Ketamine as a prophylactic resilience-enhancing agent

Stress exposure is one of the greatest risk factors for psychiatric illnesses, including major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Enhancing stress resilience could potentially protect against the development of stress-induced psychiatric disorders, yet no resilience-enhancing pharmaceuticals have been developed to date. This review serves to consider the existing evidence for a potential pro-resilience effect of ketamine in rodents as well as the preliminary evidence of ketamine as a prophylactic treatment for postpartum depression (PPD) in humans. Several animal studies have demonstrated that ketamine administered 1 week prior to a stressor (e.g., chronic social defeat and learned helplessness) may protect against depressive-like behavior. A similar protective effect has been demonstrated against PTSD-like behavior following Contextual Fear Conditioning (CFC). Recent work has sought to explore if the administration of ketamine prevented the development of postpartum depression (PPD) in humans. Researchers administered ketamine immediately following caesarian-section and found a significantly reduced prevalence of PPD in the ketamine-treated groups compared to the control groups. Utilizing ketamine as a resilience-enhancing treatment may have unique applications, including leading to a deeper understanding of the neurobiological mechanism underlying resilience. Future trials aiming to translate and replicate these findings with humans are warranted

Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant Depression

Background Intravenous ketamine has shown rapid antidepressant effects in early trials, making it a potentially attractive candidate for depressed patients at imminent risk of suicide. The Implicit Association Test (IAT), a performance-based measure of association between concepts, may have utility in suicide assessment. Methods Twenty-six patients with treatment-resistant depression were assessed using the suicidality item of the Montgomery-Asberg Depression Rating Scale (MADRS-SI) 2 hours before and 24 hours following a single subanesthetic dose of intravenous ketamine. Ten patients also completed IATs assessing implicit suicidal associations at comparable time points. In a second study, nine patients received thrice-weekly ketamine infusions over a 12-day period. Results Twenty-four hours after a single infusion, MADRS-SI scores were reduced on average by 2.08 points on a 0 to 6 scale (p < .001; d = 1.37), and 81% of patients received a rating of 0 or 1 postinfusion. Implicit suicidal associations were also reduced following ketamine (p = .003; d = 1.36), with reductions correlated across implicit and explicit measures. MADRS-SI reductions were sustained for 12 days by repeated-dose ketamine (p < .001; d = 2.42). Conclusions These preliminary findings support the premise that ketamine has rapid beneficial effects on suicidal cognition and warrants further study.Psycholog

Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant Depression

Background Intravenous ketamine has shown rapid antidepressant effects in early trials, making it a potentially attractive candidate for depressed patients at imminent risk of suicide. The Implicit Association Test (IAT), a performance-based measure of association between concepts, may have utility in suicide assessment. Methods Twenty-six patients with treatment-resistant depression were assessed using the suicidality item of the Montgomery-Asberg Depression Rating Scale (MADRS-SI) 2 hours before and 24 hours following a single subanesthetic dose of intravenous ketamine. Ten patients also completed IATs assessing implicit suicidal associations at comparable time points. In a second study, nine patients received thrice-weekly ketamine infusions over a 12-day period. Results Twenty-four hours after a single infusion, MADRS-SI scores were reduced on average by 2.08 points on a 0 to 6 scale (p < .001; d = 1.37), and 81% of patients received a rating of 0 or 1 postinfusion. Implicit suicidal associations were also reduced following ketamine (p = .003; d = 1.36), with reductions correlated across implicit and explicit measures. MADRS-SI reductions were sustained for 12 days by repeated-dose ketamine (p < .001; d = 2.42). Conclusions These preliminary findings support the premise that ketamine has rapid beneficial effects on suicidal cognition and warrants further study.Psycholog

Recognition of facial emotions among maltreated children with high rates of post–traumatic stress disorder

Objective. The purpose of this study is to examine processing of facial emotions in a sample of maltreated children showing high rates of post-traumatic stress disorder (PTSD). Maltreatment during childhood has been associated independently with both atypical processing of emotion and the development of PTSD. However, research has provided little evidence indicating how high rates of PTSD might relate to maltreated children’s processing of emotions. Method. Participants’ reaction time and labeling of emotions were measured using a morphed facial emotion identification task. Participants included a diverse sample of maltreated children with and without PTSD and controls ranging in age from 8 to 15 years. Maltreated children had been removed from their homes and placed in state custody following experiences of maltreatment. Diagnoses of PTSD and other disorders were determined through combination of parent, child, and teacher reports. Results. Maltreated children displayed faster reaction times than controls when labeling emotional facial expressions, and this result was most pronounced for fearful faces. Relative to children who were not maltreated, maltreated children both with and without PTSD showed enhanced response times when identifying fearful faces. There was no group difference in labeling of emotions when identifying different facial emotions. Conclusions. Maltreated children show heightened ability to identify fearful faces, evidenced by faster reaction times relative to controls. This association between maltreatment and atypical processing of emotion is independent of PTSD diagnosis

The Genetic Interacting Landscape of 63 Candidate Genes in Major Depressive Disorder: An Explorative Study

Background: Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear. This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach. Results: Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e.g. additive dominant model Puncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with Puncorrected = 6.95E-5 with odds ratio (OR estimated from β3) value = 4.99) the area under the curve (AUC) estimates were low (\u3c 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (\u3c 0.15). Conclusions: We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied

Ventrolateral Prefrontal Cortex Activation and Attentional Bias in Response to Angry Faces in Adolescents with Generalized Anxiety Disorder

Objective: While adolescent anxiety disorders represent prevalent, debilitating conditions, few studies explore their brain physiology. Using event-related functional MRI (fMRI) and a behavioral measure of attention to angry faces, we evaluated differences in response between healthy adolescents and adolescents with generalized anxiety disorder (GAD). Method: In the primary trials of interest, 18 adolescents with GAD and 15 comparisons of equivalent age/gender/IQ viewed angry/neutral face pairs during fMRI acquisition. Following the presentation of each face pair, subjects pressed a button to a probe that was either on the same (congruent) or opposite (incongruent) side as the angry face. Reaction time differences between congruent and incongruent face-trials provided a measure of attention bias to angry faces. Results: Relative to controls, patients with GAD manifested greater right ventrolateral prefrontal cortex (VLPFC) activation to trials containing angry faces. Compared with controls, patients with GAD also showed greater attentional bias away from angry faces. VLPFC activation differences were independent of differences in attentional bias. Conclusions: Adolescents with GAD show greater right VLPFC activation and attentional bias away from angry faces than controls. Enhanced VLPFC engagement may directly relate to anxiety, or may regulate abnormal functioning in another region

Abnormal Attention Modulation of Fear Circuit Function in Pediatric Generalized Anxiety Disorder

1. Context. Considerable work implicates abnormal neural activation and disrupted attention to facial-threat cues in adult anxiety disorders. However, in pediatric anxiety, no research has examined attention modulation of neural response to threat cues. 2. Objective. To determine whether attention modulates amygdala and cortical responses to facial threat cues differentially in adolescents with generalized anxiety disorder (GAD) and healthy adolescents. 3. Design. Case-control study. 4. Setting. Government clinical research institute. 5. Participants. Adolescent volunteers, 15 with GAD and 20 diagnosis-free. 6. Main Outcome Measure(s). Blood oxygenation level-dependent (BOLD) signal, as measured via functional magnetic resonance imaging (fMRI). During fMRI scans, participants completed a face-emotion rating task that systematically manipulated attention. 7. Results. While attending to their own subjective fear, patients, but not controls, showed greater activation to fearful than to happy faces (small volume corrected p’s \u3c .05) in a distributed network including the amygdala, ventral PFC (vPFC), and anterior cingulate cortex (ACC). Right amygdala findings appeared particularly strong. Functional connectivity analyses demonstrated positive correlations among the amygdala, vPFC, and cingulate. 8. Conclusions. Findings provide the first evidence in juveniles that GAD-associated patterns of pathological fear-circuit activation are particularly evident during certain attention states. Specifically, fear-circuit hyperactivation occurred in an attention state involving focus on subjectively-experienced fear. These findings underscore the importance of attention and its interaction with emotion in shaping function of the adolescent human fear circuit

Enduring Mental Health Morbidity and Social Function Impairment in World Trade Center Rescue, Recovery, and Cleanup Workers: The Psychological Dimension of an Environmental Health Disaster

Background The World Trade Center (WTC) attacks exposed thousands of workers to hazardous environmental conditions and psychological trauma. In 2002, to assess the health of these workers, Congress directed the National Institute for Occupational Safety and Health to establish the WTC Medical Monitoring and Treatment Program. This program has established a large cohort of WTC rescue, recovery, and cleanup workers. We previously documented extensive pulmonary dysfunction in this cohort related to toxic environmental exposures. Objectives Our objective in this study was to describe mental health outcomes, social function impairment, and psychiatric comorbidity in the WTC worker cohort, as well as perceived symptomatology in workers’ children. Methods Ten to 61 months after the WTC attack, 10,132 WTC workers completed a self-administered mental health questionnaire. Results Of the workers who completd the questionnaire, 11.1% met criteria for probable post-traumatic stress disorder (PTSD), 8.8% met criteria for probable depression, 5.0% met criteria for probable panic disorder, and 62% met criteria for substantial stress reaction. PTSD prevalence was comparable to that seen in returning Afghanistan war veterans and was much higher than in the U.S. general population. Point prevalence declined from 13.5% to 9.7% over the 5 years of observation. Comorbidity was extensive and included extremely high risks for impairment of social function. PTSD was significantly associated with loss of family members and friends, disruption of family, work, and social life, and higher rates of behavioral symptoms in children of workers. Conclusions Working in 9/11 recovery operations is associated with chronic impairment of mental health and social functioning. Psychological distress and psychopathology in WTC workers greatly exceed population norms. Surveillance and treatment programs continue to be needed