Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

OBJECTIVE: We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. METHODS: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. RESULTS: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). CONCLUSION: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Alterations in performance and discriminating power of the death/suicide implicit association test across the lifespan.

The Death/Suicide Implicit Association Test (d/s-IAT) has differentiated individuals with prior and prospective suicide attempts in previous studies, however, age effects on test results remains to be explored. A three-site study compared performance on the d/s-IAT among participants aged 16-80 years with depression and prior suicide attempt (n = 82), with depression and no attempts (n = 80), and healthy controls (n = 86). Outcome measures included the standard difference (D) score, median reaction times, and error rates. Higher D scores represent a stronger association between death/suicide and self, while lower scores represent a stronger association between life and self. The D scores differed significantly among groups overall. Participants with depression exhibited higher scores compared to healthy controls, but there was no difference between participants with and without prior suicide attempts(F[2,242]=8.76, p<.001). Response times for participants with prior attempts differed significantly from other groups, with no significant differences in error rates. The D score was significantly affected by age (ß =-0.007, t = 3.65, p<.001), with slowing of response times in older ages. Results suggest reaction time d/s-IAT D scores may not distinguish implicit thinking about suicide as response times slow with age, but slowed response times may be sensitive to suicide risk potentially indicating basic information processing deficits.

Intramuscular ketamine vs. midazolam for rapid risk-reduction in suicidal, depressed emergency patients: Clinical trial design and rationale.

Emergency department (ED) visits for suicidal ideation or behavior have been increasing in all age groups, particularly younger adults. A rapid-acting treatment to reduce suicidal thinking, adapted for ED use, is needed. Previous studies have shown a single dose of ketamine can improve depression and suicidal ideation within hours. However, most studies used 40 min intravenous infusions which can be impractical in a psychiatric ED. The ER-Ketamine study we describe here is a randomized midazolam-controlled clinical trial (RCT; NCT04640636) testing intramuscular (IM) ketamine's feasibility, safety, and effectiveness to rapidly reduce suicidal ideation and depression in a psychiatric ED. A pre-injection phase involves screening, informed consent, eligibility confirmation, and baseline assessment of suicidal ideation, depression, and comorbidities. The randomized double-blind IM injection is administered in the ED under research staff supervision, vital sign monitoring, pharmacokinetic blood sampling, and clinical assessments. The post-injection phase occurs on a psychiatric inpatient unit with follow-up research assessments through four weeks post-discharge. Outcome measures are feasibility, safety, and effects on suicidal ideation and depression at 24 h post-injection, and through follow-up. The target sample is N = 90 adults in a major depressive episode, assessed by ED clinicians as warranting hospitalization for suicide risk. Here we report design, rationale, and preliminary feasibility and safety for this ongoing study. Demographics of the 53 participants (ages 18 to 65 years) randomized to date suggest a diverse sample tending towards younger adults.

Impairment in recognition memory may be associated with near-term risk for suicide attempt in a high-risk sample.

INTRODUCTION: Prior work has implicated several neurocognitive domains, including memory, in patients with a history of prior suicide attempt. The current study evaluated whether a delayed recognition test could enhance prospective prediction of near-term suicide outcomes in a sample of patients at high-risk for suicide. METHODS: 132 Veterans at high-risk for suicide completed a computer-based recognition memory test including semantically-related and -unrelated words. Outcomes were coded as actual suicide attempt (ASA), other suicide-related event (OtherSE) such as aborted/interrupted attempt or preparatory behavior, or neither (noSE), within 90 days after testing. RESULTS: Reduced performance was a significant predictor of upcoming ASA, but not OtherSE, after controlling for standard clinical variables such as current suicidal ideation and history of prior suicide attempt. However, compared to the noSE reference group, the OtherSE group showed a reduction in the expected benefit of semantic relatedness in recognizing familiar words. A computational model, the drift diffusion model (DDM), to explore latent cognitive processes, revealed the OtherSE group had decreased decisional efficiency for semantically-related compared to semantically-unrelated familiar words. LIMITATIONS: This study was a secondary analysis of an existing dataset, involving participants in a treatment trial, and requires replication; ~10 % of the sample was excluded from analysis due to failure to master the practice tasks and/or apparent noncompliance. CONCLUSION: Impairments in recognition memory may be associated with near-term risk for suicide attempt, and may provide a tool to improve prediction of when at-risk individuals may be transitioning into a period of heightened risk for suicide attempt.

Plasma cytokine and growth factor response to acute psychosocial stress in major depressive disorder.

BACKGROUND: Pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α are elevated in response to psychosocial stress; however, less is known about other inflammatory markers. METHODS: We explored response to the Trier Social Stress Test (TSST) of 16 cytokines and growth factors in patients with major depressive disorder (MDD, n = 12) vs. healthy volunteers (HV, n = 16). Outcomes were baseline and post-stress levels estimated by area under the curve (AUCi) and peak change over 3 timepoints. We also explored correlations between biomarkers and clinical characteristics. RESULTS: Baseline concentrations were higher in MDD for platelet-derived growth factor (PDGF)-AB/BB (p = 0.037, d = 0.70), granulocyte-macrophage colony-stimulating factor (GM-CSF, p = 0.033, d = 0.52), and IL-8 (p = 0.046, d = 0.74). After TSST, AUCi was higher in MDD for GM-CSF (p = 0.003, d = 1.21), IL-5 (p = 0.014, d = 1.62), and IL-27 (p = 0.041, d = 0.74). In MDD, depression severity correlated positively with soluble CD40L (sCD40L) for AUCi (Spearman's ρ = 0.76, p = 0.004) and with baseline vascular endothelial growth factor A (VEGFA, r = 0.85, p < 0.001), but negatively with baseline monokine induced by gamma interferon (MIG, aka CXCL9; r = -0.77, p = 0.003). CONCLUSIONS: Effect sizes were robust in this exploratory study, although interpretation of the results must be cautious, given small sample size and multiple comparisons. Differential study of stress-induced biomarkers may have important ramifications for MDD treatment.

Plasma Phospholipid Polyunsaturated Fatty Acid Associations with Neurocognition.

Neurocognitive deficits are implicated in major depressive disorder (MDD) and suicidal behavior, and cognitive function may be affected by blood levels of polyunsaturated fatty acids (PUFAs). Neuroprotective functions have been described for omega-3 (n-3) PUFAs, while omega-6 (n-6) PUFAs exhibit broadly opposing activities. Both classes of PUFAs are linked to MDD and suicidal behavior. However, few studies have investigated the relationships between PUFAs and neurocognitive function with respect to MDD or suicidal behavior. Among participants with MDD (n = 45) and healthy volunteers (HV, n = 30) we assessed performance on tasks of attentional capacity and executive function and its relationship to plasma phospholipid PUFA levels, expressed as a percentage of total plasma phospholipids, for eicosapentaenoic acid (EPA%), docosahexaenoic acid (DHA%), and arachidonic acid (AA%). Regression models tested the correlations between PUFA levels and task performance in three groups: MDD with a history of suicide attempt (SA, n = 20), MDD with no attempts (NA, n = 25), and HV. Interaction testing indicated a significant positive correlation of EPA% with continuous performance test scores in the NA group (F = 4.883, df = 2,72, p = 0.01), a measure of sustained attention. The AA% correlated negatively with performance on two executive function tasks, object alternation (beta = -3.97, z-score = -2.67, p = 0.008) and the Wisconsin card sort (beta = 0.80, t-score = -2.16, df = 69, p = 0.035), after adjustment for group and age, with no group effects. Our findings suggest a role for PUFA imbalance in attentional functioning and executive performance; however, no MDD-specific effect was observed.

Relationship of stress-reactive cortisol to suicidal intent of prior attempts in major depression.

Higher intent suicide attempts carry elevated risk of future suicidal behavior. Abnormal functioning of the hypothalamic-pituitary-adrenal (HPA) axis is both linked to nonfatal suicidal behavior and suicide deaths in major depressive disorder. Few studies, however, have identified biological markers of a high-intent suicidal subgroup. We examined HPA axis output and reactivity to the Trier Social Stress Test (TSST) via salivary cortisol in depressed individuals (N=68) with a suicide attempt (SA) history. A median split of higher and lower suicidal intent scores was used to define groups. Individuals with high intent SA had attenuated total cortisol output (AUCg), F(1,60)=10.04, SE=5.095, p=.003, and lower HPA-axis stress responsivity to the TSST (AUCi), F(1,60)=4.50, SE=4.604, p=.039, compared with the low intent SA group. The high intent group also reported more pronounced negative affect than the low intent group (F[1,61]=6.413, SE=10.55, p=.014) both at baseline (meandiff=22.32, p=.038) and in response to the stressor task (meandiff=37.62, p=.003). Vulnerability to suicidal behavior in high-intent individuals may be related to the combined profile of impaired physiological responses to stress and greater negative affectivity. This clinical and biologic subgroup may benefit from targeted suicide prevention interventions.

Neurocognitive and clinical characteristics of elementary school-aged children with a history of suicidal thoughts and behaviors.

BACKGROUND: Suicidal thoughts and behaviors (STBs) in elementary school-aged youth have increased in recent years. Understanding the risks associated with childhood STBs is necessary for prevention efforts. METHODS: The current study examined clinical and neurocognitive characteristics of a community sample of elementary school-aged children with (STB+) and without (STB-) a history of STBs. The final sample included 93 families with children average age of 7.8 years (SD = 1.3). Children in this sample were racially diverse, evenly split by sex, and most identified as non-Hispanic. Neurocognitive functioning was assessed using computerized behavioral measures. Child clinical characteristics were assessed using self-report measures and STB history was assessed using semi-structured interviews. RESULTS: Of the 93 families, 64 STB- children and 29 STB+ children participated. On average, STB+ children were older, reported higher levels of depressive and anxiety symptoms, and were more likely to have a parental history of suicidal behavior (PH+). Regarding neurocognitive functioning, STB+ children exhibited lower raw scores for both the NIH Dimensional Change Card Sort Task (NIH-DCCS) and NIH Flanker Inhibitory Control and Attention Test (NIH-Flanker). Multivariable regression analyses revealed raw scores for NIH-DCCS and NIH-Flanker, PH+ status, and child age were associated with childhood STBs. LIMITATIONS: Prospective data is needed to confirm cross-sectional findings. CONCLUSIONS: Poorer neurocognitive functioning and PH+ status may serve as risk markers for STBs in elementary school-aged children. Targeting prevention programming for these risks may reduce the likelihood of STBs in at-risk elementary school-aged youth.

Smaller cornu ammonis (CA3) as a potential risk factor for suicidal behavior in mood disorders.

Mood disorders and suicidal behavior have moderate heritability and familial transmission, and are associated with smaller hippocampal volumes. However, it is unclear whether hippocampal alterations reflect heritable risk or epigenetic effects of childhood adversity, compensatory mechanisms, illness-related changes, or treatment effects. We sought to separate the relationships of hippocampal substructure volumes to mood disorder, suicidal behavior, and risk and resilience to both by examining high familial risk individuals (HR) who have passed the age of greatest risk for psychopathology onset. Structural brain imaging and hippocampal substructure segmentation quantified Cornu Ammonis (CA1-4), dentate gyrus, and subiculum gray matter volumes in healthy volunteers (HV, N = 25) and three groups with one or more relatives reporting early-onset mood disorder and suicide attempt: 1. Unaffected HR (N = 20); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 25); and 3. HR with lifetime mood disorder and a previous suicide attempt (HR-MOOD + SA, N = 18). Findings were tested in an independent cohort not selected for family history (HV, N = 47; MOOD, N = 44; and MOOD + SA, N = 21). Lower CA3 volume was found in HR (vs. HV), consistent with the direction of previously published findings in MOOD+SA (vs. HV and MOOD), suggesting the finding reflects a familial biological risk marker, not illness or treatment-related sequelae, of suicidal behavior and mood disorder. Familial suicide risk may be mediated in part by smaller CA3 volume. The structure may serve as a risk indicator and therapeutic target for suicide prevention strategies in high-risk families.

Cognitive flexibility in inpatient children and adolescents with a history of suicide attempts.

An increase in suicide rates during adolescence has made it the second leading cause of death for this age group. While potential deficits in cognitive flexibility have been thought to contribute to suicidality, this factor has been evaluated in only a few studies among this age group. The current study sought to evaluate cognitive flexibility in 100 psychiatric inpatient children and adolescents (age X=14.39, SD=2.53), with (n=26) and without (n=74) a history of suicide attempts, using the Wisconsin Card Sorting Test (WCST). Results showed no differences between the groups in WCST scores. However, in a small sub-sample with mood disorders only, those with a history of a suicide attempt performed better than those without such history. These findings are contrary to our hypothesis that those who attempted suicide have worse cognitive flexibility, though consistent with earlier data in adults. Further research is needed to shed light on these findings.

Language Fluency Deficits in Post-treatment Lyme Disease Syndrome.

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.

Attentional control deficits and suicidal ideation variability: An ecological momentary assessment study in major depression.

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.

Deconstructing resilience in patients at high risk for suicidal behavior.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. LIMITATIONS: Sample sizes were modest, and depression severity was low overall and significantly higher in the past suicide attempter group. CONCLUSIONS: 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.

Improving the prospective prediction of a near-term suicide attempt in veterans at risk for suicide, using a go/no-go task.

BACKGROUND: Neurocognitive testing may advance the goal of predicting near-term suicide risk. The current study examined whether performance on a Go/No-go (GNG) task, and computational modeling to extract latent cognitive variables, could enhance prediction of suicide attempts within next 90 days, among individuals at high-risk for suicide. METHOD: 136 Veterans at high-risk for suicide previously completed a computer-based GNG task requiring rapid responding (Go) to target stimuli, while withholding responses (No-go) to infrequent foil stimuli; behavioral variables included false alarms to foils (failure to inhibit) and missed responses to targets. We conducted a secondary analysis of these data, with outcomes defined as actual suicide attempt (ASA), other suicide-related event (OtherSE) such as interrupted/aborted attempt or preparatory behavior, or neither (noSE), within 90-days after GNG testing, to examine whether GNG variables could improve ASA prediction over standard clinical variables. A computational model (linear ballistic accumulator, LBA) was also applied, to elucidate cognitive mechanisms underlying group differences. RESULTS: On GNG, increased miss rate selectively predicted ASA, while increased false alarm rate predicted OtherSE (without ASA) within the 90-day follow-up window. In LBA modeling, ASA (but not OtherSE) was associated with decreases in decisional efficiency to targets, suggesting differences in the evidence accumulation process were specifically associated with upcoming ASA. CONCLUSIONS: These findings suggest that GNG may improve prediction of near-term suicide risk, with distinct behavioral patterns in those who will attempt suicide within the next 90 days. Computational modeling suggests qualitative differences in cognition in individuals at near-term risk of suicide attempt.

Delay discounting in suicidal behavior: Myopic preference or inconsistent valuation?

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) 2022 APA, all rights reserved).

Smoked Cannabis Effects in Cannabis Users at Clinical High-Risk for Psychosis: A Further Investigation of Cognition and Reward.

Objective: Some adverse cannabis effects are greater in individuals on the psychosis spectrum compared to healthy individuals. We have previously reported that smoked cannabis acutely worsened psychotic- like states and reduced cognitive performance selectively in cannabis users at clinical high-risk (CHR) for psychosis. The objective of the present study was to further investigate the acute effects of cannabis on cognition and reward processing in CHR cannabis users. Methods: Six CHR cannabis users and six psychiatrically-healthy cannabis users comparable in intellectual, demographic, and cannabis use characteristics (including nontreatment-seeking status), participated in the study. Objective and subjective measures of cognition and cannabis reward, were completed before and after smoking half of an active (5.5% Δ9tetrahydrocannabinol [Δ9-THC]) or half of a placebo (0.0% Δ9-THC) cannabis cigarette, under randomized/double-blind conditions. Repeated measures ANOVA tested main effects of drug condition (active vs. placebo) and/or the drug condition × time (baseline vs. post-administration) interactions; groups were analyzed separately due to the small sample size. Results: CHR participants exhibited evidence of decreased objective response inhibition and aversive intoxication following active cannabis, relative to placebo. Psychomotor speed and cannabis-related attentional bias were also affected by cannabis intoxication. No such effects were observed in psychiatrically-healthy cannabis users. Conclusion: These findings provide further preliminary evidence of a deleterious cognitive and reward- related response to cannabis in individuals with preexisting risk for psychosis.

Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial.

BACKGROUND: Treatment 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. METHODS: In 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. RESULTS: Greater 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. CONCLUSION: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior.

BACKGROUND: The 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. RESULTS: We 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 (ß = -0.084, SE = 0.038, P = .048) and higher cortisol reactivity to stress (ß = 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. CONCLUSIONS: 5-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.

A qualitative systematic review of neurocognition in suicide ideators and attempters: Implications for cognitive-based psychotherapeutic interventions.

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.

Ketamine vs midazolam: Mood improvement reduces suicidal ideation in depression.

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.