samples, with high-lethality suicide attempters exhibiting less consistent valuation than all other groups in Samples 1 and 3 and less consistent valuation than the healthy controls or participants with depression in Sample 2. In contrast, group differences in preference for immediate versus delayed reward were observed only in Sample 1 and were due to the high-lethality suicide attempters displaying a weaker preference for immediate reward than low-lethality suicide attempters. The findings were robust to confounds such as cognitive functioning and comorbidities. Seemingly impulsive choices in suicidal behavior are explained by inconsistent reward valuation rather than a true preference for immediate reward. In a suicidal crisis, this inconsistency may result in a misestimation of the value of suicide relative to constructive alternatives and deterrents. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: Subanesthetic ketamine rapidly reduces depressive symptoms and suicidal ideation in some depressed patients. Its effects on neurocognitive functioning in such individuals with significant suicidal ideation is not well understood, even though certain neurocognitive deficits are associated with suicide behavior beyond clinical symptoms. Methods: In this study, depressed patients with clinically significant suicidal ideation (n = 78) underwent neuropsychological testing before and 1 day after double-blind treatment with intravenous ketamine (n = 39) or midazolam (n = 39). A subgroup randomized to midazolam whose ideation did not remit after initial infusion received open ketamine and additional neurocognitive testing a day after this treatment. The primary outcome was change in performance on this neurocognitive battery. The study was conducted between November 2012 and January 2017. Results: Blinded ketamine produced rapid improvement in suicidal ideation and mood in comparison to midazolam, as we had reported previously. Ketamine, relative to midazolam, was also associated with specific improvement in reaction time (Choice RT) and interference processing/cognitive control (computerized Stroop task)-the latter a measure that has been associated with past suicide attempt in depression. In midazolam nonremitters later treated with open ketamine and retested, reaction time and interference processing/cognitive control also improved relative to both of their prior assessments. Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood. Conclusions: Overall, ketamine was found to have a positive therapeutic effect on neurocognition 1 day after treatment on at least 1 measure associated with suicidal behavior in the context of depression. Results suggest additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior. Trial Registration: ClinicalTrials.gov identifier: NCT01700829.

BACKGROUND: Studies of risk factors for suicidal behavior are typically restricted to narrow age ranges, making it difficult to determine if they have the same relevance or potency across the full adult lifespan. METHODS: This study examined selected clinical and neurocognitive risk factors for suicidal behavior – borderline personality traits, aggression, depressive rumination, memory performance, and language fluency– in a multi-site sample (N=309, ages 16–80) of depressed patients with a recent (last 5 years) suicide attempt or no history of attempt, and demographically similar non-psychiatric controls. We examined cross-sectional age and attempter/non-attempter differences on these risk factors, and whether certain risk factors were more prominent discriminators of past suicide attempt earlier or later in the lifespan. Correlations with age were computed, and logistic regression was used to classify attempter status based on each risk factor and its interaction with age. RESULTS: Nearly all risk factors were negatively correlated with age. Borderline traits, aggression, memory, and category fluency each predicted attempter status (p < 0.05), but these effects were not different across ages. In contrast, the association between rumination and suicide attempt status differed across the lifespan, becoming a stronger discriminator of past suicidal behavior at older ages. LIMITATIONS: The cross-sectional design limits our developmental findings. CONCLUSIONS: Despite age-related changes in symptom severity or neurocognitive performance, key risk factors for suicidal behavior previously identified in studies with more restricted age-ranges are salient throughout the adult lifespan. In contrast, depressive rumination may be particularly salient in later life.

BackgroundLittle is known about the neural substrates of suicide risk in mood disorders. Improving the identification of biomarkers of suicide risk, as indicated by a history of suicide-related behavior (SB), could lead to more targeted treatments to reduce risk.MethodsParticipants were 18 young adults with a mood disorder with a history of SB (as indicated by endorsing a past suicide attempt), 60 with a mood disorder with a history of suicidal ideation (SI) but not SB, 52 with a mood disorder with no history of SI or SB (MD), and 82 healthy comparison participants (HC). Resting-state functional connectivity within and between intrinsic neural networks, including cognitive control network (CCN), salience and emotion network (SEN), and default mode network (DMN), was compared between groups.ResultsSeveral fronto-parietal regions (k > 57, p < 0.005) were identified in which individuals with SB demonstrated distinct patterns of connectivity within (in the CCN) and across networks (CCN-SEN and CCN-DMN). Connectivity with some of these same regions also distinguished the SB group when participants were re-scanned after 1–4 months. Extracted data defined SB group membership with good accuracy, sensitivity, and specificity (79–88%).ConclusionsThese results suggest that individuals with a history of SB in the context of mood disorders may show reliably distinct patterns of intrinsic network connectivity, even when compared to those with mood disorders without SB. Resting-state fMRI is a promising tool for identifying subtypes of patients with mood disorders who may be at risk for suicidal behavior.

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.

Objective To test whether Mindfulness-Based Cognitive Therapy to Prevent Suicide (MBCT-S) is associated with improvement in attentional control, an objective marker of suicide attempt. Method In the context of a randomized clinical trial targeting suicide risk in Veterans, computerized Stroop and emotion Stroop (E-Stroop) tasks were administered 3 times over 6-months follow-up to 135 high suicide risk Veterans. Seventy were randomized to receive MBCT-S in addition to enhanced treatment as usual (eTAU), and 65 were randomized to eTAU only. E-Stroop word types included positively- and negatively-valenced emotion, suicide, and combat-related words. Interference scores and mixed effects linear regression analyses were used. Results Veterans receiving MBCT-S showed a more favorable trajectory of attentional control over time, as indicated by performance on two E-Stroop tasks. Combat-stress interference scores improved over time among Veterans in MBCT-S. Interference processing time for negative affective words deteriorated over time among Veterans receiving eTAU only. Conclusions MBCT-S may effectively target attentional control, and in particular reduce processing time during affective interference, in high suicide risk Veterans. Future studies to replicate these findings are warranted.

Background Growing evidence suggests cognitive deficits may represent neurocognitive markers with predictive utility in identifying those at risk for suicide. Characterizing these deficits may offer the opportunity to develop targeted interventions. Aim The aim of this systematic qualitative review is to provide a synthesis of the published data on neurocognition in suicide ideators and attempters in order to clarify which neurocognitive targets may be most relevant to address using cognitive-based psychotherapeutic strategies in patients at risk for suicide. Results A total of 63 studies met criteria for inclusion. The most consistent findings were in depressed suicide attempters, where deficits in executive subdomains of inhibition, selective attention and decision-making, as well as in working memory, were identified. In contrast, no clear pattern of neurocognitive deficits emerged from studies in suicide ideators across diagnoses. Conclusions More studies are needed to clarify the role of cognitive deficits in specific subtypes of individuals at risk for suicide. The findings are discussed in the context of promising research on cognitive remediation and other psychological interventions.

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.

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.

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.

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.

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.

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.

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

Neurocognitive detection of suicidal states has the potential to significantly advance objective risk assessment. This goal requires establishing that neurocognitive deficits fluctuate around the time of a suicide attempt. The current study therefore evaluated whether neurocognitive performance is temporally related to suicide attempt, in a sample at highrisk for suicide (n = 141). Evaluations consisted of a clinician-administered interview, self-report questionnaires, and neurocognitive tasks assessing response inhibition, attentional control, and memory recognition. Analyses examined whether neurocognitive scores significantly differed according to the following temporal suicide attempt categories: (a) past-week attempt; (b) past-year attempt (not in past week); and (c) no past-year attempt. Univariate results showed that response inhibition and memory recognition were significantly related to suicide attempt recency. Post-hoc pairwise tests showed that participants with a past-week suicide attempt showed greater impairments than those without a past-year attempt. Multivariate tests showed the same pattern of results, adjusting for age, suicide attempts prior to past year, mood disturbance, and suicidal ideation. These results show that neurocognitive assessment of response inhibition and memory recognition shows sensitivity to the recency of a suicide attempt. While future prospective studies are needed, results suggest that phasic neurocognitive deficits may serve as objective markers of short-term suicide risk.

BACKGROUND: Face processing deficits characterize schizophrenia, including in prodromal stages. Baseline face processing deficits predict psychosis onset in clinical high-risk (CHR) youths, specifically in fear/anger processing (Corcoran, 2015). Here, we evaluate the predictive value for psychosis onset, specifically of speed of face processing in CHR youths. METHODS: In a cohort of 49 CHR patients (of whom 7 later transitioned to psychosis), and 31 healthy controls, we examined reaction times for face processing using the UPenn battery, including the Emotion Recognition (ER-40; Kohler 2005), Emotion Discrimination (EMODIFF), Emotional Acuity (PEAT), Facial Identification, as well as motor praxis. RESULTS: CHR converters had significantly slower reaction time for face emotion recognition (FER) (p=.008), but not discrimination, acuity or facial identification. They also had slower motor praxis and greater baseline prodromal symptom severity (p

To test changes to cognitive functioning among high-suicide risk outpatients participating in an adjunct mindfulness-based intervention combining mindfulness-based cognitive therapy and safety planning (MBCT-S).Ten outpatients with a 6-month history of suicide attempt or active suicidal ideation plus suicidal ideation at study entry received 9 weeks of adjunct group-based MBCT-S. Executive attention, sustained attention, visual memory, and semantic memory encoding were measured by neuropsychological assessment. Rumination, mindfulness, cognitive reactivity (defined as the tendency towards depressogenic information processing and thought content in response to mild mood deterioration), and self-compassion were assessed using self-report measures. Changes in pre- to post-treatment functioning on these constructs were analyzed by using dependent t-tests. Where significant improvements were found, correlations between changes to cognitive functioning and depression and suicidal ideation during treatment were calculated.Executive attention improved with MBCT-S in high-suicide risk outpatients (Stroop interference effect = 0.39 [standard deviation (SD), 27] at baseline and 0.27 (SD, 0.15) at post-treatment, t[9] = 2.35, p = 0.04, d = 0.75). One mindfulness skill, acting with awareness, increased with MBCT-S (average change in Five Facet Mindfulness Questionnaire-acting with awareness subscale score with treatment, 3.3 [SD, 3.0], t[9] = 3.46, p 0.01, d = 1.1). Self-reported rumination and cognitive reactivity to suicidality and hopelessness decreased among participants (Ruminative Responses Brooding subscale score change, -3.4 [SD, 1.1], t[9] = 10, p 0.001, d = 3.2; Leiden Index of Depression Sensitivity-Revised-Hopelessness/Suicidality subscale score change, -3 [SD, 2.7], t[9] = 3.56, p 0.01, d = 1.1). None of these changes were related to improvements in depression or reductions in suicidal ideation during treatment.Findings from the present pilot study suggest that treatment with MBCT-S may improve cognitive deficits specific to suicide ideators and attempters among depressed patients. Future controlled trials using follow-up assessments are needed to determine the specificity of these improvements in cognitive functioning to MBCT-S and their durability and to formally test whether the observed improvements in cognitive functioning explain MBCT-S treatment gains.

Marijuana use is associated with psychosis, but its effects are understudied in individuals with preexisting risk for psychotic disorders. This preliminary study examined the acute psychological and physiological effects of smoked marijuana (0.0% or 5.5% Δ9-THC) in marijuana users at clinical high-risk (CHR; n = 6) to develop a psychotic disorder, and those not at risk (n = 6), under controlled laboratory conditions. CHR marijuana users exhibited temporary increases in psychotic-like states and decreases in neurocognitive performance during marijuana intoxication but control marijuana smokers did not. These findings, if replicated, may support a psychotogenic role for marijuana in CHR individuals.

Importance A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. Objective To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. Design, Setting, and Participants This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication–free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Intervention Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Main Outcomes and Measures Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. Results A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36 = 2.81;P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 2.25;P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33 = −2.400;P = .02; slope estimate, −9.85 [95% CI, −18.2 to −1.50]). Although GABA levels correlated with Glx (t33 = 8.117;P Conclusions and Relevance In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. Trial Registration ClinicalTrials.gov Identifier:NCT01558063

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.

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.

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

Aim Individuals at clinical high risk for psychosis (CHR) exhibit neurocognitive deficits in multiple domains. The aim of this study is to investigate whether several components of neurocognition are predictive of conversion to psychosis. Methods Fifty-two CHR individuals were assessed with the Structured Interview for Psychosis Risk Syndromes and completed a battery of neurocognitive tests at baseline including measures of executive functioning, attention, working memory, processing speed and reaction time. Neurocognitive functioning at baseline was scored based on an external normative control group. Most subjects were followed for 2.5 years to determine conversion status. Results Significant differences in neurocognitive functioning between CHR individuals and the control group were present in all domains. Twenty-six per cent of the participants converted to psychosis within 9.8 (standard deviation = 8.0) months on average (median 9 months), but there were no significant differences in neurocognition converters and non-converters. Conclusions Individuals at CHR have deficits in neurocognitive functioning, but such deficits do not appear to be related to conversion risk.

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

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

Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.

Background Suicide is a heterogeneous phenomenon, and thus defining more homogeneous subgroups may help in understanding its underlying biology and ultimately in its prevention. Suicidal ideation is far more common than suicidal behavior and predicts future suicide attempts. Hypothalamic–pituitary–adrenal (HPA)-axis reactivity has been implicated in individuals with suicidal ideation but findings are mixed with some studies showing increased and others demonstrating decreased reactivity. This suggests that dysregulation of HPA-axis is related to a specific character of suicidal ideation. We hypothesized that individuals with brief suicidal ideation are more stress responsive than those with longer/continuous ideation. Methods Thirty-five individuals with major depressive disorder (MDD) and 23 healthy volunteers (HVs), aged 18–65 years, underwent the Trier Social Stress Test (TSST). Salivary cortisol was measured at 6 time-points before and during TSST. Total severity and duration of current suicidal ideation were assessed using the Beck Scale for Suicidal Ideation (SSI). Brief suicidal ideators (N = 18), longer/continuous ideators (N = 17) and HVs were compared regarding cortisol response, baseline cortisol and total output. Results Participants with brief suicidal ideation had greater cortisol response compared to those with longer/continuous ideation and HVs, even after controlling for relevant covariates. However, total SSI score was not associated with cortisol response. Baseline cortisol and total output were not related to overall severity or duration of suicidal ideation. Limitations The cross-sectional design and modest sample limit generalizability of the results. Conclusions Hyper-responsiveness of HPA-axis to social stress is associated with brief suicidal ideation, possibly defining a pathway for exploring the biological subtyping of suicidal individuals.

Background Suicidal ideation appears to be more strongly associated with subjective rather than neurovegetative symptoms of depression. Effective treatment, then, should produce reductions in suicidal ideation to the degree that these subjective symptoms are alleviated relative to treatment effects on other symptoms. Methods In a randomized clinical trial comparing paroxetine and bupropion for treatment of depression in patients with either suicidal ideation or past attempt, depression severity and suicidal ideation were assessed weekly during the 8-week study. Depression rating scales - the 24-item Hamilton Depression Rating Scale [HDRS] and the Beck Depression Scale [BDI] - were decomposed into symptom clusters based on our published factor analyses, and their change over time compared to changes on the Beck Scale for Suicidal Ideation [SSI]. Results Improvement in factor scores associated with subjective symptoms of depression - HDRS Psychic Depression, BDI Subjective Depression, and BDI Self-Blame - were the best predictors of declining scores on the SSI regardless of type of drug treatment. BDI Subjective Depression was the best single predictor in the context of all other significant univariate predictors, accounting for 31.4% of the variance in the change in SSI. The three factors together accounted for 35.3%. Limitations This is a secondary analysis of clinical trial data, with fixed treatments. Conclusions Effective treatments to reduce suicidal ideation are associated with the reduction of the subjective symptoms of depression, which may not always decline in synchrony with improvement in neurovegetative symptoms. This asynchrony may result in a period of elevated risk after the initiation of therapy. Data indicate that subjective depression symptoms should be a primary target in the treatment of depressed suicidal patients.