Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials.

BACKGROUND: A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as first-generation monoamine-based antidepressants. OBJECTIVES: The objective of this systematic review was to assess the efficacy, safety, and mechanisms of action of AXS-05, a combination of the NMDA-receptor antagonist dextromethorphan with bupropion, in adults with MDD. METHODS: We searched PubMed, Embase, Google Scholar, and ClinicalTrials.gov for current studies reporting on efficacy and/or safety of AXS-05 in patients with MDD. The search terms included: "AXS-05" OR "dextromethorphan and bupropion" AND "depression". Studies from database inception to January 2023 were evaluated. Risk of bias was assessed using the Cochrane Risk of Bias tool. RESULTS: The search yielded 54 studies of which 5 were included. All studies had low risk of bias. Depression severity, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) significantly decreased as early as 1-week post-treatment from baseline when compared to a placebo-controlled group (LS mean difference 2.2; 95% CI 0.6-3.9; p = 0.007) and at 2 weeks compared to an active control group (LS mean difference 4.7; 95% CI 0.6-8.8; p = 0.024). Treatment efficacy could be maintained for up to 12 months with mean MADRS score reduction of 23 points from baseline. Clinical remission and response rates also improved at week 1 and were maintained for 12 months. The treatment was well-tolerated, with some transient adverse events reported. CONCLUSION: Current evidence suggests that the combination of dextromethorphan and bupropion is a well-tolerated, rapid-acting treatment option for adults with MDD. Initial success with AXS-05 supports the mechanistic role of glutamatergeric and sigma 1 signaling in the pathophysiology of MDD.

Added burden of major depressive disorder on cardiovascular morbidity and mortality among patients with cardiovascular disease and the modifying effects of antidepressants: A national retrospective cohort study.

BACKGROUND: To evaluate the likelihood of a future cardiovascular event (i.e., in-hospital mortality or cardiovascular disease [CVD] complications/interventions) among patients with CVD and major depressive disorder (MDD) compared to those without MDD, and the antidepressant use on future cardiovascular events between the two groups. METHODS: This is a retrospective cohort with propensity score matching with 8941 patients with CVD and MDD, and 8941 non-MDD patients using data from the Longitudinal Health Insurance Database from 1999 to 2013 in Taiwan. The outcome was in-hospital mortality and the incidence of revascularization (i.e., percutaneous transluminal coronary angioplasty [PTCA] and coronary artery bypass graft surgery [CABG]). RESULTS: Patients with CVD and MDD were more likely to need revascularization (an adjusted hazard ratio [aHR]: 1.26 and 95% CI: 1.12-1.43) than those without MDD, regardless of whether PTCA (aHR: 1.23 and 95% CI: 1.07-1.40) or CABG (aHR: 1.60 and 95% CI: 1.16-2.21) had occurred. Antidepressant use was associated with a tendency of reduced risk of mortality (aHR: 0.92 and 95% CI: 0.84-1.00). Although the magnitude of aHR ranged from 0.92 to 0.95 with revascularization, they did not reach significant levels. LIMITATIONS: Some covariates could not be controlled because they were not included in the national register dataset, and the causality is limited in an observational study. CONCLUSIONS: Patients with CVD with MDD are more likely to experience a cardiovascular complication requiring intervention than CVD patients without MDD. Antidepressant use is associated with reduced in-hospital mortality.

Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment.

Intravenous (IV) ketamine has been shown to have rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD). Urological toxicity has been observed in chronic ketamine abusers as evidenced by dysuria, urgency, and hematuria. The foregoing observation provides the basis for evaluating whether ketamine-induced urological toxicity (KIUT) is associated with sub-anesthetic doses of ketamine (0.5-1.0 mg/kg) in adults with mood disorders. The overarching objective of this article is to identify potential mechanisms of KIUT which appears to be dose and frequency dependent. Available research indicates that high-frequency ketamine is associated with disruption of the urothelial barrier as well as direct ketamine toxicity (i.e., decreased expression of junction proteins) in KIUT of the bladder. Chronic and high-frequency ketamine use is also associated with bladder inflammation mediated via neurogenic and IgE inflammation. Other non-mutually exclusive causes are nerve hyperplasia, hypersensitivity, cell apoptosis, microvascular damage, and overexpression of carcinogenic genes. Notwithstanding the evidence of KIUT in ketamine abusers, there is no evidence that ketamine and/or esketamine treatment in adults with mood disorders is associated with KIUT. However, all patients receiving ketamine/esketamine for mood disorder treatment should be queried about genitourinary symptoms during acute and, where applicable, maintenance dosing.

A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions.

BACKGROUND: Dissociation is a treatment-emergent adverse event commonly associated with IV ketamine, often measured using the 23-item Clinician-Administered Dissociative States Scale (CADSS). The objective of this study was to develop a short form version of the CADSS for easier clinical use. METHODS: Retrospective data of 260 patients with treatment-resistant depression (TRD) receiving IV ketamine were randomly divided into two datasets. The first dataset (n = 130) was leveraged to develop a brief 6-item version of the CADSS (CADSS-6) based on items most sensitive to ketamine-induced dissociation. The CADSS-6 questions were then applied to the second dataset (n = 130) and the Spearman's correlation between the full-length CADSS and the CADSS-6 were assessed. RESULTS: The CADSS-6 was developed from questions 1, 2, 6, 7, 15, and 22 from the full length CADSS. There was a strong significant correlation between the CADSS-6 total score and the CADSS total score at infusions 1 (rs(106) = 0.92, p < 0.001), 2 (rs(100) = 0.91, p < 0.001), 3(rs(99) = 0.95, p < 0.001) and 4 (rs(102) = 0.94, p < 0.001). LIMITATIONS: The CADSS-6 was developed using a retrospective data; therefore, the scale remains unvalidated in this population. CONCLUSIONS: The CADSS-6 presented herein was sensitive to dissociation experienced by patients receiving IV ketamine. Overall, the CADSS-6 was strongly correlated at each infusion with the full-length CADSS. While future studies should look to validate the CADSS-6 in a TRD sample, this scale offers clinicians a brief assessment that can be used to characterize symptoms of dissociation.

Characterizing the gut microbiota in adults with bipolar disorder: a pilot study.

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

Effects of infliximab on brain neurochemistry of adults with bipolar depression.

OBJECTIVES: To explore the relationship between inflammation and neuronal metabolism in bipolar disorder (BD) by evaluating the neurochemical effects of the tumor necrosis factor-α (TNF-α) antagonist infliximab among individuals with bipolar depression METHODS: This is a post-hoc, exploratory analysis from a 12-week, randomized, double-blind, placebo-controlled trial with infliximab for adults with bipolar depression. We assessed the effects of infliximab on concentration of metabolites in the prefrontal cortex, using proton-magnetic resonance spectroscopy (1H-MRS), as well as its association with clinical outcomes (i.e. depressive symptom severity and cognitive function). RESULTS: Eighteen participants in the placebo and 15 in the infliximab group were included in this analysis. In the pre-specified primary outcome, there were no significant effects of treatment on prefrontal concentrations of N-acetylaspartate (NAA; p = 0.712). In the secondary analyses, there was a significant treatment by time interaction for glutamate (Glx; p = 0.018), indicating that Glx levels decreased in infliximab-treated patients, relative to placebo. Treatment group significantly moderated the association between changes in Glx levels and changes in a neurocognitive test (i.e. Digit Symbol Substitution Test; p = 0.014), indicating that in infliximab-treated participants reductions in Glx were associated with cognitive improvement. CONCLUSIONS: Treatment with infliximab did not affect prefrontal NAA concentration in adults with BD. Exploratory analysis suggested a potential effect of treatment on the glutamate system, a finding that should be confirmed and validated by additional studies.

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3ß, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.

Leptin mediates improvements in cognitive function following treatment with infliximab in adults with bipolar depression.

A potential role for leptin in the pathophysiology of bipolar disorder (BD) has been proposed. We recently investigated the effects of the tumor necrosis factor-alpha (TNF-α) antagonist infliximab in individuals with bipolar depression. Leptin is known to interact with the TNF-α system. Herein, we aimed to explore infliximab's effects on leptin and its relationship with brain structure and function. Sixty adults with bipolar depression were enrolled in this randomized, double-blind, 12-week clinical trial of adjunctive infliximab (n = 29) and saline control (n = 31), which were administered intravenously at weeks 0, 2, and 6. Plasma concentrations of leptin, TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. We observed a significant decrease in leptin levels in infliximab-treated patients, relative to placebo. Infliximab treatment also significantly reduced TNF-α and sTNFR2, but not sTNFR1 levels. Changes in sTNR2 levels at week 6 significantly determined changes in leptin at week 12 in infliximab-, but not placebo-treated participants. Improvements in verbal memory and increases in global cortical volume were associated with reduction in leptin levels in the treatment group. Mediation analysis indicated that cognitive improvement in infliximab-treated patients was mediated by reductions in leptin levels, which in its turn were determined by decreases in sTNR2 levels. In conclusion, infliximab treatment reduced plasma leptin levels in individuals with BD, through modulation of sTNFR2. Decreases in leptin signaling were associated with an increase in global cortical volume and better performance in a verbal memory task.

Efficacy of adjunctive infliximab vs. placebo in the treatment of anhedonia in bipolar I/II depression.

We investigated the efficacy of tumour necrosis factor (TNF)-α antagonist infliximab on a measure of anhedonia amongst individuals with bipolar I/II depression (ClinicalTrials.gov identifier NCT02363738). Adults (ages 18-65) with bipolar I/II disorder currently experiencing a major depressive episode with a higher probability of inflammatory activity (i.e., meeting one or more of the following inflammatory/metabolic criteria: obesity and dyslipidemia/hypertension, daily cigarette smoking, diabetes mellitus, migraine, inflammatory bowel disease, and/or C-reactive protein level of ⩾5 mg/L) were enrolled in a double-blind, 12-week clinical trial of adjunctive infliximab (5 mg/kg) and saline control, which were administered at weeks 0, 2, and 6. The primary outcome measure for the present secondary analysis was change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score between placebo- and infliximab-treated subjects from baseline to weeks 6 and 12. Plasma concentrations of TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. Sixty eligible adults received treatment with infliximab (n=29) or placebo (n=31); 47 subjects completed the study (infliximab: n=21, placebo: n=26). Overall, infliximab-randomized subjects exhibited significantly larger increases in SHAPS total score, denoting greater reductions in anhedonic symptoms, when compared to placebo-randomized subjects (treatment × time interaction effect: χ2=7.15,df=2,p=0.03). Anti-anhedonic efficacy was moderated by baseline plasma levels of TNF-α and sTNFR1, but not by changes in TNF-α or sTNFR1 concentrations. Baseline and changes in sTNFR2 concentrations did not moderate anti-anhedonic efficacy. Infliximab significantly improved a measure of anhedonia relative to placebo in adults with bipolar I/II depression at week 6; intervention efficacy was not sustained 6 weeks after the final infusion.

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression.

Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab's effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab's effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ2 = 9.275, p = 0.026), NF-κB (χ2 = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα) (χ2 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ2 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = -0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II Depression: A Randomized Clinical Trial.

Importance: To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms. Objective: To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions. Design, Setting, and Participants: This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5-defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis. Interventions: Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study. Main Outcomes and Measures: The primary efficacy outcome was baseline-to-end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes. Results: A total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to-end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04). Conclusions and Relevance: Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo. Trial Registration: ClinicalTrials.gov identifier: NCT02363738.

A clinical model for identifying an inflammatory phenotype in mood disorders.

Increasingly, clinical research has found inflammatory correlates of psychiatric disorders, particularly mood symptomatology. Biological measures may provide greater precision in many cases and may capture clinically-relevant inflammatory signposts, such as central obesity risk, inflammation-associated co-morbid medical conditions, or proinflammatory lifestyle choices. In order to expand understanding of the role of inflammation in mood disorders, we propose a more inclusive clinical model for capturing an inflammatory phenotype of depression by identifying clinically-relevant inflammatory phenotypes grounded in biology. Our model includes chronic conditions and lifestyle behaviors associated with clinically elevated inflammation in mood disorders. Elements of this "inflamed depression" model include: obesity, low HDL concentrations, elevated triglyceride concentrations, chronically elevated blood pressure, clinical diagnosis of hypothyroidism, migraines, rheumatoid arthritis, adult onset diabetes, inflammatory bowel diseases, inflammatory skin conditions, and lifestyle factors including smoking cigarettes and chronic stress.

Peripheral interleukin-6 levels and working memory in non-obese adults: A post-hoc analysis from the CALERIE study.

OBJECTIVES: This analysis aimed to investigate the association among interleukin 6 (IL-6) levels, caloric intake, and working memory and to explore the potential mediators of these associations using the public dataset from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) clinical trial. METHODS: The CALERIE study was designed to evaluate the effects of 2 y of prolonged caloric restriction in humans. Individuals were randomized to caloric restriction (CR; n = 145) or an ad libitum diet (AL; n = 75) for 2 y. The outcome measures used herein were spatial working memory tests (i.e., total number of errors and strategy). Generalized estimating equations were used to assess the effects of treatment, time, and potential moderators (e.g., sleep and physical activities). RESULTS: At baseline, there was an effect of hours of sleep, alcohol intake, and physical activities (i.e., mean total metabolic equivalent of task hours per day [MET-hours/day]) on IL-6 levels. The association between IL-6 and energy intake was moderated by MET-hours/day. The longitudinal analysis indicated that there was an effect of time, but not of treatment, on IL-6 levels, with decreasing values in both the CR and AL groups. Changes in IL-6 levels were associated with changes in working memory performance, but there were no between-group (i.e., CR vs. AL) differences. CONCLUSIONS: We observed an association between changes in IL-6 levels and improvement in spatial working memory tests. IL-6 was associated with higher caloric consumption, poorer sleep quality, and lower levels of physical activity.

Cognitive impairment as measured by the THINC-integrated tool (THINC-it): The association with self-reported anxiety in Major Depressive Disorder.

BACKGROUND AND OBJECTIVES: This study evaluated the association between self-reported anxiety and objective/subjective measures of cognitive performance in adults with Major Depressive Disorder (MDD). METHODS: Acutely depressed subjects with recurrent MDD (n = 100) and age-, sex-, and education-matched healthy controls (HC; n = 100) between the ages of 18 and 65 completed the cross-sectional validation study of the THINC-integrated tool (THINC-it; ClinicalTrials.gov: NCT02508493). Objective cognitive performance was assessed using the THINC-it, and subjective cognitive impairment with the Perceived Deficits Questionnaire for Depression-5-item. Subjects also completed the Generalized Anxiety Disorder-7-item (GAD-7) questionnaire. RESULTS: Subjects with MDD reported significantly more anxiety symptoms, as assessed by the GAD-7, compared to HC (p < 0.001). Linear regression analysis determined that anxiety symptoms significantly accounted for 70.4% of the variability in subjective cognitive impairment, adjusting for depression severity. Moreover, subjects' ratings of the difficulties caused by their anxiety were reported as significantly more severe among subjects with MDD when compared to HC (p < 0.001). Likewise, greater self-reported difficulties with anxiety significantly predicted 57.8% of the variability in subjective cognitive impairment, adjusting for depression severity. Neither anxiety symptoms nor impairment due to anxiety symptoms predicted objective cognitive performance. LIMITATIONS: Subjects were not prospectively verified to have a clinical diagnosis of GAD. Rather, this study examined the relationships between symptoms of generalized anxiety, assessed using a brief screening tool, and subjective and objective cognitive function. CONCLUSIONS: Results from the current study indicate that adults with MDD and high levels of self-reported anxiety are significantly more likely to report experiencing subjective cognitive dysfunction.

Evidence supporting a mechanistic role of sirtuins in mood and metabolic disorders.

Sirtuins are NAD+-dependent histone deacetylases that play essential roles in cell survival, energy metabolism, inflammation, and aging; therefore, sirtuins are potential therapeutic targets in the treatment of type 2 diabetes, cancer, inflammatory and metabolic disorders, and neurodegenerative diseases. Available evidence provides the basis for hypothesizing that sirtuins 1, 2, and 3 (SIRT1, SIRT2, and SIRT3) may have a mechanistic role subserving mood disorders (i.e. downregulation) and associated co-morbidity (e.g. metabolic disorders). Specifically, the domains of general cognitive processes, as well as cognitive emotional processing may be particularly relevant to sirtuin physiology. Given the role of sirtuins in the perpetuation of circadian rhythmicity, and evidence of dysfunctional circadian cycling in mood disorders, sirtuins may be an underlying etiological factor that links circadian rhythm functionality with mood disorders. Caloric restriction, and caloric restriction mimetics (e.g. resveratrol) are all capable of upregulating sirtuin isoforms implicated in stress response syndromes. Repurposing existing treatments and/or discovery of novel agents capable of modulating sirtuin physiology may represent genuinely novel approaches for trans-diagnostic domains affected in mood disorders and other brain-based illnesses.

Cognitive dysfunction and metabolic comorbidities in mood disorders: A repurposing opportunity for glucagon-like peptide 1 receptor agonists?

Major depressive disorder and bipolar disorder are highly prevalent and disabling conditions. Cognition is considered a core domain of their psychopathology and a principle mediator of psychosocial impairment, disproportionately accounting for overall illness-associated costs. There are few interventions with replicated evidence of efficacy in treating cognitive deficits in mood disorders. Evidence also indicates that cognitive deficits are associated with obesity and involve significant impairment across multiple domains. Conversely, weight-loss interventions, such as physical exercise and bariatric surgery, have been shown to beneficially affect cognitive function. This convergent phenomenology suggests that currently available agents that target metabolic systems may also be capable of mitigating deficits in cognitive functions, and are, therefore, candidates for repurposing. The incretin glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors (GLP-1R) are widely expressed in the central nervous system. Activation of GLP-1R leads to facilitation of glucose utilization and antiapoptotic effects in various organs. Pre-clinical trials have demonstrated significant neuroprotective effects of GLP-1, including protection from cell death, promotion of neuronal differentiation and proliferation; and facilitation of long-term potentiation. Liraglutide is a GLP-1R agonist that has been approved for the treatment of type 2 diabetes mellitus and obesity. Convergent preclinical and clinical evidence, including a proof-of-concept pilot study from group, has suggested that liraglutide may improve objective measures of cognitive function in adults with mood disorders. The safety and availability of GLP-1R agonists indicate that they are promising candidates for repurposing, and that they may be viable therapeutic options for mood disorders. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Sex differences in the mediators of functional disability in Major Depressive Disorder.

The aim of this study was to investigate sex differences in discrete domains of psychopathology as mediators of functional disability among individuals with Major Depressive Disorder (MDD). Adults (ages 18-65) with moderate-to-severe MDD (n = 100) and age-, sex-, and education-matched healthy controls (HC; n = 100) participated in a clinical trial validating the THINC-integrated tool, a newly developed cognitive assessment tool for patients with MDD. Variables assessed as possible mediators included depression symptom severity, anxiety symptoms, sleep disturbance, perceived cognitive deficits, and objective cognitive performance. Functional disability was assessed using the total score on the Sheehan Disability Scale. Separate mediation analyses were conducted for men and women. No significant differences were detected between men and women on the assessed domains of psychopathology or functional disability (ps > 0.05). However, the mediation analyses demonstrated different patterns with respect to determinants of functional disability in MDD between men and women. Functional disability was mediated by anxiety (95% CI: -3.17, -0.28) and sleep disturbance (95% CI: -0.69, -0.05) among men and by depressive symptom severity (95% CI: -7.82, -0.32) among women. These preliminary results instantiate the need to dimensionalize psychopathology in MDD. Our results at least in part support the hypothesis that, consistent with the sex differences in the prevalence and illness presentation of MDD, determinants of functional outcomes also differ between men and women, underscoring the need to consider sex differences in order to improve functional outcomes in the treatment of MDD.

The relationship between moderate-to-vigorous physical activity and executive function among individuals with schizophrenia: differences by illness duration

Objective: Schizophrenia is a chronic mental illness characterized by positive and negative symptoms. Cognitive impairment continues to be a core and consistent deficit. Previous studies have shown that physical activity (PA) is positively associated with cognitive performance. Thus, it may play a supportive role in mitigating cognitive impairments among individuals with schizophrenia. The aim of this study was to analyze the relationship between moderate-to-vigorous physical activity (MVPA) and executive function among adults with schizophrenia. Methods: The weekly amount of MVPA (assessed using accelerometers) and executive function (as per Brief Neurocognitive Assessment for Schizophrenia) of 78 adults with schizophrenia (mean [SD] age 42.4 [11.4] years; illness duration 17.0 [11.0] years; 58.2% male) were assessed in this cross-sectional study. Pearson correlations were calculated, followed by a linear regression. Participants were first analyzed together and then dichotomized on the basis of illness duration. Results: There was no significant association between MVPA and executive function, independent of the duration of illness. For individuals with < 15 years of illness, there was a significant association between weekly MVPA and working memory performance. Conclusion: PA appears to be associated with executive function in some, but not all, individuals with schizophrenia.

The THINC-Integrated Tool (THINC-it) Screening Assessment for Cognitive Dysfunction: Validation in Patients With Major Depressive Disorder.

OBJECTIVE: To validate the THINC-integrated tool (THINC-it)-a freely available, patient-administered, computerized screening tool integrating subjective and objective measures of cognitive function in adults with major depressive disorder (MDD). METHODS: Subjects aged 18 to 65 years (n = 100) with recurrent MDD experiencing a major depressive episode of at least moderate severity were evaluated and compared to age-, sex-, and education-matched healthy controls (n = 100). Between January and June 2016, subjects completed the THINC-it, which includes variants of the Choice Reaction Time Identification Task (IDN), One-Back Test, Digit Symbol Substitution Test, Trail Making Test-Part B, and the Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D). RESULTS: The THINC-it required approximately 10 to 15 minutes for administration and was capable of detecting cognitive deficits in adults with MDD. A total of 44.4% of adults with MDD exhibited cognitive performance at ≥ 1.0 SD below that of healthy controls on standardized mean scores of the THINC-it. Concurrent validity of the overall tool, based on a calculated composite score, was acceptable (r = 0.539, P < .001). Concurrent validity of the component tests ranged from -0.083 (IDN) to 0.929 (PDQ-5-D). Qualitative survey results indicated that there was a high level of satisfaction and perceived value in administering the THINC-it regarding its impact on the appropriateness and quality of care being received. CONCLUSIONS: The THINC-it is a valid and sensitive tool for detecting cognitive dysfunction in adults with MDD that is free, easy to use, and rapidly administered. The THINC-it should be incorporated into the assessment and measurement of all patients with MDD, particularly among those with enduring functional impairment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02508493.