Effect of olanzapine exposure on relapse and brain structure in patients with major depressive disorder with psychotic features.

Some data suggest that antipsychotics may adversely affect brain structure. We examined the relationship among olanzapine exposure, relapse, and changes in brain structure in patients with major depressive disorder with psychotic features. We analyzed data from the Study of the Pharmacotherapy of Psychotic Depression II trial (STOP-PD II), a randomized, placebo-controlled trial in patients with psychotic depression who attained remission on sertraline and olanzapine and were randomized to continue sertraline plus olanzapine or placebo for 36 weeks. Olanzapine steady state concentration (SSC) were calculated based on sparsely-sampled levels. Rates of relapse and changes in brain structure were assessed as outcomes. There were significant associations between dosage and relapse rates (N = 118; HR = 0.94, 95% CI [0.897, 0.977], p = 0.002) or changes in left cortical thickness (N = 44; B = -2.0 × 10-3, 95% CI [-3.1 × 10-3, -9.6 × 10-4], p < 0.001) and between SSC and changes in left cortical thickness (N = 44; B = -8.7 × 10-4, 95% CI [-1.4 × 10-3, -3.6 × 10-4], p = 0.001). Similar results were found for the right cortex. These associations were no longer significant when the analysis was restricted to participants treated with olanzapine. Our findings suggest that, within its therapeutic range, the effect of olanzapine on relapse or cortical thickness does not depend on its dosage or SSC. Further research is needed on the effect of olanzapine and other antipsychotics on mood symptoms and brain structure.

A computer-assisted telephone collaborative care intervention provided by lay providers for the treatment of comorbid depression and at-risk drinking: Analysis of a randomized controlled trial.

INTRODUCTION: Virtual collaborative care for people with comorbid depression and at-risk drinking lacks strong evidence. Our aim was to assess the impact of 12 months of telephone collaborative care (tCC) versus enhanced usual care (eUC) on depression and drinking. METHODS: We performed a secondary analysis of the Primary care Assessment and Research of a Telephone intervention for Neuropsychiatric conditions with Education and Resources study (PARTNERs), a blinded randomized controlled trial. We examined 144 participants with comorbid depression and at-risk drinking, of which 129 were from the original sample whose data have been published, and 15 were studied since the original report had been published. PARTNERs compared eUC consisting of usual care plus assessment of symptoms at baseline, and 4, 8, and 12 months later vs. tCC consisting of eUC plus telephone-based coaching and symptom monitoring provided by a lay mental health technician to patients supervised by a psychiatrist. The study assessed depression response and remission using logistic regression; we assessed trajectory of drinking using Generalized-estimating equations (GEE). Baseline factors associated with likelihood of not exceeding number of drinks at 12 months were identified using decision trees. RESULTS: tCC produced a faster decline in the number of drinks than eUC (Wald Χ2 = 9.47, p = 0.02). However, drinking and depression outcomes did not differ significantly between the two groups at the end of treatment. Higher alcohol consumption at baseline (≥18 standard drinks per week in the tCC group and ≥11 standard drinks per week in the eUC group) was associated with a higher likelihood of having at-risk drinking after 12 months of treatment. CONCLUSIONS: Our findings suggest that, compared to eUC, tCC may accelerate drinking reductions in patients with comorbid depression and at-risk drinking. Both treatments were equally effective at the end of treatment for both depression and drinking outcomes.

AKI treated with kidney replacement therapy in critically Ill allogeneic hematopoietic stem cell transplant recipients.

Acute kidney injury (AKI) is a frequent complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but few studies have focused on AKI treated with kidney replacement therapy (AKI-KRT), particularly among critically ill patients. We investigated the incidence, risk factors, and 90-day mortality associated with AKI-KRT in 529 critically ill adult allo-HSCT recipients admitted to the ICU within 1-year post-transplant at two academic medical centers between 2011 and 2021. AKI-KRT occurred in 111 of the 529 patients (21.0%). Lower baseline eGFR, veno-occlusive disease, thrombotic microangiopathy, admission to an ICU within 90 days post-transplant, and receipt of invasive mechanical ventilation (IMV), total bilirubin ≥5.0 mg/dl, and arterial pH <7.40 on ICU admission were each associated with a higher risk of AKI-KRT. Of the 111 patients with AKI-KRT, 97 (87.4%) died within 90 days. Ninety-day mortality was 100% in each of the following subgroups: serum albumin ≤2.0 g/dl, total bilirubin ≥7.0 mg/dl, arterial pH ≤7.20, IMV with moderate-to-severe hypoxemia, and ≥3 vasopressors/inotropes at KRT initiation. AKI-KRT was associated with a 6.59-fold higher adjusted 90-day mortality in critically ill allo-HSCT vs. non-transplanted patients. Short-term mortality remains exceptionally high among critically ill allo-HSCT patients with AKI-KRT, highlighting the importance of multidisciplinary discussions prior to KRT initiation.

The Impact of COVID-19 on the Cardiovascular Health of Emerging Adults Aged 18-25: Findings From a Scoping Review.

There is limited knowledge regarding the cardiovascular impact of coronavirus disease 2019 (COVID-19) on emerging adults aged 18-25, a group that disproportionately contracts COVID-19. To guide future cardiovascular disease (CVD) research, policy, and practice, a scoping review was conducted to: (i) examine the impact of the COVID-19 pandemic on the cardiovascular health of emerging adults; and (ii) identify strategies to screen for and manage COVID-19-related cardiovascular complications in this age group. A comprehensive search strategy was applied to several academic databases and grey literature sources. An updated search yielded 6738 articles, 147 of which were extracted and synthesized. Reports identified COVID-19-associated cardiac abnormalities, vascular alterations, and multisystem inflammatory syndrome in emerging adults; based on data from student-athlete samples, prevalence estimates of myocarditis and cardiac abnormalities were 0.5%-3% and 0%-7%, respectively. Obesity, hypertension, CVD, congenital heart disease, and marginalization are potential risk factors for severe COVID-19, related cardiovascular complications, and mortality in this age group. As a screening modality for COVID-19-associated cardiac involvement, it is recommended that cardiac magnetic resonance imaging be indicated by a positive cardiac history and/or abnormal "triad" testing (cardiac troponin, electrocardiogram, and transthoracic echocardiogram) to improve diagnostic utility. To foster long-term cardiovascular health among emerging adults, cardiorespiratory fitness, health literacy and education, and telehealth accessibility should be priorities of health policy and clinical practice. Ultimately, surveillance data from the broader emerging adult population will be crucial to assess the long-term cardiovascular impact of both COVID-19 infection and vaccination, guide screening and management protocols, and inform CVD prevention efforts.

Il existe peu de données portant sur les répercussions de la maladie à coronavirus 2019 (COVID-19) sur le plan cardiovasculaire chez les jeunes adultes âgés de 18 à 25 ans, un groupe contractant la COVID-19 de façon disproportionnée. Afin d'orienter la recherche, les poli-tiques et les pratiques en matière de maladies cardiovasculaires (MCV), un examen exploratoire a été réalisé dans le but i) d'examiner les conséquences de la pandémie de la COVID-19 sur la santé cardiovasculaire des jeunes adultes, et ii) de proposer des stratégies de dépistage et de prise en charge des complications cardiovasculaires associées à la COVID-19 chez les personnes de cette tranche d'âge. Une recherche initiale exhaustive a été réalisée dans plusieurs bases de données universitaires et sources de littérature grise. Les résultats actualisés de cette recherche ont permis de recenser 6 738 articles, dont 147 ont été extraits et synthétisés. Les rapports faisaient état d'anomalies cardiaques, d'altérations vasculaires et de cas du syndrome inflammatoire multisystémique, tous associés à la COVID-19 chez les jeunes adultes. À la lumière des données sur les échantillons d'étudiants-athlètes, la prévalence des myocardites et des anomalies cardiaques se situait respectivement entre 0,5 et 3 %, et entre 0 et 7 % environ. Chez ce même groupe d'âge, l'obésité, l'hypertension, les MCV, les cardiopathies congénitales et la marginalisation constituent des facteurs de risque de COVID-19 sévère, de complications cardiovasculaires associées à la COVID-19 et de mortalité. Dans le cadre du dépistage des atteintes cardiaques associées à la COVID-19, il est recommandé, pour améliorer l'utilité diagnostique, d'indiquer l'imagerie par résonance magnétique cardiaque lors de l'existence d'antécédents cardiaques ou à la suite d'une « triade ¼ de dépistages anormaux (la troponine cardiaque, l'électrocardiogramme et l'échocardiographie transthoracique). Afin de favoriser une bonne santé cardiovasculaire à long terme chez les jeunes adultes, il est recommandé que la capacité cardiorespiratoire, la littératie dans le domaine de la santé, l'éducation et l'accès à la télésanté soient intégrés à titre de priorités dans les politiques de santé et la pratique clinique. En définitive, les données de surveillance portant sur cette large tranche d'âge seront essentielles pour évaluer les répercussions cardiovasculaires à long terme (autant celles d'infections à la COVID-19 que celles de la vaccination), pour orienter les protocoles de dépistage et de prise en charge, ainsi que pour éclairer les efforts de prévention des MCV.

Cross-disorder GWAS meta-analysis of endocannabinoid DNA variations in major depressive disorder, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorder, and schizophrenia.

The endocannabinoid system (ECS) is implicated in multiple mental disorders. In this study, we explored DNA variations in the ECS across major depressive disorder (MDD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia by performing a cross-disorder genome-wide association study (GWAS) meta-analysis. We obtained six datasets from the Psychiatric Genomics Consortium containing GWAS summary statistics from European cohorts (284,023 cases and 508,515 controls). Effective sample size weighted meta-analysis was performed for 2241 single nucleotide polymorphisms (SNPs) pertaining to gene bodies of 33 endocannabinoid genes using METAL, where an overall z-statistic is calculated for each marker based on a weighted sum of individual statistics. Heterogeneity was examined with I2 and X2 tests. MAGMA gene-based analysis was also performed. We identified nine SNPs significantly associated with a change in risk of having a mental disorder. The lead SNP was rs12805732 (Gene: Diacylglycerol Lipase Alpha; DAGLA). Four SNPs had substantial heterogeneity (I2>60 %). DAGLA had the strongest association with disease risk in gene-based analysis. Our findings suggest that the ECS may be a shared pathway in mental disorders. Future studies validating these findings would contribute to the identification of biomarkers of disease risk across multiple mental disorders.

Liposomal delivery of gene therapy for ovarian cancer: a systematic review.

OBJECTIVE: To systematically identify and narratively synthesize the evidence surrounding liposomal delivery of gene therapy and the outcome for ovarian cancer. METHODS: An electronic database search of the Embase, MEDLINE and Web of Science from inception until July 7, 2023, was conducted to identify primary studies that investigated the effect of liposomal delivery of gene therapy on ovarian cancer outcomes. Retrieved studies were assessed against the eligibility criteria for inclusion. RESULTS: The search yielded 564 studies, of which 75 met the inclusion criteria. Four major types of liposomes were identified: cationic, neutral, polymer-coated, and ligand-targeted liposomes. The liposome with the most evidence involved cationic liposomes which are characterized by their positively charged phospholipids (n = 37, 49.3%). Similarly, those with neutrally charged phospholipids, such as 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, were highly researched as well (n = 25, 33.3%). Eight areas of gene therapy research were identified, evaluating either target proteins/transcripts or molecular pathways: microRNAs, ephrin type-A receptor 2 (EphA2), interleukins, mitogen-activated protein kinase (MAPK), human-telomerase reverse transcriptase/E1A (hTERT/EA1), suicide gene, p53, and multidrug resistance mutation 1 (MDR1). CONCLUSION: Liposomal delivery of gene therapy for ovarian cancer shows promise in many in vivo studies. Emerging polymer-coated and ligand-targeted liposomes have been gaining interest as they have been shown to have more stability and specificity. We found that gene therapy involving microRNAs was the most frequently studied. Overall, liposomal genetic therapy has been shown to reduce tumor size and weight and improve survivability. More research involving the delivery and targets of gene therapy for ovarian cancer may be a promising avenue to improve patient outcomes.

Gene expression alterations in the postmortem hippocampus from older patients with bipolar disorder - A hypothesis generating study.

Bipolar disorder (BD) presents with a progressive course in a subset of patients. However, our knowledge of molecular changes in older BD is limited. In this study, we examined gene expression changes in the hippocampus of BD from the Biobank of Aging Studies to identify genes of interest that warrant further exploration. RNA was extracted from the hippocampus from 11 subjects with BD and 11 age and sex-matched controls. Gene expression data was generated using the SurePrint G3 Human Gene Expression v3 microarray. Rank feature selection was performed to identify a subset of features that can optimally differentiate BD and controls. Genes ranked in the top 0.1% with log2 fold change >1.2 were identified as genes of interest. Average age of the subjects was 64 years old; duration of disease was 21 years and 82% were female. Twenty-five genes were identified, of which all but one was downregulated in BD. Of these, CNTNAP4, MAP4, SLC4A1, COBL, and NEURL4 had been associated with BD and other psychiatric conditions in previous studies. We believe our findings have identified promising targets to inform future studies aiming to understand the pathophysiology of BD in later life.

Systematic review of structured care pathways in major depressive disorder and bipolar disorder.

BACKGROUND: Structured care pathways (SCPs) consist of treatment algorithms that patients advance through with the goal of achieving remission or response. These SCPs facilitate the application of current evidence and adequate treatment, which potentially benefit patients with mood disorders. The aim of this systematic review was to provide an updated synthesis of SCPs for the treatment of depressive disorders and bipolar disorder (BD). METHOD: PubMed, PsycINFO, and Embase were searched through June 2022 for peer-reviewed studies examining outcomes of SCPs. Eligibility criteria included being published in a peer-reviewed journal in the English language, reporting of intervention used in the SCP, and having quantitative outcomes. Studies Cochrane risk of bias tool was used to assess quality of RCTs. RESULTS: Thirty-six studies including 15,032 patients were identified for qualitative synthesis. Six studies included patients with BD. The studies were highly heterogeneous in design, outcome measures, and algorithms. More than half of the studies reported superiority of SCPs over treatment as usual, suggesting that the standardized structure and consistent monitoring inherent in SCPs may be contributing to their effectiveness. We also found accumulating evidence supporting feasibility of SCPs in different settings, although dropout rates were generally higher in SCPs. The studies included were limited to being published in peer-reviewed journals in English language. The heterogeneity of studies did not allow quantitative evaluation. CONCLUSIONS: The findings of our study suggest that SCPs are equally or more effective than treatment as usual in depression and BD. Further studies are required to ascertain their effectiveness, particularly for BD, and to identify factors that influence their feasibility and success.

Marked Increase in Amphetamine-Related Emergency Department Visits and Inpatient Admissions in Toronto, Canada, 2014-2021.

BACKGROUND: We report emergency department and inpatient amphetamine-related trends focusing on co-occurring substance use and psychiatric diagnoses at the Centre for Addiction and Mental Health, the largest mental health teaching hospital in Canada. METHODS: We describe yearly trends in amphetamine-related Centre for Addiction and Mental Health emergency department visits and inpatient admissions out of all emergency department visits and inpatient admissions between 2014 and 2021, along with proportions of concurrent substance-related admissions and mental/psychotic disorders emergency department visits and inpatient admissions among amphetamine-related contacts; joinpoint regression analyses assessed changes in amphetamine-related emergency department visits and inpatient admissions. RESULTS: Amphetamine-related emergency department visits rose from 1.5% in 2014 to 8.3% in 2021, with a peak of 9.9% in 2020. Amphetamine-related inpatient admissions rose from 2.0% to 8.8% in 2021, with a peak of 8.9% in 2020. Significant increasing trends in the percentage of amphetamine-related emergency department visits happened especially between the second and the fourth quarter of 2014 (quarterly percent change = + 71.4, P <0.01). Similarly, the percentage of amphetamine-related inpatient admissions increased mostly between the second quarter of 2014 and the third quarter of 2015 (quarterly percent change = + 32.6, P <0.01). The proportion of concurrent opioid-related contacts among amphetamine-related emergency department visits and inpatient admission increased markedly between 2014 and 2021; psychotic disorders in amphetamine-related inpatient admissions more than doubled from 2015 to 2021. DISCUSSION: Prevalence of amphetamine use, mostly from methamphetamine, has been increasing in Toronto as have co-occurring psychiatric disorders and opioid use. Our findings highlight the need for increases in accessible efficacious treatments for complex populations with polysubstance use and co-occurring disorders.

Venlafaxine XR treatment for older patients with major depressive disorder: decision trees for when to change treatment.

BACKGROUND: Predictors of antidepressant response in older patients with major depressive disorder (MDD) need to be confirmed before they can guide treatment. OBJECTIVE: To create decision trees for early identification of older patients with MDD who are unlikely to respond to 12 weeks of antidepressant treatment, we analysed data from 454 older participants treated with venlafaxine XR (150-300 mg/day) for up to 12 weeks in the Incomplete Response in Late-Life Depression: Getting to Remission study. METHODS: We selected the earliest decision point when we could detect participants who had not yet responded (defined as >50% symptom improvement) but would do so after 12 weeks of treatment. Using receiver operating characteristic models, we created two decision trees to minimise either false identification of future responders (false positives) or false identification of future non-responders (false negatives). These decision trees integrated baseline characteristics and treatment response at the early decision point as predictors. FINDING: We selected week 4 as the optimal early decision point. Both decision trees shared minimal symptom reduction at week 4, longer episode duration and not having responded to an antidepressant previously as predictors of non-response. Test negative predictive values of the leftmost terminal node of the two trees were 77.4% and 76.6%, respectively. CONCLUSION: Our decision trees have the potential to guide treatment in older patients with MDD but they require to be validated in other larger samples. CLINICAL IMPLICATIONS: Once confirmed, our findings may be used to guide changes in antidepressant treatment in older patients with poor early response.

Acoustic and postural displays in a miniature and transparent teleost fish, Danionella dracula.

Acoustic behavior is widespread across vertebrates, including fishes. We report robust acoustic displays during aggressive interactions for a laboratory colony of Danionella dracula, a miniature and transparent species of teleost fish closely related to zebrafish (Danio rerio), which are hypothesized to be sonic based on the presence of a hypertrophied muscle associated with the male swim bladder. Males produce bursts of pulsatile sounds and a distinct postural display - extension of a hypertrophied lower jaw, a morphological trait not present in other Danionella species - during aggressive but not courtship interactions. Females show no evidence of sound production or jaw extension in such contexts. Novel pairs of size-matched or -mismatched males were combined in resident-intruder assays where sound production and jaw extension could be linked to individuals. In both dyad contexts, resident males produced significantly more sound pulses than intruders. During heightened sonic activity, the majority of the highest sound producers also showed increased jaw extension. Residents extended their jaw more than intruders in size-matched but not -mismatched contexts. Larger males in size-mismatched dyads produced more sounds and jaw extensions compared with their smaller counterparts, and sounds and jaw extensions increased with increasing absolute body size. These studies establish D. dracula as a sonic species that modulates putatively acoustic and postural displays during aggressive interactions based on residency and body size, providing a foundation for further investigating the role of multimodal displays in a new model clade for neurogenomic and neuroimaging studies of aggression, courtship and other social interactions.

Identification of Endocannabinoid Predictors of Treatment Outcomes in Major Depressive Disorder: A Secondary Analysis of the First Canadian Biomarker Integration Network in Depression (CAN-BIND 1) Study.

INTRODUCTION: An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes. METHODS: The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels. RESULTS: Lower methylation of CpG islands of the diacylglycerol lipase alpha gene (DAGLA) was associated with non-remission at week 16 (DAGLA; OR=0.337, p<0.003, q=0.050). Methylation of DAGLA was correlated with improvement in Clinical Global Impression (p=0.026), Quick Inventory of Depressive Symptomatology (p=0.010), and Snaith-Hamilton Pleasure scales (p=0.028). We did not find any association between SNPs or mRNA levels and treatment outcomes. DISCUSSION: Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further.

Increased levels of TAR DNA-binding protein 43 in the hippocampus of subjects with bipolar disorder: a postmortem study.

Bipolar disorder shares symptoms and pathological pathways with other neurodegenerative diseases, including frontotemporal dementia (FTD). Since TAR DNA-binding protein 43 (TDP-43) is a neuropathological marker of frontotemporal dementia and it is involved in synaptic transmission, we explored the role of TDP-43 as a molecular feature of bipolar disorder (BD). Homogenates were acquired from frozen hippocampus of postmortem brains of bipolar disorder subjects. TDP-43 levels were quantified using an ELISA-sandwich method and compared between the postmortem brains of bipolar disorder subjects and age-matched control group. We found higher levels of TDP-43 protein in the hippocampus of BD (n = 15) subjects, when compared to controls (n = 15). We did not find associations of TDP-43 with age at death, postmortem interval, or age of disease onset. Our results suggest that protein TDP-43 may be potentially implicated in behavioral abnormalities seen in BD. Further investigation is needed to validate these findings and to examine the role of this protein during the disease course and mood states.

Antidepressant treatment outcomes in patients with and without comorbid physical or psychiatric disorders: A systematic review and meta-analysis.

BACKGROUND: Many patients with major depressive disorder (MDD) experience substantial impairment despite the availability of efficacious treatments. We performed a systematic review and meta-analysis to compare antidepressant outcomes in MDD with or without physical or psychiatric comorbidities. METHODS: Pubmed, EMBASE, and PsycInfo were searched up to May 14th, 2020 using keywords including MDD, antidepressant, medication, and comorbid. 1915 studies were reviewed. Studies that performed a direct and quantitative comparison of antidepressant effect in patients with MDD with or without comorbidities were included. Study characteristics and primary outcomes were extracted. Continuous and dichotomous variables were considered using standardized mean difference (SMD). Heterogeneity was measured using χ2 and I2 tests. Risk of bias was assessed using Cochrane Risk of Bias tool and NIH Quality Assessment Tool. RESULTS: 26 studies met selection criteria. Studies of physical (6 studies; I2 = 57.69%, p = 0.04) and psychiatric comorbidities (20 studies; I2 = 75.75%, p < 0.001) were heterogeneous. When compared to patients with MDD without comorbidities, those with physical (SMD = -0.19, 95% CI: -0.30 to -0.08, p = 0.001; 1910 and 2905 patients with or without comorbidities) or psychiatric comorbidities (SMD = -0.20, 95% CI: -0.31 to -0.095, p < 0.001; 4308 and 6867 patients with or without comorbidities) had worse antidepressant outcomes. LIMITATIONS: Our limitations included aggregating the comorbidities into physical and psychiatric comorbidities and the high heterogeneity of the studies. CONCLUSIONS: Our review provides updated evidence demonstrating that patients with MDD and physical or psychiatric comorbidities experience worse antidepressant outcomes.

Changes in RNA expression levels during antidepressant treatment: a systematic review.

More than a third of patients treated with antidepressants experience treatment resistance. Furthermore, molecular pathways involved in antidepressant effect have yet to be fully understood. Therefore, we performed a systematic review of clinical studies that examined changes in RNA expression levels produced by antidepressant treatment. Literature search was performed through April 2021 for peer-reviewed studies measuring changes in mRNA or non-coding RNA levels before and after antidepressant treatment in human participants following PRISMA guidelines. Thirty-one studies were included in qualitative synthesis. We identified a large amount of heterogeneity between the studies for genes/RNAs measured, antidepressants used, and treatment duration. Of the six RNAs examined by more than one study, expression of the brain-derived neurotrophic factor (BDNF) gene and genes in the inflammation pathway, particularly IL-1ß, were consistently reported to be altered by antidepressant treatment. Limitations of this review include heterogeneity of the studies, possibility of positive publication bias, and risk of false-negative findings secondary to small sample sizes. In conclusion, our systematic review provides an updated synthesis of RNA expression changes produced by antidepressant treatment in human participants, where genes in the BDNF and inflammatory pathways were identified as potential targets of antidepressant effect. Importantly, these findings also highlight the need for replication of the included studies in multiple strong, placebo-controlled studies for the identification of evidence-based markers that can be targeted to improve treatment outcomes.

The Impact of COVID-19 on Psychiatric Emergency and Inpatient Services in the First Month of the Pandemic in a Large Urban Mental Health Hospital in Ontario, Canada.

The World Health Organization characterized COVID-19 (coronavirus disease 2019) as a pandemic on March 11, 2020 (WHO). Within a couple of days, all Canadian provinces announced the implementation of social distancing measures. We evaluated the immediate effect of COVID-19 on psychiatric emergency and inpatient services in Canada's largest psychiatric hospital in the first month of the pandemic. We extracted data from the electronic medical records of the Center for Addiction and Mental Health in Toronto, Canada. We compared emergency department visits, inpatient occupancy rates, and length of stay in March 2019 and March 2020, and during the first and second half of March 2020. There was a decrease in the number of emergency department visits and inpatient occupancy rates in March 2020 compared to March 2019. There was also a significant decrease in the number of emergency department visits and inpatient occupancy rates in the second half of March 2020 compared to the first half. Our findings suggest that the pandemic was followed by a rapid decrease in the usage of psychiatric emergency and inpatient services in a large mental health hospital. Future studies will need to assess whether this decrease will be followed by a return to baseline or an increase in need for these services.

Systematic review of biological markers of therapeutic repetitive transcranial magnetic stimulation in neurological and psychiatric disorders.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is an evidenced based treatment for depression and an emerging treatment for several other neuropsychiatric disorders. The objective of this systematic review was to assess molecular changes produced by rTMS or molecular markers that predict treatment response in neuropsychiatric disorders. METHODS: PubMed, PsycINFO, and Embase were searched through July 2019 for studies published in peer-reviewed journals. Eighty-nine studies were identified examining healthy adults and patients with neuropsychiatric disorders including depression, chronic pain, post-stroke deficits, and movement disorders. RESULTS: Our ability to synthesize the information was limited by the large variability in treatment parameters and a limited number of placebo-controlled studies. While few findings were replicated by multiple strong studies, brain derived neurotrophic factor (BDNF) and gamma aminobutyric acid (GABA) in depression, BDNF in post-stroke deficits, and ß-endorphin in chronic pain may be altered by rTMS. CONCLUSION: BDNF, GABA and ß-endorphin were identified as potential molecular markers of rTMS and warrant further exploration. SIGNIFICANCE: This study, which is the first systematic review to examine molecular markers of rTMS in both neurological and psychiatric disorders, provides an updated review of this subject and highlight the need for more placebo-controlled and adequately powered studies to identify biomarkers of rTMS.

Neurophysiological Biomarkers in Schizophrenia-P50, Mismatch Negativity, and TMS-EMG and TMS-EEG.

Impaired early auditory processing is a well characterized finding in schizophrenia that is theorized to contribute to clinical symptoms, cognitive impairment, and social dysfunction in patients. Two neurophysiological measures of early auditory processing, P50 gating ("P50") and mismatch negativity (MMN), which measure sensory gating and detection of change in auditory stimuli, respectively, are consistently shown to be impaired in patients with schizophrenia. Transcranial magnetic stimulation (TMS) may also be a potential method by which sensory processing can be assessed, since TMS paradigms can be used to measure GABAB-mediated cortical inhibition that is linked with sensory gating. In this review, we examine the potential of P50, MMN and two TMS paradigms, cortical silent period (CSP) and long-interval intracortical inhibition (LICI), as endophenotypes as well as their ability to be used as predictive markers for interventions targeted at cognitive and psychosocial functioning. Studies consistently support a link between MMN, P50, and cognitive dysfunction, with robust evidence for a link between MMN and psychosocial functioning in schizophrenia as well. Importantly, studies have demonstrated that MMN can be used to predict performance in social and cognitive training tasks. A growing body of studies also supports the potential of MMN to be used as an endophenotype, and future studies are needed to determine if MMN can be used as an endophenotype specifically in schizophrenia. P50, however, has weaker evidence supporting its use as an endophenotype. While CSP and LICI are not as extensively investigated, growing evidence is supporting their potential to be used as an endophenotype in schizophrenia. Future studies that assess the ability of P50, MMN, and TMS neurophysiological measures to predict performance in cognitive and social training programs may identify markers that inform clinical decisions in the treatment of neurocognitive impairments in schizophrenia.

Plasma microRNA expression levels and their targeted pathways in patients with major depressive disorder who are responsive to duloxetine treatment.

Major depressive disorder (MDD) is a complex disorder with many pathways known to contribute to its pathogenesis, such as apoptotic signaling, with antidepressants having been shown to target these pathways. In this study, we explored microRNAs as predictive markers of drug response to duloxetine, a serotonin-norepinephrine reuptake inhibiter, using peripheral blood samples from 3 independent clinical trials (NCT00635219; NCT0059991; NCT01140906) comparing 6-8 weeks of treatment with duloxetine to placebo treatment in patients with MDD. Plasma microRNA was extracted and sequenced using the Ion Proton Sequencer. Rank feature selection analysis was used to identify microRNAs in the top 10th percentile for their differentiating ability between patients who remitted and did not remit with duloxetine treatment. The results were then compared between the 3 trials to see their replicability. To further validate our findings, we reasoned that the pathways targeted by these microRNAs would be those shown to be altered in MDD in pathway enrichment analysis. Hsa-miR-23a-3p, hsa-miR-16-5p, hsa-miR-146a-5p and hsa-miR-21-5p were identified in 2 or more trials as being able to differentiate patients who would remit with duloxetine treatment using samples collected before treatment initiation, suggesting that they may be good candidates for identification of predictive biomarkers of duloxetine response. Pathway enrichment analysis further showed that microRNAs identified as differentiating for duloxetine response target the apoptosis signaling pathway. Future studies examining these microRNAs outside of a clinical trial setting and exploring their role in MDD may further our understanding of MDD and antidepressant response.