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Background: The clinical effects of smartphone‐based interventions for bipolar disorder (BD) have yet to be established. Objectives: To examine the efficacy of smartphone‐based interventions in BD and how the included studies reported user‐engagement indicators. Methods: We conducted a systematic search on January 24, 2022, in PubMed, Scopus, Embase, APA PsycINFO, and Web of Science. We used random‐effects meta‐analysis to calculate the standardized difference (Hedges' g) in pre‐post change scores between smartphone intervention and control conditions. The study was pre‐registered with PROSPERO (CRD42021226668). Results: The literature search identified 6034 studies. Thirteen articles fulfilled the selection criteria. We included seven RCTs and performed meta‐analyses comparing the pre‐post change in depressive and (hypo)manic symptom severity, functioning, quality of life, and perceived stress between smartphone interventions and control conditions. There was significant heterogeneity among studies and no meta‐analysis reached statistical significance. Results were also inconclusive regarding affective relapses and psychiatric readmissions. All studies reported positive user‐engagement indicators. Conclusion: We did not find evidence to support that smartphone interventions may reduce the severity of depressive or manic symptoms in BD. The high heterogeneity of studies supports the need for expert consensus to establish ideally how studies should be designed and the use of more sensitive outcomes, such as affective relapses and psychiatric hospitalizations, as well as the quantification of mood instability. The ISBD Big Data Task Force provides preliminary recommendations to reduce the heterogeneity and achieve more valid evidence in the field. [ABSTRACT FROM AUTHOR]

Background: Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) may reduce appetite and caloric intake and may be able to play a role as an adjunct treatment for obesity. Stimulation of this brain area is also used for the treatment of depression, which shares a common pathophysiology with obesity. As a result, the effect of tDCS on mental health and its impact on the quality of life of subjects with excess weight needs to be addressed. Objective: To assess the effect of daily tDCS of the right DLPFC on mood, daytime sleepiness, anxiety and quality of life in subjects with excess weight on a hypocaloric diet. Methods: We randomly assigned 28 subjects to receive 20 sessions of active or sham tDCS over the right DLPFC for 20 consecutive weekdays. The severity of depressive and anxiety symptoms was assessed by the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory-State (STAI-S). Sleepiness was measured by a daytime sleepiness questionnaire (DSQ), and quality of life was measured by the 36-Item Short Form Health Survey (SF-36). Results: There were no significant changes in BDI, STAI-S and DSQ scores between groups, even after adjustments for the use of antidepressant medications and changes in body weight. There were also no significant changes in different subscales of the SF-36 quality of life questionnaire between groups. Conclusion: Repetitive tDCS on the right DLPFC is not associated with impairment in mental health or quality of life in overweight and obese subjects. [ABSTRACT FROM AUTHOR]

Since the COVID-19 outbreak, studies across diverse countries have strongly pointed toward the emergence of a mental health crisis, with a dramatic increase in the prevalence of depressive psychopathology and suicidal tendencies. Vitamin D deficiency has been associated with an increased risk of mental health problems as well as individual responses to stress. Studies have discussed the relationship between low serum vitamin D concentrations and depressive symptoms, suggesting that maintaining adequate concentrations of serum vitamin D seems to have a protective effect against it. Vitamin D was found to contribute to improved serotonergic neurotransmission in the experimental model of depression by regulating serotonin metabolism. The signaling of 1,25-dihydroxyvitamin D3, the active form of vitamin D, through vitamin D receptor (VDR) induces the expression of the gene of tryptophan hydroxylase 2 (TPH2), influences the expression of serotonin reuptake transporter (SERT) as well as the levels of monoamine oxidase-A (MAO-A), the enzyme responsible for serotonin catabolism. Vitamin D also presents a relevant link with chronobiological interplay, which could influence the development of depressive symptoms when unbalance between light-dark cycles occurs. In this Perspective, we discussed the significant role of vitamin D in the elevation of stress-related depressive symptoms during the COVID-19 pandemic. It is suggested that vitamin D monitoring and, when deficiency is detected, supplementation could be considered as an important healthcare measure while lockdown and social isolation procedures last during the COVID-19 pandemic. Role of vitamin D in the development of depressive symptoms. The synthesis of vitamin D from sunlight is impaired by lockdown and social distance measures imposed by the governments around the world during COVID-10 pandemic. Endogenous vitamin D synthesis initiates in the skin when 7-dehydrocholesterol (7-DHC) is converted in pre-vitamin D3 and then vitamin D3 [25(OH)D3]. It is transported through blood circulation by the vitamin D binding protein (VDBP) to the liver, the kidney, and the brain, where can be converted in its the active form [1,25(OH)2D3]. In the brain, the biological effects of 1,25(OH)2D3 are largely mediated by vitamin D receptor (VDR) through genomic mechanisms, which influence several aspects of serotonin metabolism, such as increasing serotonin synthesis by induction of the tryptophan hydroxylase 2 (TPH2) gene expression; influencing the expression of serotonin reuptake transporter (SERT) and the levels of monoamine oxidase-A (MAO-A), responsible to serotonin catabolism; and indirectly may regulate the synthesis of melatonin that improve the circadian rhythm. This mechanism can be impaired during social isolation and consequent reduction of vitamin D due to low sun exposure during the pandemic, which could contribute to the development of depressive symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Psychiatry is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Major depressive disorder (MDD) is a highly prevalent and disabling condition for which the currently available treatments are not fully effective. Existing unmet needs include rapid onset of action and optimal management of concurrent agitation. Dexmedetomidine (DEX) is a selective and potent α2-adrenergic receptor (α2-AR) agonist, with unique pharmacokinetic and pharmacodynamic properties. In this review, we discuss pre-clinical and clinical studies which focused on DEX in the context of its putative antidepressant effects for the management of MDD. Preliminary data support DEX as an antidepressant with fast onset of action, which would be especially helpful for patients experiencing treatment resistant depression, and agitation. We further explore the mechanistic and clinical implications of considering DEX as a putative antidepressant agent, and the next steps to explore the efficacy of low dose DEX infusion among patients with treatment resistant depression. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms – for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant. [ABSTRACT FROM AUTHOR]

Objectives: Metabolically based distinctions for disturbances in glucose and insulin may provide meaningful insights both clinically and mechanistically. Methods: Data were derived from 352 subjects of previously completed clinical studies with a mood disorder (MD) (bipolar disorder: n = 179, major depressive disorder: n = 173) and 218 healthy controls from the Comprehensive Assessment of Long‐Term Effects of Reducing Intake of Energy. We conducted a factor analysis to replicate a priori dissociable factors informed by glucose and insulin levels and indices of insulin resistance and beta‐cell function: elevated insulin and insulin resistance ("insulin‐IR"), and increased fasting glucose and reduced insulin secretion ("glucotoxicity"). Cluster analyses were conducted, separately in men and women, to evaluate the clinical relevance of subtyping individuals with MDs using insulin‐IR and glucotoxicity (GT) factor scores. Results: Factors insulin‐IR and GT explained 92.64% and 92.09% of the variance in men and women respectively. Three clusters were replicated in men and women separately: metabolically healthy (MH), high GT, and insulin‐resistant (IR). After adjusting for age, gender, study cohort, MD diagnosis, and antipsychotics use, body mass index (BMI) and mean arterial pressure were higher in IR‐ vs GT‐ or MH‐clustered individuals; GT‐clustered individuals had more metabolic syndrome components and higher C‐reactive protein. Glucotoxic‐clustered subjects reported greater impairments in cognitive function and global functioning when compared to MH‐ or IR‐clustered subjects. Conclusions: Using simple, cost‐effective, and accessible measures, we identified stable, gender‐convergent, subgroups of individuals that significantly diverged on measures of cognitive dysfunction, self‐reported anhedonia, functional disability, BMI, and blood pressure. [ABSTRACT FROM AUTHOR]

• Digital phenotyping is the continuous acquisition of data on human‐machine interactions and behaviors via smartphones/personal devices. • Using digital phenotypes for the assessment of mood disorders may help identify clinically meaningful inter/intra-individual variabilities. • Integration of digital phenotypes with other traditional biomarkers may increase the predictive power of critical outcomes in mood disorders. Major Depressive Disorder (MDD) and bipolar disorder (BD) are still under recognized and undertreated, especially in primary care settings. One of the challenges faced by clinicians is the remarkable inter-individual variability among patients with these conditions. In addition, each patient with MDD and BD experiences a unique pattern of longitudinal changes across time, i.e., intra-individual variability can also be problematic. The immense amount of data generated and collected through the use of smartphones or personal devices offers an opportunity to obtain continuous and reliable information on each individual's behavior, a less burdensome way to capture both intra and inter-individual variability over time. Digital phenotypes (DP) are a promising strategy to be integrated with other "Omics" platforms for prediction of relevant outcomes in mood disorders, including but not restricted to, relapse, recurrence, cognitive decline and functional impairment. Despite existing limitations and some skepticism, digital phenotyping represents a field in great expansion and might eventually constitute a feasible strategy in biomarkers research for mood disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Heterogeneity in response to conventional antidepressants is a well-recognized limitation of evidence-based pharmacological treatments of major depressive disorder (MDD). Abnormal activation of inflammatory pathways is postulated as one likely mechanism contributing to treatment resistance in MDD. In a subset of depressed patients, the balance between pro- and anti-inflammatory cytokines is thought to be altered, causing mood symptoms due to inflammation, as seen in co-morbid depression associated with inflammatory conditions (e.g. psoriasis, hepatitis C, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis). The objectives of the current narrative review are to critically evaluate the literature about the effects of cytokine blockers on clinical outcomes in MDD and in the reduction of depressive symptom severity in individuals using these medications primarily to treat inflammatory conditions. A small number of clinical trials assessing the effects of cytokine blockers for depression and depressive symptoms have been completed. These trials suggest that in individuals with immune dysfunction (e.g. elevated pro-inflammatory cytokine levels), cytokine blockers may allow for improved clinical outcomes in MDD that would not be achievable with current conventional antidepressants alone. Additional well-designed clinical trials to assess the clinical utility of anti-inflammatory medications for the treatment of depression and depressive symptoms are merited. Further, the use of anti-inflammatories show promise for disease modifying effects that may alter illness trajectory, rather than solely ameliorating current mood symptoms. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) and bipolar disorder (BD) are among the leading causes of burden and disability worldwide. Despite intensified research efforts to improve the treatment options and remission rates in mood disorders, no disease modifying treatment exists for these disorders. Accumulating evidence implicates the involvement of the gut microbiota in processes relevant to etiopathology of central nervous system-based disorders. The objective of this article was to critically evaluate the evidence supporting the link between gastrointestinal microbiota and mood disorders and to discuss the potential benefits of using probiotics in the treatment of MDD and BD. The concept of psychobiotics, which is bacterial- based interventions with mental health benefit, is emerging in the field. On the other hand, while probiotics might potentially represent a significant advance, specific roles of microbiota in the pathophysiology of mood disorders still need further investigation along with intervention studies. [ABSTRACT FROM AUTHOR]

Copyright of Trends in Psychiatry & Psychotherapy is the property of Associacao de Psiquiatria do Rio Grande do Sul and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: Several lines of evidence suggest that major depressive disorder is associated with an inflammatory status. Tumor necrosis factor-α has been investigated as a potential molecular target in mood disorders. Tumor necrosis factor-α exerts its activity through binding to specific cell membrane receptors named as TNFR1 and TNFR2. The aim of the present study was to investigate soluble plasma TNFR1 (sTNFR1) and TNFR2 levels (sTNFR2) in major depressive disorder patients. Methods: Female outpatients with major depressive disorder ( n = 30) were compared with a healthy control group ( n = 19). Severity of depressive symptoms was evaluated on Beck Depression Inventory; post-traumatic stress disorder (PTSD) symptoms were evaluated on PTSD Checklist–Civilian Version; and childhood abuse and neglect on the Childhood Trauma Questionnaire. Plasma tumor necrosis factor-α and its soluble receptors were measured by ELISA. Results: Patients had no changes in tumor necrosis factor-α concentrations but did have increased sTNFR1 ( P < 0.001) and sTNFR2 ( P < 0.001) levels compared to controls. Plasma level of sTNFR1 was positively predicted by age (B = 0.25, P = 0.05) and PTSD-like symptoms (B = 0.41, P = 0.002) and plasma levels of sTNFR2 by depression severity (B = 0.67, P < 0.001). Conclusions: Soluble tumor necrosis factor-α receptors could be reliable markers of inflammatory activity in major depression. [ABSTRACT FROM AUTHOR]

Epidemiological and mechanistic studies support the association between Diabetes Mellitus and mood disorders, such as Major Depressive Disorder and Bipolar Disorder. This association is especially relevant in specific domains of depressive psychopathology, such as disturbances in reward systems and cognitive functions. Several anti-hyperglycemic agents have demonstrated effects on depressive symptoms and cognitive decline and this efficacy is probably the result of an action in shared brain targets between these two groups of conditions. These medications include subcutaneous insulin, intranasal insulin, metformin, and liraglutide. The study of the mechanisms involved in the relationship between Diabetes Mellitus and mood disorders offers a new avenue of investigation, and this understanding can be applied when examining whether antidiabetic agents can be repurposed as antidepressants and mood stabilizers. The objective of this narrative review is to critically appraise the literature surrounding drugs commonly used as anti-hyperglycemic agents and their effects on the brain, while discussing their potential as a new treatment for mental illnesses, and specifically, mood disorders. • Findings on metabolism opened new avenues for repurposing drugs used for the treatment of general illnesses. • Depression and bipolar disorder are associated with the risk of subsequent development of diabetes. • The association between mental illnesses and diabetes opened a new avenue of treatment. [ABSTRACT FROM AUTHOR]

Suicide accounts for approximately 800,000 deaths per year globally. Previous research has shown that intranasal esketamine and intravenous ketamine can rapidly decrease the severity of depressive symptoms and suicidal ideation. However, the majority of clinical trials excluded individuals with moderate to high baseline suicidality scores (e.g., suicidal ideation with plan/intent at the time of recruitment). The current review aims to evaluate the effect of esketamine and ketamine in patients with suicidal ideation at baseline. A systematic search was conducted on EMBASE, PsychInfo and PubMed from inception to July 2020 following the PRISMA guidelines. 15 studies met inclusion criteria. Results from esketamine trials did not demonstrate antisuicidal effects, as between-group differences were not found. Intravenous ketamine appeared to rapidly decrease the severity of suicidal ideation and depressive symptoms in individuals with baseline suicidal ideation, though retrospective studies suggest that these effects may be short-lasting. During the double-blind treatment phases, 2.4% of patients from the treatment groups and 1.5% of patients from control groups attempted suicide, with zero deaths by suicide in both the treatment and control groups during this phase. Based on the overall pooled samples, studies were assessed to be relatively safe, and the continual inclusion of this study population in future clinical trials is encouraged. Future research should aim to assess the longitudinal efficacy of ketamine in patients with baseline suicidality. • IV ketamine is associated with rapid & robust decreases in suicidal ideations. • Esketamine has antidepressant effects in patients with baseline suicidality. • The proportion of suicide attempts and death by suicide during these trials was low. • Future trials should consider including patients with baseline suicidality. [ABSTRACT FROM AUTHOR]

Objectives: To explore differences in adipokine levels (i.e., leptin and adiponectin levels) between adults with Major Depressive Disorder (MDD) and healthy controls (HC), and to discuss the possible role of adipokine regulation in the development and progression of MDD.Methods: A systematic review and meta-analysis were conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. A systematic search was conducted for all English and Chinese peer-reviewed articles from inception to November 2017. A random effects model was used to calculate the standardized mean difference (SMD) of leptin and/or adiponectin levels in subjects diagnosed with MDD versus HC within a 95% confidence interval (CI).Results: Thirty-three studies were included in this meta-analysis. In total, 4,372 (52.3%) subjects with MDD and 3,984 (47.7%) HC were compared. We identified significant lower adiponectin levels in MDD compared to HC with a small effect size (ES) (SMD = -0.25; 95% CI: -0.48, -0.02; P < 0.001). However, no significant difference was observed in leptin levels between MDD subjects and HC (SMD = 0.13; 95% CI: -0.06, 0.31; P = 0.170). The heterogeneity in the results of our meta-analysis could not be completely explained by dividing subjects into subgroups. Results from subgroup analyses suggested that studies involving samples with BMI ≥ 25 had lower adiponectin levels in subjects with MDD compared to HC, and older age samples (i.e., age ≥ 40) with BMI ≥ 25 had both higher leptin levels and lower adiponectin levels in MDD subjects as compared to HC.Limitations: The heterogeneity of included studies, small sample sizes, and potential publication bias were significant limitations.Conclusions: The current systematic review and meta-analysis indicated that lower adiponectin levels may be associated with MDD. Moreover, the results suggest that males expressing lower adiponectin and leptin levels have an increased likelihood of developing MDD. Future studies should aim to investigate the manifestation of depressive phenotypes in older, obese populations with altered metabolic profiles resulting from adipokine dysregulation. The review has been registered with PROSPERO (registration number CRD42018082733). [ABSTRACT FROM AUTHOR]

The association between obesity and depressive symptoms has been described in the literature, but there is a scarcity of longitudinal data. This study aimed to verify the association between body mass index (BMI) and waist circumference and the incidence of depressive symptoms over a 10-year follow-up in a cohort of older adults. Data from the first (2009–2010), second (2013–2014), and third (2017–2019) waves of the EpiFloripa Aging Cohort Study were used. Depressive symptoms were assessed by the 15-item Geriatric Depression Scale (GDS-15) and classified in significant depressive symptoms for those with ≥6 points. The Generalized Estimating Equations model was used to estimate the longitudinal association between BMI and waist circumference and depressive symptoms across a 10-year follow-up. The incidence of depressive symptoms (N = 580) was 9.9 %. The relationship between BMI and the incidence of depressive symptoms in older adults followed a U-shaped curve. Older adults with obesity had an incidence relative ratio of 76 % (IRR = 1.24, p = 0.035) for increasing the score of depressive symptoms after 10 years, compared to those with overweight. The higher category of waist circumference (Male: ≥102; Female: ≥88 cm) was associated with depressive symptoms (IRR = 1.09, p = 0.033), only in a non-adjusted analysis. Relatively high follow-up dropout rate; Few individuals in the underweight BMI category; BMI must be considered with caution because it does not measure only fat mass. Obesity was associated with the incidence of depressive symptoms when compared with overweight in older adults. • Older adults have a low probability to change their body mass index (BMI) over 10 years. • Obesity increased the incident rate ratio for depressive symptoms over 10 years. • BMI was associated with depressive symptoms following a U-shaped curve. [ABSTRACT FROM AUTHOR]

Background: Subthreshold depression is highly prevalent in adolescence, but compared to major depressive disorder, the clinical impact is under-researched. The aim of this review was to compare subthreshold depression and major depressive disorder in adolescents by reviewing available literature on epidemiology, risk factors, illness trajectories, brain anatomy and function, genetics, and treatment response.Methods: We conducted a scoping review of papers on subthreshold depression and major depressive disorder in adolescence published in English. Studies in adults were included when research in adolescence was not available.Results: We found that individuals with subthreshold depression were similar to individuals with major depressive disorder in several regards, including female/male ratio, onset, functional impairment, comorbidity, health care utilization, suicidal ideation, genetic predisposition, brain alterations, and treatment response. Further, subthreshold depression was about two times more common than major depressive disorder.Limitations: The definition of subthreshold depression is highly variable across studies. Adolescent-specific data are limited in the areas of neurobiology and treatment.Conclusions: The findings of the current review support the idea that subthreshold depression is of clinical importance and provide evidence for a spectrum, versus categorical model, for depressive symptomatology. Given the frequency of subthreshold depression escalating to major depressive disorder, a greater recognition and awareness of the significance of subthreshold depression in research, clinical practice and policy-making may facilitate the development and application of early prevention and intervention. [ABSTRACT FROM AUTHOR]

Abstract: Mood disorders are marked by high rates of non-recovery, recurrence, and chronicity, which are insufficiently addressed by current therapies. Several patho-etiological models have been proposed that are not mutually exclusive and include but are not limited to the monoamine, inflammatory, neurotrophic, gliotrophic, excitatory, and oxidative stress systems. A derivative of these observations is that treatment(s) which target one or more of these mechanistic steps may be capable of mitigating, or preventing, disparate psychopathological features. Minocycline is an agent with pleiotropic properties that targets multiple proteins and cellular processes implicated in the patho-etiology of mood disorders. Moreover, preclinical and preliminary clinical evidence suggests that minocycline possesses antidepressant properties. Herein, we provide the rationale for conducting a randomized, controlled trial to test the antidepressant properties of minocycline. [Copyright &y& Elsevier]

Objectives: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late‐life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults. Methods/design: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM‐V criteria), aged 60–90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve. Results: TL was significantly shorter in the LLD compared with control participants (p =.039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale‐21, r = −0.325, p =.004) and medical burden (r = −0.271, p =.038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p =.21). Conclusions: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age‐associated adverse outcomes linked to depression. [ABSTRACT FROM AUTHOR]

Background: The bidirectional association between Major Depressive Disorder (MDD) and obesity suggests that body mass index (BMI) at the baseline could influence remission rates (RR) with pharmacological treatment. We evaluated the influence of baseline BMI on the chances of remission among patients with MDD administered antidepressants.Methods: Based on the guidelines of the PRISMA statement, we conducted a systematic review on PubMed, Cochrane and Embase databases with subsequent meta-analysis and meta-regression. We included only randomized controlled trials evaluating the efficacy of antidepressants of different classes (monotherapy and combined therapies) that evidenced baseline BMI assessment. We created a model to describe the linear relationship between baseline BMI and RR.Results: Our systematic review yielded 70 studies with a total of 9,779 patients in the active group and 7,136 patients in the placebo group. In placebo controlled studies, BMI influenced the RR of patients randomized to active treatment. The RR for antidepressants in monotherapy was higher in normal weight to overweight patients rather than obese patients (33% vs 12%, respectively). Also in monotherapy, the RR is higher when the study is conducted on patients with a lower baseline BMI (p=0.029). For combined therapies, the pooled RR was higher in obese patients rather than in normal weight to overweight patients (75% vs 17%, respectively).Limitations: BMI provides no information about body composition and obesity can be related to several potential confounders that potentially influence RR.Conclusion: The RR with antidepressant therapy seems to be associated with baseline BMI in patients with MDD, although this simple variable was insufficiently explored so far. [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]

• Mood disorders are associated with an increased prevalence of irritable bowel syndrome (IBS) and history of adverse childhood experiences (ACEs) • In total, 69 of the 498 mood disorder participants reported a diagnosis of IBS (13.8%) • BD was associated with elevated rates of IBS compared to MDD • History of childhood sexual abuse was associated with increased rates of IBS in mood disorder participants • In the subgroups, history of sexual abuse was associated with an increased prevalence of IBS in BD, but not in MDD. The objective of the current study was to assess the association between adverse childhood experiences (ACEs) and irritable bowel syndrome (IBS) in mood disorder patients. Self-report data from the International Mood Disorders Collaborative Project were cross-sectionally analyzed to compare rates of IBS in participants with confirmed diagnoses of major depressive disorder (MDD; n = 279) or bipolar disorder (BD; n = 219). Data was sub-grouped and compared based on history of ACEs. In total, 69 of the 498 participants reported a diagnosis of IBS (13.8%). BD was associated with significantly elevated rates of IBS compared to MDD (18.5% versus 10.1% respectively). After adjusting for age and sex, history of childhood sexual abuse was associated with increased rates of IBS in mood disorder participants [adjusted odds ratio (aOR) = 1.95]. In the MDD subgroup, ACEs (all categories and individual categories) were not associated with increased rates of IBS. In the BD subgroup, history of childhood sexual abuse was associated with significantly increased rates of IBS (38% versus 14%; aOR = 3.7). In summary, BD was associated with a higher prevalence of IBS compared to MDD. Additionally, history of sexual abuse was associated with an increased prevalence of IBS in BD, but not in MDD. [ABSTRACT FROM AUTHOR]

Background: The effectiveness, tolerability, and safety of intravenous (IV) ketamine in adults with treatment resistant depression (TRD) receiving care in real-word settings is insufficiently characterized. Herein, results from a naturalistic, retrospective study are presented from a Canadian outpatient IV ketamine clinic.Methods: Adults (N = 213; Mage = 45) with Major Depressive Disorder or Bipolar Disorder, with a minimum of Stage 2 antidepressant resistance, received IV ketamine at a community-based multi-disciplinary clinic. The primary outcome measure was change from baseline to post-infusion 4 on the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16; n = 190). Secondary measures included QIDS-SR16-measured response and remission rates, changes from baseline to endpoint in Generalized Anxiety Disorder-7 Scale (GAD-7; n = 188) and the Sheehan Disability Scale (SDS; n = 168).Results: Significant improvement in total depressive symptoms severity (p < 0.0001) was observed after four infusions of IV ketamine 0.5-0.75 mg/kg. Moreover, the response rate (QIDS-SR16 total score change ≥ 50%) was 27% and remission (QIDS-SR16 total score ≤5) rate was 13%. Patients receiving IV ketamine exhibited anxiolytic effects (p < 0.0001,), improved overall psychosocial function (p < 0.0001), and reduced suicidal ideation (p < 0.0001). Compared to the baseline infusion, dissociation severity significantly reduced in subsequent infusions.Limitations: This was a naturalistic, retrospective study, without a control group.Conclusions: IV ketamine was safe, well-tolerated, and effective at improving depressive, anxiety, and functional impairment symptoms in a well-characterized cohort of adults with TRD. [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]

Metabolomics is defined as the study of the global metabolite profile in a system under a given set of conditions. The objective of this review is to comprehensively assess the literature on metabolomics in mood disorders and schizophrenia and provide data for mental health researchers about the challenges and potentials of metabolomics. The majority of studies in metabolomics in Psychiatry uses peripheral blood or urine. The most widely used analytical techniques in metabolomics research are nuclear magnetic resonance (NMR) and mass spectrometry (MS). They are multiparametric and provide extensive structural and conformational information on multiple chemical classes. NMR is useful in untargeted analysis, which focuses on biosignatures or 'metabolic fingerprints' of illnesses. MS targeted metabolomics approach focuses on the identification and quantification of selected metabolites known to be involved in a particular metabolic pathway. The available studies of metabolomics in Schizophrenia, Bipolar Disorder and Major Depressive Disorder suggest a potential in investigating metabolic pathways involved in these diseases' pathophysiology and response to treatment, as well as its potential in biomarkers identification. • Nuclear magnetic resonance (NMR) and mass spectrometry (MS) are widely used analytical techniques in research in mental disorders. • NMR is useful in untargeted analysis, which focuses on biosignatures or metabolic fingerprints of illness. • MS targeted metabolomics approach focuses on the identification of selected metabolites known to be involved in a particular metabolic pathway. • The available data suggest a potential of metabolomics in investigation of biomarkers in mental illnesses. [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]

Cognitive dysfunction is a principal determinant of functional impairment in major depressive disorder (MDD) and often persists during periods of euthymia. Abnormalities in the glutamate system, particularly in N -methyl- d -aspartate receptors (NMDARs) activity, have been shown to contribute to both mood and cognitive symptoms in MDD. The current narrative review aims to evaluate the potential pro-cognitive effects of targeting the glycine site of NMDARs in the treatment of psychiatric disorders, with a special focus on how these results may apply to MDD. Literature databases were searched from inception to May 2018 for relevant pre-clinical and clinical studies evaluating antidepressant and pro-cognitive effects of NMDAR glycine site modulators in both MDD and non-MDD samples. Six glycine site modulators with pro-cognitive and antidepressant properties were identified: d -serine (co-agonist), d -cycloserine (partial agonist), d -alanine (co-agonist), glycine (agonist), sarcosine (co-agonist) and rapastinel (partial agonist). Preclinical animal studies demonstrated improved neuroplasticity and pro-cognitive effects with these agents. Numerous proof-of-concept clinical trials demonstrated pro-cognitive and antidepressant effects trans-diagnostically (e.g., in healthy participants, MDD, schizophrenia, anxiety disorders, major neurocognitive disorders). The generalizability of these clinical studies was limited by the small sample sizes and the paucity of studies directly evaluating cognitive effects in MDD samples, as most clinical trials were in non-MDD samples. Taken together, preliminary results suggest that the glycine site of NMDARs is a promising target to ameliorate symptoms of depression and cognitive dysfunction. Additional rigorously designed clinical studies are required to determine the cognitive effects of these agents in MDD. • The NMDAR has been previously implicated in cognitive dysfunction in MDD • Pro-cognitive effects of targeting the glycine site of NMDARs was evaluated • Preclinical studies demonstrated improved neuroplasticity and pro-cognitive effects • Preliminary clinical trials demonstrated pro-cognitive and antidepressant effects • Preliminary results suggest that the glycine site of NMDARs is a promising target [ABSTRACT FROM AUTHOR]

Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry. The objectives of the current review are to comprehensively evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD. Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology. Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD. Orexin antagonists have been shown to treat insomnia effectively without disrupting normal sleep architecture in both preclinical (e.g., animal models) and clinical studies. Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence. Orexin antagonists have also been shown to possess antidepressant-like properties in some animal models of MDD. Extant evidence indicates that orexin-modulating treatments exert pleiotropic effects on multiple neural systems implicated in the phenomenology of mood disorders and suggests orexins as a promising target for investigation and intervention in mood disorders. To date, no human clinical trials evaluating the antidepressant effects of orexin antagonists in MDD have been completed. Given the promising results from preclinical studies, clinical trials are merited to evaluate the antidepressant effects of orexin antagonists in MDD. • Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry • Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology • Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD • Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence and has shown to possess antidepressant properties • The objectives are to evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD [ABSTRACT FROM AUTHOR]

Background: No previous review has comprehensively assessed long-term changes in anxiety and depressive symptoms in bariatric surgery patients. This systematic review assessed the effects of bariatric surgery on long-term reductions (≥ 24 months) in anxiety and depressive symptom severity in morbidly obese (≥ 35 BMI kg/m2) participants. Short term effects (< 24 months) are briefly reviewed for context.Methods: PsychINFO, Google Scholar and PubMed databases were systematically searched for prospective cohort studies published from inception to 14 June 2018 that evaluated long-term (≥ 24 months) changes in anxiety and depressive symptom severity in bariatric surgery patients with a BMI ≥ 35 kg/m2 using a combination of the following search terms: bariatric surgery (and surgical approaches included under this term), obesity, depression, depressive disorder, anxiety, anxious, psychiatric disorders, mood disorders.Results: We reviewed 2058 articles for eligibility; 14 prospective studies were included in the systematic review. 13 studies (93%) reported significant reductions in depressive symptom severity 2-3 years after bariatric surgery. However, all studies recorded statistically significant reductions in depressive symptoms at the conclusion of the study. Similarly, there were reductions in overall anxiety symptom severity at ≥ 24 months follow-up (k = 8 studies, n = 1590 pooled). Pre-operative anxiety or depression scores did not predict outcomes of post-operative BMI. Similarly, post-surgery weight loss did not predict changes in anxiety symptoms.Limitations: Very few studies assessed anxiety or depression as a primary outcome. Therefore, we cannot suggest bariatric surgery as a stand-alone therapeutic tool for anxiety and depression based on our findings.Conclusion: Currently available evidence suggests that bariatric surgery is associated with long-term reductions in anxiety and depressive symptoms. This supports existing literature showing that metabolic treatments may be a viable therapeutic intervention for mood disorders. [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]

Type 2 diabetes mellitus (T2DM) is a severe metabolic condition which is commonly comorbid with depression. Lifestyle factors are involved in the pathophysiology of both conditions; however, the role of lifestyle interventions remains unclear. The objective of this study is to systematically review the literature on randomized controlled trials evaluating the effect of lifestyle interventions on depressive scores in patients with T2DM. A systematic search was conducted in computerized databases before October 2022. A random-effects model was used to investigate the effect of lifestyle interventions on depression scores and meta-regression was conducted to assess the influence of age and disease onset. Six trials met the eligibility criteria for inclusion. A statistically significant reduction in depression scores was found for groups receiving lifestyle interventions compared to controls (SMD = −0.49 [95%CI -0.89 to −0.08]; p = 0.0269]). Interventions increased in efficacy with the age of the participants but no significant correlation was found with years since disease onset. Participants in a control group receiving a less intense lifestyle intervention demonstrated improved depression scores when compared to those who received standard care or no intervention at all. Trial design and outcome measurement tools were heterogeneous between studies and limited data on antidepressant use was available which may introduce bias into the results. Lifestyle interventions were effective at improving depressive symptom severity in patients with T2DM. • People with Type 2 diabetes mellitus (T2DM) often present depressive symptoms. • There is potential for lifestyle interventions to improve mental health outcomes. • We meta-analyzed RCTs on the antidepressant effect of lifestyle interventions. • Lifestyle intervention significantly improved depression scores in people with T2DM. • Even a less intense lifestyle intervention improved depression scores in controls. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder.Methods: In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy.Results: Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohen's d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohen's d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality.Limitations: Small sample size, open-label design, lack of a placebo group.Conclusions: Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein. [ABSTRACT FROM AUTHOR]

Background: The longitudinal course of bipolar disorder (BD) is highly heterogeneous, and is moderated by the presence of general medical comorbidities. This study aimed to investigate the moderating effects of impaired glucose metabolism (IGM) on variables of illness course and severity in a BD population.Methods: Fifty-five patients with BD were evaluated. All subjects were evaluated with respect to current and past psychiatric and medical disorders, as well as lifetime use of any medication. Body mass index (BMI) and metabolic parameters were obtained. IGM was operationalized as pre-diabetes or type 2 diabetes mellitus.Results: Thirty (54.5%) individuals had IGM. After adjustment for age, gender, ethnicity, alcohol use, smoking, BMI and past and current exposure to psychotropic medications, individuals with IGM, when compared to euglycemic participants, had an earlier age of onset (RR: 0.835, p=0.024), longer illness duration (RR: 1.754, p=0.007), a higher number of previous manic/hypomanic episodes (RR: 1.483, p=0.002) and a higher ratio of manic/hypomanic to depressive episodes (RR: 1.753, p=0.028). Moreover, we observed a moderating effect of IGM on the association between number of mood episodes and other variables of illness course, with the correlation between lifetime mood episodes and frequency of episodes being significantly greater in the IGM subgroup (RR: 1.027, p=0.029). All associations observed herein remained significant after adjusting for relevant confounding factors (e.g. age, alcohol and tobacco use, exposure to psychotropic agents, BMI).Limitations: Cross-sectional design, small sample size.Conclusions: Comorbid IGM may be a key moderator of illness progression in BD. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) affects millions of individuals and is highly comorbid with many age-associated diseases such as diabetes mellitus, immune-inflammatory dysregulation and cardiovascular diseases. Oxidative/nitrosative stress plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative/neuropsychiatric disorders including MDD. In this review, we critically review the evidence for an involvement of oxidative/nitrosative stress in acceleration of aging process in MDD. There are evidence of the association between MDD and changes in molecular mechanisms involved in aging. There is a significant association between telomere length, enzymatic antioxidant activities (SOD, CAT, GPx), glutathione (GSH), lipid peroxidation (MDA), nuclear factor κB, inflammatory cytokines with MDD. Major depression also is characterized by significantly lower concentration of antioxidants (zinc, coenzyme Q10, PON1). Since, aging and MDD share a common biological base in their pathophysiology, the potential therapeutic use of antioxidants and anti-aging molecules in MDD could be promising. [ABSTRACT FROM AUTHOR]

Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune–inflammatory abnormalities described. [ABSTRACT FROM AUTHOR]

Objective: The purpose of the study was to define the latent structure of parent-reported manic symptoms and their association with functional impairment and familial risk in a community sample of Brazilian children. Method: We screened for manic symptoms in a community sample of 2,512 children 6 to 12 years of age. Parents of children with "episodes of going abnormally high" completed a detailed mania section (n = 479; 19.1%). Confirmatory factor analysis (CFA) tested a solution with "Under-Control (UC)" and "Exuberant (EX)" dimensions, investigating the severity (threshold) and factor loading of each symptom. We also used latent class analysis (LCA) to evaluate the latent categorical structure of manic symptoms. Associations of these latent constructs with psychiatric comorbidity, psychosocial impairment, and family history of psychopathology were tested. Results: The 2-dimensional model fit the data well. Only the UC dimension was associated with psychiatric morbidity, psychosocial impairment, and a family history of mania, depression, or suicide attempts. Both UC and EX items discriminated subjects with "episodes of going abnormally high," but EX items lay at the mild end of the severity spectrum, whereas UC items lay at the severe end. The LCA yielded a small group of children with high levels of manic symptoms and a distinct profile of psychiatric comorbidity and impairment ("high-symptom group"). Conclusion: In a large, community-based sample, we found a 2-dimensional latent structure for parent-reported manic symptoms in youth, and demonstrated familial associations between the UC dimension and affective disorders. Both UC and EX items are clinically useful, but their contributions vary with symptom severity. [ABSTRACT FROM AUTHOR]

Abstract: Emergence of depressive symptoms in schizophrenia results in a deteriorating course and poor prognosis. Schizophrenia and depressive disorder are both associated with low levels of brain-derived neurotrophic factor (BDNF) and with a longstanding low grade inflammatory state. The objective of this study is to analyze the relationship between these serum biomarkers and depressive and psychotic symptoms in schizophrenic patients. Thirty-nine individuals diagnosed with schizophrenia or schizoaffective disorder by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), assessed by Structured Clinical Interview for DSM-IV (SCID), were included. Interviews were conducted with The Positive and Negative Syndrome Scale (PANSS) and The Calgary Depression Scale for Schizophrenia (CDSS). Blood samples were collected for determination of BDNF, IL-1beta, IL-6, IL-8, IL-10, IL-12 and TNF-alpha measurements. Positive correlations between BDNF and CDSS and between IL-1beta and severity in PANSS scores were found. BDNF levels were not correlated with any cytokine or with PANSS scores. The results of this study suggest that depressive and psychotic symptoms may be associated with different profiles of biomarkers in the association between schizophrenia and depression. [Copyright &y& Elsevier]

Treatment for major depressive disorder (MDD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the non-transcranial magnetic stimulation (non-TMS) neurostimulation treatment for MDD. The authors reviewed non-TMS neurostimulation clinical trials for MDD between 2010 and 2020. Electroconvulsive therapy was not included in this review. A systematic review was performed in MEDLINE database through PubMed, the Cochrane Collaboration's Clinical Trials Register (CENTRAL), PsycINFO and Thomson Reuters's Web of Science. Only 20 articles met the inclusion criteria. Randomized controlled trials demonstrated efficacy of transcranial direct current stimulation (tDCS) in five of seven trials. tDCS augmented with sertraline, fluoxetine, citalopram and escitalopram was superior to placebo and to tDCS only. A comparative trial demonstrated that the duration of tDCS sessions can modulate the effectiveness of this treatment. Open trials indicated that deep brain stimulation, epidural cortical stimulation, trigeminal nerve stimulation, magnetic seizure therapy and vagus nerve stimulation may be effective in treatment-resistant depression. This review confirmed the efficacy of tDCS in MDD. Despite new evidence showing effectiveness for other non-TMS neurostimulation, their effectiveness is still unclear. Non-TMS neurostimulation RCTs with large samples and head-to-head studies comparing non-TMS neurostimulation and gold standard pharmacological treatments are still lacking. • tDCS is well tolerated and likely effective in MDD. • tDCS with duration of 4 or more weeks may be effective in women diagnosed with MDD in the perinatal period. • 10 Hz-tACS was more effective in improving depressive symptoms after 2 weeks compared to 40 Hz-tACS and to sham. • DBS, EpCS, MST, TNS and taVNS are well tolerated and may improve the course of illness in patients with TRD. [ABSTRACT FROM AUTHOR]

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. 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. 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. This is a post-hoc analysis of an open-label study. 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. • Early symptom improvement was associated with greater antidepressant effects following four ketamine infusions. • ~40% of individuals with early improvement responded to the full treatment course versus 14–19% in non-early improvers. • 58% of individuals who did not experience early improvement experienced a partial to full response after the fourth infusion. [ABSTRACT FROM AUTHOR]