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Therapeutic deficiencies with monoaminergic antidepressants invites the need to identify and develop novel rapid-acting antidepressants. Hitherto, ketamine and esketamine are identified as safe, well-tolerated rapid-acting antidepressants in adults with treatment-resistant depression, and also mitigate measures of suicidality. Psilocybin is a naturally occurring psychoactive alkaloid and non-selective agonist at many serotonin receptors, especially at serotonin 5-HT 2A receptors, and is found in the Psilocybe genus of mushrooms. Preliminary studies with psilocybin have shown therapeutic promise across diverse populations including major depressive disorder. The pharmacodynamic mechanisms mediating the antidepressant and psychedelic effects of psilocybin are currently unknown but are thought to involve the modulation of the serotonergic system, primarily through agonism at the 5-HT 2A receptors and downstream changes in gene expression. It is also established that indirect effects on dopaminergic and glutamatergic systems are contributory, as well as effects at other lower affinity targets. Along with the direct effects on neurochemical systems, psilocybin alters neural circuitry and key brain regions previously implicated in depression, including the default mode network and amygdala. The aim of this review is to synthesize the current understanding of the receptor pharmacology and neuronal mechanisms underlying the psychedelic and putative antidepressant properties of psilocybin., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The emerging roles of ketamine and esketamine as effective rapid-acting antidepressants hold promise for patients suffering from treatment-resistant depression and/or major depressive disorder with suicidality. Practitioner familiarity with common tolerability/safety concerns along with pragmatic prevention and management strategies are needed to reduce patient burden and improve the acceptability and accessibility of these treatments. The most common treatment-emergent adverse events associated with ketamine/esketamine are dissociation, anxiety, nausea, increased blood pressure, and headache. The majority of side effects are mild, transient, dose dependent, and attenuate with subsequent treatments. Patient selection, baseline physical and psychiatric assessments, and an appropriate setting are critical first steps in the prevention and mitigation of adverse events. Patient education and supportive interventions play central roles in the prevention and management of select adverse events. Severe and/or clinically significant adverse effects may necessitate the judicious use of adjunctive medications. Moreover, practitioners must remain vigilant to the potential for abuse liability and long-term adverse events, for which there are insufficient data. This article succinctly reviews common treatment-emergent adverse events of ketamine and esketamine within the context of mood disorders, and provides practical suggestions for prevention and management at point-of-care., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

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.

Background: Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions., Method: 134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report 16 (QIDS-SR 16 ) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR 16 scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR 16 scores after controlling for baseline characteristics., Results: Early improvement post-infusion 1 (β = -3.52, 95% BCa CI [-5.40, -1.78]) and 2 (β = -3.16, 95% BCa CI [-5.75, -1.59]) both significantly predicted QIDS-SR 16 scores post-infusion 4. Early improvers had significantly lower QIDS-SR 16 scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR 16 ) post-infusion 4., Limitations: This is a post-hoc analysis of an open-label study., Conclusion: Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antidepressant medications are the first-line treatment option for moderate to severe major depressive disorder. However, most antidepressants have numerous documented adverse events, including cardiometabolic effects and weight gain, which are major public health concerns. Antidepressant agents provide varying risk of associated weight gain, including significant within-class differences. Some agents, such as mirtazapine, show significant levels of weight gain, while others, such as bupropion, demonstrate weight-loss effects. Current findings suggest the role of histamine and serotonin off-target appetite-promoting pathways in adverse weight-gain effects. Therefore, controlling for undesired weight effects is an important consideration for the selection of antidepressants., (© 2020 The Obesity Society.)

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 (χ 2 = 9.275, p = 0.026), NF-κB (χ 2 = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα) (χ 2 = 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 (χ 2 = 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.

Antidepressant pharmacotherapy dominates current treatment in psychiatry, including treatment for major depressive disorder (MDD). However, the current trial-and-error process of medication selection contributes to treatment failure and unnecessarily exposes patients to lengthy and insufficient treatment trials. Notably, improvements in measures of cognition have been demonstrated to occur early during treatment and prior to improvements in clinical state. Cognitions have been categorized based on emotional valence (i.e., cold versus hot cognitions). Cold cognitions describe cognitive operations that are relevant to the processing of non-emotional information. The current analysis investigates whether early changes in cold cognition can predict response after 8 weeks of vortioxetine treatment in adults with MDD. This was secondary analysis of an 8-week, open-label study. Cognition was assessed at week 0 and week 2 to measure early cognitive change. Depressive symptom severity was assessed at week 0 and week 8 to measure treatment response. Eighty-one subjects were analyzed using binomial logistic regression models. Early change in cognition was a non-significant predictor of response (p = 0.845, SE = 0.599, OR = 1.124), which may have resulted from high data variability. The overall predictive accuracy of the model was low (sensitivity = 37.5%, specificity = 89.8%, PPV = 70.6%, NPV = 68.8%). Future studies should include larger samples and stratify patients based on potentially moderating variables, such as baseline cognitive impairment and occupation. Stratification would likely produce more homogenous samples, reducing the amount of variability observed for early cognitive change., Competing Interests: Declaration of Competing Interest Roger S. McIntyre is a consultant to speak on behalf for, and/or has received research support from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Stanley Medical Research Institute, and CIHR/GACD/Chinese National Natural Research Foundation. All other authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

Context: The effect of antidepressant (ATD) use on mortality in patients with diabetes mellitus (DM) has not yet been sufficiently studied, although comorbid depression is common in this population., Objective: To explore the impact of ATDs on mortality among DM patients., Design: A retrospective cohort study in a national database., Setting: This population-based study used the National Health Insurance Research Database in Taiwan. Since 2000, we identified 53,412 cases of newly diagnosed patients with DM and depression. Patient cases were followed for assessing mortality until 2013., Main Outcome Measure: The association between mortality and ATD use was explored adjusting for cumulative dosing., Results: Using the time-dependent Cox regression model, ATD use was associated with significantly reduced mortality among patients with DM [in the highest dose group: hazard ratio (HR), 0.65; 95% CI, 0.59 to 0.71]. Further analysis showed that differences in mortality existed across ATD categories: selective serotonin reuptake inhibitors (HR, 0.63; 95% CI, 0.56 to 0.71), serotonin-norepinephrine reuptake inhibitors (HR, 0.58; 95% CI, 0.44 to 0.78), norepinephrine-dopamine reuptake inhibitors (HR, 0.20; 95% CI, 0.07 to 0.63), mirtazapine (HR, 0.60; 95% CI, 0.45 to 0.82), tricyclic/tetracyclic antidepressants (HR, 0.73; 95% CI, 0.54 to 0.97), and trazodone (HR, 0.52; 95% CI, 0.29 to 0.91). However, reversible inhibitor of monoamine oxidase A (RIMA) was found to be associated with an increase, rather than a decrease, in total mortality (HR, 1.48; 95% CI, 1.09 to 1.99)., Conclusion: Most ATDs, but not RIMA, were associated with significantly reduced mortality among a population with comorbid DM and depression., (Copyright © 2019 Endocrine Society.)

Background: 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., Methods: 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., Results: 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 (χ 2  = 1.137) and magnitude of reward (χ 2  = 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., Conclusion: 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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018. Published by Elsevier B.V.)

Background: Pharmacogenomic testing has recently become scalable and available to guide the treatment of major depressive disorder (MDD). The objective of the current meta-analysis was to determine if guidance from pharmacogenomic testing results in relatively higher rates of remission and response compared to treatment as usual (i.e., 'unguided' trial-and-error method) in adults with MDD., Methods: Article databases were systematically searched from inception to December 2, 2017 for human studies assessing the clinical utility of pharmacogenomics in the acute treatment of MDD. Treatment outcomes in MDD may be defined continuously or categorically (i.e., response/remission). Herein, we delimit our focus on categorical outcomes. Using a random-effects model, data was pooled to determine the risk ratio (RR) of response and remission, respectively, in the pharmacogenomic-guided treatment group compared to the unguided group., Results: Four randomized controlled trials (RCTs) and two open-label, controlled cohort studies were included. The pooled RR for treatment response comparing guided versus unguided treatment was 1.36 (95% confidence interval [CI] = 1.14 to 1.62; p = 0.0006; n = 799) in favour of guided treatment. The pooled RR for remission was 1.74 (95%CI = 1.09 to 2.77; p = 0.02, n = 735) also in favour of guided treatment. Heterogeneity in study results suggest that different genetic tests may variably impact response and remission rates., Limitations: The available evidence is limited, with significant methodological deficiencies., Conclusion: The current analysis provides preliminary support for improved response and remission rates in MDD when treatment is guided by pharmacogenomics., (Copyright © 2018. Published by Elsevier B.V.)

Background: Despite the widespread use of antidepressants in clinical practice, the current trial-and-error approach to medication selection contributes to treatment failure and underscores the need to identify reliable predictors of antidepressant response. Since changes in measures of cognition have been reported to occur early in treatment and prior to improvements in overall mood symptoms, the present review aims to determine whether early changes in measures of cognition can predict response in individuals with MDD., Methods: A systematic review of studies evaluating early cognitive change as a predictor of later treatment response in MDD was conducted using PubMed/Medline, Embase and PsychINFO., Results: A total of seven articles were identified. The available evidence suggests the early changes in cognition may predict treatment response in individuals with MDD. This was shown across antidepressant classes (i.e., SSRIs, SNRIs, NRIs, melatonergic antidepressants) and forms of therapy (i.e., pharmacotherapy, rTMS). The results depict an emerging trend towards early changes in facial emotion recognition (i.e., a hot cognitive process) as a predictor of treatment outcome., Limitations: Our qualitative analysis reflects a very limited number of studies. Moreover, there was significant heterogeneity in the evaluation of cognition across studies. Future research should aim to parse out this heterogeneity by evaluating the relative predictive value of different measures of cognition., Conclusion: The identification of reliable early treatment predictors of antidepressant response would be clinically significant, enabling clinicians to more accurately evaluate the efficacy of selected treatment avenues., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD., Method: Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to January 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors , and response and/or remission ., Results: Multiple baseline pretreatment predictors of response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels), polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of alcohol use disorder were the most replicated predictors., Conclusions: A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.

Introduction: Work-related disability and productivity loss in Major Depressive Disorder (MDD) are critical determinants of patient quality of life and contribute significantly to the human and economic costs of MDD. Notwithstanding the return to work and pre-morbid levels of functioning as a critical therapeutic objective among individuals with MDD, it is unclear whether antidepressant treatment significantly and reliably improves measures of workplace functioning. Herein, we investigate to what extent antidepressant treatment improves workplace functioning among adults with MDD., Methods: We conducted a systematic review of randomized, double-blind, placebo-controlled or active comparator clinical trials primarily or secondarily investigating the efficacy of antidepressant agents on subjective ratings of workplace functioning and/or measures of work absence., Results: Thirteen placebo-controlled and four active comparator clinical trials reported on the efficacy of agomelatine, bupropion, desvenlafaxine, duloxetine, fluoxetine, levomilnacipran, paroxetine, sertraline, venlafaxine, or vortioxetine on subjective measures of workplace impairment. Overall, antidepressant treatment improved standardized measures of workplace functioning (e.g., Sheehan Disability Scale-work item). One placebo-controlled trial of agomelatine and one clinical trial comparing the efficacy of vortioxetine to that of venlafaxine had mixed results on measures of work absence., Limitations: Included interventional trials evaluated work-related disability as a secondary outcome using subjective rating scales., Conclusion: Extant data suggest that antidepressant treatment improves workplace outcomes in MDD. The capability of antidepressants in improving measures of workplace functioning should be considered in cost-benefit analyses to better inform cost-modelling studies pertaining to antidepressant therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Using a nation-wide, population-based dataset, we aimed to investigate the risk of road injury among individuals with bipolar disorder (BD) compared to individuals without BD. In addition, we investigated the putative moderating effects of prescription for lithium, anticonvulsants, antidepressants, and/or first- or second-generation antipsychotic agents on the association between BD and risk of road injury., Method: As part of an16-year longitudinal cohort study, we compared the risk of road injuries among study subjects aged 16 and above with a diagnosis of BD, with ten age- and sex-matched sample of individuals without BD. Individuals were compared on measures of incidence on road injuries using medical claims data based on the ICD-9-CM codes: E800~807, E810~817, E819~830, E840~848. Time dependent Cox regression models were used to adjust for time-varying covariates such as age, and medication uses. Hazard ratios before and after adjusting for age, sex, other comorbidities, and drug use were calculated., Results: 3953 people with BD were matched with 39,530 controls from general population. Adjusted hazard ratios revealed a 1.66-fold (95% CI 1.40-1.97) increase in risk of road injuries among bipolar subjects when compared to controls. Female gender, older age (i.e. over 80), residence in areas of highest levels of urbanization, and use of antidepressants were associated with a lower risk of road injuries., Conclusions: In this large, national, population-based cohort, BD was associated with an elevated risk of road injuries. However, prescriptions of antidepressants might help mitigate the foregoing risk., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is the second leading cancer-related cause of mortality worldwide. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are commonly used worldwide. Available evidence investigating the association between SSRIs use and HCC risk is limited., Objective: The present study aimed to investigate if the effect of all kinds of SSRIs on HCC was the same or not using population-based study., Methods: The nationwide population-based study herein using Taiwan's National Health Insurance Research Database included a total of 59 859 cases with HCC and 285 124 matched controls. Conditional logistic regression analyses were adjusted for confounding variables., Results: All common kinds of SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine were associated with lower HCC risk, and the findings were dose-dependent (eg, fluoxetine: 1-28 DDD [defined daily dose]: adjusted odds ratio [aOR]: 0.81, 95% confidence interval [CI], 0.73-0.89; 29-365 DDD: aOR: 0.71, 95% CI, 0.64-0.79; and ≥366 DDD: aOR: 0.55, 95% CI, 0.45-0.67) (P for trend < .001)., Conclusions: All kinds of SSRIs were associated with decreased risk of HCC., (Copyright © 2017 John Wiley & Sons, Ltd.)

Hepatocellular carcinoma (HCC) is highly prevalent in Asia. Antidepressants have been associated with increase in hepatocellular carcinoma. This is the first Asian population-based study to evaluate the association between antidepressant use and risk of HCC. Based on Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study. A total of 49,998 cases with HCC were identified and paired with 244,236 randomly selected controls. The data was analyzed via the conditional logistic regression model adjusting for several confounding factors. Use of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) was associated with lower risk for HCC. No apparent association was found between use of other classes of antidepressants and HCC, including monoamine oxidase inhibitors (MAOIs), serotonin norepinephrine reuptake inhibitors (SNRIs), trazodone, mirtazapine and bupropion. The findings of a protective effect of TCAs and SSRIs for HCC should be interpreted with caution and warrants further research.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Background: Selective serotonin reuptake inhibitors (SSRIs) are one of the most commonly prescribed classes of antidepressants. Glaucoma is the second leading cause of blindness globally and iatrogenic glaucoma has been implicated across disparate medication classes. Available studies that have sought to determine the association between SSRI exposure and glaucoma have provided mixed results. The aim of the study herein was to investigate whether an association exists between SSRI exposure and glaucoma incidence., Methods: Glaucoma cases were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of glaucoma between 1997 and 2009. The date wherein the cases were diagnosed with glaucoma was operationalized as the index date. The control group was comprised of individuals within the database who were not diagnosed with glaucoma. 15,865 glaucoma cases were compared to 77,014 sex-, age-, residence- and insurance premium-matched controls on measures of prescribed duration and dosage of SSRIs up to 365 days before index date to proxy SSRIs exposure., Results: Individuals receiving SSRIs were at greater risk of glaucoma incidence (OR = 1.39; 95% CI = 1.29-1.50); the foregoing increased likelihood was reduced after adjusting for confounding variables (aOR = 1.09; 95% CI = 1.00,1.18). SSRI treatment of longer duration (i.e. >365 days) and higher doses (≥1 defined daily dose) were associated with greater risk of glaucoma incidence (aOR = 1.36; 95% CI = 1.08-1.71). Subgroup analysis showed that the effect of SSRIs on glaucoma was limited to individuals younger than 65 years of age (aOR = 1.37; 95% CI = 1.25-1.50), without diabetes (aOR = 1.39; 95% CI = 1.27-1.52), without hypertension (aOR = 1.46; 95% CI = 1.31-1.63) or hypercholesterolemia (aOR = 1.35; 95% CI = 1.23-1.48)., Conclusion: Treatment with SSRIs was associated with greater risk of having a diagnosis of glaucoma, particularly in individuals with longer duration and/or higher average dose of SSRI. Our findings suggest that individuals receiving SSRIs treatment for extended periods of time and/or at relatively higher therapeutic doses should be monitored for symptoms associated with glaucoma.

Background: Experimental evidence indicates that serotonin is associated with both proliferative and pro-carcinogenic effects on colorectal tumors. The present study aims to investigate the associations between antidepressant use and colorectal cancer in an epidemiological sample., Methods: We conducted a population-based case-control study utilizing Taiwan's National Health Insurance Research Database (NHIRD). We identified 49,342 cases with colorectal cancer and 240,985 controls between 1997 and 2008. We conducted conditional logistic regression analyses to assess the association between antidepressant use and colorectal cancer risk. Sensitivity analyses were conducted to assess whether genotoxic antidepressants (i.e. antidepressants which may exert procarcinogenic effects) would increase risk for colorectal cancer., Results: Selective serotonin reuptake inhibitors (adjusted OR=1.00, 95% CI=0.94-1.06), tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and serotonin antagonist and reuptake inhibitors were not associated with increased incidence of colorectal cancer. Monoamine oxidase inhibitors were, however, associated with an increased incidence of colorectal cancer (adjusted OR=1.22, 95% CI=1.06-1.41). Higher cumulative dose of mirtazapine was associated with a decreased incidence of colorectal cancer (adjusted OR=0.39, 95% CI=0.17-0.90). A small sample size of individuals who received mirtazapine, however, precludes definitive conclusions regarding protective effects with mirtazapine., Limitations: We could not discern the effects of obesity and other risk factors for colorectal cancer from the NHIRD., Conclusions: Contemporary first-line antidepressants (i.e. SSRI, SNRI), as well as older agents (i.e. TCA), are not associated with increased incidence of colorectal cancer., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Cognitive dysfunction is a core transdiagnostic domain of Major Depressive Disorder (MDD) and is a principal determinant of functional recovery. However, it has been insufficiently targeted within the current therapeutic framework for MDD., Objective: To highlight these unmet cognitive needs in MDD., Method: An article search was conducted using PubMed from inception to November 2016: Major Depressive Disorder (and/or variant) was cross-referenced with the following terms: antidepressants, augmentation, cognition, cognitive deficits, cognitive dysfunction, functional outcomes, mechanism of action, and treatment. Articles informed by observational studies, clinical trials, and review articles relevant to the discussion of cognition and cognitive impairment in MDD were included for review. Additional terms and citations previously not identified in the initial search were obtained from a manual review of article reference lists., Results: Cognitive deficits in MDD are replicable, non-specific, and clinically significant. Abnormalities in the domains of learning/memory, executive function, attention, concentration, and processing speed are consistently reported. Only two antidepressants (i.e., duloxetine and vortioxetine) have established procognitive effects utilizing rigorous methodology in MDD. Most antidepressants improve cognitive function(s), but the extent to which they directly exert pro-cognitive effects is not yet understood., Conclusion: Cognitive dysfunction in MDD is a principal determinant of patient-reported outcomes (e.g., psychosocial function). Healthcare providers are encouraged to screen for cognitive dysfunction in MDD and familiarize themselves with the efficacy profiles of antidepressants on disparate cognitive domains., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

To our knowledge, the association between antidepressant exposure and endometrial cancer has not been previously explored. Herein, we aim to investigate the association between antidepressant prescription, including novel antidepressants, and the risk for endometrial cancer in a population-based study.Data for the analysis were derived from National Health Insurance Research Database. We identified 8392 cases with a diagnosis of endometrial cancer and 82,432 matched controls. A conditional logistic regression model was used, with adjusting for potentially confounding variables (e.g., comorbid psychiatric diseases, comorbid physical diseases, and other medications). Risk for endometrial cancer in the population-based study sample was categorized by, and assessed as a function of, antidepressant prescription and cumulative dosage.We report no association between endometrial cancer incidence and antidepressant prescription, including those prescribed either selective serotonin reuptake inhibitors (adjusted odds ratio [OR] = 0.98; 95% confidence interval [CI], 0.84-1.15) or serotonin norepinephrine reuptake inhibitors (adjusted OR = 1.14; 95% CI, 0.76-1.71). We also did not identify an association between higher cumulative doses of antidepressant prescription and endometrial cancer.There was no association between antidepressant prescription and endometrial cancer., Competing Interests: The authors have no conflicts of interest to disclose.

Purpose of Review: Cognitive dysfunction in major depressive disorder (MDD) is common, pervasive across multiple subdomains of cognitive function, and is a principle determinant of health outcomes from patient, provider, and societal perspectives. The overarching aim herein is to provide rationale for the evaluation, measurement, and specific treatment of cognitive function in adults with MDD., Recent Findings: Evidence indicates that cognitive dysfunction in MDD is a critical mediator of workplace disability. Systematic evaluation and measurement of cognitive function is warranted. All individuals with MDD should be evaluated for both objective and subjective cognitive dysfunction. Although differences between antidepressants in overall antidepressant efficacy are not consistent, unequivocal differences in improving measures of cognitive function are noted with evidence indicating that vortioxetine has multidomain cognitive benefits, whereas duloxetine has replicated evidence of improving measures of acquisition and recall (i.e. memory)., Summary: The probability of functional recovery in MDD is likely to increase with interventions that specifically target and improve measures of cognitive function. Clinicians are encouraged to evaluate patients using a validated measure (e.g. the THINC-it tool); prevention of cognitive impairment in MDD is a critical therapeutic priority. Vortioxetine and duloxetine benefit measures of cognitive function in MDD. Preliminary evidence of beneficial effects on cognitive emotional processing are reported with ketamine.

Background: To our knowledge, no epidemiological study has reported on whether an association between antidepressant exposure and gastric cancer exists. Herein, we aim to investigate the possible association between antidepressant exposure and gastric cancer incidence., Methods: Using a nested case-control design, we identified 26289 cases with gastric cancer and 127984 controls from Taiwan's National Health Insurance Research Database (NHIRD). The data were analyzed using a conditional logistic regression model adjusting for possible confounding variables., Results: We found antidepressant use did not increase the risk of gastric cancer. The lack of an association between antidepressant prescription and elevated gastric cancer incidence was apparent for across selective serotonin-reuptake inhibitors (SSRIs), tricyclic agents (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), reversible inhibitors of monoamine oxidase A (RIMA), trazodone, mirtazapine and bupropion. There were slightly decreased gastric cancer risks of SSRIs use (≧28 DDD group, adjusted OR = 0.87; 95% CI = 0.78-0.96). Sensitive analysis showed SSRIs, TCAs, and SNRIs did not increase gastric cancer risks significantly even in the group with peptic ulcer history., Conclusions: An association between antidepressant exposure and gastric cancer was not apparent in this analysis.

To our knowledge, no prior population-based study has been published wherein the primary aim was to evaluate whether an association between psychotropic drug prescription and cervical cancer exists. Herein we have conducted the first study that primarily aimed to determine the association between antidepressants use and risk of invasive cervical cancer in the general population.This is a population-based study utilizing Taiwan's National Health Insurance Research Database. We identified 26,262 cases with invasive cervical cancer and 129,490 controls. We adopted the conditional logistic regression model as the statistical method and adjusted for potential confounding factors.The prescription of selective serotonin reuptake inhibitors (SSRIs) (adjusted OR = 0.93, 95% CI = 0.84-1.04), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine and bupropion, adjusting for cumulative dose, was not associated with an increased, or decreased, risk for invasive cervical cancer. An association between trazodone prescription and invasive cervical cancer was observed (adjusted OR = 1.22, 95% CI = 1.03-1.43).An association between the major classes of antidepressants and invasive cervical cancer was not observed herein. Our preliminary finding regarding a possible association between trazodone and cervical cancer requires replication.

Hitherto no therapeutic has received regulatory approval for the treatment of post-COVID-19 condition (PCC). Cognitive deficits, mood symptoms and significant reduction in health-related quality of life (HRQoL) are highly replicated and debilitating aspects of PCC. We sought to determine the impact of vortioxetine on the foregoing symptoms and HRQoL in persons living with PCC. An 8-week randomized, double-blind, placebo-controlled study of adults ≥ 18 years of age residing in Canada and who are experiencing symptoms of World Health Organization (WHO)-defined PCC, with a history of confirmed SARS-CoV-2 infection, was conducted. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled (487 invited: 121 ineligible and 59 eligible but declined participation; 307 cleared pre-screening stage), a total of 149 participants were randomized (1:1) to receive either vortioxetine (5–20 mg, n = 75) or placebo (n = 74) daily for 8 weeks of double-blind treatment (i.e. end point). The primary outcome was the change from baseline-to-end point in the Digit Symbol Substitution Test. Secondary outcomes included the effect on depressive symptoms and HRQoL, as measured by changes from baseline-to-end point on the Quick Inventory of Depressive Symptomatology 16-item and WHO Wellbeing Scale 5-item, respectively. A total of 68 (90.7%) participants randomized to vortioxetine and 73 (98.6%) participants randomized to placebo completed all 8 weeks. Between-group analysis did not show a significant difference in the overall change in cognitive function [ P = 0.361, 95% confidence interval (CI) (−0.179, 0.492)]. However, in the fully adjusted model, a significant treatment × time interaction was observed in favour of vortioxetine treatment with baseline c-reactive protein (CRP) as a moderator (P = 0.012). In addition, a significant improvement in Digit Symbol Substitution Test scores were observed in vortioxetine versus placebo treated participants in those whose baseline CRP was above the mean (P = 0.045). Moreover, significant improvement was obtained in measures of depressive symptoms [ P < 0.001, 95% CI (−4.378, −2.323)] and HRQoL [ P < 0.001, 95% CI (2.297, 4.647)] in vortioxetine-treated participants and between the treatment groups [depressive symptoms: P = 0.026, 95% CI (−2.847, −0.185); HRQoL: P = 0.004, 95% CI (0.774, 3.938)]. Although vortioxetine did not improve cognitive function in the unadjusted model, when adjusting for CRP, a significant pro-cognitive effect was observed; antidepressant effects and improvement in HRQoL in this debilitating disorder were also noted. [ABSTRACT FROM AUTHOR]