Occurrence and characteristics of suicidal ideation in psychiatrically healthy individuals based on ecological momentary assessment.

Decedents with no known mental disorder comprise 5-40% of suicides, suggesting that suicide ideation (SI) and behavior may occur in the psychiatrically healthy with important implications for suicide risk screening. Healthy Volunteers (HV) and patients with Major Depressive Disorder (MDD) provided 7 days of Ecological Momentary Assessment (EMA) data about SI and stressors. Longitudinal mixed effects logistic regression models compared HV and patient SI and stressors. Mixed effects linear regression models compared HVs' and patients' SI score change from the previous epoch's SI score when each stressor occurred. HVs (n = 42) reported less frequent (p < 0.001) and less intense SI (p < 0.003) than patients (n = 80), yet did endorse SI and/or SI-related items in 44% of EMA epochs, endorsing SI items in 25% of epochs with non-zero SI scores. For 7 of 8 stressors, patients reported stressors more often than HVs (all p < 0.001) responding to them with increased SI (0.0001 < p < 0.0472). HVs were relatively resilient to stressors, reporting SI increases only in response to neglect (p < 0.0147). Although SI and SAs are documented among psychiatrically healthy individuals, scientific attention to these observations has been scant. Real-time SI measurement showed that HVs' SI was less pronounced than MDD patients', but was endorsed, nonetheless. Patients were more likely to report stressors than HVs, perhaps due to greater sensitivity to the environment, and reported SI in response to stressors, which was less common in HVs. Both MDD patients and HVs most often manifested passive SI (viz, "decreased wish to live"). However, passive SI (viz, "desire for death"), may predict suicide, even absent SI per se (thinking about killing yourself). This study validates the utility of real-time SI assessment, showing that HVs endorse SI items in 11% of epochs, which implies that suicide risk screening focused on those with mental disorders may be too narrow an approach.

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.

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.

Antisuicidal effect of lithum in bipolar disorder: is there an age-specific effect?

OBJECTIVE: Our group reported previously a comparable overall antisuicidal effect of lithium and valproate in bipolar patients. We investigated factors associated with higher antisuicidal efficacy of lithium in older individuals. METHODS: The age-related antisuicidal effect of lithium and valproate was compared in ninety-four (n = 94) high-risk bipolar suicide attempters who participated in a 2.5-year randomized, double-blind trial. RESULTS: Age significantly moderated the effect of lithium vs. valproate on the risk of suicide event during the study (z = -1.98, p = 0.049). We found that those who were 42 years or older (above the 75th percentile), and on lithium had significantly lower risk of suicidal behavior than older patients on valproate (>42y) or younger (<42 y) patients on either medication (interaction HR = 0.09, 95%CI: 0.01-0.89, z = -2.07, p = 0.039). This difference in risk differences was not explained away by age-related differences in the proportion of participants with bipolar II disorder (Fisher's test p = 0.020) or higher lethality of past suicide attempts in younger participants (Wilcoxon test p = 0.024); neither was there any correlation with age in the longitudinally measured blood lithium levels (t = 1.04, df = 36, p = 0.307) or valproate levels (t = -0.50, df = 41, p = 0.621). LIMITATIONS: Besides the fact that this is a secondary analysis, a limitation is that the study is not powered to detect suicide deaths or suicide attempts. CONCLUSION: Bipolar patients randomized to lithium and older than 42 years had less suicidal behavior compared to same aged patients on valproate or younger patients (<42 y) on either medication. This effect was independent of clinical and sociodemographic characteristics.

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.

Brain serotonin 1A receptor binding: relationship to peripheral blood DNA methylation, recent life stress and childhood adversity in unmedicated major depression.

BACKGROUND: Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms. AIMS: We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls). METHOD: Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (-1019, -1007, -681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF. RESULTS: Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD. CONCLUSIONS: These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

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.

Avoidant attachment transmission to offspring in families with a depressed parent.

BACKGROUND: Insecure attachment is associated with mental health morbidity. We explored associations between parent and offspring attachment style in a longitudinal study of families with a depressed parent. METHODS: Parents (N = 169) with a DSM-IV mood disorder and their adult offspring (N = 267), completed the Adult Attachment Questionnaire at one or more time points during up to 9.7 years of follow-up. Linear mixed effects models explored associations between parent and offspring anxious and avoidant attachment scores. Residualized models accounted for parent and offspring depression severity. RESULTS: Avoidant attachment scores were associated between parents and offspring with (p = .034) and without (p = .012) adjustment for baseline age and sex of parent and offspring. Depressed father-offspring relationships showed more avoidant attachment in offspring compared to depressed mother-offspring pairs (p = .010). After accounting for depression severity, parent average residualized avoidant attachment scores did not significantly correlate with those of offspring (unadjusted p = .052; adjusted p = .085), though the effect sizes did not change substantially, and 75 % of the correlation was retained. Parent-son relationships exhibited stronger avoidant attachment correlations compared to parent-daughter pairs (p = .048). LIMITATIONS: Small sub-sample of fathers, parent and offspring assessments not always completed at the same time, and use of a self-report attachment style instrument. CONCLUSIONS: Familial transmission of insecure avoidant attachment, a risk factor for negative mental health outcomes, merits research as a potential treatment target. In this preliminary study, its transmission to offspring seemed mostly independent of depression. Depressed fathers and their sons may deserve focus to reduce insecure avoidant attachment and improve clinical course.

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.

The Temporal Dynamics of Emotion Regulation in Subjects With Major Depression and Healthy Control Subjects.

BACKGROUND: Emotion regulation (ER) processes help support well-being, but ineffective ER is implicated in several psychiatric disorders. Engaging ER flexibly by going online and offline as needs and capacities shift may be more effective than engaging ER rigidly across time. Here, we sought to observe the neural temporal dynamics of an ER process, reappraisal, during regulation of responses to negative memories in healthy control subjects (n = 33) and subjects with major depressive disorder (n = 36). METHODS: To track the temporal dynamics of reappraisal neural systems, we used a functional magnetic resonance imaging neural decoding approach. In task 1, subjects explicitly engaged reappraisal on instruction in response to aversive images, and we used this task to develop the decoder for detecting reappraisal. In task 2, subjects experienced negative autobiographical memories from a distant (third person, ER condition) or immersed (first person, control condition) perspective. RESULTS: The neural decoder, trained to detect reappraisal in task 1, predicted greater reappraisal occurring during the task 2 distance versus immerse trials and was engaged more intensely during memories that were rated as being more negative. Across time, decoder output manifested a temporal dynamic of early engagement followed by disengagement. These results were replicated in an independent subject dataset (n = 59). Relative to healthy control subjects, subjects with major depressive disorder had a comparable initial increase in decoder engagement at the beginning of the trial but an attenuated decrease at the end. CONCLUSIONS: Subjects with major depressive disorder evidenced a more rigid neural dynamic of reappraisal compared with healthy control subjects. Rigid ER may indicate diminished ability to flexibly and effectively regulate emotion.

Mood Disorders and Aggressive Traits Mediate Effects of Reported Childhood Adversity on Suicide Attempt Risk.

BACKGROUND: Childhood adversity (CA) is linked to suicidal behavior as well as to mood disorders and aggressive traits. This raises the possibility that depression and aggressive traits mediate the relationship of childhood adversity to suicide risk. Moreover, it is not known if they operate independently or interactively. AIMS: To determine whether, and how, mood disorders and aggressive traits mediate the effects of reported physical and sexual abuse on future suicidal behavior. METHODS: Five hundred and forty-eight subjects, offspring of parents with mood disorders, were interviewed at baseline and at yearly follow-ups with questionnaires assessing aggression, mood disorders, and suicidal behavior. The mediation analysis involved a three-step process, testing the relationships between (1) CA and attempt; (2) CA and putative mediators; and (3) putative mediators and suicide attempt, adjusting for CA. RESULTS: Aggressive trait severity and mood disorder onset each mediated the relationship between CA and future suicide attempts. Greater aggression severity also raised the hazard of the development of a mood disorder. If aggressive trait severity was clearly elevated, then onset of mood disorder did not increase further the hazard of the suicide attempt. Including family as a random effect had a much bigger effect on attempt outcome for physical abuse compared with sexual abuse. CONCLUSIONS: Amelioration of aggressive traits and treatment of mood disorders in CA-exposed offspring of a parent with a mood disorder may prevent future suicide attempts and may reduce the risk of mood disorder. Familial factors influence the impact of childhood physical abuse but not sexual abuse. HIGHLIGHTSChildhood Adversity (CA) predicted future mood disorder and aggression severity.Depression and aggression mediate the relationship between CA and suicide attempts.When one mediator is present, the presence of the other does not increase the hazard.Between family variation contributed much more to suicidal behavior outcomes relative to the effect of physical abuse, but sexual abuse contributed to suicidal outcomes more than family variation.

Ventral prefrontal serotonin 1A receptor binding: a neural marker of vulnerability for mood disorder and suicidal behavior?

Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD + SA, N = 20). Findings were tested in an independent cohort not selected for family history (HV, MOOD, and MOOD + SA, total N = 185). We tested for regional BPND differences and whether brain-wide patterns distinguished between groups. Low ventral prefrontal 5-HT1A BPND was associated with lifetime mood disorder diagnosis and suicide attempt, but only in subjects with a family history of mood disorder and suicide attempt. Brain-wide 5-HT1A BPND patterns including low ventral prefrontal and mesiotemporal cortical binding distinguished HR-MOOD + SA from HV. A biological endophenotype associated with resilience was not observed. Low ventral prefrontal 5-HT1A BPND may reflect familial mood disorder and suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND confers resilience, reducing risk of suicidal behavior in the context of familial risk, and thereby offer a potential prevention target.

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.

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.

Effects of Ketamine Versus Midazolam on Neurocognition at 24 Hours in Depressed Patients With Suicidal Ideation.

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.

Age effects on clinical and neurocognitive risk factors for suicide attempt in depression - Findings from the AFSP lifespan study.

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.

Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder.

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

Highly variable suicidal ideation: a phenotypic marker for stress induced suicide risk.

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

Examining the relationship between gray matter volume and a continuous measure of bipolarity in unmedicated unipolar and bipolar depression.

BACKGROUND: It has been argued that unipolar major depressive disorder (MDD) and bipolar disorder (BD) exist on a continuous spectrum, given their overlapping symptomatology and genetic diatheses. The Bipolarity Index (BI) is a scale that considers bipolarity as a continuous construct and was developed to assess confidence in bipolar diagnosis. Here we investigated whether BI scores correlate with gray matter volume (GMV) in a sample of unmedicated unipolar and bipolar depressed individuals. METHODS: 158 subjects (139 with MDD, 19 with BD) in a major depressive episode at time of scan were assigned BI scores. T1-weighted Magnetic Resonance Imaging scans were obtained and processed with Voxel-Based Morphometry using SPM12 (CAT12 toolbox) to assess GMV. Regression was performed at the voxel level to identify clusters of voxels whose GMV was associated with BI score, (p<0.001, family-wise error-corrected cluster-level p<0.05), with age, sex and total intracranial volume as covariates. RESULTS: GMV was inversely correlated with BI score in four clusters located in left lateral occipital cortex, bilateral angular gyri and right frontal pole. Clusters were no longer significant after controlling for diagnosis. GMV was not correlated with BI score within the MDD cohort alone. LIMITATIONS: Incomplete clinical data required use of a modified BI scale. CONCLUSION: BI scores were inversely correlated with GMV in unmedicated subjects with MDD and BD, but these correlations appeared driven by categorical diagnosis. Future work will examine other imaging modalities and focus on elements of the BI scale most likely to be related to brain structure and function.

Characteristics of depressed suicide attempters with remitted substance use disorders.

Substance use disorder (SUD) comorbidity in mood disorders increases suicide risk. Suicide attempters with active SUD appear to have distinct characteristics but little is known whether these characteristics persist during remission and if they are related to different aspects of suicidal behavior. In this study, suicide attempters with a DSM mood disorder and remitted SUD (AT+SUD) (N = 135) were compared to those without lifetime SUD (AT-SUD) (N = 219) in terms of demographic, clinical and suicidal behavioral characteristics. Factor analyses were conducted to generate subjective distress and impulsivity/aggression factors - previously identified by our group to predict suicide risk in mood disorders. Associations between these traits and SUD history and suicidal behavior characteristics were then tested. Compared with AT-SUD, AT+SUD were more likely to be male, less educated and to have a Cluster B personality disorder. AT+SUD individuals had greater impulsivity/aggression factor scores, but comparable subjective distress scores. AT+SUD made a greater number of suicide attempts, with higher lethality, despite comparable suicide intent and degree of planning with AT-SUD. Impulsivity/aggression was higher in multiple versus single attempters, but did not correlate with suicide attempt lethality. Among suicide attempters with mood disorders, a history of lifetime SUD was associated with more frequent and more lethal suicide attempts. Among other correlates of lifetime SUD in this sample, impulsive/aggressive traits may explain greater frequency of suicide attempts. The results underscore that persons with mood disorders and lifetime SUD are at particularly high risk of frequent and lethal suicide attempts where more intensive prevention efforts are warranted.