Programmed cell death factor 4-mediated hippocampal synaptic plasticity is involved in early life stress and susceptibility to depression.

Early life stress (ELS) increases the risk of depression later in life. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases. However, its involvement in a person's susceptibility to ELS-related depression is unknown. To examine the effects and underlying mechanisms of PDCD4 on ELS vulnerability, we used a "two-hit" stress mouse model: an intraperitoneal injection of lipopolysaccharide (LPS) into neonatal mice was performed on postnatal days 7-9 (P7-P9) and inescapable foot shock (IFS) administration in adolescent was used as a later-life challenge. Our study shows that compared with mice that were only exposed to the LPS or IFS, the "two-hit" stress mice developed more severe depression/anxiety-like behaviors and social disability. We detected the levels of PDCD4 in the hippocampus of adolescent mice and found that they were significantly increased in "two-hit" stress mice. The results of immunohistochemical staining and Sholl analysis showed that the number of microglia in the hippocampus of "two-hit" stress mice significantly increased, with morphological changes, shortened branches, and decreased numbers. However, knocking down PDCD4 can prevent the number and morphological changes of microglia induced by ELS. In addition, we confirmed through the Golgi staining and immunohistochemical staining results that knocking down PDCD4 can ameliorate ELS-induced synaptic plasticity damage. Mechanically, the knockdown of PDCD4 exerts neuroprotective effects, possibly via the mediation of BDNF/AKT/CREB signaling. Combined, these results suggest that PDCD4 may play an important role in the ELS-induced susceptibility to depression and, thus, may become a therapeutic target for depressive disorders.

Risk of VMAT2 inhibitors on suicidality and parkinsonism: report utilizing the United States Food and Drug Administration adverse event reporting system.

Prescription of vesicular monoamine transporter 2 (VMAT2) inhibitors, valbenazine, deutetrabenazine, and tetrabenazine, is becoming increasingly common in persons treated with antipsychotics. Reported suicidality and parkinsonism are safety concerns with VMAT2 inhibitors. Herein, we aim to evaluate the aforementioned safety outcomes using the FDA Adverse Event Reporting System. Reporting odds ratios (RORs) and lower limits of 95% confidence intervals of information components (IC025) were calculated to quantify VMAT2 inhibitor-associated adverse events. Acetaminophen was the reference agent. Suicidal ideation was significantly associated with VMAT2 inhibitors, with RORs ranging from 2.38 to 10.67 and IC025 ranging from 0.73 to 2.39. Increased odds of suicidal behavior was observed with tetrabenazine (ROR 3.011, IC025 0.0087), but not deutetrabenazine or valbenazine. Decreased odds of suicide attempts and completed suicide were observed with VMAT2 inhibitors, with RORs ranging from 0.011 to 0.10 (all IC025 < 0). Increased odds of parkinsonism were reported for all VMAT2 inhibitors, with RORs and IC025 ranging from 19.49 to 25.37 and 1.66 to 2.93, respectively. The mixed results with VMAT2 inhibitor-associated suicidality and parkinsonism do not establish causal relationships. The parameters of suicidality may be explained by underlying psychiatric disorders.

Number needed to treat (NNT) for ketamine and esketamine in adults with treatment-resistant depression: A systematic review and meta-analysis.

BACKGROUND: Ketamine has been established as efficacious in adults living with Treatment-resistant Depression (TRD). Toward providing a quantifiable estimate of the clinical meaningfulness of the therapeutic benefit of ketamine, herein, we conduct a systematic review that aims to report the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH). METHODS: This systematic review searched Embase, Medline/Pubmed, PsycINFO and ClinicalTrials.gov from inception up to October 15th 2023, for placebo-controlled, Randomized Controlled Trials (RCTs) assessing racemic ketamine or esketamine therapy for unipolar TRD. We calculated NNT and NNH for ketamine treatments over various time points. RESULTS: A total of 21 studies with 2042 participants were included. Racemic ketamine treatments had pooled NNTs for response of 7 at 4 h, 3 from one day to one week and 9 for studies at four weeks. Esketamine treatment was found to have a similar efficacy with an NNT of 2 at one day and 11 at four weeks. NNH values indicated low risk for ketamine treatments. LIMITATIONS: Limitations in the data used include the possibility of functional unblinding and selective reporting bias. Moreover, the meta-analysis may have been limited in its precision by including low threshold definitions of treatment resistance (≥ 1 failed antidepressant) and low-dose ketamine treatments. CONCLUSION: Herein, we determined that the NNT for ketamine treatment in adults living with TRD across different intervals of observation was <10. We conclude that the NNTs observed herein are highly clinically meaningful in this difficult to treat disorder.

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.

Effects of anhedonia on health-related quality of life and functional outcomes in major depressive disorder: A systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous group of mood disorders. A prominent symptom domain is anhedonia narrowly defined as a loss of interest and ability to experience pleasure. Anhedonia is associated with depressive symptom severity, MDD prognosis, and suicidality. We perform a systematic review and meta-analysis of extant literature investigating the effects of anhedonia on health-related quality of life (HRQoL) and functional outcomes in persons with MDD. METHODS: A literature search was conducted on PubMed, OVID databases, and SCOPUS for published articles from inception to November 2023, reporting on anhedonia and patient-reported outcomes in persons with MDD. The reported correlation coefficients between anhedonia and self-reported measures of both HRQoL and functional outcomes were pooled using a random effects model. RESULTS: We identified 20 studies that investigated anhedonia with HRQoL and/or functional outcomes in MDD. Anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS) scores had a statistically significant correlation with patient-reported HRQoL (r = -0.41 [95 % CI = -0.60, -0.18]) and functional impairment (r = 0.39 [95 % CI = 0.22, 0.54]). LIMITATIONS: These preliminary results primarily investigate correlations with consummatory anhedonia and do not distinguish differences in anticipatory anhedonia, reward valuation or reward learning; therefore, these results require replication. CONCLUSIONS: Persons with MDD experiencing symptoms of anhedonia are more likely to have worse prognosis including physical, psychological, and social functioning deficits. Anhedonia serves as an important predictor and target for future therapeutic and preventative tools in persons with MDD.

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.

Evaluation of activities and instrumental activities of daily living and correlated factors of traumatic brain injury patients in Vietnam.

Traumatic brain injury (TBI) is among the leading causes of death in Vietnam. Survivors of TBI suffer from functional and cognitive deficits. Understanding that Activities of Daily Living (ADLs) and Instrumental Activities of Daily Living (IADLs) are crucial in measuring the treatment and health-related quality of life among patients with TBI. This study aims to evaluate ADLs and IADLs among the TBI population in Vietnam and determine the correlated factors to these two indices. A cross-sectional study was conducted on 212 patients with TBI in Vietnam from February to September 2020. ADLs and IADLs scales were applied. Depression, quality of sleep, and social support scales were used. Multivariate Tobit regression was adopted to identify factors associated with ADLs and IADLs. Patients who received first aid had higher ADLs scores than those who had not, by a statistical difference with a p value = 0.04. The mean ADLs score was 5.4 (SD = 1.4). The mean score of IADLs was 7.3 (SD = 1.7). Female patients (Mean = 7.6, SD = 1.1) performed better in IADLs than male patients (Mean = 7.1, SD = 1.9). Both ADLs and IADLs were affected strongly by depression and Injury Severity scores (p < 0.01), whereas IADLs were significantly correlated to caregiver types and quality of sleep (p < 0.01). Family support was observed as a negatively correlated factor to IADLs. Findings from the study provided evidence for authorities to adjust the health strategies among patients with TBI. Proper prehospital care, a basic low-cost hospital care model, and mental health counseling services should be considered when developing health interventions in Vietnam.

Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review.

BACKGROUND: Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS: We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS: Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS: The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS: Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.

Subjective and Objective Measures of Cognitive Function are Correlated in Persons with Post-COVID-19 Condition: A Secondary Analysis of a Randomized Controlled Trial.

Background: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications. Methods: This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively. Results: A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, N combinedDSST ), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (ß = -0.003, p = 0.002) and TMT-B (ß = 0.003, p = 0.008) scores, but not with TMT-A scores (ß = -0.001, p = 0.751). Conclusions: Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

Greater Role of Cognitive Impairment Over Fatigue in Post-COVID-19 Quality of Life: A Post-Hoc Analysis of a Randomized Controlled Trial.

Background: Post COVID-19 Condition (PCC) is a common and debilitating condition with significant reports of fatigue and psychosocial impairment globally. The extent to which cognitive symptoms and fatigue contribute to reduced quality of life in affected individuals remains clear. Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial that evaluated the effect of vortioxetine on cognitive function in adults with PCC. The post-hoc analysis herein aimed to determine the overall effect of baseline cognitive function [as measured by the Digit Symbol Substitution Test (DSST)] and baseline fatigue severity [as measured by the Fatigue Severity Scale (FSS)] on baseline health-related quality of life (HRQoL) [as measured by the 5-item World Health Organisation Well-Being Index (WHO-5)]. Results: A total of 200 participants were enrolled in the primary trial. Due to missing baseline data, our statistical analysis included baseline measures of 147 individuals. Our generalized linear model analysis revealed a significant positive correlation between DSST-measured objective cognitive function and self-reported WHO-5-measured HRQoL (ß = 0.069, 95% CI [0.006, 0.131], p = 0.032). In contrast, our analysis revealed a significant negative correlation between FSS and WHO-5 scores (ß = -0.016, 95% CI [-0.021, -0.011], p < 0.001). The beta-coefficient ratio (ß DSST / ß FSS = 0.069 / 0.016) is calculated as 4.313. Conclusions: Overall, we observed that increased cognitive function was associated with increased HRQoL at baseline in adults with PCC. Moreover, we observed that increased severity of fatigue symptoms was associated with decreased HRQoL at baseline in adults with PCC. Furthermore, we observed that an improvement in cognitive function would have a four-fold greater impact on HRQoL than the effect generated by improvement in fatigue.

Risk factors and cognitive correlates of white matter hyperintensities in ethnically diverse populations without dementia: The COSMIC consortium.

INTRODUCTION: White matter hyperintensities (WMHs) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well documented in populations of different ethnicities and/or from different geographical regions. METHODS: We investigated how WMHs were associated with vascular risk factors and cognition in both Whites and Asians, using data from five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N = 1946). WMH volumes (whole brain, periventricular, and deep) were quantified with UBO Detector and harmonized using the ComBat model. We also harmonized various vascular risk factors and scores for global cognition and individual cognitive domains. RESULTS: Factors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake, and insufficient physical activity. Hypertension and stroke had stronger associations with WMH volumes in Whites than in Asians. No associations between WMH volumes and cognitive performance were found after correction for multiple testing. CONCLUSION: The current study highlights ethnic differences in the contributions of vascular risk factors to WMHs.

Assessing the Effects of Metabolic Disruption, Body Mass Index and Inflammation on Depressive Symptoms in Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine.

INTRODUCTION: To date, there are no therapeutics that have gained regulatory approval by the United States Food and Drug Administration (FDA) for the treatment of post-COVID-19 condition (PCC), a debilitating condition characterized by cognitive impairment and mood symptoms. Additionally, persistent inflammation, metabolic dysfunction, and risks associated with an elevated body mass index (BMI) have been observed. Herein, we aimed to assess the efficacy of vortioxetine in improving depressive symptoms among individuals with PCC,  as modulated by inflammation, metabolic dysfunction, and BMI. METHODS: In this post-hoc analysis, we present preliminary data obtained from an 8-week randomized, double-blind, placebo-controlled trial. Participants included  adults aged 18 years and older residing in Canada who were experiencing symptoms of World Health Organization (WHO)-defined PCC. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled, 147 were randomized (1:1) to receive vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change from baseline to endpoint in the 16-Item Quick Inventory of Depressive Symptomatology Self-Report Questionnaire (QIDS-SR-16). RESULTS: Our findings revealed significant effects for time (χ2 = 9.601, p = 0.002), treatment (χ2 = 9.135, p = 0.003), and the treatment × time × CRP × TG-HDL × BMI interaction (χ2 = 26.092, p < 0.001) on PCC-related depressive symptoms in the adjusted model. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint as compared to placebo (mean difference = - 5.41, SEM = 1.335, p < 0.001). CONCLUSION: Overall, vortioxetine significantly improved depressive symptoms among participants with PCC in the adjusted model. Notably, individuals with baseline markers of increased inflammation, metabolic disruption, and elevated BMI exhibited a more pronounced antidepressant effect at endpoint. TRIAL REGISTRATION NUMBER: NCT05047952 (ClinicalTrials.gov).

Efficacy, safety, and tolerability of xanomeline for schizophrenia spectrum disorders: a systematic review.

INTRODUCTION: We systematically reviewed extant studies evaluating the efficacy and tolerability of xanomeline and xanomeline-trospium (KarXT) for treatment of adults with schizophrenia. METHODS: In accordance with PRISMA guidelines, articles were systematically searched for in databases and clinical trial registries. RESULTS: A total of 4 preclinical trials and 3 randomized controlled trials (RCTs) were included in this review. A 4-week RCT observed a difference of 24.0 points (SD 21.0) in the Positive and Negative Syndrome Scale (PANSS) total score between xanomeline and placebo groups (p = 0.039). A 5-week RCT observed PANSS total score changes from baseline to week 5, including -17.4 and -5.9 points in KarXT and placebo groups, respectively (LSMD -11.6 points; 95% CI -16.1 to -7.1; p < 0.001; d = 0.75). Another 5-week RCT observed PANSS total score changes from baseline to week 5, including -21.2 (SE 1.7) and -11.6 (SE 1.6) points in KarXT and placebo groups, respectively (LSMD -9.6; 95% CI -13.9 to -5.2; p < 0.0001; d = 0.61). Side effects include constipation, nausea, vomiting, dyspepsia, and dry mouth. CONCLUSION: KarXT offers an innovative non-D2 blocking approach, representing a promising treatment avenue for schizophrenia.

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).

Preferences for childbirth delivery and pain relief methods among pregnant women in Vietnam.

Background: Understanding childbirth delivery and pain relief method preferences is important as a part of the shared decision-making process between pregnant women and health professionals. This study aimed to examine the preferences for childbirth delivery modes and pain relief methods and factors related to these preferences among pregnant women in Vietnam. Methods: A cross-sectional survey on pregnant women was conducted in two obstetrics hospitals in Vietnam. Face-to-face interviews using a structured questionnaire were performed to collect information about sociodemographic characteristics, pregnancy characteristics, preferences for different childbirth delivery modes, and pain relief methods. Multivariate logistic regression was employed for determining associated factors with the preferences. Results: Of 576 pregnant women, 34% of participants preferred cesarean section. Most of the sample did not have any preferences for specific pharmacological pain relief methods (70.1%), while support from partner/relatives was the most preferable non-pharmacological method (61.3%), following by water birth (11.1%) and acupuncture (9.9%). Desire to have another baby, relatives' experience, selection date of birth, and instrumental social support were major drivers of the cesarean section selection. This preference was an important factor in the preference for pharmacological pain relief. Meanwhile, high levels of informational and emotional support were associated with non-pharmacological method preference. Conclusion: This study highlighted a high preference rate for cesarean section in urban pregnant women in Vietnam. Holistic approaches from family, health facility, and policy should be performed to diminish the cesarean rate preference and promote the use of non-pharmacological pain relief methods during birth.

Association of depression with all-cause and cancer-specific mortality in older adults with cancer: Systematic review, meta-analysis, and meta-regression.

INTRODUCTION: The incidence and mortality of cancer is increasing worldwide with studies reporting that cumulative risk of cancer rises as age increases. Against the backdrop of the increasing prevalence of cancer amongst older patients, we conducted a systematic review and meta-analysis examining the depression-mortality relationship in older adults with cancer (OAC). MATERIALS AND METHODS: This PRISMA-adherent systematic review involved a systematic search of PubMed, Medline, EMBASE, and PsycINFO for prospective and retrospective cohort studies comparing the risk of all-cause and cancer-related mortality among OAC with depression. Random effects meta-analyses and meta-regressions were used for the primary analysis. RESULTS: From 5,280 citations, we included 14 cohort studies. Meta-analyses of hazard ratios (HRs) showed an increased incidence of all-cause mortality in OAC with depression (pooled HR: 1.40; 95% confidence interval [CI]: 1.25, 1.55). Subgroup analyses of other categorical study-level characteristics were insignificant. While risk of cancer-related mortality in OAC with depression was insignificantly increased with a pooled HR of 1.21 (95% CI: 0.98, 1.49), subgroup analysis indicated that risk of cancer-related mortality in OAC with depression significantly differed with cancer type. Our systematic review found that having fewer comorbidities, a higher education level, greater socioeconomic status, and positive social supportive factors lowered risk of all-cause mortality in OAC with depression. DISCUSSION: Depression in OAC significantly increases risk of all-cause mortality and cancer-related mortality among different cancer types. It is imperative for healthcare providers and policy makers to recognize vulnerable subgroups among older adults with cancer to individualize interventions.

A comparison between psilocybin and esketamine in treatment-resistant depression using number needed to treat (NNT): A systematic review.

BACKGROUND: Inadequate outcomes with monoamine-based treatments in depressive disorders are common and provide the impetus for mechanistically-novel treatments. Esketamine is a proven treatment recently approved for adults with Treatment-Resistant Depression (TRD) while psilocybin is an investigational treatment. Translation of the clinical meaningfulness for these foregoing agents in adults with TRD is required. Herein we evaluate the Number Needed to Treat (NNT) and Harm (NNH) of esketamine and psilocybin in adults with TRD. METHODS: We conducted a systematic review of randomized controlled trials, comparing the clinical efficacy of oral psilocybin to the co-commencement of intranasal esketamine with an oral antidepressant in adults with TRD. RESULTS: 25 mg psilocybin had a significant reduction in depressive symptoms at 21-days post-dose, the NNT was 5 [95 % CI = 3.1, 18.5]. Psilocybin-induced nausea had a significant NNH = 5. Fixed-dosed esketamine at 56 mg and 84 mg had a significant effect at 28-days post-dose, (NNT of 7 [95 % CI56mg = 3.5, 46.7], [95 % CI84mg = 3.6, 142.2]). Esketamine-induced headache, nausea, dizziness, and dissociation had NNHs <10. LIMITATIONS: The preliminary results may only reflect a small portion of the patient population. These results require replication and longer term studies investigating maintenance therapy. CONCLUSION: Relatively few pharmacologic agents are proven safe and effective in adults with TRD. NNT estimates for investigational psilocybin and esketamine in TRD indicate clinical meaningfulness. The NNH profile for both aforementioned agents is clinically acceptable. Our results underscore the clinical relevance of these treatment options in adults with TRD.

Interpretable deep learning model for major depressive disorder assessment based on functional near-infrared spectroscopy.

BACKGROUND: Major depressive disorder (MDD) affects a substantial number of individuals worldwide. New approaches are required to improve the diagnosis of MDD, which relies heavily on subjective reports of depression-related symptoms. AIM: Establish an objective measurement and evaluation of MDD. METHODS: Functional near-infrared spectroscopy (fNIRS) was used to investigate the brain activity of MDD patients and healthy controls (HCs). Leveraging a sizeable fNIRS dataset of 263 HCs and 251 patients with MDD, including mild to moderate MDD (mMDD; n = 139) and severe MDD (sMDD; n = 77), we developed an interpretable deep learning model for screening MDD and staging its severity. RESULTS: The proposed deep learning model achieved an accuracy of 80.9% in diagnostic classification and 78.6% in severity staging for MDD. We discerned five channels with the most significant contribution to MDD identification through Shapley additive explanations (SHAP), located in the right medial prefrontal cortex, right dorsolateral prefrontal cortex, right superior temporal gyrus, and left posterior superior frontal cortex. The findings corresponded closely to the features of haemoglobin responses between HCs and individuals with MDD, as we obtained a good discriminative ability for MDD using cortical channels that are related to the disorder, namely the frontal and temporal cortical channels with areas under the curve of 0.78 and 0.81, respectively. CONCLUSION: Our study demonstrated the potential of integrating the fNIRS system with artificial intelligence algorithms to classify and stage MDD in clinical settings using a large dataset. This approach can potentially enhance MDD assessment and provide insights for clinical diagnosis and intervention.

The efficacy of zuranolone in postpartum depression and major depressive disorder: a review & number needed to treat (NNT) analysis.

INTRODUCTION: Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABAA receptors, is an attractive alternative as a rapid-acting antidepressant treatment. AREAS COVERED: This article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants. EXPERT OPINION: Zuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).

Early life stress enhances the susceptibility to depression and interferes with neuroplasticity in the hippocampus of adolescent mice via regulating miR-34c-5p/SYT1 axis.

Early life events are major risk factors for the onset of depression and have long-term effects on the neurobiological changes and behavioral development of rodents. However, little is known about the specific mechanisms of early life adversity in the susceptibility to subsequent stress exposure in adolescence. This study characterized the effect of maternal separation (MS), an animal model of early life adversity, on the behavioral responses to restraint stress in mice during adolescence and investigated the molecular mechanism underlying behavioral vulnerability to chronic stress induced by MS. Our results showed that MS exposure could further reinforce the depressive vulnerability to restraint stress in adolescent mice. In addition, miR-34c-5p expression was obviously up-regulated in the hippocampi of MS mice at postnatal day (P) 14 and P42. Further, synaptotagmin-1 (SYT1) was deemed as a target gene candidate of miR-34c-5p on the basis of dual luciferase assay. It was found that the downregulation of miR-34c-5p expression in the hippocampi of MS mice could ameliorate dysfunction of synaptic plasticity by targeting molecule SYT1, effects which were accompanied by alleviation of depressive and anxious behaviors in these mice. The results demonstrated that the miR-34c-5p/SYT1 pathway was involved in the susceptibility to depression induced by MS via regulating neuroplasticity in the hippocampi of mice.