Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.
ABSTRACT: Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.
Project description:This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10-20 mg) on cognitive function in adults (aged 18-65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P < 0.05), PDQ (P < 0.01), CGI-I (P < 0.001), MADRS (P < 0.05), and UPSA (P < 0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ? 5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.
Project description:AIM:The burden of major depressive disorder (MDD) in Japan is high. This study aimed to evaluate the efficacy and safety of the multimodal antidepressant vortioxetine in Japanese patients with MDD. METHODS:Japanese patients aged 20-75?years with recurrent MDD and a Montgomery-Åsberg Depression Rating Scale (MADRS) score???26 were randomized to vortioxetine 10 or 20?mg or placebo in a phase-3, double-blind, 8-week study. The primary end-point was change in MADRS total score from baseline. Secondary end-points included MADRS response and remission rates, change in Hamilton Rating Scale for Depression-17 item (HAM-D17) score, and other measures of depressive symptoms, including Clinical Global Impression of Severity (CGI-S), Clinical Global Impression of Improvement (CGI-I), and Sheehan Disability Scale (SDS). Cognitive function was assessed using Digit Symbol Substitution Test (DSST) score and Perceived Deficits Questionnaire-5 item (PDQ-5) score. RESULTS:Vortioxetine 10?mg (n = 165) and 20?mg (n = 163) reduced MADRS total score by 2.66 and 3.07 points versus placebo (n = 161) after 8?weeks (P?<?0.01 for each dose), respectively. MADRS response and remission rates were also significantly greater with vortioxetine than with placebo (P?<?0.05 for both doses). Vortioxetine 10 and 20?mg significantly improved HAM-D17 score, CGI-I score, and SDS total score after 8?weeks. PDQ-5 score was significantly improved in subjects administered vortioxetine, while DSST scores showed no significant difference. Vortioxetine was generally well tolerated. CONCLUSION:Vortioxetine at both the 10- and 20-mg/day doses demonstrated robust antidepressant efficacy in Japanese patients with MDD, and was well tolerated over the 8-week treatment period.
Project description:The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18-65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were -4.7 (10 mg: p < 0.0001) and -6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.
Project description:<h4>Objective</h4>Age-related cognitive decline, the deterioration in functions such as memory and executive function, is faced by most older adults and affects function and quality of life. No approved treatments exist for age-related cognitive decline. Computerized cognitive training has been shown to provide consistent albeit modest improvements in cognitive function as measured by neuropsychological testing. Vortioxetine, an antidepressant medication, has putative procognitive and proneuroplastic properties and therefore may be able to augment cognitive training. In this placebo-controlled study, the authors tested the cognitive benefits of vortioxetine added to cognitive training for adults age 65 or older with age-related cognitive decline.<h4>Methods</h4>After a 2-week lead-in period of cognitive training, 100 participants were randomly assigned to receive either vortioxetine or placebo in addition to cognitive training for 26 weeks. The primary outcome measure was global cognitive performance, assessed by the NIH Toolbox Cognition Battery Fluid Cognition Composite. The secondary outcome measure was functional cognition, assessed by the UCSD Performance-Based Skills Assessment. All participants received motivational messaging and support from study staff to maximize adherence to the training.<h4>Results</h4>Participants who received vortioxetine with cognitive training showed a greater increase in global cognitive performance compared with those who received placebo with cognitive training. This separation was significant at week 12 but not at other assessment time points. Both groups showed improvement in the secondary outcome measure of functional cognition, with no significant difference between groups.<h4>Conclusions</h4>Vortioxetine may be beneficial for age-related cognitive decline when combined with cognitive training. These findings provide new treatment directions for combating cognitive decline in older adults.
Project description:Depression and cerebrovascular atherosclerosis often occur in comorbidity showing neuropsychological impairment and poor response to antidepressant treatment. Objective is to evaluate if new antidepressant vortioxetine may be a potential treatment option. Mechanism of Action : Vortioxetine has 5-HT3, 5-HT7 and 5-HT1D antagonists, 5-HT1B partial agonist and a 5-HT1A agonist and serotonin transporter inhibitor property. Efficacy and safety in Major Depressive Disorders and in cognitive impairment : The majority of trials (one of them in older people) showed efficacy for vortioxetine against placebo and no differences against other active treatments. The Adverse Effects ranged from 15.8% more to 10.8% less than placebo. In the elderly, only nausea was found higher than placebo. Effects on arterial blood pressure and cardiac parameters including the ECG-QT segment were similar to placebo. Elderly depressive patients on vortioxetine showed improvement versus placebo and other active comparators in Auditory Verbal Learning Test and Digit Symbol Substitution Test scores. The inclusion criteria admitted cases with middle cerebrovascular disease. Conclusion : The mechanism of action, the efficacy on depression and safety profile and early data on cognitive impairment make Vortioxetine a strong candidate for use in depression associated with cerebrovascular disease. This information must be supported by future randomized controlled trials.
Project description:Background:Last decades of psychiatric investigations have been marked by a search for biological markers that can clarify etiology and pathogenesis, confirm the diagnosis, screen individuals at risk, define the severity, and predict the course of mental disorders. In our study, we aimed to evaluate if BDNF and IGF-1 serum concentrations separately and in combination might be used as biomarkers for major depressive disorder (MDD) diagnosis and treatment efficacy and to evaluate the relationships among those proteins and clinical parameters of MDD. Methods:Forty-one MDD patients (according to DSM-5) and 32 healthy controls (HC) were included in this study. BDNF and IGF-1 serum concentrations, psychopathological (MADRS, CGI) and neuropsychological parameters (PDQ-5, RAVLT, TMT-B, DSST), functioning according to Sheehan Disability Scale were analyzed in all subjects at admission and 30 MDD patients after 8 weeks of vortioxetine treatment. Correlational analyses were performed to explore relationships between BDNF and IGF-1 and clinical characteristics. AUC-ROCs were calculated to determine if the value of serum BDNF and IGF-1 levels could serve for MDD diagnosis. Results:MDD patients had significantly lower serum BDNF (727.6 ± 87.9 pg/ml vs. 853.0 ± 93.9 pg/ml) and higher serum IGF-1 levels (289.15 ± 125.3 ng/ml vs. 170.2 ± 58.2 ng/ml) compared to HC. Significant correlations were obtained between BDNF levels and MDD status, depressive episode (DE) severity, precipitating factors, executive functions disruption (TMT-B, RAVLT immediate recall scores) and all subdomains of functioning. As for IGF-1, correlations were found between IGF-1 level and MDD status, DE severity, number and duration of DE, parameters of subjective and objective cognitive functioning (PDQ-5, RAVLT, TMT-B, DSST scores), and all subdomains of functioning. The associations between IGF-1 concentrations and cognitive tests' performance were stronger than those of BDNF. Separately both BDNF and IGF-1 demonstrated good discriminating ability for MDD diagnosis with AUC of 0.840 and 0.824, respectively. However, the combination of those neurotrophins had excellent diagnostic power to discriminate MDD patients from HC, providing an AUC of 0.916. Vortioxetine treatment significantly increased BDNF and attenuated IGF-1 serum concentrations, improved all psychopathological and neuropsychological parameters and functioning. Conclusions:The combination of IGF-1 and BDNF might be considered as a diagnostic combination for MDD.
Project description:INTRODUCTION:The Parkinson's disease questionnaire-39 (PDQ-39) is a common measure of health related quality of life (HRQoL) that is widely used with Parkinson disease (PD) patients. Previous evidence suggests that the PDQ-39 reflects at least 8 dimensions (i.e., Emotion, Cognitions, Mobility, etc). To date, little research has examined the external/convergent validity of the Cognitions and Emotional Well-being domains of the PDQ-39. METHODS:A convenience sample of 303 PD patients underwent a comprehensive multi-domain neuropsychological evaluation, including tests of execution function, episodic verbal memory, processing speed, language and working memory, as well as completing measures of depression, apathy, state and trait anxiety and HRQoL (PDQ-39). Hierarchical regressions were conducted in order to examine the relationship between scores on neuropsychological tests and the Cognitions index, as well as mood measures and the Emotional Well-being index of the PDQ-39. RESULTS:Neuropsychological test performance did not account for a significant amount of variance in the PDQ-39 Cognitions index scores. Instead, it was depression that significantly contributed to the Cognitions index, above and beyond neuropsychological performance. The PDQ-39 Emotional Well-being index was also related to mood measures, primarily depression and trait anxiety. CONCLUSIONS:The PDQ-39 Cognition index may be more related to mood functioning, as opposed to cognitive functioning, and should not be considered a "proxy" for cognitive functioning. Future studies are needed to better explain the construct of this index.
Project description:BACKGROUND:Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. METHODS:Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5-20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen's d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). RESULTS:Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25-0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). CONCLUSIONS:Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.
Project description:BACKGROUND:Efficacy has been proven for vortioxetine in short-term and long-term treatment of major depressive disorder (MDD), with broad beneficial effects on emotional, physical and cognitive symptoms. Limited specific data on the effects of vortioxetine on depression-related physical symptoms have been published. METHODS:A meta-analysis was carried out of five short-term multinational, double-blind, placebo-controlled studies. These studies were conducted in a total of 2105 adult MDD outpatients (18-75 years) with a major depressive episode of ?3 months' duration. Only patients treated with a dose of 5 or 10 mg vortioxetine (therapeutic doses) or placebo were included in this analysis. Efficacy assessment of vortioxetine on the physical symptoms of depression included all items of the Hamilton Depression Scale (HAM-D) assessing physical symptoms, and all somatic items in the Hamilton Anxiety Scale (HAM-A). A subgroup analysis in MDD patients with coexisting anxiety symptoms (i.e. those with a HAM-A ?20 at baseline) was also performed. RESULTS:A significant improvement ( p<0.05) of vortioxetine versus placebo was observed on all HAM-D items measuring physical symptoms, except for the somatic gastrointestinal symptoms and loss of weight items. Significant effects were also observed on the HAM-A somatic items: general somatic symptoms, gastrointestinal symptoms, and autonomic symptoms. In patients with a high baseline level of anxiety, a significant effect of vortioxetine was also observed on the physical symptoms of depression. CONCLUSIONS:These analyses indicate that patients with MDD, including those with a high level of anxiety symptoms, have significant improvements in MDD-associated physical symptoms when treated with vortioxetine.
Project description:OBJECTIVE:The Assessment in Work Productivity and the Relationship with Cognitive Symptoms (AtWoRC) study aimed to assess the association between cognitive symptoms and work productivity in gainfully employed patients receiving vortioxetine for a major depressive episode (MDE). METHODS:Patients diagnosed with major depressive disorder (MDD) and treated with vortioxetine independently of study enrollment were assessed over 52 weeks at visits that emulated a real-life setting. Patients were classified as those receiving vortioxetine as the first treatment for their current MDE (first treatment) or having shown inadequate response to a previous antidepressant (switch). The primary endpoint was the correlation between changes in patient-reported cognitive symptoms (20-item Perceived Deficits Questionnaire [PDQ-D-20]) and changes in work productivity loss (Work Limitations Questionnaire [WLQ]) at week 12. Additional assessments included changes in symptom and disease severity, cognitive performance, functioning, work loss, and safety. RESULTS:In the week 12 primary analysis, 196 eligible patients at 26 Canadian sites were enrolled, received at least one treatment dose, and attended at least one postbaseline study visit. This analysis demonstrated a significant, strong correlation between PDQ-D-20 and WLQ productivity loss scores (r=0.634; p<0.001), and this correlation was significant in both first treatment and switch patients (p<0.001). A weaker correlation between Digit Symbol Substitution Test and WLQ scores was found (r=-0.244; p=0.003). CONCLUSION:At 12 weeks, improvements in cognitive dysfunction were significantly associated with improvements in workplace productivity in patients with MDD, suggesting a role for vortioxetine in functional recovery in MDD.