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.

Effects of cannabidiol and Δ9-tetrahydrocannabinol on cytochrome P450 enzymes: a systematic review.

Due to legal, political, and cultural changes, the use of cannabis has rapidly increased in recent years. Research has demonstrated that the cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) inhibit and induce cytochrome P450 (CYP450) enzymes. The objective of this review is to evaluate the effect of CBD and THC on the activity of CYP450 enzymes and the implications for drug-drug interactions (DDIs) with psychotropic agents that are CYP substrates. A systematic search was conducted using PubMed, Scopus, Scientific Electronic Library Online (SciELO) and PsychINFO. Search terms included 'cannabidiol', 'tetrahydrocannabinol', and 'cytochrome P450'. A total of seven studies evaluating the interaction of THC and CBD with CYP450 enzymes and psychotropic drugs were included. Both preclinical and clinical studies were included. Results from the included studies indicate that both CBD and THC inhibit several CYP450 enzymes including, but not limited to, CYP1A2, CYP3C19, and CYP2B6. While there are a few known CYP450 enzymes that are induced by THC and CBD, the induction of CYP450 enzymes is an understudied area of research and lacks clinical data. The inhibitory effects observed by CBD and THC on CYP450 enzymes vary in magnitude and may decrease the metabolism of psychotropic agents, cause changes in plasma levels of psychotropic medications, and increase adverse effects. Our findings clearly present interactions between THC and CBD and several CYP450 enzymes, providing clinicians evidence of a high risk of DDIs for patients who consume both cannabis and psychotropic medication. However, more clinical research is necessary before results are applied to clinical settings.

Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (ß - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (ß - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Recent Advances in the Treatment of Treatment-Resistant Depression: A Narrative Review of Literature Published from 2018 to 2023.

PURPOSE OF REVIEW: We review recent advances in the treatment of treatment-resistant depression (TRD), a disorder with very limited treatment options until recently. We examine advances in psychotherapeutic, psychopharmacologic, and interventional psychiatry approaches to treatment of TRD. We also highlight various definitions of TRD in recent scientific literature. RECENT FINDINGS: Recent evidence suggests some forms of psychotherapy can be effective as adjunctive treatments for TRD, but not as monotherapies alone. Little recent evidence supports the use of adjunctive non-antidepressant pharmacotherapies such as buprenorphine and antipsychotics for the treatment of TRD; side effects and increased medication discontinuation rates may outweigh the benefits of these adjunctive pharmacotherapies. Finally, a wealth of recent evidence supports the use of interventional approaches such as electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation for TRD. Recent advances in our understanding of how to treat TRD have largely expanded our knowledge of best practices in, and efficacy of, interventional psychiatric approaches. Recent research has used a variety of TRD definitions for study inclusion criteria; research on TRD should adhere to inclusion criteria based on internationally defined guidelines for more meaningfully generalizable results.

Impact of vortioxetine on psychosocial functioning moderated by symptoms of fatigue in post-COVID-19 condition: a secondary analysis.

INTRODUCTION: Fatigue is a prominent symptom in post-COVID condition (PCC) sequelae, termed "long COVID." Herein, we aim to ascertain the effect of fatigue on psychosocial function in persons living with PCC. METHODS: This post hoc analysis evaluated the effects of vortioxetine on measures of fatigue as assessed by the Fatigue Severity Scale (FSS) in psychosocial function as measured by the Sheehan Disability Scale (SDS) in persons with PCC. We also evaluated the change in FSS on psychosocial functioning as measured by the Sheehan Disability Scale (SDS). This post hoc analysis obtained data from a recently published placebo-controlled study evaluating vortioxetine's effect on objective cognitive functions in persons living with PCC. RESULTS: One hundred forty-four participants meeting World Health Organization (WHO) criteria for PCC were included in this analysis. At the end of 8 weeks of vortioxetine treatment, significant improvement of all domains was observed for psychosocial functioning. There was a significant between-group difference at treatment endpoint in the family, social, and work SDS subcategories (p < 0.001). There was a statistically significant interaction effect between the treatment condition time point and FSS effect on the SDS social (χ2 = 10.640, p = 0.014) and work (χ2 = 9.342, p = 0.025) categories but a statistically insignificant effect on the family categories ((χ2 = 5.201, p = 0.158)). DISCUSSION: This post hoc analysis suggests that vortioxetine treatment significantly improves psychosocial function in persons with PCC. Our results also indicate that the improvement in psychosocial function was significantly mediated by improvement in measures of fatigue. Our results provide empirical support for recommendations to identify therapeutics for fatigue in persons living with PCC with a broader aim to improve psychosocial function in this common and severely impaired population.

Impacts of metabolic disruption, body mass index and inflammation on cognitive function in post-COVID-19 condition: a randomized controlled trial on vortioxetine.

BACKGROUND: Post-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI. METHODS: This is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint. RESULTS: Our findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047). CONCLUSION: Overall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo. TRIAL REGISTRATION: NCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021).

Impact of elevated body mass index (BMI) on cognitive functioning and inflammation in persons with post-COVID-19 condition: a secondary analysis.

BACKGROUND: Individuals who have recovered from the acute stage of SARS-CoV-2 infection may be at risk of developing post-COVID-19 condition (PCC), characterised by a spectrum of persisting, non-specific, and functionally impairing symptoms across multiple organ systems. Obesity has been implicated as a risk factor for PCC, mediated by chronic systemic inflammation. The foregoing has also been separately reported to mediate cognitive dysfunction in PCC. METHODS: This is a post-hoc analysis of a randomised, double-blinded, placebo-controlled clinical trial evaluating vortioxetine treatment for cognitive impairments in persons with PCC who received vortioxetine or placebo for eight weeks. This analysis comprises baseline data, examining the impact of BMI on cognitive functioning measured by the Digit Symbol Substitution Test (DSST) and Trails Making Tests (TMT)-A/B, as well as inflammation, via serum c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: Complete data from 70 participants were statistically analysed and adjusted for age and sex. BMI was negatively correlated with performance on the DSST (ß = -0.003, p = 0.047), TMT-A (ß = -0.006, p = 0.025), and TMT-B (ß = -0.006, p = 0.002). BMI was positively correlated with serum CRP (unstandardized ß = 0.193, standardized ß = 0.612, p < 0.001) and ESR (ß = 0.039, p < 0.001) levels. CONCLUSION: We observed a significant negative correlation between BMI and cognitive functioning, and a significant positive correlation between BMI and inflammation in persons with PCC, suggesting a bidirectional interplay between BMI, PCC, and cognitive function; individuals with an elevated BMI may be at a greater risk of developing PCC and/or presenting with greater cognitive deficits mediated by chronic systemic inflammation.

Childhood maltreatment and subsequent depressive symptoms: a prospective study of the sequential mediating role of self-esteem and internalizing/externalizing problems.

BACKGROUND: Depression among adolescents is a seriously disabling public health problem with an extremely high prevalence. Identifying risk factors of depression at an early stage is important to reduce the disease burden. Childhood maltreatment (CM) is one of the major risk factors for depression. The key mediating processes that how CM affects the development of depression, however, still need further clarification. The present study tested the mediating effect of self-esteem, internalizing problems, and externalizing problems between CM and depressive symptoms. Potential sex differences in the foregoing associations were also explored. METHODS: A three-wave longitudinal study was carried out among 1,957 middle and high school students from 69 classes in 10 public schools in the Guangdong province of China. Data collection started when students were in grades 7 and 10 (median age: 13.0, range: 11-18) between January and April 2019, and the students were followed up once a year thereafter. Self-reported CM, depressive symptoms, self-esteem, internalizing and externalizing problems, and other demographics were collected. The multiple serial mediation analysis was conducted. RESULTS: We found that CM was positively related to subsequent internalizing and externalizing problems, as well as depressive symptoms, while self-esteem was negatively related to depressive symptoms. Serial mediation analysis indicated that self-esteem (mediator 1) and internalizing problems (mediator 2) sequentially mediated the path from CM to depressive symptoms in the overall and male population. Moreover, with externalizing problems as mediator 2, self-esteem (mediator 1) acted as a partial mediator in the association between CM and depressive symptoms in males, whereas externalizing problems played a complete mediating role in females. CONCLUSION: Findings revealed that self-esteem and internalizing problems sequentially mediated the influence of CM on depressive symptoms whereas externalizing problems played an independent mediating role. In addition, sex differences need to be taken into consideration when designing prevention and intervention strategies, given the different psychosocial processes between boys and girls.

The Effect of Internet-Based Cognitive Behavioral Therapy on Major Depressive Disorder: Randomized Controlled Trial.

BACKGROUND: Many people living with major depressive disorder (MDD) in China do not receive treatment owing to a lack of mental health services, along with significant stigma toward mental illness. Internet-based cognitive behavioral therapy (ICBT) has been proposed to increase access to mental health care for people with MDD. OBJECTIVE: The aims of this study were to (1) evaluate the efficacy of ICBT for depressive symptoms in patients with MDD; (2) evaluate the effect of ICBT on anxiety symptoms, nonspecific psychological distress, general self-efficacy, depression stigma, social function, and health-related quality of life (HRQoL); and (3) explore the acceptability of and satisfaction with the ICBT program among participants. METHODS: Patients with MDD were enrolled and randomized to the ICBT group or the waiting-list control (WLC) group. The ICBT group received ICBT delivered through a WeChat mini-program with general support by nonspecialists. Participants in the 2 groups were self-evaluated online at baseline and posttreatment for changes in the primary outcome (ie, depressive symptoms) and secondary outcomes (ie, anxiety symptoms, nonspecific psychological distress, general self-efficacy, depression stigma, social functional impairment, and HRQoL). Changes in outcomes were measured by changes in overall scores on respective scales, and response and remission rates were calculated based on depressive symptoms. The acceptability of and satisfaction with the ICBT program were measured by treatment adherence and participants' feelings (ie, modules seriously completed, perceived benefit, and satisfaction). RESULTS: We included 40 patients who were randomly assigned to the ICBT group and 44 who were assigned to the WLC group. Compared with the WLC group, the ICBT group had fewer depressive symptoms, fewer anxiety symptoms, less nonspecific psychological distress, and greater general self-efficacy. Moreover, the ICBT group had higher response (18/31, 58%) and remission rates (17/31, 55%). The adherence rate in the ICBT group was 78% (31/40), and the majority of participants who completed all ICBT modules were satisfied with the ICBT program. CONCLUSIONS: ICBT demonstrated greater improvements in depressive symptoms, anxiety symptoms, nonspecific psychological distress, and general self-efficacy among selected patients with MDD in comparison with the findings in waiting-list controls. The ICBT program in this study had good acceptability and satisfaction among participants. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100046425); https://tinyurl.com/bdcrj4zv.

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis.

IMPORTANCE: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. OBJECTIVE: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome. DATA SOURCES: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists. STUDY SELECTION: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected. DATA EXTRACTION & SYNTHESIS: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model. MAIN OUTCOMES & MEASURES: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome. RESULTS: The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2 = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2 = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals. CONCLUSIONS & RELEVANCE: A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena. STUDY REGISTRATION: PROSPERO (CRD42021256965).

Deficits of social cognition in bipolar disorder: Systematic review and meta-analysis.

BACKGROUND: The association between impaired social cognition and bipolar disorder (BD) is well established. However, to our knowledge, there has not been a recent systematic review that characterizes disparate dimensions of social cognition in BD. Herein, this systematic review and meta-analysis aimed to synthesize the literature on core aspects of social cognition (i.e., Theory of Mind, emotion recognition, and social judgment) to identify potential areas of impairment. METHODS: Online databases (i.e., PubMed, Cochrane Libraries, PsycINFO) and Google Scholar were searched from inception to May 2021. Studies with populations ages ≥16 with DSM-IV or DSM-5 defined BD (I or II) either in a euthymic or symptomatic state were included. The risk of bias was measured using the ROBINS-1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively measured by synthesizing Hedge's g effect sizes through a random effects meta-analytic approach. RESULTS: A total of 29 studies were included in the final review (i.e., 12 studies on the Theory of Mind, 11 on emotion recognition, and 6 on social judgment). Overall, results demonstrated social cognition to be moderately impaired in individuals with BD (d = 0.59). The individual domains ranged in effect size (0.38 < d < 0.70), providing evidence for variation in impairment within social cognition. DISCUSSION: Individuals with BD exhibit clinically significant deficits in social cognition during euthymic and symptomatic states. Social cognition impairments in individuals with BD are an important therapeutic target for treatment discovery and development.

Do sleep changes mediate the anti-depressive and anti-suicidal response of intravenous ketamine in treatment-resistant depression?

Sleep disturbances are commonly reported in patients with treatment-resistant depression (TRD). Available data have shown that intravenous (IV) ketamine is an effective treatment for patients with TRD and growing data suggest ketamine may improve overall sleep architecture. In the present study, we evaluated whether changes in sleep symptoms mediated the anti-depressive and/or anti-suicidal effects of IV ketamine and whether improvement in sleep correlated with a higher likelihood of achieving response or remission. Adults with TRD received four infusions of IV ketamine at a community-based clinic. Total depressive symptom severity was measured with the Quick Inventory Depressive Symptoms Self-Report 16-Item (QIDS-SR16 ) at baseline and was repeated across four infusions. Suicidal ideation (SI) and four sleep symptoms were measured using the SI item and the five sleep items on the QIDS-SR16 . A total of 323 patients with TRD received IV ketamine. Self-reported improvements in insomnia, night-time restlessness, hypersomnia, early morning waking, and total sleep were significant partial mediators to the improvements observed in depression severity. Similarly, insomnia, night-time restlessness, early morning waking and total sleep improvements mediated the reduction of IV ketamine on SI. All sleep items, except for hypersomnia, were associated with an increased likelihood of achieving response or remission. Notably, each point improvement in total sleep score was significantly associated with achieving responder/remitter status (odds ratio 3.29, 95% confidence interval 2.00-5.41). Insomnia, sleep restlessness, early morning waking and total sleep improvements were significant mediators of antidepressant and anti-suicidal improvements in patients with TRD receiving IV ketamine.

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.

The association of FKBP5 gene methylation, adolescents' sex, and depressive symptoms among Chinese adolescents: a nested case-control study.

BACKGROUND: Depressive symptoms among adolescents are a serious health concern around the world. Altered DNA methylation in the FK506 binding protein 5 (FKBP5) gene has been reported to regulate stress response, which has been reported to be closely associated with depressive symptoms. However, most of the contributing studies have been conducted among adults and relatively few studies have considered the effect of disparate social influences and sex differences on the DNA methylation of FKBP5 in persons with depressive symptoms. The present study aimed to test the associations of FKBP5 DNA methylation and depressive symptoms among adolescents and explore possible sex differences in the foregoing associations. METHODS: This study was conducted using a nested case-control design within a longitudinal cohort study from January 2019 to December 2019. Adolescents aged 12 to 17 years from 69 classes in 10 public high schools located in Guangdong province of China participated in this research. Students with persistent depressive symptoms that reported having depressive symptoms at both baseline and follow-up were treated as the case group, and those without depressive symptoms were randomly selected as the control group. Our study finally included 87 cases and 151 controls. Quantitative methylation analyses of the selected gene were carried out by MassARRAY platform System. RESULTS: The overall DNA methylation trend of FKBP5 CpG sites in the case group was lower in comparison to the control group. Compared to healthy controls, lower methylation percentage of FKBP5-12 CpG 1 was observed in adolescents with persistent depressive symptoms after adjusting for covariates (case: 0.94 ± 2.00, control: 0.47 ± 0.92; F = 5.41, P = 0.021), although the statistical significance of the difference was lost after false discovery rate correction (q > 0.05). In addition, the hypomethylation of FKBP5-12 CpG 1 was approaching significance after adjustment for social-environmental factors (aOR = 0.77; P = 0.055), which indicated that no independent association was detected between hypomethylation of FKBP5 CpG sites and persistent depressive symptoms. Furthermore, in the present study, we were unable to identify sex differences in the association of FKBP5 gene methylation with depressive symptoms. CONCLUSION: The decreased methylation level of FKBP5 was observed in adolescents with persistent depressive symptoms, albeit non-significant after correction for multiple testing. Our results presented here are preliminary and underscore the complex gene-environment interactions relevant to the risk for depressive symptoms.

Association between childhood trauma and medication adherence among patients with major depressive disorder: the moderating role of resilience.

BACKGROUND: Suboptimal medication adherence is a major reason for failure in the management of major depressive disorder (MDD), childhood trauma might be an essential risk factor of suboptimal medication adherence. This study aimed to comprehensively explore the associations between different types of childhood trauma and medication adherence among patients with MDD, and to test whether resilience has moderating effects on the foregoing associations. METHODS: Participants were from the Depression Cohort in China (ChiCTR registry number 1900022145), 282 MDD patients with completed both baseline and 12-weeks follow-up investigations were included in this study. The diagnosis of MDD was assessed by trained psychiatrists using the Mini-International Neuropsychiatric Interview (M.I.N.I.). Childhood trauma was evaluated using the Childhood Trauma Questionnaire-28 item Short Form (CTQ-SF), and resilience was evaluated using the Connor-Davidson Resilience Scale (CD-RISC). Demographic characteristics, depression symptoms, anxiety symptoms, suicidal ideation, suicidal attempt, insomnia symptoms, and painful somatic symptoms were also investigated. Participants were divided into groups of optimal and suboptimal adherence based on their Medication Adherence Rating Scale scores. Logistic regression and stratified analyses were performed. RESULTS: A total of 234 participants (83%) reported suboptimal medication adherence. After adjusting for covariates, CTQ total scores (AOR = 1.03, 95%CI = 1.01-1.06), CTQ measures of sexual abuse (AOR = 1.17, 95%CI = 1.01-1.37), and CTQ measures of physical neglect (AOR = 1.12, 95%CI = 1.02-1.23) were all associated with an increased likelihood of suboptimal adherence. There were significant moderating effects of resilience on the associations of childhood trauma (P = 0.039) and physical neglect (P = 0.034) with medication adherence. The stratification analyses showed that CTQ total scores and CTQ measures of physical neglect were independently associated with an increased risk of suboptimal adherence among patients with MDD with low-resilience or moderate-resilience, while not significantly associated with suboptimal adherence in those with high-resilience. CONCLUSION: Childhood trauma was a significant risk factor of suboptimal adherence among patients with MDD, and resilience moderated the foregoing association. Obtaining a history of childhood trauma and assessing resilience may help identify patients with suboptimal adherence when providing MDD pharmacotherapy. Psychiatrists may consider enhancing resilience to cope with the adverse effects of childhood trauma on medication adherence.

Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials.

INTRODUCTION: The large percentage of adults with major depressive disorder (MDD) insufficiently responding and/or tolerating conventional monoamine-based antidepressants invites the need for mechanistically novel treatments. Convergent evidence implicates glutamatergic signaling as a potential therapeutic target in MDD. AREAS COVERED: The synthesis herein of preclinical and clinical studies indicates that dextromethorphan (DXM) is well tolerated and exhibits clinically significant antidepressant effects; DXM combined with bupropion has demonstrated replicated and relatively rapid onset efficacy in adults with MDD. DXM efficacy has been preliminarily reported in adults with bipolar depression. The combination of DXM and bupropion represents a pharmacokinetic and pharmacodynamic synergy which may account for the rapidity of action in MDD. EXPERT OPINION: The combination of DXM and bupropion is a safe, well tolerated and efficacious treatment option in adults with MDD. Priority questions are whether DXM/bupropion is uniquely effective across discrete domains of psychopathology (e.g. anhedonia, reward processing, general cognitive systems) and/or whether it is able to significantly improve patient-reported outcomes (e.g. quality of life, psychosocial functioning). The availability of ketamine/esketamine and DXM/bupropion instantiates the relevance of glutamate as a treatment target in MDD. Studies in bipolar depression with DXM/bupropion are warranted as well as in MDD with suicidality.

Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series.

OBJECTIVE: To evaluate the safety, tolerability, and effectiveness of repeated doses of intravenous (IV) ketamine in older adults (i.e., ≥60 years of age) with treatment-resistant depression. METHOD: In this case series, fifty-three older adults (Mage = 67, SD = 6; 57% female [n = 30]) received 4 IV ketamine infusions, administered over 1-2 weeks. Effectiveness of IV ketamine was measured using the Quick Inventory for Depressive Symptomatology-Self Report 16 (QIDS-SR16) approximately 2 days after infusions 1-3, and 1-2 weeks after infusion 4. Safety was measured as hemodynamic changes before, during, immediately after, and 20 minutes after each infusion. Tolerability was assessed via systematic reporting of treatment-emergent adverse events during and after each infusion, in addition to symptoms of dissociation measured using the Clinician Administered Dissociative States Scale. Partial response (25%-50% symptomatic improvement from baseline), response (≥50% symptomatic improvement from baseline), clinically significant improvements (≥25% symptomatic improvement from baseline), and remission rates (QIDS-SR16 ≤5) were also calculated. RESULTS: Participants reported significant decreases in depressive symptoms (i.e., as measured by the QIDS-SR16) with repeated ketamine infusions (F(4, 92) = 7.412, p <0.001). The mean QIDS-SR16 score was 17.12 (SD = 5.33) at baseline and decreased to 12.52 (SD = 5.79) following 4 infusions. After 4 infusions, 31% (n = 8) of participants partially responded to IV ketamine, 27% (n = 7) responded, 58% (n = 15) experienced clinically significant improvements, and 10% (n = 3) met remission criteria. Thirty-six participants (69%) experienced treatment-emergent hypertension during at least 1 infusion, and 10 (19%) required intervention with an antihypertensive. Drowsiness was the most commonly reported adverse event (50% of infusions; n = 73). CONCLUSION: Ketamine was associated with transient treatment-emergent hypertension. Response and remission rates were comparable to those reported in general adult samples. Findings are limited by the open-label, chart review nature of this study.

Comparative Efficacy of Omega-3 Fatty Acid with Other Interventions for Depression in Children and Adolescents: A Systematic Review and Network Meta-Analysis.

Background: The administration of omega-3 polyunsaturated fatty acid supplements is recommended as an adjuvant therapy for adults diagnosed with major depressive disorder. The evaluation of replicated data in combination treatment with omega-3 has been extensively conducted in adults over the past decade. However, the generalizability of these findings to pediatric groups is still uncertain. The objectives of this evaluation were twofold: (1) to evaluate the effectiveness of omega-3 and associated combination therapies in reducing the severity of depressive symptoms, and (2) to include remission rates (i.e., reduction of more than 50% in depression symptoms) as a measure of therapeutic efficacy. Methods: We conducted a literature search on PubMed/EMBASE from inception to October 2023. Data analyses were conducted using Stata (version 17.0). Results: We identified a total of 3168 articles. After eligibility screening of identified studies, nine studies (n = 561 participants) were included in our analysis herein. Pairwise comparisons revealed no significant improvement in depression symptoms for any intervention versus placebo. However, a clustered ranking plot identified omega-3 plus inositol as the most effective treatment for pediatric depression (77.3% efficacy). Omega-3 paired with psychoeducational psychotherapy significantly lowered the remission rate compared to placebo (standardized mean difference = 0.44, 95% confidence interval: 0.00-0.87, p = 0.048), resulting in a 91.5% remission rate, making it the most effective treatment in the study. Conclusions: Taken together, this network meta-analysis presents compelling evidence supporting the antidepressant effects of omega-3 in pediatric groups with depression. Future research should aim to investigate omega-3 as monotherapy for young individuals with depression, as well as investigate the efficacy of omega-3 in comparison to psychosocial interventions for affected individuals.

Psychotropic Drug-Related Weight Gain and Its Treatment.

Psychotropic drug-related weight gain (PDWG) is a common occurrence and is highly associated with non-initiation, discontinuation, and dissatisfaction with psychiatric drugs. Moreover, PDWG intersects with the elevated risk for obesity and associated morbidity that has been amply reported in the psychiatric population. Evidence indicates that differential liability for PDWG exists for antipsychotics, antidepressants, and anticonvulsants. During the past two decades, agents within these classes have become available with significantly lower or no liability for PDWG and as such should be prioritized. Although lithium is associated with weight gain, the overall extent of weight gain is significantly lower than previously estimated. The benefit of lifestyle and behavioral modification for obesity and/or PDWG in psychiatric populations is established, with effectiveness similar to that in the general population. Metformin is the most studied pharmacological treatment in the prevention and treatment of PDWG, and promising data are emerging for glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide, exenatide, semaglutide). Most pharmacologic antidotes for PDWG are supported with low-confidence data (e.g., topiramate, histamine-2 receptor antagonists). Future vistas for pharmacologic treatment for PDWG include large, adequately controlled studies with GLP-1 receptor agonists and possibly GLP-1/glucose-dependent insulinotropic polypeptide co-agonists (e.g., tirzepatide) as well as specific dietary modifications.

The association between ketamine and esketamine with alcohol and substance misuse: Reports to the Food and Drug Administration adverse event reporting system (FAERS).

INTRODUCTION: Ketamine and esketamine have been proven to be effective in treating adults with treatment resistant depression (TRD). Preliminary evidence indicates that, when combined with behavioral and psychological interventions, both agents may offer benefits for individuals with substance use disorder (SUD) and alcohol use disorder (AUD). Notwithstanding, concerns have been raised as to whether either or both agents are associated with abuse and/or gateway activity. METHODS: Herein, we evaluate disproportionate reporting expressed as reporting odds ratios (ROR) for esketamine and ketamine. The outcomes of interest include alcohol problem, alcoholism, alcohol abuse, substance dependence, SUD, substance abuse, drug dependence, drug use disorder and drug abuse as codified by the Medical Dictionary for Regulatory Activities (MedDRA) within the FAERS. The IC025 values were significant for ketamine in cases of alcohol abuse (0.28), substance dependence (1.88), substance use disorder (0.996), substance abuse (0.61), drug dependence (0.56), drug use disorder (1.17) and drug abuse (1.22). Additionally, oxycontin showed significant IC025 values for substance dependence (0.067), substance use disorder (0.094), substance abuse (0.035), and drug dependence (0.27). RESULTS: We observed significant increases in the reporting odds ratios (RORs) for ketamine with respect to various outcomes: alcohol abuse (ROR 2.84, 95 % CI 1.53-5.28; p = 0.0010), substance dependence (ROR 18.72, 95 % CI 8.49-41.30; p ≤ 0.0001), SUD (ROR 11.40, 95 % CI 4.24-30.65; p ≤ 0.0001), substance abuse (ROR 2.29, 95 % CI 1.73-3.04; p ≤ 0.0001), drug dependence (ROR 1.99, 95 % CI 1.64-2.42; p ≤ 0.0001), drug use disorder (ROR 4.50, 2.94-6.88; p ≤ 0.0001) and drug abuse (ROR 3.72, 3.36-4.12; p ≤ 0.0001). For esketamine, we observed that the ROR was significantly reduced for substance abuse (ROR 0.37, 95 % CI 0.22-0.63; p = 0.0003), drug dependence (ROR 0.13, 95 % CI 0.076-0.23; p ≤ 0.0001) and drug abuse (ROR 0.048, 95 % CI 0.030-0.078; p ≤ 0.0001). To our knowledge, this is the first report of spontaneous adverse events related to these outcomes of interest in the FAERS. CONCLUSION: Mixed RORs were observed across aspects of SUD and AUD for both ketamine and esketamine. Due to limitations in the FAERS, establishing causal links between new onset alcohol and substance misuse with either agent remains inconclusive. Possible beneficial effects on measures of SUD and AUD were observed. It is currently unclear, but possible, whether both agents have differential ameliorative effects across dimensions of SUD and AUD, which is a focus of ongoing research.