Clinical associations with treatment resistance in depression: An electronic health record study.

Treatment resistance is common in major depressive disorder (MDD), yet clinical risk factors are not well understood. Using a discovery-replication design, we conducted phenome-wide association studies (PheWASs) of MDD treatment resistance in two electronic health record (EHR)-linked biobanks. The PheWAS included participants with an MDD diagnosis in the EHR and at least one antidepressant (AD) prescription. Participant lifetime diagnoses were mapped to phecodes. PheWASs were conducted for three treatment resistance outcomes based on AD prescription data: number of unique ADs prescribed, ≥1 and ≥2 CE switches. Of the 180 phecodes significantly associated with these outcomes in the discovery cohort (n = 12,558), 71 replicated (n = 8,206). In addition to identifying known clinical factors for treatment resistance in MDD, the total unique AD prescriptions was associated with additional clinical variables including irritable bowel syndrome, gastroesophageal reflux disease, symptomatic menopause, and spondylosis. We calculated polygenic risk of specific-associated conditions and tested their association with AD outcomes revealing that genetic risk for many of these conditions is also associated with the total unique AD prescriptions. The number of unique ADs prescribed, which is easily assessed in EHRs, provides a more nuanced measure of treatment resistance, and may facilitate future research and clinical application in this area.

Suicidal behaviour is pathological: implications for psychiatric euthanasia.

Some have challenged the validity of labelling suicidal thoughts and behaviours (STB) as pathological. In this paper, we argue that STB is indeed pathological, thereby, situating suicide prevention within the realm of medicine, complicating calls for the legalisation of medical assistance in dying for individuals whose sole condition is psychiatric (psychiatric medical assistance in dying (MAID)). Evidence shows STB predicts the risk of suicide; moreover, several mental illnesses are associated with STB, and 70%-90% of suicide deaths are linked to psychiatric illness. Treating psychiatric illnesses can prevent suicide. We contend that this clinical evidence not only warrants the classification of STB as pathological but also necessitates its treatment and prevention. This perspective poses a challenge to legislation that would legalise psychiatric MAID.

Prefrontal cortex engagement during an fMRI task of emotion regulation as a potential predictor of treatment response in borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a severe mental illness, with high rates of co-morbid depression and suicidality. Despite the importance of optimizing treatment in BPD, little is known about how neural processes relate to individual treatment response. This study examines how baseline regional brain blood oxygen level dependent (BOLD) activation during a functional magnetic resonance imaging (fMRI) task of emotion regulation is related to treatment response following a six-month randomized clinical trial of Dialectical Behavior Therapy (DBT) or Selective Serotonin Reuptake Inhibitor (SSRI) treatment. METHODS: Unmedicated females with BPD (N = 37), with recent suicidal behavior or self-injury, underwent an fMRI task in which negative personal memories were presented and they were asked to distance (i.e., downregulate their emotional response) or immerse (i.e., experience emotions freely). Patients were then randomized to DBT (N = 16) or SSRI (N = 21) treatment, with baseline and post-treatment depression and BPD severity assessed. RESULTS: BOLD activity in prefrontal cortex, anterior cingulate, and insula was associated with distancing. Baseline BOLD during distancing in dorsolateral, ventrolateral, and orbital prefrontal cortex (dlPFC, vlPFC, OFC) differentially predicted depression response across treatment groups, with higher activity predicting better response in the SSRI group, and lower activity predicting better response in the DBT group. LIMITATIONS: All female samples. DISCUSSION: Findings indicate that greater prefrontal engagement during emotion regulation may predict more antidepressant benefit from SSRIs, whereas lower engagement may predict better response to DBT. These results suggest different mechanisms of action for SSRI and DBT treatment, and this may allow fMRI to guide individualized treatment selection.

Line tension and line entropy associated with the monolayer/trilayer boundary of smectic liquid crystal at the air-water interface.

Molecularly thin films of the smectic liquid crystal 4'-octyl-4-biphenylcarbonitrile (8CB) at the air-water interface phase separate into regions with different numbers of layers, in analogy with freestanding smectic liquid crystalline films. This paper reports the line tension associated with the boundary of coexisting trilayer and monolayer phases of in Langmuir films of 8CB at the air-water interface as a function of temperature and humidity and infers information on the boundary profile between the coexisting phases. Two complementary techniques are used to characterize the 8CB thin films: surface pressure-area isotherm and Brewster angle microscopy (BAM). We determine the line tension by stretching isolated domains from their equilibrium circular shape and analyzing the free relaxation with a hydrodynamic model. Then, we interpret the line tension vs temperature data in terms of an excess line entropy for the domain boundary, which requires careful consideration of the thermodynamics of inhomogeneous monolayer systems.

Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies.

Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.

A Neural Signature for Reappraisal as an Emotion Regulation Strategy: Relationship to Stress-Related Suicidal Ideation and Negative Affect in Major Depression.

BACKGROUND: Impaired emotion regulation (ER) contributes to major depression, and suicidal ideation (SI) and behavior. ER is typically studied by explicitly directing participants to regulate, but this may not capture depressed individuals' spontaneous tendencies to engage ER in daily life. METHODS: In N=82 participants with major depressive disorder (MDD), we examined the relationship of spontaneous engagement of ER to real-world responses to stress. We used a machine learning-derived neural signature reflecting neural systems underlying cognitive reappraisal (an ER strategy) to identify reappraisal-related activity while participants recalled negative autobiographical memories under the following conditions: 1) unstructured recall; 2) distanced recall, a form of reappraisal; and 3) immersed recall (comparison condition). Participants also completed a week of ecological momentary assessment (EMA) measuring daily stressors, suicidal ideation (SI), and negative affect. RESULTS: Higher reappraisal signature output for the unstructured period, a proxy for the spontaneous tendency to engage ER, was associated with greater increases in SI following stressors (b=0.083, p=0.041). Higher signature output for distanced recall, a proxy for the capacity to engage ER when directed, was associated with lower negative affect following stressors (b=-0.085, p=0.029). Output for the immerse period was not associated with EMA outcomes. CONCLUSIONS: Findings suggest that, in MDD, the spontaneous tendency to react to negative memories with attempts to reappraise may indicate greater reactivity to negative cues; while intact capacity to use reappraisal when directed may be associated with more adaptive responses to stress. These data have implications for understanding stress-related increases in suicide risk in depression.

Relationships between serotonin 1A receptor DNA methylation, self-reported history of childhood abuse and gray matter volume in major depression.

BACKGROUND: Early life adversity is a risk factor for psychopathology and is associated with epigenetic alterations in the 5-HT1A receptor gene promoter. The 5-HT1A receptor mediates neurotrophic effects, which could affect brain structure and function. We examined relationships between self-reported early childhood abuse, 5-HT1A receptor promoter DNA methylation, and gray matter volume (GMV) in Major Depressive Disorder (MDD). METHODS: Peripheral DNA methylation of 5-HT1A receptor promoter CpG sites -681 and -1007 was assayed in 50 individuals with MDD, including 18 with a history of childhood abuse. T1-weighted structural magnetic resonance imaging (MRI) was performed. Voxel-based morphometry (VBM) was quantified in amygdala, hippocampus, insula, occipital lobe, orbitofrontal cortex, temporal lobe, parietal lobe, and at the voxel level. RESULTS: No relationship was observed between DNA methylation and history of childhood abuse. We observed regional heterogeneity comparing -681 CpG site methylation and GMV (p = 0.014), with a positive relationship to GMV in orbitofrontal cortex (p = 0.035). Childhood abuse history was associated with higher GMV considering all ROIs simultaneously (p < 0.01). In whole-brain analyses, childhood abuse history was positively correlated with GMV in multiple clusters, including insula and orbitofrontal cortex (pFWE = 0.005), and negatively in intracalcarine cortex (pFWE = 0.001). LIMITATIONS: Small sample size, childhood trauma assessment instrument used, and assay of peripheral, rather than CNS, methylation. CONCLUSIONS: These cross-sectional findings support hypotheses of 5-HT1A receptor-related neurotrophic effects, and of increased regional GMV as a potential regulatory mechanism in the setting of childhood abuse. Orbitofrontal cortex was uniquely associated with both childhood abuse history and 5-HT1A receptor methylation.

Low-cost and scalable projected light-sheet microscopy for the high-resolution imaging of cleared tissue and living samples.

Light-sheet fluorescence microscopy (LSFM) is a widely used technique for imaging cleared tissue and living samples. However, high-performance LSFM systems are typically expensive and not easily scalable. Here we introduce a low-cost, scalable and versatile LSFM framework, which we named 'projected light-sheet microscopy' (pLSM), with high imaging performance and small device and computational footprints. We characterized the capabilities of pLSM, which repurposes readily available consumer-grade components, optimized optics, over-network control architecture and software-driven light-sheet modulation, by performing high-resolution mapping of cleared mouse brains and of post-mortem pathological human brain samples, and via the molecular phenotyping of brain and blood-vessel organoids derived from human induced pluripotent stem cells. We also report a method that leverages pLSM for the live imaging of the dynamics of sparsely labelled multi-layered bacterial pellicle biofilms at an air-liquid interface. pLSM can make high-resolution LSFM for biomedical applications more accessible, affordable and scalable.

Immune-Targeted Therapies for Depression: Current Evidence for Antidepressant Effects of Monoclonal Antibodies.

Importance: Increasing evidence suggests a potential role of immune-modulatory drugs for treatment-resistant depression. This scoping review explores the emerging evidence regarding the antidepressant effects of monoclonal antibodies (mAbs), a relatively newer class of immune therapeutics with favorable safety profile.Observations: PubMed was searched up to November 2023 for English publications addressing the antidepressant effects of mAbs, including meta-analyses, randomized controlled trials, open-label, single-arm studies, and case series. Several mAbs have shown potential antidepressant effects, but most studies in primary inflammatory disorders included patients with mild depression. Only infliximab and sirukumab were directly examined in individuals with primary depression. mAbs that do not require laboratory monitoring, such as ixekizumab and dupilumab, could hold potential promise if future studies establish their safety profile regarding suicide risk.Conclusions and Relevance: The use of several mAbs for the treatment of primary inflammatory disorders has been associated with improvement of comorbid depressive symptoms. Given their unique mechanisms of action, mAbs may offer a new hope for depressed patients who do not respond to currently available antidepressants. Further research addressing individuals with more severe depressive symptoms is essential. Direct examination of antidepressant effects of mAbs in people with primary depressive disorders is also crucial to refine their clinical use in the treatment of depression.

Changes in Rates of Suicide by Mass Shooters, 1980-2019.

OBJECTIVE: The rate of worldwide mass shootings increased almost 400% over the last 40 years. About 30% are followed by the perpetrator's fatal or nonfatal suicide attempt. METHOD: We examined the rate of fatal and nonfatal attempts among 528 mass shooters over the last 40 years and their relationship to detected mental illness to better understand this specific context of suicide. We collected information on U.S.-based, personal-cause mass murders that involved one or more firearms, from online sources. RESULTS: A greater proportion of mass shooters from 2000 to 2019 took or attempted to take their own lives (40.5%) compared with those from 1980 to 1999 (23.2%, p < 0.001). More than double the proportion of perpetrators who made a fatal or nonfatal suicide attempt had a history of non-psychotic psychiatric/neurologic symptoms (38.9%), compared with perpetrators who did not make a fatal or nonfatal suicide attempt (18.1%; p < 0.001). Among mass shooters who made fatal or nonfatal suicide attempts, 77 of 175 (44%) did not have any recorded psychiatric, neurologic, or substance use condition. Of the 98 mass shooters who made fatal or non-fatal suicide attempts and had a psychiatric, substance use, or neurologic condition, 41 had depressive disorders. CONCLUSION: It is possible that a lack of information about the perpetrators' mental health or suicidal ideation led to an underestimation of their prevalence. These data suggest that suicide associated with mass shootings may represent a specific context for suicide, and approaches such as psychological autopsy can help to ascertain when psychiatric illness mediates the relationship between mass shootings and suicide.

We examined 528 mass shootings.A greater proportion of mass shooters from 2000-2019 made a fatal or nonfatal suicide attempt (123/304, 40.5%) compared with mass shooters from 1980-1999 (52/224, 23.2%), χ2 = 17.3, p<.001.More than double the proportion of perpetrators who made a fatal or nonfatal suicide attempt had a history of non-psychotic psychiatric/neurologic symptoms (38.9%), compared with those who did not (18.1%; p < 0.001).Among mass shooters who made a fatal or nonfatal suicide attempt, 77 of 175 (44%) did not have any recorded psychiatric, neurologic, or substance use condition. However, it is possible that a lack of information about the perpetrators' mental health or suicidal ideation led to an underestimation of their prevalence.These results suggest that perpetrators may have considered suicide a potential outcome of such an event, and/or that the perpetrators' high levels of aggression and anger, accompanied by an impaired capacity for restraint, resulted in homicide followed by suicidal behavior.Psychological autopsies can clarify the role of psychiatric illness and more extreme aggressive traits in homicide-suicide instances of mass shootings.

Velocity-Based Training Affects Function, Strength, and Power in Persons with Parkinson's Disease.

ABSTRACT: Calaway, CC, Martinez, KJ, Calzada Bichili, AR, Caplan, JH, Milgrim, WP, Mann, JB, Haq, I, and Signorile, JF. Velocity-based training affects function, strength, and power in persons with Parkinson's disease. J Strength Cond Res XX(X): 000-000, 2024-Velocity-based training (VBT) is commonly associated with high-level athletes. No study has examined the effects of VBT on performance in persons with Parkinson's disease (PD). The objective of the study was to compare the effects of 10 and 30% velocity-loss threshold protocols on changes in functional performance, strength, and power in persons with PD after 12 weeks of supervised VBT, 3 days per week. Twenty-one subjects with PD (72.9 ± 5.9 y) were randomly assigned to the 10% or 30% velocity-loss threshold group and performed the 6-m walk test at habitual and maximal gait speed (6MWTMax), the 5 time sit-to-stand test (5 × STS), 1 repetition maximum (1RM), and peak power (PP) testing for the chest press (CP) and leg press (LP) exercise. A mixed ANOVA with significance was set a priori at 0.05 revealed that significant time effects were seen for the 6MWT at maximal speed (MDiff ± SD = 0.22 ± 0.04 m·s-1, p < 0.001), 5-time sit-to-stand time (-1.48 ± 0.45 seconds, p = 0.005) and power (75.5 ± 22.7 W, p = 0.005), 1RM for CP (5.1 ± 1.1 kg, p < 0.001) and LP (12.6 ± 3.7 kg, p = 0.005), and LP-PP (43.6 ± 13.2 W, p = 0.006). Secondary analyses revealed time effects for the load at which PP was achieved for the CP exercise. A Wilcoxon signed-rank test revealed no significant differences in the percentage of 1RM at which PP was achieved for either condition. Results indicate that VBT is an effective training modality for improving functional capacity, strength, and power in persons with PD; however, shifts in force-velocity relationships were not evidenced.

Temporal Interactions between Neural Proxies forMemory Recall, Negative Affect, and EmotionRegulation in Major Depression.

Dysfunction in emotion regulation (ER) and autobiographical memory are components of major depressive disorder (MDD). However, little is known about how they mechanistically interact with mood disturbances in real time. Using machine learning-based neural signatures, we can quantify negative affect (NA), ER, and memory continuously to evaluate how these processes dynamically interact in MDD. Unmedicated individuals with MDD (N=45) and healthy volunteers (HV; N=38) completed a negative autobiographical memory functional magnetic resonance imaging task wherein they recalled, distanced from (an ER strategy), and immersed into memories. We used a negative affect signature (PINES) and an emotion regulation signature (ERS) to quantify moment-to-moment NA and ER. We then examined whether memory engagement, indexed by hippocampal activity, predicted subsequent change in PINES and ERS over time. During memory recall and immersion, greater hippocampal activity predicted increased PINES across groups. During distancing, greater hippocampal activity in HVs predicted increased ERS but not PINES. In MDD, greater hippocampal activity predicted increased PINES but not ERS. Findings suggest abnormalities in the real-time relationship between memory, NA, and ER in MDD. During distancing, as predicted, HVs showed an attenuation of the linkage between memory engagement and NA, and they had subsequent increases in ER following memory reactivation. In contrast, MDD was characterized by continued linkage between memory engagement and NA, without subsequent increases in ER. Deficits in engagement of ER and ineffective modulation of NA following negative memory recall may contribute to the mood disturbances in MDD and are potential targets for clinical intervention.

Relationships of DSM-5 PTSD symptom clusters to suicidal ideation and death ideation in outpatient military veterans.

Veterans with PTSD are at higher risk for suicide. This study examined the specific associations of PTSD symptom clusters with suicidal ideation (SI) and death ideation (DI), independently from depressive symptom clusters. Participants included 695 Israeli male outpatient military veterans (M = 25.35 years, SD = 5.65), divided into subsamples of probable PTSD (PTSD Checklist for DSM-5 [PCL-5] ≥ 33) and subthreshold PTSD scores (PCL-5 < 33). Data were extracted from medical chartsand self-report questionnaires. The main analyses included logistic regression to evaluate the associations between SI and DI (Brief Symptom Inventory, items 9 and 39) and PTSD symptom clusters (PCL-5), controlling for depressive symptom clusters (Beck Depression Inventory; cognitive-affective and somatization) in each subsample. The results showed that, for veterans with probable PTSD, the negative alterations in cognition and mood symptom cluster was positively correlated with SI and DI, while avoidance was negatively correlated with SI, independently from depressive symptoms clusters. In those with sub-syndromal PTSD, the re-experiencing cluster was positively correlated with DI, independently from the depressive symptom clusters. These findings highlight the importance of targeting PTSD components, such as negative alterations in cognition and mood symptoms experienced by veterans with PTSD, as part of suicide prevention efforts.

Temporal prediction of suicidal ideation in an ecological momentary assessment study with recurrent neural networks.

INTRODUCTION: Ecological Momentary Assessment (EMA) holds promise for providing insights into daily life experiences when studying mental health phenomena. However, commonly used mixed-effects linear statistical models do not fully utilize the richness of the ultidimensional time-varying data that EMA yields. Recurrent Neural Networks (RNNs) provide an alternative data analytic method to leverage more information and potentially improve prediction, particularly for non-normally distributed outcomes. METHODS: As part of a broader research study of suicidal thoughts and behavior in people with borderline personality disorder (BPD), eighty-four participants engaged in EMA data collection over one week, answering questions multiple times each day about suicidal ideation (SI), stressful events, coping strategy use, and affect. RNNs and mixed-effects linear regression models (MEMs) were trained and used to predict SI. Root mean squared error (RMSE), mean absolute percent error (MAPE), and a pseudo-R2 accuracy metric were used to compare SI prediction accuracy between the two modeling methods. RESULTS: RNNs had superior accuracy metrics (full model: RMSE = 3.41, MAPE = 42 %, pseudo-R2 = 26 %) compared with MEMs (full model: RMSE = 3.84, MAPE = 56 %, pseudo-R2 = 16 %). Importantly, RNNs showed significantly more accurate prediction at higher values of SI. Additionally, RNNs predicted, with significantly higher accuracy, the SI scores of participants with depression diagnoses and of participants with higher depression scores at baseline. CONCLUSION: In this EMA study with a moderately sized sample, RNNs were better able to learn and predict daily SI compared with mixed-effects models. RNNs should be considered as an option for EMA analysis.

Omics Approaches to Investigate the Pathogenesis of Suicide.

Suicide is the second leading cause of death in U.S. adolescents and young adults and is generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This article is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that while bulk tissue studies provide comprehensive information, single-nucleus approaches that identify cell type-specific changes are needed. While single-nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches that combine cell type-specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression and how these interact with epigenetic marks, single-nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole-genome sequencing and genome-wide association databases. The workshop concluded with a recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarker discovery to guide suicide prevention.

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.

Relationship of Major Depressive Disorder and Schizophrenia Polygenic Risk Scores to Suicide: A Comparison Between European and Asian Ancestry Populations.

Psychiatric diagnosis rates in suicide decedents appear higher in European ancestry populations compared with East Asians. Shared genetic components exist between major depressive disorder (MDD)/schizophrenia (SCZ) and suicide, but no study has compared these shared polygenic architectures between Europeans and East Asians. We compared polygenic risk scores (PRSs) for MDD/SCZ determined from large data sets specific to each ancestry in European and East Asian suicide decedent samples. MDD/SCZ PRSs appeared more prominent in European suicides compared with Japanese suicides. A greater coexistence of psychiatric disorders in European suicide decedents than in East Asian suicide decedents may be partly explained by genetics. Our results are limited by the smaller sample size of our suicide decedents and sample size disparities between the European discovery data set and the East Asian data set for MDD/SCZ, resulting in less statistical power to detect robust difference between the two ancestries.

Psychiatric diagnosis in suicides appears more common in Europeans than in East Asians.This is the first comparison of suicide genome-wide association studies between Europeans and East Asians.Major depressive disorder/schizophrenia polygenic risk scores for suicide were more significant for Europeans than for East Asians.

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.

PET Imaging of the Serotonin 1A Receptor in Major Depressive Disorder: Hierarchical Multivariate Analysis of [11C]WAY100635 Overcomes Outcome Measure Discrepancies.

The serotonin 1A receptor has been linked to both the pathophysiology of major depressive disorder (MDD) and the antidepressant action of serotonin reuptake inhibitors. Most PET studies of the serotonin 1A receptor in MDD used the receptor antagonist radioligand, [carbonyl-11C]WAY100635; however the interpretation of the combined results has been contentious owing to reports of higher or lower binding in MDD with different outcome measures. The reasons for these divergent results originate from several sources, including properties of the radiotracer itself, which complicate its quantification and interpretation; as well as from previously reported differences between MDD and healthy volunteers in both reference tissue binding and plasma free fraction, which are typically assumed not to differ. Recently, we have developed two novel hierarchical multivariate methods which we validated for the quantification and analysis of [11C]WAY100635, which show better accuracy and inferential efficiency compared to standard analysis approaches. Importantly, these new methods should theoretically be more resilient to many of the factors thought to have caused the discrepancies observed in previous studies. We sought to apply these methods in the largest [11C]WAY100635 sample to date, consisting of 160 individuals, including 103 MDD patients, of whom 50 were not-recently-medicated and 53 were antidepressant-exposed, as well as 57 healthy volunteers. While the outcome measure discrepancies were substantial using conventional univariate analysis, our multivariate analysis techniques instead yielded highly consistent results across PET outcome measures and across pharmacokinetic models, with all approaches showing higher serotonin 1A autoreceptor binding potential in the raphe nuclei of not-recently-medicated MDD patients relative to both healthy volunteers and antidepressant-exposed MDD patients. Moreover, with the additional precision of estimates afforded by this approach, we can show that while binding is also higher in projection areas in this group, these group differences are approximately half of those in the raphe nuclei, which are statistically distinguishable from one another. These results are consistent with the biological role of the serotonin 1A autoreceptor in the raphe nuclei in regulating serotonin neuron firing and release, and with preclinical and clinical evidence of deficient serotonin activity in MDD due to over expression of autoreceptors resulting from genetic and/or epigenetic effects. These results are also consistent with downregulation of autoreceptors as a mechanism of action of selective serotonin reuptake inhibitors. In summary, the results using multivariate analysis approaches therefore demonstrate both face and convergent validity, and may serve to provide a resolution and consensus interpretation for the disparate results of previous studies examining the serotonin 1A receptor in MDD.

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4, underscoring the need to define the brain's molecular energetic landscape5-10. To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.