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Objective Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder.Methods A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria.Results Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient.Conclusions There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

AbstractObjectiveMore than 50% patients with major depressive disorder (MDD) have severe functional impairment. The restoration of patient functioning is a critical therapeutic goal among patients with MDD. We conducted a systematic review and network meta-analysis to evaluate the efficacy of pharmacological treatments on self-rated functional outcomes using the Sheehan Disability Scale in adults with MDD in randomized clinical trials.MethodsPubMed, EMBASE, PsycINFO, Cochrane Library, and ClinicalTrials.gov were searched from inception to December 10, 2019. Summary statistics are reported as weighted mean differences with 95% confidence intervals. Interventions were ranked using the surface under the cumulative ranking probabilities.ResultsWe included 42 randomized controlled trials (RCTs) (n = 18 998) evaluating the efficacy of 13 different pharmacological treatments on functional outcomes, as measured by the Sheehan Disability Scale (SDS). Duloxetine was the most effective pharmacological agent on functional outcomes, followed by (ranked by efficacy): paroxetine, levomilnacipran, venlafaxine, quetiapine, desvenlafaxine, agomelatine, escitalopram, amitriptyline, bupropion, sertraline, vortioxetine, and fluoxetine. Serotonin and norepinephrine reuptake inhibitors were more effective than other drug classes. Additionally, the comparison-adjusted funnel plot suggested the publication bias between small and large studies was relatively low.ConclusionsOur results indicate that there may be differences across antidepressant agents and classes with respect to self-reported functional outcomes. Validation and replication of these findings in large-scale RCTs are warranted. Our research results will be clinically useful for guiding psychiatrists in treating patients with MDD and functional impairment. PROSPERO registration number CRD42018116663.

AbstractCognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.

AbstractBackgroundHigher body mass index (BMI) has been found to predict greater antidepressant response to intravenous (IV) ketamine treatment. We evaluated the association between BMI and response to repeat-dose IV ketamine in patients with treatment-resistant depression (TRD).MethodsAdults (N = 230) with TRD received four infusions of IV ketamine at a community-based clinic. Changes in symptoms of depression (ie, Quick Inventory for Depressive Symptomatology-Self-Report 16; QIDS-SR16), suicidal ideation (SI; ie, QIDS-SR16SI item), anxiety (ie, Generalized Anxiety Disorder-7 Scale), anhedonic severity (ie, Snaith–Hamilton Pleasure Scale), and functioning (ie, Sheehan Disability Scale) following infusions were evaluated. Participants were stratified by BMI as normal (18.0-24.9 kg/m2; n = 72), overweight (25-29.9 kg/m2; n = 76), obese I (30-34.9 kg/m2; n = 47), or obese II (≥35.0 kg/m2; n = 35).ResultsSimilar antidepressant effects with repeat-dose ketamine were reported between BMI groups (P= .261). In addition, categorical partial response (P= .149), response (P= .526), and remission (P= .232) rates were similar between the four BMI groups.ConclusionsThe findings are limited by the observational, open-label design of this retrospective analysis. Pretreatment BMI did not predict response to IV ketamine, which was effective regardless of BMI.

AbstractBackgroundBenzodiazepine (BZD) prescription rates have increased over the past decade in the United States. Available literature indicates that sociodemographic factors may influence diagnostic patterns and/or prescription behaviour. Herein, the aim of this study is to determine whether the gender of the prescriber and/or patient influences BZD prescription.MethodsCross-sectional study using data from the Florida Medicaid Managed Medical Assistance Program from January 1, 2018 to December 31, 2018. Eligible recipients ages 18 to 64, inclusive, enrolled in the Florida Medicaid plan for at least 1 day, and were dually eligible. Recipients either had a serious mental illness (SMI), or non-SMI and anxiety.ResultsTotal 125 463 cases were identified (i.e., received BZD or non-BZD prescription). Main effect of patient and prescriber gender was significant F(1, 125 459) = 0.105, P= 0 .745, partial η2< 0.001. Relative risk (RR) of male prescribers prescribing a BZD compared to female prescribers was 1.540, 95% confidence intervals (CI) [1.513, 1.567], whereas the RR of male patients being prescribed a BZD compared to female patients was 1.16, 95% CI [1.14, 1.18]. Main effects of patient and prescriber gender were statistically significant F(1, 125 459) = 188.232, P< 0.001, partial η2= 0.001 and F(1, 125 459) = 349.704, P< 0.001, partial η2= 0.013, respectively.ConclusionsMale prescribers are more likely to prescribe BZDs, and male patients are more likely to receive BZDs. Further studies are required to characterize factors that influence this gender-by-gender interaction.

AbstractBackgroundPatients unsuccessfully treated by neurostimulation may represent a highly intractable subgroup of depression. While the efficacy of intravenous (IV) ketamine has been established in patients with treatment-resistant depression (TRD), there is an interest to evaluate its effectiveness in a subpopulation with a history of neurostimulation.MethodsThis retrospective, posthoc analysis compared the effects of four infusions of IV ketamine in 135 (x̄ = 44 ± 15.4 years of age) neurostimulation-naïve patients to 103 (x̄ = 47 ± 13.9 years of age) patients with a history of neurostimulation. The primary outcome evaluated changes in depression severity, measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). Secondary outcomes evaluated suicidal ideation (SI), anxiety severity, measured by the Generalized Anxiety Disorder 7-Item (GAD-7), and consummatory anhedonia, measured by the Snaith–Hamilton Pleasure Scale (SHAPS).ResultsFollowing four infusions, both cohorts reported a significant reduction in QIDS-SR16Total Score (F(4, 648) = 73.4, P< .001), SI (F(4, 642) = 28.6, P< .001), GAD-7 (F(2, 265) = 53.8, P< .001), and SHAPS (F(2, 302) = 45.9, P< .001). No between-group differences emerged. Overall, the neurostimulation-naïve group had a mean reduction in QIDS-SR16Total Score of 6.4 (standard deviation [SD] = 5.3), whereas the history of neurostimulation patients reported a 4.3 (SD = 5.3) point reduction.ConclusionIV ketamine was effective in reducing symptoms of depression, SI, anxiety, and anhedonia in both cohorts in this large, well-characterized community-based sample of adults with TRD.

For decades, the role of glial cells has attracted attention in the neuroscience field. Particularly, although the astrocyte is the most abundant glial cell type, it was believed to function as a passive support cell. However, recent evidence suggests that astrocytes actively release various gliotransmitters and signaling entities that regulate the excitability of pre-and post-synaptic neurons in the brain. In this study, we optimized the ratio of astrocytes and neurons to investigate the interaction between astrocytes and neurons. To this end, postnatal day 0–1 rodent hippocampi were dissociated and cultured. The neuron–astrocyte ratio was monitored for up to 3 weeks after treating the cultures with 0, 1, and 5 µM of cytosine arabinoside (Ara-C) at DIV 2. Subsequently, from postnatal transgenic (TG) mouse expressing ChR2 on astrocytes, hippocampi were cultured on the microelectrode array (MEA) with the desired neuron–astrocyte ratio. The astrocyte was irradiated using a 473 nm blue laser for 30 s in a cycle of 10 Hz and electrophysiological recording was performed to verify the activities of neurons induced by the stimulated astrocytes. Astrocytes and neurons in both co-cultures increased at an identical ratio when treated with 1 µM Ara-C, whereas they decreased significantly when treated with 5 µM Ara-C. Particularly, the laser-stimulated astrocytes induced an increase in the frequency of neuronal activities and lasted after illumination. The proposed co-culture platform is expected to be used in experiments to investigate the network between astrocytes and neurons in vitro.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n= 21, 80.8%), NS (n= 3, 11.5%), NS/CFC (n= 1, 3.8%), and undefined syndromic intellectual disability (ID) (n= 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n= 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

ABSTRACTBackground:Convergent evidence implicates gut microbiota in human health and disease. Hitherto, relatively few studies have evaluated the gut microbiota profile in individuals with bipolar disorder (BD) relative to healthy controls (HC).Methods:Fecal samples were collected from subjects (aged 18–65) meeting DSM-5-defined criteria for BD and age- and sex-matched HC without current or past history of mental or major medical disorders. Samples were sequenced using Illumina sequencing and association of specific taxa and co-occurrence of taxa with sample groups including the effect of diet was assessed using cluster analysis and analysis of communities of microorganisms (ANCOM). Nutritional composition was evaluated using the Dietary Questionnaire for Epidemiological Studies (DQES v2) Food Frequency Questionnaire.Results:Forty-six subjects were enrolled (n=23 BD, n=23 HC). Cluster analyses did not identify any significant differences between BD and HC (p=0.38). Lower microbiota diversity was observed among BD subjects relative to HC (p=0.04). A greater abundance of a ClostridiaceaeOTU was observed among BD subjects when compared to HC and of Collinsellaamong BD-II subjects relative to BD-I. Cluster analysis revealed that neither diagnosis (p=0.38) nor diet (p=0.43) had a significant effect on overall gut microbiota composition.Limitations:This study has a small sample size and insufficient control for some potential moderating factors (e.g. psychotropic medication and smoking).Conclusion:This study suggests that individuals with BD may have a distinct gut microbiota profile compared to healthy controls, with a greater abundance of Clostridiaceaeand Collinsella. These findings need to be replicated in future studies with larger sample sizes.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith–Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab’s hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor “NEV1,” whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted “NEV2”. Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2= 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

ABSTRACTObjectivesRigorous clinical trials suggest ketamine is safe and well-tolerated in patients with treatment-resistant depression (TRD). There is a paucity of data on the safety and tolerability of ketamine in community-based clinics treating patients with TRD.MethodsRetrospective data was analyzed from 203 patients with TRD who received repeat-dose IV ketamine. Safety was operationalized as hemodynamic changes. Tolerability was evaluated through the reporting of adverse events and dissociation symptom severity, as measured by the Clinician-Administered Dissociative States Scale.ResultsKetamine was well-tolerated, with less than 5% of patients withdrawing due to tolerability concerns. Blood pressure significantly increased during infusion, with 44.3% meeting criteria for treatment-emergent hypertension (i.e., blood pressure ≥ 165/100 mmHg). 12% of patients exhibiting hypertension required pharmacological intervention. The most frequently reported adverse events included drowsiness (56.4%), dizziness (45.2%), dissociation (35.6%), and nausea (13.3%). Dissociation severity significantly attenuated after the first infusion, but plateaued for subsequent infusions.ConclusionIntravenous ketamine was safe and well-tolerated. Hypertension was commonly observed and was often transient. Dissociation was most frequently reported after the first infusion but remained a consistent but not treatment-limiting adverse event thereafter. No patients exhibited psychosis, mania, or new onset suicidality with IV ketamine.

The effect of antidepressant (ATD) use on mortality in patients with diabetes mellitus (DM) has not yet been sufficiently studied, although comorbid depression is common in this population.

Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.

The etiology of mood disorders is mechanistically heterogeneous, underscoring the need for a dimensional approach to identify and develop targeted treatments in psychiatry. Accumulating evidence implicates inflammation as an important contributor to the pathophysiology of depression and presents the immune system as a viable therapeutic target that may be more proximate to the pathogenic nexus of brain-based disorders in specific subpopulations. Anhedonia is a transdiagnostic (e.g. Parkinson’s disease, diabetes mellitus, rheumatic diseases), yet specific, and clinically relevant symptom dimension subserved by well-characterized neurobiological and neurophysiological substrates of the positive valence systems (PVS). Brain circuits, nodes, and networks, as well as cellular and molecular pathways (e.g. dopaminergic transmission; excitotoxicity; synaptic plasticity), subserving anhedonia are preferentially affected by inflammatory processes. To our knowledge, no published randomized, controlled clinical trial in populations with mood disorders has, to date, primarily sought to determine the effects of an anti-inflammatory agent on PVS functions or pathophysiology. Three ongoing clinical trials aim to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia [ClinicalTrials.gov identifier: NCT02363738], motivational behavior and circuitry [ClinicalTrials.gov identifier: NCT03006393], and glutamatergic changes in the basal ganglia [ClinicalTrials.gov identifier: NCT03004443] in clinical populations with unipolar or bipolar depression. Positive results would further instantiate the relevance of inflammatory processes and the immune system in the pathophysiology of mood disorders and provide the impetus to develop scalable treatments targeting inflammation and the immune system to mitigate transdiagnostic, dimensional disturbances in brain-based disorders.

Type 2 diabetes mellitus (DM) is associated with substantial impairments in workplace function; however, the mediators of workplace performance in DM are not well characterized. Herein, we investigate depressive symptomatology and cognitive dysfunction as mediators of workplace productivity and hypothesize that workplace impairment is mediated principally by cognitive dysfunction in DM.

ABSTRACTIntroduction: To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents.Areas covered: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabiswas cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), both in vitroand in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper.Expert opinion: Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

Technology is becoming increasingly intertwined with our lives every year. As technology advances, it offers promising new methods to help detect, manage, and improve the care of major depressive disorder (MDD). Unlike other specialties in medicine, psychiatry has been slow to adopt new technologies. Other areas of medicine, primarily cardiology and oncology, have made use of technological methods to patients’ great benefits. In psychiatry, new technological methods can predict which antidepressants will be most effective, provide therapies to patients, and empower patients to manage their own medical records. We offer an overview to new technologies and their applications to psychiatry for novices. Our particular focus is big data, machine learning, mobile applications, and blockchain technology. We summarise the uses of technology as assisting physicians in decision making, facilitating patient-patient interaction, and securely storing and managing health-care data. We suggest possible advantages and challenges to adopting these methods. Continued research and technological innovation is needed to improve the psychiatrist’s toolbox and to monitor the adoption and consequences of new technologies.

* * * * * * This week, delegates of China's National People's Congress overhauled the country's 2014 counterespionage law, giving the state more power to block potential threats. BEIJING -- With most of China's public health measures having been relaxed and no current surge in cases, this year's May Day "golden week" holiday is the first to be celebrated free of concerns over COVID-19 since the start of the pandemic. [Extracted from the article]

As the investigation gets underway, the tragedy hashighlighted two issues: the lack of media freedom in China,and the shady operations of the private health care sector. While appearing as a guest on a French politicaltalk show Friday, Lu Shaye--the PRC's top envoy inParis--suggested that none of the former Soviet republics arerecognized under international law. BEIJING--In a rare move, China's Foreign Ministry haspublicly distanced itself from statements made by a sittingambassador. [Extracted from the article]

BEIJING Last week, French President Emmanuel Macron embarked on a three-day state visit to China. Macron's remarks on Taiwan betray a misunderstanding of developments in China and the broader region and undercut Paris' stated foreign-policy objectives. Macron was joined on his visit to China by more than 50 French business leaders, and France and China signed 20 deals ranging from agriculture to aviation. [Extracted from the article]

Supplemental digital content is available in the text.

ABSTRACTIntroduction: Alterations in neurogenic and neurotrophic processes as well as intracellular signalling cascades provides the basis for hypothesizing that neurogenic agents may be therapeutic across multiple RDoC-defined domains (e.g. positive valence systems, general cognitive processes). Moreover, using the DSM-5 taxonomy, neurogenic agents may mitigate symptoms in adults with depressive and bipolar disorders as well as individuals with cognitive disorders.Areas covered: NSI-189 is a benzylpiperizine-aminiopyridine, a novel chemical entity that stimulates neurogenesis of human hippocampus-derived neural stem cells in vitroand stimulates neurogenesis in murine hippocampus in vivo. Emerging evidence also indicates that NSI-189 phosphate has regionally specific effects insofar as neurogenesis is observed largely in the subventricular zone of the hippocampus. Results from a preliminary proof of concept study suggests that NSI-189 may be capable of mitigating depressive symptoms and improve cognitive function in adults with DSM-5-defined Major Depressive Disorder (MDD).Expert opinion: Preliminary proof-of-concept studies indicate both antidepressant and procognitive effects. Beneficial effects in cognitive-emotional processing as well as whether the procognitive effects are independent of antidepressant effects are vistas of future research. Taken together, NSI-189 is a multi-domain neurogenic compound with brain-therapeutic properties with potential therapeutic applications across disparate psychiatric disorders.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM–5 codified a new nosological entity, the “mixed features specifier,” referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM–IV definition of “mixed states” wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

BEIJING--In more than five hours of questioning during a hearingon Capitol Hill last Thursday, TikTok CEO Shou Zi Chew failed toconvince a bipartisan U.S. congressional committee that his app issafe from the Chinese government's meddling. That suggests that for Washington,the biggest problem is the tech firm's Chinese ownership, amid fearsthat TikTok would be pressured into supplying user data to theChinese government for political purposes. [Extracted from the article]

Xi's Visit to Russia Was About China's Interests, not Ukraine Following up Xi's state visit toMoscow with a phone call to Kyiv would allow Beijing toclaim neutrality and tout its status as a major world power. BEIJING--President Xi Jinping was in Moscow thisweek for a three-day state visit at the invitation of RussianPresident Vladimir Putin, a man he often refers to as his"best friend.". [Extracted from the article]

Late Friday night, China's Foreign Ministry published photosof China's top diplomat, Wang Yi, standing between theenvoys of the two nations shaking hands. BEIJING--As was widely expected, China's rubber-stampparliament reappointed Xi Jinping for an unprecedented thirdterm as president of the People's Republic of China onFriday. [Extracted from the article]

Mixed features specifier (MFS) is a new nosological entity defined and operationalized in the Diagnostic and Statistical Manual of Mental Disorders(DSM), 5th Edition. The impetus to introduce the MFS and supplant mixed states was protean, including the lack of ecological validity, high rates of misdiagnosis, and guideline discordant treatment for mixed states. Mixed features specifier identifies a phenotype in psychiatry with greater illness burden, as evidenced by earlier age at onset, higher episode frequency and chronicity, psychiatric and medical comorbidity, suicidality, and suboptimal response to conventional antidepressants. Mixed features in psychiatry have historical, conceptual, and nosological relevance; MFS according to DSM-5, is inherently neo-Kraepelinian insofar as individuals with either Major Depressive Disorder (MDD) or Bipolar Disorder (BD) may be affected by MFS. Clinicians are encouraged to screen all patients presenting with a major depressive episode (or hypomanic episode) for MFS. Although “overlapping symptoms” were excluded from the diagnostic criteria (eg, agitation, anxiety, irritability, insomnia), clinicians are encouraged to probe for these nonspecific symptoms as a possible proxy of co-existing MFS. In addition to conventional antidepressants, second generation antipsychotics and/or conventional mood stabilizers (eg, lithium) may be considered as first-line therapies for individuals with a depressive episode as part of MDD or BD with mixed features.

BackgroundCognitive dysfunction is common in major depressive disorder (MDD) and a critical determinant of health outcome. Anhedonia is a criterion item toward the diagnosis of a major depressive episode (MDE) and a well-characterized domain in MDD. We sought to determine the extent to which variability in self-reported cognitive function correlates with anhedonia.MethodA post hoc analysis was conducted using data from (N=369) participants with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR)-defined diagnosis of MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. The IMDCP is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Canada, and the Cleveland Clinic, Cleveland, Ohio. Measures of cognitive function, anhedonia, and depression severity were analyzed using linear regression equations.ResultsA total of 369 adults with DSM-IV-TR–defined MDD were included in this analysis. Self-rated cognitive impairment [ie, as measured by the Adult ADHD Self-Report Scale (ASRS)] was significantly correlated with a proxy measure of anhedonia (r=0.131, p=0.012). Moreover, total depression symptom severity, as measured by the total Montgomery–Åsberg Depression Rating Scale (MADRS) score, was also significantly correlated with self-rated measures of cognitive dysfunction (r=0.147, p=0.005). The association between anhedonia and self-rated cognitive dysfunction remained significant after adjusting for illness severity (r=0.162, p=0.007).ConclusionsThese preliminary results provide empirical data for the testable hypothesis that anhedonia and self-reported cognitive function in MDD are correlated yet dissociable domains. The foregoing observation supports the hypothesis of overlapping yet discrete neurobiological substrates for these domains.

Objectives: The aim of the study was to evaluate the prevalence of and illness characteristics in adults with major depressive disorder (MDD) with anxious distress specifier (ADS) enrolled in the International Mood Disorders Collaborative Project, which is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Canada and the Cleveland Clinic, Cleveland, Ohio, USA.Methods: Data from participants who met criteria for a current major depressive episode as part of MDD (n= 830) were included in this post hocanalysis. Diagnostic and Statistical Manual Version-5-defined ADS was operationalized as the presence of at least two out of three proxy items instead of two out of five specifiers.Results: A total of 464 individuals (i.e. 56%) met criteria for ADS. There were no between-group differences in sociodemographic variables (e.g. gender, employment, marital status). Greater severity of illness was observed in adults with ADS as evidenced by a higher number of hospitalizations, higher rates of suicidal ideation, greater depressive symptom severity, greater workplace impairment, decreased quality of life, and greater self-reported cognitive impairment.Conclusions: Our findings underscore the importance of evaluating ADS in adults with MDD as its presence identifies a subpopulation with greater illness-associated burden and hazards.

Available evidence indicates that a single, low-dose administration of ketamine is a robust, rapid-onset intervention capable of mitigating depressive symptoms in adults with treatment-resistant mood disorders. Additional evidence also suggests that ketamine may offer antisuicide effects. Herein, we propose that the antidepressant effects reported with ketamine administration are mediated, in part, by targeting neural circuits that subserve cognitive processing relevant to executive function and cognitive emotional processing. Empirical support for the conceptual framework of the cognitive domain as a critical target of ketamine's action is the additional observation that pretreatment cognitive function predicts treatment outcomes with ketamine administration. The proposal that beneficial effects on cognitive function may be, in some individuals, the proximate mechanism mitigating symptom relief in mood disorders exists alongside the well-established deleterious effect of ketamine on cognitive function. During the past 5 years, there have been several reviews and meta-analyses concluding that ketamine has possible clinical benefits in refractory mood disorders. We introduce the conceptual framework that ketamine's salutary effects, notably in suicidality, may in part be via procognitive mechanisms.

Treating to target in chronic diseases [e.g. Major Depressive Disorder (MDD)] fosters precision, consistency, and appropriateness of treatment selection and sequencing. Therapeutic target definitions/endpoints in MDD should satisfy patient-, provider-, and societal expectations. Functional recovery in depression and return to both physical and mental health are the overarching therapeutic objectives. Treating to target in MDD implies multidimensional symptomatic remission, with a particular emphasis on cognitive function and aspects of positive mental health. Several atypical antipsychotic agents (i.e. brexpiprazole, aripiprazole, quetiapine) are FDA-approved as augmentation agents in MDD. Vortioxetine, duloxetine, and psychostimulants have evidence of independent, direct, and robust effects on cognitive function in MDD. Vortioxetine is the only agent that demonstrates efficacy across multiple cognitive domains in MDD associated with functional recovery. Measurement-based care, health information technology/systems, and integrated care models (e.g. medical homes) provide requisite tools and health environments for optimal health outcomes in MDD. Achieving remission in MDD does not equate to health. Return to positive mental health as well as full functioning provide the impetus to pivot away from traditional provider-defined outcomes toward an inclusive perspective involving patient- and society-defined outcomes (i.e. optimization of human capital). As in other chronic diseases, treating to target (e.g. cognitive function) further increases the probability of achieving optimal health outcomes.

For several decades, the intracortical penetrating microelectrode arrays have been widely employed for the purpose of neural recording and stimulation in nervous system. However, the long-term application is limited due to the tissue reaction to the implanted electrode array. The tissue response includes the degeneration of nerve cells as well as the formation of dense glial sheath adjacent the implanted electrode called gliosis. The glial encapsulation deteriorates the capacity of electrodes to communicate with neurons by electrically isolating the devices from the neighboring brain regions. To examine and overcome these critical obstacles of microelectrode array for chronic applications, a number of studies have been performed to date including the reduction of electrode geometry, the use of flexible materials for electrode substrates, the pharmacological suppression of the cellular reaction, and the optimized surgical techniques. In this review, the studies to clarify the mechanism of the glial response in central nerve system (CNS) will be described and a variety of strategies for minimizing the glial responses in CNS will be examined.

Since in vitro neural recording and imaging applications based on a surface plasmon resonance (SPR) technique have expanded dramatically in recent years, cytotoxicity assessment to ensure the biosafety and biocompatibility for those applications is crucial. Here, we report the cytotoxicity of the SPR substrate incorporating a flint glass whose refractive index is larger than that of a conventional crown glass. A high refractive index glass substrate is essential in neural signal detection due to the advantages such as high sensitivity and wide dynamic range. From experimental data using primary hippocampal neurons, it is found that a lead-based flint glass is not appropriate as a neural recording template although the neuron cells are not directly attached to the toxic glass. We also demonstrate that the adhesion layer between the glass substrate and the gold film plays an important role in achieving the substrate stability and the cell viability.

•53 older adults (≥60 years of age) with treatment-resistant depression received repeat-doses of intravenous ketamine (i.e., four infusions)•27% of older adults responded to IV ketamine after four infusions (i.e., 50% decrease in symptoms compared to pre-treatment)•36 participants experienced transient treatment-emergent hypertension•3 participants dropped out of treatment due to increased anxiety and/or inability to tolerate dissociative symptoms

In this article, an optimization-based framework is proposed for integrated production and distribution planning of industrial gas supply chains. The main goal is to minimize the overall cost, which is composed of raw material, product sourced from external suppliers, production, truck, and rail-car costs, while satisfying customer demands. The overall problem is formulated as a mixed-integer linear programming (MILP) model while a two-phase hierarchical solution strategy is developed to solve the resulting optimization problem efficiently. The first phase relies on truck scheduling decisions being relaxed, whereas the second phase solves the original model at reduced space by fixing product allocation as determined by phase one. Finally, an industrial-size case study is used to illustrate the applicability and efficiency of the proposed optimization framework.

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