Vortioxetine for the treatment of post-COVID-19 condition: a randomized controlled trial.

Hitherto no therapeutic has received regulatory approval for the treatment of post-COVID-19 condition (PCC). Cognitive deficits, mood symptoms and significant reduction in health-related quality of life (HRQoL) are highly replicated and debilitating aspects of PCC. We sought to determine the impact of vortioxetine on the foregoing symptoms and HRQoL in persons living with PCC. An 8-week randomized, double-blind, placebo-controlled study of adults ≥ 18 years of age residing in Canada and who are experiencing symptoms of World Health Organization (WHO)-defined PCC, with a history of confirmed SARS-CoV-2 infection, was conducted. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled (487 invited: 121 ineligible and 59 eligible but declined participation; 307 cleared pre-screening stage), a total of 149 participants were randomized (1:1) to receive either vortioxetine (5-20 mg, n = 75) or placebo (n = 74) daily for 8 weeks of double-blind treatment (i.e. end point). The primary outcome was the change from baseline-to-end point in the Digit Symbol Substitution Test. Secondary outcomes included the effect on depressive symptoms and HRQoL, as measured by changes from baseline-to-end point on the Quick Inventory of Depressive Symptomatology 16-item and WHO Wellbeing Scale 5-item, respectively. A total of 68 (90.7%) participants randomized to vortioxetine and 73 (98.6%) participants randomized to placebo completed all 8 weeks. Between-group analysis did not show a significant difference in the overall change in cognitive function [P = 0.361, 95% confidence interval (CI) (-0.179, 0.492)]. However, in the fully adjusted model, a significant treatment × time interaction was observed in favour of vortioxetine treatment with baseline c-reactive protein (CRP) as a moderator (P = 0.012). In addition, a significant improvement in Digit Symbol Substitution Test scores were observed in vortioxetine versus placebo treated participants in those whose baseline CRP was above the mean (P = 0.045). Moreover, significant improvement was obtained in measures of depressive symptoms [P < 0.001, 95% CI (-4.378, -2.323)] and HRQoL [P < 0.001, 95% CI (2.297, 4.647)] in vortioxetine-treated participants and between the treatment groups [depressive symptoms: P = 0.026, 95% CI (-2.847, -0.185); HRQoL: P = 0.004, 95% CI (0.774, 3.938)]. Although vortioxetine did not improve cognitive function in the unadjusted model, when adjusting for CRP, a significant pro-cognitive effect was observed; antidepressant effects and improvement in HRQoL in this debilitating disorder were also noted.

Glucagon-like peptide 1 (GLP-1) receptor agonists as a protective factor for incident depression in patients with diabetes mellitus: A systematic review.

Glucagon-like peptide 1 (GLP-1) receptor agonists are widely used for glycemic control in patients with diabetes mellitus (DM) and are primarily indicated for type 2 diabetes mellitus (T2DM). GLP-1 receptor agonists have also been shown to have neuroprotective and antidepressant properties. Replicated evidence suggests that individuals with DM are significantly more likely to develop depression. Herein, we aim to investigate whether GLP-1 receptor agonists can be used prophylactically on patients with DM to lower the risk of incident depression. We conducted a systematic search for English-language articles published on the PubMed/MEDLINE, Scopus, Embase, APA, PsycInfo, Ovid and Google Scholar databases from inception to June 6, 2022. Four retrospective observational studies were identified that evaluated the neuroprotective effects of GLP-1 receptor agonists on incident depression in patients with DM. We found mixed results with regards to lowering the risk of incident depression, with two studies demonstrating a significant reduction in risk and two studies showing no such effect. A single study found that dulaglutide may lower susceptibility to depression. Our results were limited by high interstudy heterogeneity, paucity of literature, and lack of controlled trials. While we did not find evidence of GLP-1 receptor agonists significantly lowering risk of incident depression in patients with DM, promising neuroprotective data presented in two of the included papers, specifically on dulaglutide where information is scarce, provide the impetus for further investigation. Future research should focus on better elucidating the neuroprotective potential of different classes and doses of GLP-1 receptor agonists using controlled trials.

Efficacy, safety, and tolerability of ulotaront (SEP-363856, a trace amine-associated receptor 1 agonist) for the treatment of schizophrenia and other mental disorders: a systematic review of preclinical and clinical trials.

INTRODUCTION: Schizophrenia is a mental illness that can disrupt emotions, perceptions, and cognition and reduce quality of life. The classical approach to treat schizophrenia is to use typical and atypical antipsychotics; however, limitations include low efficacy in mitigating negative symptoms and cognitive dysfunctions and a range of adverse effects. Evidence has accumulated on trace amine-associated receptor 1 (TAAR1) as a novel therapeutic target for treating schizophrenia. This systematic review investigates the available evidence on a TAAR1 agonist, ulotaront, as a treatment for schizophrenia. METHODS: A systematic search was conducted on PubMed/MEDLINE and Ovid databases for English-published articles from inception to 18 December 2022. The literature focusing on the association between ulotaront and schizophrenia was evaluated based on an inclusion/exclusion criterion. Selected studies were assessed for the risk of bias, using the Cochrane Collaboration tool, and summarized in a table to generate discussion topics. RESULTS: Three clinical, two comparative, and five preclinical studies examining ulotaront's pharmacology, tolerability and safety, and/or efficacy were identified. Results indicate that ulotaront has a differing adverse effect profile from other antipsychotics, may mitigate metabolic-related adverse effects commonly associated with antipsychotics, and may be effective for treating positive and negative symptoms. CONCLUSIONS: Findings from the available literature present ulotaront as a potential and promising alternative treatment method for schizophrenia. Despite this, our results were limited due to the lack of clinical trials on ulotaront's long-term efficacy and mechanisms of action. Future research should focus on these limitations to elucidate ulotaront's efficacy and safety for the treatment of schizophrenia and other mental disorders with similar pathophysiology.

COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis.

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

Presence of Depression Is Associated with Functional Impairment in Middle-Aged and Elderly Chinese Adults with Vascular Disease/Diabetes Mellitus-A Cross-Sectional Study.

Objectives: The association between chronic diseases and depression has received increasing attention, and are both considered to increase the risk of functional impairment. However, previous research evidence is controversial. Our study aimed to investigate the association between depression, three types of vascular disease (i.e., hypertension, myocardial infarction, stroke), diabetes mellitus, and functional impairment in middle-aged and elderly Chinese people. Methods: We designed a cross sectional study. Data were collected from the China Health and Retirement Longitudinal Study (CHARLS) in 2018. Logistic regression models were used to explore the association between independent variables and functional status. Results: Lower functional status was significantly associated with comorbid depression and vascular disease/diabetes mellitus (Activity of Daily Living/Instrumental Activity of Daily Living: Adjusted OR of Hypertension, Diabetes mellitus, Myocardial infarction, Stroke is 3.86/4.30, 3.80/4.38, 3.60/4.14, 6.62/7.72, respectively; all p < 0.001). Conclusions: Depression is associated with functional decline in middle-aged and elderly Chinese individuals with vascular disease/diabetes mellitus. Identifying mediational factors and preventative strategies to reduce concurrent depression in persons with vascular diseases should be a priority therapeutic vista.

Canadian Healthcare System and Individuals with Severe Mental Disorders During Coronavirus Disease 2019: Challenges and Unmet Needs.

The Coronavirus Disease 2019 (COVID-19) pandemic is a syndemic of viral infection and mental health adversity. The pandemic has exacerbated inequalities of access to care in vulnerable populations within the Canadian mental healthcare system. Primary care services are first-line health services in Canada, and are necessary to access specialized services. However, as a result of the limited availability of primary health services, and subsequently, specialized providers (eg, psychiatrists), the demand for these services outweigh the supply. Hitherto, timely access to appropriate services has been cited as a common challenge in Canada as a result of limitations as it relates to resources and in-person activities and support services. While there has been an increase in virtual care opportunities, concerns have been raised with respect to the digital divide. Moreover, while individuals with serious mental illness (SMI) and psychosis are at an increased risk for hospitalization and death from COVID-19, testing and vaccination services have not been prioritized for this population. Taken together, increased funding for mental health service delivery should be emphasized especially for individuals with SMI. There should also be a focus on increased collaboration among individuals with lived experience and health care providers to ensure future policies are developed specifically for this population. Addressing the social determinants of health and prioritizing a continuum of care across various stakeholders may lead to strong integration of care both during and after the pandemic.

Ketamine as potential treatment for postpartum depression: A narrative review.

BACKGROUND: Postpartum depression (PPD) is a severe, debilitating mood disorder with consequences for both mothers and children, highlighting the need for rapid-acting and effective treatments for PPD. The aim of this narrative review is to synthesize the available literature on the administration of ketamine for PPD and propose ketamine as a viable and advantageous treatment. METHODS: A search was conducted on MEDLINE/PubMed, PsycInfo, and Embase databases from inception to October 10, 2021 for preclinical studies, interventional studies (ie, open-label and randomized controlled trials), as well as systematic reviews and meta-analyses evaluating the use of ketamine in postpartum populations. Completed and ongoing clinical trials were identified on ClinicalTrials.gov. RESULTS: Four clinical trials were identified. Results from this review support additional investigation into ketamine as a potential treatment for PPD. CONCLUSIONS: Ketamine may be a favorable option for treating PPD due to its antidepressive and analgesic effects, short infusion time, and rapid clearance from the maternal bloodstream. However, there is insufficient evidence to support its use in this population, underscoring the importance of additional clinical research investigating ketamine for PPD.

Brain-Derived Neurotrophic Factor (BDNF) as a biomarker of treatment response in patients with Treatment Resistant Depression (TRD): A systematic review & meta-analysis.

Multiple lines of evidence have implicated brain-derived neurotrophic factor (BDNF) in treatment-resistant depression (TRD). The aim of this synthesis was to determine the impact of TRD treatments on peripheral BDNF levels, and ascertain whether these changes are associated with antidepressant effects. Thirty-six articles involving 1198 patients with TRD were included herein. Electroconvulsive therapy (ECT), ketamine, and repetitive transcranial magnetic stimulation (rTMS) were the most common TRD treatments investigated. Serum BDNF levels significantly increased in six, two, four and one studies following ECT, ketamine, rTMS and atypical antipsychotics, respectively. The estimated mean baseline serum BDNF concentration in TRD patients ± 95% CI was 15.5 ± 4.34 ng/mL. Peripheral BDNF levels significantly increased overall (Hedges' g ± 95% CI = 0.336 ± 0.302; p < 0.05), but no association with depressive symptoms was found (p ≥ 0.05). These results demonstrate that peripheral measurements of total BDNF (i.e., mature and percursor forms of BDNF) are inadequate predictors of treatment response in TRD patients, and other considerations suggest that this would still apply to separable measurements of mature BDNF and its precursor.

The association between stage of treatment-resistant depression and clinical utility of ketamine/esketamine: A systematic review.

OBJECTIVE: Ketamine has demonstrated rapid and significant antidepressant effects in patients with treatment resistant depression (TRD). Herein, we conducted a systematic review to determine ketamine's efficacy as a function of the stage of treatment resistance (e.g., number of failed treatments) among individuals with TRD. METHODS: A systematic search of PubMed and Scopus from inception to August 2021 was conducted. Where applicable, the studies were categorized into low and high stages of resistance, where low category included studies where the mean number of failed antidepressants was <3 or had a higher proportion of subjects with ≤2 antidepressant trials. Reported indicators of treatment resistance and efficacy were extracted from randomized-controlled trials (RCTs) assessing ketamine or esketamine for TRD. RESULTS: In total, 18 RCTs were included in the current review. There was variability across reported indicators of disease severity, definition of treatment resistance, as well as treatment protocols, preventing clear direct and indirect comparison of relative efficacy of ketamine at different stages of treatment resistance. Ketamine was effective in reducing depressive symptoms in RCTs at both lower and higher stages of treatment resistance; however, the effect size and duration of effects was greater in RCTs of lower stage of treatment resistance. CONCLUSIONS: Our findings suggested that ketamine has antidepressant efficacy across all identified stages of treatment resistance, however with increasing failed treatment trials, treatment might be less efficacious. At this time, the comparative efficacy as a function of resistance stage remains to be well-established. Evaluation of participant level data is required to more clearly determine the association between level of treatment resistance and likelihood of response.

A Research Domain Criteria (RDoC)-Guided Dashboard to Review Psilocybin Target Domains: A Systematic Review.

BACKGROUND: Preliminary results from randomized controlled studies as well as identified molecular, cellular, and circuit targets of select psychedelics (e.g., psilocybin) suggest that their effects are transdiagnostic. In this review, we exploit the Research Domain Criteria (RDoC) transdiagnostic framework, to synthesize extant literature on psilocybin. OBJECTIVE: We aimed to identify RDoC-based effects of psilocybin and vistas for future mechanistic and interventional research. METHODS: A systematic search in electronic databases (i.e., PubMed, Scopus, PsycINFO, and Web of Science) performed in January and February 2021 identified English articles published between 1990 and 2020 reporting the effects of psilocybin on mental health measures. Data from included articles were retrieved and organized according to the RDoC bio-behavioral matrix and its constituent six main domains, namely: positive valence systems, negative valence systems, cognitive systems, social processes, sensorimotor systems, and arousal and regulatory systems. RESULTS: The preponderance of research with psilocybin has differentially reported beneficial effects on positive valence systems, negative valence system, and social process domains. The data from the included studies support both short-term (23 assessments) and long-term (15 assessments) beneficial effects of psilocybin on the positive valence systems. While 12 of the extracted outcome measures suggest that psilocybin use is associated with increases in the "fear" construct of the negative valence systems domain, 19 findings show no significant effects on this construct, and seven parameters show lowered levels of the "sustained threat" construct in the long term. Thirty-four outcome measures revealed short-term alterations in the social systems' construct namely, "perception and understanding of self," and "social communications" as well as enhancements in "perception and understanding of others" and "affiliation and attachment". The majority of findings related to the cognitive systems' domain reported dyscognitive effects. There have been relatively few studies reporting outcomes of psilocybin on the remaining RDoC domains. Moreover, seven of the included studies suggest the transdiagnostic effects of psilocybin. The dashboard characterization of RDoC outcomes with psilocybin suggests beneficial effects in the measures of reward, threat, and arousal, as well as general social systems. CONCLUSIONS: Psilocybin possesses a multi-domain effectiveness. The field would benefit from highly rigorous proof-of-mechanism research to assess the effects of psilocybin using the RDoC framework. The combined effect of psilocybin with psychosocial interventions with RDoC-based outcomes is a priority therapeutic vista.

Impact of cognitive-affective and somatic symptoms in subthreshold depression transition in adults: Evidence from Depression Cohort in China (DCC).

BACKGROUND: Symptoms of subthreshold depression may differentially affect the illness transition. We examined the impact of cognitive-affective and somatic symptoms on different subthreshold depression transitions as well as risk factors influencing the aforementioned symptoms changes. METHODS: Adults with subthreshold depression in the Depression Cohort in China were enrolled. Data collection was conducted at baseline, 6 and 12 months from 2019 to 2020. Cognitive-affective and somatic symptoms were assessed using the Patient Health Questionnaire-9. A total of 993 participants completed 12-month follow-up and were divided into persistent, intermittent and remission groups according to change in depressive symptoms. The longitudinal change of cognitive-affective and somatic symptoms in the three groups, as well as risk factors was analyzed using the generalized linear mixed-model. RESULTS: There were 24.07 %, 34.04 % and 41.89 % of participants proceeding into persistent, intermittent and remission subthreshold depression groups, respectively. Cognitive-affective symptoms were the core symptoms for predicting the deterioration in persistent subthreshold depression (t = 2.48, P = 0.013), whereas somatic symptoms improved over time (t = -2.82, P = 0.005). Anxiety symptoms were the primary risk factors for worsening cognitive-affective symptoms (P < 0.001), following by insomnia symptoms, age, marital status, resilience and social functions. Somatic symptoms were affected by insomnia symptoms, anxiety symptoms and Body Mass Index successively. LIMITATIONS: Major Depressive Episode was not explored in follow-up. CONCLUSION: Cognitive-affective symptoms in subthreshold depression are at greater risk of illness deterioration. Future studies should endeavor to identify specific risk factors in different symptoms to forestall the transition from subthreshold to Major Depressive Disorder.

Lumateperone for the Treatment of Adults With Schizophrenia: a Systematic Review.

PURPOSE OF REVIEW: Lumateperone (LUM) is the U.S. Food and Drug Administration approved atypical antipsychotic agent for adults with schizophrenia (SCZ) and bipolar depression (for both bipolar I and bipolar II disorder as as monotherapy or as adjunctive treatment to lithium or valproate). LUM simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. The foregoing pleiotropic mechanism of action is predictive of therapeutic benefits across multiple domains of psychopathology in SCZ (i.e., positive, negative, cognitive, and prosocial symptoms). Herein, the overarching aim is to synthesize the extant literature reporting on the efficacy, safety, and tolerability of LUM in adults with SCZ. RECENT FINDINGS: Four clinical studies (i.e., three RCTs and one open-label trial) were included in this synthesis. Overall, LUM significantly reduced the severity of SCZ compared with placebo. The open label study provided the real-world effectiveness of shifting stable patients with SCZ to LUM from other atypical antipsychotics. With respect to safety and tolerability profile, LUM demonstrated placebo-level rates of weight gain, metabolic shift, prolactin elevation, extrapyramidal side effects (EPS), and akathisia across short term trials (i.e., 4-6 weeks). Taken together, our results indicate that LUM significantly improves symptoms severity in adults with SCZ. LUM also exhibits a favorable tolerability and safety profile with placebo level rates of weight gain, metabolic disruption, akathisia, extrapyramidal side effects (excluding akathisia), and prolactin elevation. Lumateperone should be conceptualized as a first-line treatment strategy for adults with SCZ.

Active mechanisms of ketamine-assisted psychotherapy: A systematic review.

BACKGROUND: Few studies have evaluated the efficacy of ketamine-assisted psychotherapy (KAP) in the treatment of treatment-resistant depression (TRD) and substance use disorders (SUD). METHODS: A systematic review of clinical trials reporting on the efficacy of KAP and discussing mechanisms of action, identified on PubMed and PsycInfo. RESULTS: Five randomized-controlled trials reported on the efficacy of KAP treatment and discussed active mechanisms. Four of the studies treated adults with SUD and a single study treated adults with TRD. Overall, KAP had a significant positive effect on primary outcome measures compared to controls, however, the data is mixed. The study examining KAP for TRD found no benefit. LIMITATIONS: Lack of large, replicated clinical trials. No studies actively examining mechanisms of action. CONCLUSION: Evidence suggests that temporary neural changes caused by ketamine such as n-methyl-d-aspartate receptor (NMDAR) inhibition and increase of synaptic neuroplasticity affect treatment outcomes of KAP. Based on reports of preliminary findings, we speculate that adjunct psychotherapy, changes in perspective, and spirituality may also play a role.

Evaluating cognitive function in unaffected relatives of individuals with bipolar disorders: A meta-analysis.

BACKGROUND: Available studies have evaluated cognition in the unaffected relatives of bipolar disorder patients; however, to our knowledge, there has been no quantitative analysis evaluating the foregoing association. Herein, this meta-analysis aims to provide a quantitative synthesis of the extant literature reporting on the association between performance in cognitive domains (i.e., executive function, attention, learning and memory or global cognition) amongst unaffected individuals of probands with bipolar disorders. METHODS: Online databases (i.e., PubMed, PsycINFO) and Google Scholar were searched from inception to 20 September 2021. Studies with unaffected, first-degree relatives of individuals with DSM-IV or DSM-5 defined bipolar disorders were included. The risk of bias was assessed using the ROBINS-1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively synthesized using Cohen's d effect sizes via a random-effects meta-analytic approach on JASP. RESULTS: A total of 15 studies were included in the final review. Overall, results indicate that cognitive performance across all domains is moderately impaired in unaffected relatives of individuals with bipolar disorders (d = 0.488). Sub-analysis suggests there is a higher level of impairment in executive functioning (d = 0.612). DISCUSSION: The identification of cognitive deficits in unaffected relatives of probands with bipolar disorders indicates that cognitive impairment is endophenotypic and a core disturbance in persons with bipolar disorders; future studies should endeavour to target cognition as a potential pre-emptive and prevention strategy of bipolar disorders.

A review of potential neuropathological changes associated with ketamine.

INTRODUCTION: Ketamine is an established intervention for treatment-resistant depression (TRD). However, long-term adverse effects with repeated doses remain insufficiently characterized. Although several animal models have shown N-methyl-D-aspartate glutamate receptor antagonists to produce various neuropathological reactions, attention surrounding the risk of brain lesions has been minimal. AREAS COVERED: The current review focuses on potential neuropathological changes associated with ketamine. Search terms included variations of ketamine, Olney lesions, tau hyperphosphorylation, and parvalbumin interneurons. EXPERT OPINION: Daily high-dose ketamine use in substance use disorder (SUD) populations was associated with clear neurotoxic effects, while no studies specifically evaluated effects of ketamine protocols used for TRD. It is difficult to discern effects directly attributable to ketamine due to methodological factors, such as comorbidities and dramatic differences in dose in SUD populations versus infrequent sub-anesthetic doses typically prescribed for TRD. Taken together, animal models and human ketamine SUD populations suggest potential neuropathology with chronic high-dose ketamine exposure exceeding those recommended for adults with TRD. It is unknown whether repeat sub-anesthetic dosing of ketamine in adults with TRD is associated with Olney lesions or other neuropathologies. In the interim, practitioners should be vigilant for this possibility recognizing that the condition itself is associated with neurodegenerative processes.

Sex differences in ketamine's therapeutic effects for mood disorders: A systematic review.

Replicated clinical trials have demonstrated rapid and robust antidepressant effects with ketamine in treatment resistant mood disorders. Sex (biological) and gender differences in therapeutic effects for any new intervention is an important consideration, however, the differential efficacy, safety and tolerability of ketamine in males versus females remains underexplored. The objective of the present systematic review is to identify and qualitatively synthesize all published clinical studies relevant to the sex differential effects of ketamine for mood disorders. A systematic search of PubMed, Medline, and PsycInfo from inception until January 20, 2021, yielded 27 reports including 1715 patients (742 males and 973 females) that met inclusion criteria. Results from the vast majority of studies (88.8%) do not support significant sex differences in antidepressant response, tolerability or safety of ketamine. Nine (33.3%) of the reports included a bioanalytical component in the analysis and only one reported on sex differences. Evidence from the present review does not support clinically or statistically significant sex differences in therapeutic effects with ketamine. Nevertheless, future studies should continue to consider sex and biological sex differences in study design and data analytic plans.

The abuse liability of ketamine: A scoping review of preclinical and clinical studies.

While ketamine has been used clinically over the past decades, it has only been recently shown to be a promising therapy for treatment-resistant depression (TRD). However, ketamine and related dissociative agents may also be misused recreationally, creating significant concerns for abuse liability when prescribed for depression. Although the abuse potential of ketamine is widely recognized, there is limited evidence on the differential abuse liability of ketamine enantiomers, (S)-ketamine and (R)-ketamine. The current scoping review aims to summarize the extant literature on the abuse liability of (R,S)-ketamine and the enantiomers. A systematic search was conducted on the Embase, Medline, and APA PsycInfo databases from 1947 to July 29, 2021. Clinical and preclinical studies that assessed the abuse potential of (R,S)-ketamine, (S)-ketamine, and (R)-ketamine were screened and assessed for eligibility by two independent reviewers. A total of 65 eligible studies were identified; 55 were preclinical studies and 10 were clinical studies. Only 4 preclinical studies evaluated the abuse liability of ketamine enantiomers. Available preclinical evidence suggests that (R,S)-ketamine and (S)-ketamine have greater risk for abuse compared to (R)-ketamine. (R)-ketamine, at the antidepressant-relevant doses in rodents, appears to be safe with minimal liability for abuse. Although the abuse potential of (R,S)-ketamine is well-established in animals, limited clinical studies indicate that single or repeated ketamine administrations in professionally controlled settings did not result in misuse, dependence, diversion and/or gateway activity in patients with TRD. However, most clinical studies were retrospective and did not systematically evaluate the abuse liability of ketamine via validated psychological scales/questionnaires. Future randomized controlled trials are warranted to ascertain the abuse liability of racemic, (S)- and (R)-ketamine in TRD population, especially among patients with comorbid substance use disorders.

Screening Depressive Symptoms and Incident Major Depressive Disorder Among Chinese Community Residents Using a Mobile App-Based Integrated Mental Health Care Model: Cohort Study.

BACKGROUND: Depression is associated with significant morbidity and human capital costs globally. Early screening for depressive symptoms and timely depressive disorder case identification and intervention may improve health outcomes and cost-effectiveness among affected individuals. China's public and academic communities have reached a consensus on the need to improve access to early screening, diagnosis, and treatment of depression. OBJECTIVE: This study aims to estimate the screening prevalence and associated factors of subthreshold depressive symptoms among Chinese residents enrolled in the cohort study using a mobile app-based integrated mental health care model and investigate the 12-month incidence rate and related factors of major depressive disorder (MDD) among those with subthreshold depressive symptoms. METHODS: Data were drawn from the Depression Cohort in China (DCC) study. A total of 4243 community residents aged 18 to 64 years living in Nanshan district, Shenzhen city, in Guangdong province, China, were encouraged to participate in the DCC study when visiting the participating primary health care centers, and 4066 (95.83%) residents who met the DCC study criteria were screened for subthreshold depressive symptoms using the Patient Health Questionnaire-9 at baseline. Of the 4066 screened residents, 3168 (77.91%) with subthreshold depressive symptoms were referred to hospitals to receive a psychiatric diagnosis of MDD within 12 months. Sleep duration, anxiety symptoms, well-being, insomnia symptoms, and resilience were also investigated. The diagnosis of MDD was provided by trained psychiatrists using the Mini-International Neuropsychiatric Interview. Univariate and multivariate logistic regression models were performed to explore the potential factors related to subthreshold depressive symptoms at baseline, and Cox proportional hazards models were performed to explore the potential factors related to incident MDD. RESULTS: Anxiety symptoms (adjusted odds ratio [AOR] 1.63, 95% CI 1.42-1.87) and insomnia symptoms (AOR 1.13, 95% CI 1.05-1.22) were associated with an increased risk of subthreshold depressive symptoms, whereas well-being (AOR 0.93, 95% CI 0.87-0.99) was negatively associated with depressive symptoms. During the follow-up period, the 12-month incidence rate of MDD among participants with subthreshold depressive symptoms was 5.97% (189/3168). After incorporating all significant variables from the univariate analyses, the multivariate Cox proportional hazards model reported that a history of comorbidities (adjusted hazard ratio [AHR] 1.49, 95% CI 1.04-2.14) and anxiety symptoms (AHR 1.13, 95% CI 1.09-1.17) were independently associated with an increased risk of incident MDD. The 5-item World Health Organization Well-Being Index was associated with a decreased risk of incident MDD (AHR 0.90, 95% CI 0.86-0.94). CONCLUSIONS: Elevated anxiety symptoms and unfavorable general well-being were significantly associated with subthreshold depressive symptoms and incident MDD among Chinese residents in Shenzhen. Early screening for subthreshold depressive symptoms and related factors may be helpful for identifying populations at high risk of incident MDD.

The efficacy and safety of adjunctive intranasal esketamine treatment in major depressive disorder: a systematic review and meta-analysis.

INTRODUCTION: Intranasal (IN) esketamine represents an innovative treatment for individuals with treatment resistant depression and depression with suicidal ideation and behavior. Herein, we synthesize extant long-term studies (≥ 4 weeks) regarding this treatment. RESEARCH DESIGN AND METHODS: The interventional studies of IN esketamine in patients with depression having a study period of at least four weeks were included for our synthesis. A meta-analysis was undertaken for the efficacy and safety parameters of adjunctive IN esketamine vs IN placebo with an oral antidepressant. The data excluded from meta-analysis were synthesized narratively. RESULTS: After pooling data from seven randomized controlled trials, treatment with adjunctive IN esketamine vs IN placebo was safe overall, and more effective at decreasing depressive symptoms (d = -0.239; 95%CI = -0.335,-0.142;p < 0.0001), with higher response (RR = 1.221; 95% CI = 1.055,1.428; p = 0.017) and remission (RR = 1.366; 95% CI = 1.182,1.578; p < 0.0001) rates. The year-long trials showed that treatment with adjunctive IN esketamine led to lower relapse rates with no considerable long-term side effects. CONCLUSION: Intranasal esketamine was demonstrated to be safe, well tolerated, and rapidly effective in individuals with treatment resistant depression, suicidal ideation, and suicidal behavior.