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Background: Insulin resistance (IR) is a potential predictor of antidepressant treatment response. Aims: We assess changes in IR after antidepressant treatment and whether these changes have any effect on treatment response. Also, to see whether changes in IR mediates relationship between C-reactive protein (CRP) and antidepressant efficacy. Methods: This is a secondary analysis of an 8-week, open-label clinical trial with 95 adults experiencing a major depressive episode. Response to vortioxetine was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS). Generalized estimating equation models were utilized for this intent-to-treat analysis. Results: When adjusted for age, sex, and body mass index, there was a significant increase in IR following treatment in the overall sample (p = 0.035). This finding was detected in treatment non-responders (p = 0.019), whereas it was not observed in responders (p = 0.329). Mediation analysis revealed that change in IR during treatment was responsible for change in MADRS as well as the relationship between baseline CRP and treatment response. Conclusions: Exacerbation of IR during antidepressant treatment mediated non-response. Conversely in treatment responders IR reduced. Like previous studies, baseline CRP moderated treatment response. This relationship was also mediated by changes in IR. These findings further elucidate the role of IR in terms of antidepressant response as well as potentially explain inflammation's relationship with the latter. [ABSTRACT FROM AUTHOR]

Background: Herein, we sought to determine the sensitivity to change in cognitive function, as measured by the THINC-it tool, in a sample of adults with major depressive disorder (MDD) receiving standardized antidepressant therapy. Methods: Adults meeting the DSM-5 criteria for MDD with at least moderate depressive symptom severity [ i.e. , Montgomery Åsberg Depression Rating Scale (MADRS) total score ≥ 20] were treated with open-label vortioxetine (10–20 mg/day, flexibly-dosed) for 8 weeks. The previously validated THINC-it tool was the primary dependent measure. The THINC-it tool was validated against the paper and pencil version of the Digit Symbol Substitution Test (DSST) and the Trails Making Test B (TMTB). Results: After 8 weeks of treatment, adults with MDD exhibited improvement in cognitive function relative to healthy controls (e.g. , processing speed) (p = 0.031). A subdomain measure of working memory (i.e. , symbol check; SC) exhibited significant improvement at Weeks 2 and 8 in latency (p = 0.032), SC accuracy (p = 0.046), and objective z-score (p = 0.001) independent of depressive symptoms. A linear regression analysis determined that the THINC-it tool measures of processing speed, as well as executive function were significantly associated with changes observed on the pencil and paper version the Digit Symbol Substitution Test (DSST) (p = 0.002) and in Trails Making Test B (TMTB) (p = 0.003), respectively. Conclusion: The THINC-it tool demonstrates sensitivity to change in adults with MDD and is highly correlated with improvements on pencil and paper versions of DSST and TMTB. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03053362. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances are frequently reported in patients with major depressive disorder. We aimed to investigate the effects of vortioxetine on sleep quality and association between changes in sleep and treatment response.Methods: This study is a post-hoc analysis of a clinical trial that sought to evaluate the sensitivity to cognitive change of THINC-integrated tool in patients with major depressive disorder. In total, 92 patients (aged 18 to 65) meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for moderate or severe major depressive disorder and 54 healthy controls were included. All patients received open-label vortioxetine (10-20 mg/day, flexibly dosed) for 8 weeks. Herein, the primary outcomes of interest were changes in sleep, as measured by the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index, between weeks 0, 2, and 8. The association between changes in sleep and depressive symptom severity was secondarily assessed.Results: We observed that sleep, as indicated by scores of Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index, was significantly poorer in patients with major depressive disorder compared to healthy controls at weeks 0, 2, and 8 (p < 0.05). Among patients with major depressive disorder, we observed significant improvements on the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Insomnia Severity Index between weeks 0 and 8 (p < 0.05). We observed a significant association between improvements on the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Insomnia Severity Index and improvement of depressive symptoms.Conclusion: Improvement of depressive symptoms in major depressive disorder patients treated with vortioxetine was associated with significant improvements in sleep. Furthermore, improvements in sleep were predictive of antidepressant response and were linearly correlated with improvement in overall depressive symptom severity. [ABSTRACT FROM AUTHOR]

• Childhood maltreatment is an important stressor associated with stress & depression. • Stress- and depression-associated changes were mostly found in NRC31 and SLCA4. • Epigenetic changes occurring at different loci may have variable downstream effects. • Most studies measured epigenetic changes using peripheral tissue samples. • Future studies should evaluate epigenetic effects of psychotropic medication use. Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic changes are a key mechanism by which stressors interact with the genome leading to stable changes in DNA structure, gene expression, and behaviour. The current review aimed to evaluate the relationship between stress-associated epigenetic changes and depression. Human studies were identified via systematic searching of PubMed/Medline from inception to February 2018. Seventeen articles were identified. Stress-associated epigenetic changes in the following genes were correlated with depression: NRC31, SLCA4, BDNF, FKBP5, SKA2, OXTR , LINGO3, POU3F1 and ITGB1. Epigenetic changes in glucocorticoid signaling (e.g., NR3C1, FKBP5), serotonergic signaling (e.g. SLC6A4), and neurotrophin (e.g., BDNF) genes appear to be the most promising therapeutic targets for future research. However, continued research is warranted due to inconsistent findings regarding the directionality of epigenetic modification. Future studies should also aim to control for the use of psychotropic agents due to their widespread use in depressed populations and established effects on DNA methylation. [ABSTRACT FROM AUTHOR]

Background: Anhedonia is a common, persistent, and disabling phenomenon in treated adults with Major Depressive Disorder (MDD). Hitherto, relatively few antidepressant agents have been evaluated with respect to their effect on anhedonia in MDD. Methods: This is a post-hoc analysis of a primary study that sought to evaluate the sensitivity to change of the THINC-integrated tool (THINC-it) in MDD (ClinicalTrials.gov Identifier: NCT03053362). Adults meeting DSM-5 criteria for MDD with at least moderate depressive symptom severity [i.e., Montgomery Åsberg Depression Rating Scale (MADRS) total score ≥20] were eligible. Subjects were recruited between October 2017 and August 2018 in Toronto, Ontario at the Brain and Cognition Discovery Foundation. All subjects received open-label vortioxetine (10–20 mg/day, flexibly-dosed) for 8 weeks. Herein, the primary outcome of interest was the change from baseline to endpoint in the Snaith-Hamilton Pleasure Scale (SHAPS) total score, as well as the MADRS anhedonia factor. The mediational effects of improvements in anhedonia on general function and quality of life, as measured by the Sheehan Disability Scale (SDS) and the 5-Item World Health Organization Well-Being Index (WHO-5), were secondarily assessed. Results: A total of 100 subjects with MDD were enrolled in the primary study and began treatment with vortioxetine. Vortioxetine significantly improved anhedonia as evidenced by significant baseline to endpoint improvements in SHAPS and MADRS anhedonia factor scores (p < 0.0001). Improvements in the SHAPS and the MADRS anhedonia factor correlated with improvements in general function (i.e., SDS) and quality of life (i.e., WHO-5) (p < 0.0001). Notably, improvements in anhedonia were found to mediate the association between improvements in overall depressive symptom severity (i.e., MADRS total score) and social functioning (i.e., social life component of the SDS) (p = 0.026). Conclusion: The unmet need in depression is to improve patient functioning and other patient-reported outcomes (e.g., quality of life). Antidepressant interventions capable of attenuating anhedonia as well as cognitive dysfunction in MDD may help in this regard, as improvement in these domains have been associated with improvement in psychosocial function and quality of life. [ABSTRACT FROM AUTHOR]

Highlights • Numerous studies indicate that probiotics have anti-inflammatory effects. • Immune-inflammatory modulation may mediate the antidepressant effects of probiotics. • Probiotics may be more effective in depressed subgroups with elevated inflammation. • Future studies should parse out the heterogeneous effects of different probiotics. Abstract During the past decade, there has been renewed interest in the relationship between brain-based disorders, the gut microbiota, and the possible beneficial effects of probiotics. Emerging evidence suggests that modifying the composition of the gut microbiota via probiotic supplementation may be a viable adjuvant treatment option for individuals with major depressive disorder (MDD). Convergent evidence indicates that persistent low-grade inflammatory activation is associated with the diagnosis of MDD as well as the severity of depressive symptoms and probability of treatment response. The objectives of this review are to (1) evaluate the evidence supporting an anti-inflammatory effect of probiotics and (2) describe immune system modulation as a potential mechanism for the therapeutic effects of probiotics in populations with MDD. A narrative review of studies investigating the effects of probiotics on systemic inflammation was conducted. Studies were identified using PubMed/Medline, Google Scholar, and clinicaltrials.gov (from inception to November 2017) using the following search terms (and/or variants): probiotic , inflammation , gut microbiota , and depression. The available evidence suggests that probiotics should be considered a promising adjuvant treatment to reduce the inflammatory activation commonly found in MDD. Several controversial points remain to be addressed including the role of leaky gut, the role of stress exposure, and the role of blood-brain-barrier permeability. Taken together, the results of this review suggest that probiotics may be a potentially beneficial, but insufficiently studied, antidepressant treatment intervention. [ABSTRACT FROM AUTHOR]

It is well established that deficits in motivation, reward, and cognition are common during and in between syndromal episodes of depression as part of Major Depressive Disorder (MDD). Informed by evidence indicating functional and structural interconnectivity between cognitive and reward brain circuits, we preliminarily evaluate the association between measures of cognitive performance and reward/motivation. This is a post-hoc analysis of a primary study (i.e. the THINC-it sensitivity to change study). Adults (18–65 years of age) meeting DSM-5 criteria for MDD, single-episode or recurrent confirmed by M.I.N.I. with moderate severity or greater (i.e. Montgomery Asberg Depression Rating Scale ≥20). All eligible subjects received vortioxetine 10–20 mg open-label for 8 weeks. The Effort Expenditure Reward Task (EEfRT) was the principal measure of motivation and reward. We directly compare the effects of cognitive measures and depressive symptoms on effort-based decision-making using the THINC-it composite score and MADRS total score. Twenty-one participants with MDD (Mean age = 38.47, SD = 12.85) and 20 healthy volunteers (Mean age = 41.50, SD = 14.21) completed the optional EEfRT task. Amongst individuals with MDD, performance in processing speed, executive function (i.e. Trails B) and overall composite cognitive score was positively associated with the proportion of hard-task choices in the high reward condition (i.e. greater reward valuation). Across both groups, a greater probability (χ2 = 1.137) and magnitude of reward (χ2 = 0.045) was associated with increased effort (i.e. choosing the hard task more frequently). Using fully factored GEE models, we observed a positive association between performance on the Trails test (β = 2.223, SE = 0.928, p = 0.017) as well as the composite score (β = 0.978, SE = 0.0.459, p = 0.033), and greater effort for high rewards. In addition, it was observed that a positive association (i.e. greater effort for reward in higher probability) was observed with depressive symptoms and overall cognitive measures. Herein, we observed that an association exists between overall cognitive function, notably processing speed and executive function and reward function. Specifically, a greater effort for hard task rewards (using the EEfRT task) was manifested in individuals exhibiting higher levels of cognitive performance in a well-characterized sample of MDD treated with Vortioxetine. • Cognitive function highly correlates with measures of reward and motivation in adults with major depressive disorder (MDD) • Processing speed, executive function and overall cognition was positively associated with greater reward valuation • Overall cognition positively correlated (i.e. greater effort for reward in higher probability) with depressive symptoms • Self-reported measures of anhedonia and reward valuation are distinct domains of psychopathology in those with MDD [ABSTRACT FROM AUTHOR]

Ecological momentary assessment (EMA) for mental disorders, using application-based (app) technology capable of passive and ambient data collection, has been insufficiently evaluated and validated with rigorous, adequately-powered, high-quality studies. Herein, we sought to validate the mind.me application for the assessment of depressive symptoms in adults. Adults (ages 18–65) who self-identified as having clinically significant depressive symptoms [i.e. Patient Health Questionnaire 9 (PHQ-9) ≥ 5] utilized the mind.me app—a mobile phone technology that collects data passively and continuously, and is capable of integrating broad multimodal data [e.g., location variance (e.g. GPS), behavioural (e.g. social network activity), and communication data (e.g. SMS texting, phone calls)]. The primary outcome was predictive accuracy (i.e. convergent validity with depressive symptom measurement, as captured by the PHQ-9). 200 subjects were enrolled in the study (mean age 46 ± 12.71). The average PHQ-9 score was 12.8 ± 6.9. The predictive accuracy of the mind.me app was 0.91 ± 0.06. The sensitivity was 0.98 and the specificity was 0.93. The mind.me app was rated by 200 users as highly usable and informative to their illness. The mind.me app exhibits robust predictive accuracy in detecting depressive symptoms in adults with clinically relevant depressive symptoms. The mind.me app more specifically demonstrates convergence with the PHQ-9. [ABSTRACT FROM AUTHOR]

Background: Major Depressive Disorder (MDD) is a common and debilitating mood disorder. Individuals with MDD are often misdiagnosed or diagnosed in an untimely manner, exacerbating existing functional impairments. Ecological momentary assessment (EMA) involves the repeated sampling of an individual's symptoms within their natural environment and has been demonstrated to assist in illness assessment and characterization. Capturing data in this way would set the stage for improved treatment outcomes and serve as a complementary resource in the management and treatment of depressive symptoms.Methods: Online databases PubMed/MedLine and PsycINFO were searched using PRISMA guidelines and combinations of the following keywords: EMA, depression, smartphone app, diagnosing, symptoms, phone, app, ecological momentary assessment, momentary assessment, data mining, unobtrusive, passive data, GPS, sensor.Results: A total of nineteen original articles were identified using our search parameters and ten articles met the inclusion criteria for full-text review. Among the ten relevant studies, three studies evaluated feasibility, seven evaluated detection, and three evaluated treatment of MDD.Limitations: Limitations include that the design of all of the studies included in this review are non-randomized. It should be noted that most of the studies included were pilot studies and/or exploratory trials lacking a control group.Conclusions: Available evidence suggests that the use of passive smartphone-based applications may lead to improved management of depressive symptoms. This review aids the creation of new EMA applications, highlights the potential of EMA usage in clinical settings and drug development, emphasizes the importance for regulation of applications in the mental health field, and provides insight into future directions. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to examine whether changes in physical activity predicted reductions in depression during the 8 weeks of antidepressant treatment with vortioxetine.Methods: One hundred individuals were recruited for the (THINC-it ®)-sensitivity to change study. Self-reported moderate-to-vigorous physical activity (MVPA) and depression severity were assessed at baseline, week 4 and week 8. Linear mixed model analyses were performed to examine whether increases in MVPA were associated with reduction in depression severity over the course of treatment and hierarchical logistic regression analyses were performed to assess whether treatment response (responders vs. non-responders) at week 8 was predicted by early change in physical activity (MVPA at week 4), after controlling for individuals' demographics (sex, age, race, education level, BMI) and baseline MVPA and depression severity.Results: After controlling for individuals' demographics, a significant increase in MVPA predicted reduction in depression severity, β = -2.06, 95% CI -3.18, -0.94, p <0.001. Individuals with more physical activity at week 4 relative to baseline had higher odds of treatment response at endpoint, OR 1.97, 95% CI 1.11 - 3.48, p <0.05. Twenty-one percent of total variance of depression severity was explained by change in MVPA.Conclusions: The study suggests that early increases in physical activity may be a behavioral marker of antidepressant treatment response. The inclusion of physical activity measures in future clinical treatment trials of depression is recommended to explore whether changes in physical activity mediate or moderate reductions in depression severity associated with the primary treatment. [ABSTRACT FROM AUTHOR]

Background: Anhedonia and abnormalities in reward behavior are core features of major depressive disorder (MDD). Convergent evidence indicates that overweight/obesity (OW), a highly prevalent condition in MDD, is independently associated with reward disturbances. We therefore aimed to investigate the moderating effect of OW on the willingness to expend efforts for reward in individuals with MDD and healthy controls (HC).Methods: Forty-one adults (HC n = 20, MDD n = 21) completed the Effort Expenditure for Rewards Task (EEfRT), clinical and cognitive measures. Anthropometric parameters were assessed in all participants, and an additional evaluation of laboratorial parameters were conducted solely on those with MDD. Individuals with MDD were all on vortioxetine monotherapy (10-20 mg/day).Results: Interactions between reward magnitude, group and OW were observed (χ2 = 9.192, p = 0.010); the OW-MDD group chose the hard task significantly less than normal weight (NW)-HC (p = 0.033) and OW-HC (p = 0.034), whereas there were no differences between NW-MDD and HCs. Within individuals with MDD, the proportion of hard task choices was more strongly correlated with body mass index (BMI) (r = -0.456, p = 0.043) and insulin resistance (HOMA2-IR) (r = -0.467, p = 0.038), than with depressive symptoms (r = 0.290, p = 0.214).Conclusions: OW significantly moderated the association between MDD and willingness to make efforts for rewards. These findings offer novel evidence on the potential role of metabolic factors on the basis of anhedonia, and for the heuristic models proposing a pathophysiological connection between mood and metabolic disorders. [ABSTRACT FROM AUTHOR]

Anhedonia is defined as a diminished ability to experience interest or pleasure, and is a critical psychopathological dimension of major depressive disorder (MDD). The purpose of the current systematic review is to evaluate the therapeutic efficacy of pharmacological treatments on measures of anhedonia in adults with MDD. Electronic databases Cochrane Library (CENTRAL), Ovid MEDLINE, PubMed, PsycINFO, and Google Scholar were searched from inception to June 1, 2018 for longitudinal studies utilizing pharmacotherapy for the treatment of anhedonia in patients with MDD. A total of 17 eligible studies were identified (i.e., evaluated the effects of pharmacotherapy on a measure of anhedonia). Among the identified studies, the efficacy of 14 different pharmacotherapies on measures of anhedonia were evaluated, including melatonergic agents (i.e. agomelatine), monoaminergic agents (i.e. moclobemide, clomipramine, bupropion, venlafaxine, fluoxetine, amitifadine and levomilnacipran, escitalopram, and sertraline), glutamatergic agents (i.e., ketamine and riluzole), stimulants (i.e., methylphenidate), and psychedelics (i.e., psilocybin). Based on the available evidence, most antidepressants demonstrated beneficial effects on measures of anhedonia as well as the other depressive symptoms. Only escitalopram/riluzole combination treatment was ineffective in treating symptoms of anhedonia in MDD. Continued research is warranted to further support the efficacy of mechanistically-distinct antidepressants in treating symptoms of anhedonia in MDD. Future research should also aim to parse out the heterogeneous effects of different pharmacotherapies on anhedonic symptoms. • Majority of antidepressants do not show pronounced collinear improvements in anhedonia and other depressive symptoms. • Therapies targeting melatonergic receptors and circadian rhythm imbalances are more direct targets for treating anhedonia. • Ketamine may be faster acting of anti-anhedonia due to direct effect on mitochondrial energy metabolism. [ABSTRACT FROM AUTHOR]

Background: No previous study has comprehensively reviewed the application of machine learning algorithms in mood disorders populations. Herein, we qualitatively and quantitatively evaluate previous studies of machine learning-devised models that predict therapeutic outcomes in mood disorders populations.Methods: We searched Ovid MEDLINE/PubMed from inception to February 8, 2018 for relevant studies that included adults with bipolar or unipolar depression; assessed therapeutic outcomes with a pharmacological, neuromodulatory, or manual-based psychotherapeutic intervention for depression; applied a machine learning algorithm; and reported predictors of therapeutic response. A random-effects meta-analysis of proportions and meta-regression analyses were conducted.Results: We identified 639 records: 75 full-text publications were assessed for eligibility; 26 studies (n=17,499) and 20 studies (n=6325) were included in qualitative and quantitative review, respectively. Classification algorithms were able to predict therapeutic outcomes with an overall accuracy of 0.82 (95% confidence interval [CI] of [0.77, 0.87]). Pooled estimates of classification accuracy were significantly greater (p < 0.01) in models informed by multiple data types (e.g., composite of phenomenological patient features and neuroimaging or peripheral gene expression data; pooled proportion [95% CI] = 0.93[0.86, 0.97]) when compared to models with lower-dimension data types (pooledproportion=0.68[0.62,0.74]to0.85[0.81,0.88]).Limitations: Most studies were retrospective; differences in machine learning algorithms and their implementation (e.g., cross-validation, hyperparameter tuning); cannot infer importance of individual variables fed into learning algorithm.Conclusions: Machine learning algorithms provide a powerful conceptual and analytic framework capable of integrating multiple data types and sources. An integrative approach may more effectively model neurobiological components as functional modules of pathophysiology embedded within the complex, social dynamics that influence the phenomenology of mental disorders. [ABSTRACT FROM AUTHOR]

Background: Psychosocial impairment represents an important treatment target in major depressive disorder (MDD). The majority of patients with MDD do not regain premorbid levels of psychosocial functioning despite the resolution of core depressive symptoms. This study aimed to investigate the respective effects of cognitive function and depression severity on impaired psychosocial function in MDD.Methods: Adults aged 18-65 with moderate-to-severe MDD (n = 100) and age-, sex-, and education-matched healthy controls participated in a cross-sectional study validating the THINC-integrated tool (THINC-it), a cognitive screening tool comprised of objective and subjective measures of cognitive function. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and psychosocial function was assessed using the Sheehan Disability Scale (SDS).Results: Subjects with MDD reported greater impairment in psychosocial function than healthy controls, with significant differences in SDS total and domain scores (ps < .01) after controlling for age, sex, and education. Generalized linear models indicated that subjective cognitive function was most strongly associated with SDS total score (RR = .14, p = .01) and SDS domains of work/school (RR = .15, p = .03), family and home responsibilities (RR = .15, p = .02), and economic days lost (RR = .18, p =.03). Depression severity was most strongly associated with SDS social life (RR = .08, p < .01) and economic days underproductive (RR = .07, p < .01). Objective cognitive function was not significantly associated with any SDS outcomes.Limitations: The cross-sectional, observational study design limits temporal inferences. The self-report nature of measures included may have influenced associations observed. Potential medication effects are not noted.Conclusions: Cognitive deficits, as measured by the THINC-it, are associated with significant psychosocial impairment in MDD. These results provide empirical support for the assessment of both subjective and objective measures of cognition, as they are not associated with each other and have differential effects on functional trajectory. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a condition associated with chronic pain in muscles and soft tissues. Extant literature has demonstrated an association between FM, mood symptoms and suicidal behaviour. This systematic review aims to synthesize available literature assessing the prevalence of suicidality in FM populations and qualitatively review the included articles. PsycINFO, Google Scholar and PubMed databases were systematically searched for studies published from database inception to 15 February 2020. Studies were included that assessed FM as a primary or co-primary disease condition, as well as an assessment of suicidal behaviour (suicidal ideations (SI), suicide attempts (SA) and death by suicide (SC)). The quality of the studies was assessed using the Newcastle-Ottawa Scale. 699 unique articles were reviewed for eligibility. Data were derived from nine studies (cross-sectional: k = 5; retrospective cohort: k = 4) that assessed suicidal behaviour in FM participants (SI: k = 5, SC: k = 3, SA: k = 3). Four studies assessing SI found elevated rates of SI among FM participants. Three studies found elevated risk for SC and three studies found increased SA in FM participants relative to the general population. In two studies, this association was no longer significant after adjusting for depression and other psychiatric comorbidities. Preliminary findings suggest that FM is associated with significantly higher risks for SI, SA and SC compared to the general population. There may be unique risk factors underlying suicidal behaviour in FM patients and the interaction between FM and other known risk factors (i.e., mental illness) require further investigation. • Fibromyalgia participants are at an increased risk of attempting suicide. • Suicidal ideation is elevated among participants with fibromyalgia. • Suicide mortality rates are higher in fibromyalgia than the general population. • Depression is highly comorbid with fibromyalgia. [ABSTRACT FROM AUTHOR]