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Evidence demonstrates the detrimental impact of depression in patients with congestive heart failure (CHF), however, large-scale prospective data from Low and Middle Income Countries (LMICs) is limited. We assessed the prevalence of depression in a large sample with CHF from Karachi, Pakistan, and the impact of depression on all-cause mortality, disability and health-related quality of life (QoL).1009 patients diagnosed with CHF were recruited from public hospitals in Karachi, Pakistan. Patients were screened for depression at baseline using the Beck Depression Inventory (BDI) and the diagnosis was confirmed using the Clinical Interview Schedule-Revised (CIS-R). Health-related QoL and disability were measured using the EuroQol (EQ-5D) and Brief Disability Questionnaire respectively at baseline and after a 6-month follow-up.A total of 670 (66%) patients were depressed at baseline and 821 participants completed 6-month follow up assessments (retention rate: 81%). At baseline, lower income (p 0.001) and lower education level (p = 0.03) were associated with higher BDI scores. Higher BDI scores were associated with a history of depression (p 0.001), higher NYHA class (p 0.001), diabetes (p 0.001), COPD (p = 0.007), renal disease (p 0.001) and stroke (p = 0.02). 145 participants were deceased at 6-months. Regression analysis showed that at follow up, higher BDI scores in depressed participants were associated with higher all-cause mortality (OR 1.23 (95% CI: 1.11-1.36); p 0.001).The rate of depression was high among Pakistani patients with CHF. Severity of depression correlated with increased mortality. Further research on controlled intervention trials in this population is warranted.

Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in IgM-mediated autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative-specific epitopes (OSEs), nitroso (NO), and nitro (NO2) adducts in schizophrenia remain unknown. This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl, and NO2-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls. Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO2-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2–42.2%) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO2-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall. These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in natural IgM attenuate CIRS functions and that this impairment may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.

Background:The blood–brain barrier acts as a highly regulated interface; its dysfunction may exacerbate, and perhaps initiate, neurological and neuropsychiatric disorders.Methods:In this narrative review, focussing on redox, inflammatory and mitochondrial pathways and their effects on the blood–brain barrier, a model is proposed detailing mechanisms which might explain how increases in blood–brain barrier permeability occur and can be maintained with increasing inflammatory and oxidative and nitrosative stress being the initial drivers.Results:Peripheral inflammation, which is causatively implicated in the pathogenesis of major psychiatric disorders, is associated with elevated peripheral pro-inflammatory cytokines, which in turn cause increased blood–brain barrier permeability. Reactive oxygen species, such as superoxide radicals and hydrogen peroxide, and reactive nitrogen species, such as nitric oxide and peroxynitrite, play essential roles in normal brain capillary endothelial cell functioning; however, chronically elevated oxidative and nitrosative stress can lead to mitochondrial dysfunction and damage to the blood–brain barrier. Activated microglia, redox control of which is mediated by nitric oxide synthases and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, secrete neurotoxic molecules such as reactive oxygen species, nitric oxide, prostaglandin, cyclooxygenase-2, quinolinic acid, several chemokines (including monocyte chemoattractant protein-1 [MCP-1], C-X-C motif chemokine ligand 1 [CXCL-1] and macrophage inflammatory protein 1α [MIP-1α]) and the pro-inflammatory cytokines interleukin-6, tumour necrosis factor-α and interleukin-1β, which can exert a detrimental effect on blood–brain barrier integrity and function. Similarly, reactive astrocytes produce neurotoxic molecules such as prostaglandin E2 and pro-inflammatory cytokines, which can cause a ‘leaky brain’.Conclusion:Chronic inflammatory and oxidative and nitrosative stress is associated with the development of a ‘leaky gut’. The following evidence-based approaches, which address the leaky gut and blood–brain barrier dysfunction, are suggested as potential therapeutic interventions for neurological and neuropsychiatric disorders: melatonin, statins, probiotics containing Bifidobacteria and Lactobacilli, N-acetylcysteine, and prebiotics containing fructo-oligosaccharides and galacto-oligosaccharides.

Objective Specific predictors of relapse/recurrence in major depressive disorder (MDD) have been identified but evidence across studies are inconsistent. This study aimed to identify the most relevant socio-demographic/clinical predictors of MDD recurrence in a sample of 508 outpatients. Methods This naturalistic cohort study included 508 currently euthymic MDD patients (mean age = 54.1 ± 16.2) of which 53.9% had a single and 46.1% recurrent depressive episodes. A detailed data collection was performed and illness histories were retraced through clinical files and lifetime computerized medical records. Results Compared to patients with single episode, MDD patients with recurrent episodes significantly differ regarding current age, gender, working status, positive history of psychiatric disorders in family, first-lifetime illness episode characteristics, first-episode and current psychotic symptoms, current melancholic features and seasonality, age at first treatment, duration of untreated illness, and comorbid cardiovascular/endocrinological conditions. However, after multivariate analyses controlling for current age, gender, educational level, working status differences, psychiatric conditions in family, and age of illness episode, recurrence was associated with older age (p ≤ .001), younger age at first treatment (p ≤ .005), being treated with previous psychoactive treatments (p .001), and longer duration of untreated illness (p .001). Conclusions The variables associated with MDD recurrence identified in the current study may aid in the stratification of patients who could benefit from more intensive maintenance treatments for MDD. However, clinicians should rapidly identify cases that are not likely to recur in order to avoid unnecessary treatments which are commonly considered as the standard of care.

Objective This systematic review provided a critical synthesis and a comprehensive overview of guidelines on the treatment of mixed states. Method The MEDLINE/PubMed and EMBASE databases were systematically searched from inception to March 21st, 2018. International guidelines covering the treatment of mixed episodes, manic/hypomanic, or depressive episodes with mixed features were considered for inclusion. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II. Results The final selection yielded six articles. Despite their heterogeneity, all guidelines agreed in interrupting an antidepressant monotherapy or adding mood-stabilizing medications. Olanzapine seemed to have the best evidence for acute mixed hypo/manic/depressive states and maintenance treatment. Aripiprazole and paliperidone were possible alternatives for acute hypo/manic mixed states. Lurasidone and ziprasidone were useful in acute mixed depression. Valproate was recommended for the prevention of new mixed episodes while lithium and quetiapine in preventing affective episodes of all polarities. Clozapine and electroconvulsive therapy were effective in refractory mixed episodes. The AGREE II overall assessment rate ranged between 42% and 92%, indicating different quality level of included guidelines. Conclusion The unmet needs for the mixed symptoms treatment were associated with diagnostic issues and limitations of previous research, particularly for maintenance treatment.

Objective: Recently, we reported that stable-phase schizophrenia is characterized by two interrelated symptom dimensions: PHEMN (psychotic, hostility, excitation, mannerism and negative symptoms); and DAPS (depressive, anxiety and physio-somatic symptoms) and that Major Neuro-Cognitive psychosis (MNP) is the full-blown phenotype of schizophrenia (largely overlapping with deficit schizophrenia). Herein we examined the effects of immune activation in association with tryptophan catabolite (TRYCAT) patterning and memory disorders on PHEMN/DAPS dimensions and MNP.Methods:Serum levels of macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL-10, eotaxin, IgA/IgM responses to TRYCATs, and Consortium to Establish a Registry for Alzheimer’s disease (CERAD) tests were assessed in 40 controls and 80 schizophrenia patients.Results:Schizophrenia and MNP were predicted by significantly increased levels of IL-10, eotaxin and TRYCATs. A large part of variance in both PHEMN/DAPS symptom dimensions (42.8%) was explained by cytokine levels and TRYCATs combined. The MIP+sIL-1RA+IL-10 composite score and eotaxin explained each around on the basis of 19% of the variance in symptom dimensions, and approximately 18% of memory deficits. Moreover, MIP+sIL-1RA+IL-10 was significantly associated with elevations in picolinic acid, xanthurenic acid and 3-OH-kynurenine. Partial Least Squares path modeling shows that highly significant effects of MIP+sIL-1RA+IL-10 on symptomatology are mediated by the effects of noxious TRYCATs on memory deficits.Conclusion:Current findings indicate that in schizophrenia, immune activation may underpin activation of indoleamine-2,3-dioxygenase and kynurenine monooxygenase, while impairments in episodic and semantic memory may be caused by the neurotoxic effects of TRYCATs and eotaxin. The combined effects of immune activation, eotaxin and memory defects determine to a large extent, PHEMN/DAPS symptoms and the MNP phenotype. These findings indicate that schizophrenia phenomenology is largely mediated by multiple neuro-immune pathways and that immune activation, increased production of eotaxin and neurotoxic TRYCATs (picolinic acid, xanthurenic acid and 3-HOkynurenine) are new drug targets in schizophrenia and MNP.

ObjectiveRecently, we reported that stable-phase schizophrenia is characterized by two interrelated symptom dimensions: PHEMN (psychotic, hostility, excitation, mannerism and negative symptoms); and DAPS (depressive, anxiety and physio-somatic symptoms) and that Major Neuro-Cognitive psychosis (MNP) is the full blown phenotype of schizophrenia (largely overlapping with deficit schizophrenia). Herein we examined the effects of immune activation in association with tryptophan catabolite (TRYCAT) patterning and memory disorders on PHEMN/DAPS dimensions and MNP.MethodSerum levels of macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL-10, eotaxin, IgA/IgM responses to TRYCATs, and Consortium to Establish a Registry for Alzheimer’s disease (CERAD) tests were assessed in 40 controls and 80 schizophrenia patients.ResultsSchizophrenia and MNP were predicted by significantly increased levels of IL-10, eotaxin and TRYCATs. A large part of the variance in both PHEMN/DAPS symptom dimensions (42.8%) was explained by cytokine levels and TRYCATs combined. The MTP+sTL-1R A+IL-10 composite score and eotaxin explained each around 19% of the variance in symptom dimensions, and approximately 18% of memory deficits. Moreover, MIP+sIL-1RA+IL-10 was significantly associated with elevations in picolinic acid, xanthurenic acid and 3-OH-kynurenine. Partial Least Squares path modeling shows that the highly significant effects of MIP+sIL-1RA+IL-10 on symptomatology are mediated by the effects of noxious TRYCATs on memory deficits.ConclusionsCurrent findings indicate that in schizophrenia, immune activation may underpin activation of indoleamine-2,3-dioxygenase and kynurenine monooxygenase, while impairments in episodic and semantic memory may be caused by the neurotoxic effects of TRYCATs and eotaxin. The combined effects of immune activation, eotaxin and memory defects determine to a large extent PHEMN/DAPS symptoms and the MNP phenotype. These findings indicate that schizophrenia phenomenology is largely mediated by multiple neuro-immune pathways and that immune activation, increased production of eotaxin and neurotoxic TRYCATs (picolinic acid, xanthurenic acid and 3-HO-kynurenine) are new drug targets in schizophrenia and MNP.

Generalized Anxiety Disorder (GAD) commonly co-occurs with mood disorders, especially Major Depressive Disorder (MDD) and bipolar disorder (BD), which are accompanied by activated neuro-immune and neuro-oxidative pathways. The aim of this narrative review is to review the phenomenological similarities and dissimilarities and the shared pathways between GAD and mood disorders. We searched PubMed, Scopus, and Google Scholar for articles published in English from 1980 to present. GAD and mood disorders, either MDD or BD, show some phenomenological overlaps and a high degree of comorbidity, especially between GAD and MDD. Both GAD and mood disorders are also frequently comorbid with other anxiety disorders, substance use disorders and medical conditions, including cardio- vascular disorder (CVD). Mood disorders have a worse prognosis when GAD is present. GAD and mood disorders are associated with female sex and may partly share genetic variants of risk. Moreover, both GAD and mood disorders frequently share similar environmental risks factors including Early Life Time Trauma (ELT) and Psychological Stressors in Adulthood (PSA). Increased nitro-oxidative stress and lipid peroxidation coupled to lowered lipid-associated antioxidant defenses are evident in GAD, MDD and type I bipolar patients. Patients with comorbid GAD and MDD show significantly higher nitro- oxidative biomarkers as compared with patients presenting with either GAD or MDD as well as patients with BD with or without co-occurring GAD. Activated immune-inflammatory processes characterized by increased levels of CRP and pro-inflammatory cytokines are other shared pathways that underpin GAD and mood disorders. Moreover, these pathways may explain comorbidities with medical disorders including CVD. Aberrations in HPA-axis, GABA and glutamate neurotransmission, NMDA and mu opioid-receptors and neuroimaging fields have yielded more inconsistent findings. In conclusion, here we propose a new model explaining GAD and the comorbidity between GAD and mood disorders. Common triggers such as ELT/PSA may underpin GAD and its comorbidity with mood disorders via activated neuro-oxidative, neuro-nitrosative and neuro-immune pathways.

BACKGROUND: The associations of different patterns of alcohol consumption and the incidence and persistence of depressive and anxiety symptoms in older age remain unclear. METHODS: Data on 6095 adults aged ≥ 50 years old from the Irish Longitudinal Study on Aging (TILDA) was analyzed. Participants completed the CAGE instrument to screen for problematic alcohol use at baseline between October 2009 and February 2011. Outcomes were incident (assessed by the CES-D scale) and anxiety (assessed by the Hospital Anxiety and Depressive scale) symptoms after a two-year follow-up as well as persistence of probable depression and anxiety among those with a positive screen for those disorders at baseline. Associations were adjusted for potential confounders through multivariable models. RESULTS: In the overall sample, problem drinking did not predict incident and persistent depression and anxiety in this sample. Among females, problem drinking increased the risk for incident depression (OR = 2.11; 95%CI = 1.12-4.00) and anxiety (OR = 2.22; 95%CI = 1.01-4.86). In addition, problem drinking increased the risk of persistent depressive symptoms (OR = 2.43; 95%CI = 1.05-5.06) among females. CONCLUSION: Problem drinking may increase the risk of incident probable depression and anxiety among older females. Furthermore, problem drinking led to a higher likelihood of persistent depressive symptoms in older female participants. Interventions targeting problem drinking among older females may prevent the onset and persistence of depression in this population, while also decreasing the incidence of anxiety symptoms. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:238 pages:651-658 ispartof: location:Netherlands status: published

Objective: The field of food addiction has attracted growing research attention. The modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) is a screening tool based on DSM-5 criteria for substance use disorders. However, there is no validated instrument to assess food addiction. \ud Methods: The mYFAS 2.0 has been transculturally adapted to Brazilian Portuguese. The data for this study was obtained through an anonymous web-based research platform: participants provided socio- demographic data and answered Brazilian versions of the the mYFAS 2.0 and the Barratt Impulsivity Scale (BIS-11). Analysis included an assessment of the Brazilian mYFAS 2.0’s internal consistency reliability, factor structure, and convergent validity in relation to BIS-11 scores. \ud Results: Overall, 7,639 participants were included (71.3% females; age: 27.2 6 7.9 years). The Brazilian mYFAS 2.0 had adequate internal consistency reliability (Cronbach’s alpha = 0.89). A single factor solution yielded the best goodness-of-fit parameters for both the continuous and categorical version of the mYFAS 2.0 in confirmatory factor analysis. In addition, mYFAS 2.0 correlated with BIS-11 total scores (Spearman’s rho = 0.26, p o 0.001) and subscores. \ud Conclusion: The Brazilian mYFAS 2.0 demonstrated adequate psychometric properties in our sample; however, future studies should further evaluate its discriminant validity.

The aim of current study was to conduct a systematic review and meta-analysis to explore the relationship between antidepressant use and glaucoma.Eight major electronic databases were searched from inception until March 19th, 2018 to obtain relevant studies that evaluated associations of antidepressants [including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)] treatment and the risk of primary open-angle glaucoma (POAG) or primary angle-closure glaucoma (PACG) as well as intraocular pressure (IOP), and related anterior chamber parameters compared to participants not exposed to antidepressant treatment. A random-effects meta-analysis was conducted.Six case-control studies and one cohort study were eligible (N = 801,754). The use of SSRIs was not associated with a higher risk of glaucoma (k = 7, pooled adjusted odds ratio (pAOR) = 0.956, 95% confidence interval (CI) = 0.807 to 1.133, p = 0.604). In addition, IOP was lower in participants exposed to antidepressants (SSRIs and SNRIs) (k = 4, Hedges' g = -0.519, 95% CI = -0.743 to -0.296, p 0.001). Finally, pupillary diameter was higher in participants exposed to antidepressant treatment (k = 4, Hedges' g = 0.681, 95% CI = 0.462 to 0.900, p 0.001).High heterogeneity of included studies limit the establishment of causal inferences.This meta-analysis indicates that a putative association between the use of SSRIs and a higher risk of glaucoma remains to be proven. However, antidepressant drug treatment may be associated with significantly lower IOP and higher pupillary diameter. The mechanisms underpinning these associations deserve further investigation.

We conducted a systematic review and meta-analysis to investigate whether the use of statins could be associated with the risk of all-caused dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and mild cognitive impairment (MCI). Major electronic databases were searched until December 27th, 2017 for studies investigating use of statins and incident cognitive decline in adults. Random-effects meta-analyses calculating relative risks (RRs) were conducted to synthesize effect sizes of individual studies. Twenty-five studies met eligibility criteria. Use of statins was significantly associated with a reduced risk of all-caused dementia (k = 16 studies, adjusted RR (aRR) = 0.849, 95% CI = 0.787–0.916, p = 0.000), AD (k = 14, aRR = 0.719, 95% CI = 0.576–0.899, p = 0.004), and MCI (k = 6, aRR = 0.737, 95% CI = 0.556–0.976, p = 0.033), but no meaningful effects on incident VaD (k = 3, aRR = 1.012, 95% CI = 0.620–1.652, p = 0.961). Subgroup analysis suggested that hydrophilic statins were associated with reduced risk of all-caused dementia (aRR = 0.877; CI = 0.818–0.940; p = 0.000) and possibly lower AD risk (aRR = 0.619; CI = 0.383–1.000; p = 0.050). Lipophilic statins were associated with reduced risk of AD (aRR = 0.639; CI = 0.449–0.908; p = 0.013) but not all-caused dementia (aRR = 0.738; CI = 0.475–1.146; p = 0.176). In conclusion, our meta-analysis suggests that the use of statins may reduce the risk of all-type dementia, AD, and MCI, but not of incident VaD.

Depression is a chronic and recurrent disorder, associated with high morbidity and risk of suicide. Leptin was firstly described as an anti-obesity hormone, but several actions of leptin in CNS have been reported. In fact, leptin regulates dopaminergic neurotransmission in mesolimbic areas and has antidepressant-like properties in stress-based models. In the present study, we investigated, for the first time, putative antidepressant-like effects of leptin in an animal model of depressive-like behaviors induced by lipopolysaccharide (LPS), and the potential involvement of dopamine receptors as mediators of those behavioral effects. Mice were injected leptin (1.5 mg/kg, IP) or imipramine prior to LPS administration. To evaluate the involvement of dopamine receptors, different experimental groups were pretreated with either the dopaminergic antagonist SCH23390, for D1 receptors or raclopride, for D2/D3 receptors, prior to leptin injection. Twenty-four hours post-LPS, mice were submitted to the forced swimming and sucrose preference tests. In addition, IL-1β levels were determined in the prefrontal cortex (PFC), hippocampus and striatum. BDNF levels were measured in the hippocampus. Our results showed that leptin, similarly to imipramine, prevented the core behavioral alterations induced by LPS (despair-like behavior and anhedonia), without altering locomotion. In neurochemical analysis, leptin restored LPS-induced changes in IL-1β levels in the PFC and striatum, and increased BDNF levels in the hippocampus. The blockade of dopamine D1 and D2/D3 receptors inhibited leptin's antidepressant-like effects, whilst only the blockade of D1-like receptors blunted leptin-induced increments in prefrontal IL-1β levels. Our results indicate that leptin has antidepressant-like effects in an inflammatory model of depression with the contribution, at least partial, of dopamine receptors.

Background Sedentary behavior (SB) is associated with diabetes, cardiovascular disease and low mood. There is a paucity of multi-national research investigating SB and depression, particularly among low- and middle-income countries. This study investigated the association between SB and depression, and factors which influence this. Methods Cross-sectional data were analyzed from the World Health Organization's Study on Global Ageing and Adult Health. Depression was based on the Composite International Diagnostic Interview. The association between depression and SB (self-report) was estimated by multivariable linear and logistic regression analyses. Mediation analysis was used to identify influential factors. Results A total of 42,469 individuals (50.1% female, mean 43.8 years) were included. People with depression spent 25.6 (95%CI8.5–42.7) more daily minutes in SB than non-depressed participants. This discrepancy was most notable in adults aged ≥ 65 y (35.6 min more in those with depression). Overall, adjusting for socio-demographics and country, depression was associated with a 1.94 (95%CI1.31–2.85) times higher odds for high SB (i.e., ≥ 8 h/day). The largest proportion of the SB-depression relationship was explained by mobility limitations (49.9%), followed by impairments in sleep/energy (43.4%), pain/discomfort (31.1%), anxiety (30.0%), disability (25.6%), cognition (16.1%), and problems with vision (11.0%). Other health behaviors (physical activity, alcohol consumption, smoking), body mass index, and social cohesion did not influence the SB-depression relationship. Conclusion People with depression are at increased risk of engaging in high levels of SB. This first multi-national study offers potentially valuable insight for a number of hypotheses which may influence this relationship, although testing with longitudinal studies is needed.

Rationale Deficit schizophrenia, as defined by the Schedule for Deficit Syndrome, may represent a distinct diagnostic class defined by neurocognitive impairments coupled with changes in IgA/IgM responses to tryptophan catabolites (TRYCATs). Adequate classifications should be based on supervised and unsupervised learning rather than on consensus criteria. Methods This study used machine learning as means to provide a more accurate classification of patients with stable phase schizophrenia. Results We found that using negative symptoms as discriminatory variables, schizophrenia patients may be divided into two distinct classes modelled by (A) impairments in IgA/IgM responses to noxious and generally more protective tryptophan catabolites, (B) impairments in episodic and semantic memory, paired associative learning and false memory creation, and (C) psychotic, excitation, hostility, mannerism, negative, and affective symptoms. The first cluster shows increased negative, psychotic, excitation, hostility, mannerism, depression and anxiety symptoms, and more neuroimmune and cognitive disorders and is therefore called "major neurocognitive psychosis" (MNP). The second cluster, called "simple neurocognitive psychosis" (SNP) is discriminated from normal controls by the same features although the impairments are less well developed than in MNP. The latter is additionally externally validated by lowered quality of life, body mass (reflecting a leptosome body type), and education (reflecting lower cognitive reserve). Conclusions Previous distinctions including "type 1" (positive)/"type 2" (negative) and DSM-IV-TR (eg, paranoid) schizophrenia could not be validated using machine learning techniques. Previous names of the illness, including schizophrenia, are not very adequate because they do not describe the features of the illness, namely, interrelated neuroimmune, cognitive, and clinical features. Stable-phase schizophrenia consists of 2 relevant qualitatively distinct categories or nosological entities with SNP being a less well-developed phenotype, while MNP is the full blown phenotype or core illness. Major neurocognitive psychosis and SNP should be added to the DSM-5 and incorporated into the Research Domain Criteria project.

Bipolar disorders are chronic and recurrent disorders that affect1% of the global population. Bipolar disorders are leading causes of disability in young people as they can lead to cognitive and functional impairment and increased mortality, particularly from suicide and cardiovascular disease. Psychiatric and nonpsychiatric medical comorbidities are common in patients and might also contribute to increased mortality. Bipolar disorders are some of the most heritable psychiatric disorders, although a model with gene-environment interactions is believed to best explain the aetiology. Early and accurate diagnosis is difficult in clinical practice as the onset of bipolar disorder is commonly characterized by nonspecific symptoms, mood lability or a depressive episode, which can be similar in presentation to unipolar depression. Moreover, patients and their families do not always understand the significance of their symptoms, especially with hypomanic or manic symptoms. As specific biomarkers for bipolar disorders are not yet available, careful clinical assessment remains the cornerstone of diagnosis. The detection of hypomanic symptoms and longtudinal clinical assessment are crucial to differentiate a bipolar disorder from other conditions. Optimal early treatment of patients with evidence-based medication (typically mood stabilizers and antipsychotics) and psychosocial strategies is necessary.

Background: People with schizophrenia engage in low levels of physical activity (PA). However, few large-scale studies have investigated the factors that may influence PA participation in individuals with psychosis and data from low- and middle-income countries (LMICs) is especially scarce. Thus, we investigated PA correlates in a large sample of people with a psychosis diagnosis across 47 LMICs. Methods: Cross-sectional data from the World Health Survey, restricting to those with a self-reported lifetime diagnosis of schizophrenia/psychotic disorder, was analyzed. PA was assessed by the International Physical Activity Questionnaire (IPAQ) and participants were dichotomized into those that do and do not (low PA) meet the minimum recommended PA weekly targets (≥ 150 min). A range of socio-demographic, health behavior, and mental and physical health variables were examined using random effects logistic regression. Results: Overall 2407 people (mean 42.0 years, 41.5% males) with schizophrenia/psychosis were included. The prevalence of low PA was 39.2% (95%CI = 37.0%–41.2%). Male sex (odds ratio (OR) = 1.33), increasing age, unemployment (vs. employed OR = 2.50), urban setting (vs. rural OR = 1.75), inadequate fruit consumption (vs. adequate fruit intake OR = 3.03), depression (OR = 1.33), sleep/energy disturbance, and mobility limitations were significantly associated with low PA. Marital status, education, wealth, smoking, vegetable and alcohol consumption, anxiety, cognition, pain, and chronic medical conditions were not significant correlates. Conclusion: PA is influenced by a range of factors among people with psychosis. These correlates should be considered in interventions aiming to facilitate PA in psychotic individuals living in LMICs.

Objective:\ud Pain and sleep disturbances are widespread, and are an important cause of a reduced quality of life. Despite this, there is a paucity of multinational population data assessing the association between pain and sleep problems, particularly among low- and middle-income countries (LMICs). Therefore, we investigated the relationship between pain and severe sleep disturbance across 45 LMICs.\ud \ud Method: \ud Community-based data on 240,820 people recruited via the World Health Survey were analyzed. Multivariable logistic regression analyses adjusted for multiple confounders were performed to quantify the association between pain and severe sleep problems in the last 30 days. A mediation analysis was conducted to explore potential mediators of the relationship between pain and severe sleep disturbance.\ud \ud Results: \ud The prevalence of mild, moderate, severe, and extreme levels of pain was 26.0%, 16.2%, 9.1%, and 2.2% respectively, whilst 7.8% of adults had severe sleep problems. Compared to those with no pain, the odds ratio (OR, 95% CI) for severe sleep problems was 3.65 (3.24-4.11), 9.35 (8.19-10.67) and 16.84 (13.91-20.39) for those with moderate, severe and extreme pain levels respectively. A country wide meta-analysis adjusted for age and sex demonstrated a significant increased OR across all 45 countries. Anxiety, depression and stress sensitivity explained 12.9%, 3.6%, and 5.2%, respectively, of the relationship between pain and severe sleep disturbances.\ud \ud Conclusion: \ud Pain and sleep problems are highly co-morbid across LMICs Future research is required to better understand this relationship. Moreover, future interventions are required to prevent and manage the pain and sleep disturbance comorbidity.

Objective: This study aimed to systematically appraise the meta-analyses of observational studies on risk factors and peripheral biomarkers for schizophrenia spectrum disorders. Methods: We conducted an umbrella review to capture all meta-analyses and Mendelian randomization studies that examined associations between non-genetic risk factors and schizophrenia spectrum disorders. For each eligible meta-analysis, we estimated the summary effect size estimate, its 95% confidence and prediction intervals and the I2 metric. Additionally, evidence for small-study effects and excess significance bias was assessed. Results: Overall, we found 41 eligible papers including 98 associations. Sixty-two associations had a nominally significant (P-value

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted.

Patients with a diagnosis of multiple sclerosis (MS) or major depressive disorder (MDD) share a wide array of biological abnormalities which are increasingly considered to play a contributory role in the pathogenesis and pathophysiology of both illnesses. Shared abnormalities include peripheral inflammation, neuroinflammation, chronic oxidative and nitrosative stress, mitochondrial dysfunction, gut dysbiosis, increased intestinal barrier permeability with bacterial translocation into the systemic circulation, neuroendocrine abnormalities and microglial pathology. Patients with MS and MDD also display a wide range of neuroimaging abnormalities and patients with MS who display symptoms of depression present with different neuroimaging profiles compared with MS patients who are depression-free. The precise details of such pathology are markedly different however. The recruitment of activated encephalitogenic Th17 T cells and subsequent bidirectional interaction leading to classically activated microglia is now considered to lie at the core of MS-specific pathology. The presence of activated microglia is common to both illnesses although the pattern of such action throughout the brain appears to be different. Upregulation of miRNAs also appears to be involved in microglial neurotoxicity and indeed T cell pathology in MS but does not appear to play a major role in MDD. It is suggested that the antidepressant lofepramine, and in particular its active metabolite desipramine, may be beneficial not only for depressive symptomatology but also for the neurological symptoms of MS. One clinical trial has been carried out thus far with, in particular, promising MRI findings.

The development of depression may involve a complex interplay of environmental and genetic risk factors. PubMed and PsycInfo databases were searched from inception through August 3, 2017, to identify meta-analyses and Mendelian randomization (MR) studies of environmental risk factors associated with depression. For each eligible meta-analysis, we estimated the summary effect size and its 95% confidence interval (CI) by random-effects modeling, the 95% prediction interval, heterogeneity with I 2 , and evidence of small-study effects and excess significance bias. Seventy meta-analytic reviews met the eligibility criteria and provided 134 meta-analyses for associations from 1283 primary studies. While 109 associations were nominally significant (P < 0.05), only 8 met the criteria for convincing evidence and, when limited to prospective studies, convincing evidence was found in 6 (widowhood, physical abuse during childhood, obesity, having 4–5 metabolic risk factors, sexual dysfunction, job strain). In studies in which depression was assessed through a structured diagnostic interview, only associations with widowhood, job strain, and being a Gulf War veteran were supported by convincing evidence. Additionally, 8 MR studies were included and provided no consistent evidence for the causal effects of obesity, smoking, and alcohol consumption. The proportion of variance explained by genetic risk factors was extremely small (0.1–0.4%), which limited the evidence provided by the MR studies. Our findings suggest that despite the large number of putative risk factors investigated in the literature, few associations were supported by robust evidence. The current findings may have clinical and research implications for the early identification of individuals at risk for depression. © 2018 Elsevier Ltd

ὠφελέειν, ἢ μὴ βλάπτειν (Primum non nocere) – Hιppocrates’ principle should still guide daily medical prescribing. Therefore, assessing evidence of psychopharmacologic agents’ safety and harms is essential. Randomised controlled trials (RCTs) and observational studies may provide complementary information about harms of psychopharmacologic medications from both experimental and real-world settings. It is considered that RCTs provide a better control of confounding variables, while observational studies provide evidence from larger samples, longer follow-ups, in more representative samples, which may be more reflective of real-life clinical scenarios. However, this may not always hold true. Moreover, in observational studies, safety data are poorly or inconsistently reported, precluding reliable quantitative synthesis in meta-analyses. Beyond individual studies, meta-analyses, which represent the highest level of ‘evidence’, can be misleading, redundant and of low methodological quality. Overlapping meta-analyses sometimes even reach different conclusions on the same topic. Meta-analyses should be assessed systematically. Descriptive reviews of reviews can be poorly informative. Conversely, ‘umbrella reviews’ can use a quantitative approach to grade evidence. In this editorial, we present the main factors involved in the assessment of psychopharmacologic agents’ harms from individual studies, meta-analyses and umbrella reviews. Study design features, sample size, number of the events of interest, summary effect sizes, p-values, heterogeneity, 95% prediction intervals, confounding factor adjustment and tests of bias (e.g., small-study effects and excess significance) can be combined with other assessment tools, such as AMSTAR and GRADE to create a framework for assessing the credibility of evidence.

BACKGROUND: Multiple environmental factors have been implicated in obesity, and multiple interventions, besides drugs and surgery, have been assessed in obese patients. Results are scattered across many studies and meta-analyses, and they often mix obese and overweight individuals. MATERIALS AND METHODS: PubMed and Cochrane Database of Systematic Reviews were searched through 21 January 2017 for meta-analyses of cohort studies assessing environmental risk factors for obesity, and randomized controlled trials investigating nonpharmacological and nonsurgical therapeutic interventions for obesity. We excluded data on overweight participants. Evidence from observational studies was graded according to criteria that included the statistical significance of the random-effects summary estimate and of the largest study in a meta-analysis, the number of obesity cases, heterogeneity between studies, 95% prediction intervals, small-study effects and excess significance. The evidence of intervention studies for obesity was assessed with the GRADE framework. RESULTS: Fifty-four articles met eligibility criteria, including 26 meta-analyses of environmental risk factors (166 studies) and 46 meta-analyses of nondrug, nonsurgical interventions (206 trials). In adults, the only risk factor with convincing evidence was depression, and childhood obesity, adolescent obesity, childhood abuse and short sleep duration had highly suggestive evidence. Infancy weight gain during the first year of life, depression and low maternal education had convincing evidence for association with paediatric obesity. All interventions had low or very-low-quality evidence with one exception of moderate-quality evidence for one comparison (no differences in efficacy between brief lifestyle primary care interventions and other interventions for paediatric obesity). Summary effect sizes were mostly small across compared interventions (maximum 5.1 kg in adults and 1.78 kg in children) and even these estimates may be inflated. CONCLUSIONS: Depression, obesity in earlier age groups, short sleep duration, childhood abuse and low maternal education have the strongest support among proposed risk factors for obesity. Furthermore, there is no high-quality evidence to recommend treating obesity with a specific nonpharmacological and nonsurgical intervention among many available, and whatever benefits in terms of magnitude of weight loss appear small. ispartof: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION vol:48 issue:12 ispartof: location:England status: published

Background Transcranial direct current stimulation (tDCS) holds promise as a therapeutic intervention for major depressive disorder (MDD). A more precise understanding of its underlying mechanisms may aid in the identification of subsets of patients responsive to tDCS within the context of precision psychiatry. Objective In this ancillary investigation of the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS), we investigated whether plasma levels of several cytokines and neurotrophic factors associated with major depression or antidepressant response predicted tDCS effects. Methods We examined, in 236 patients at 3 timepoints during a 10-week treatment course, plasma levels of nerve growth factor (NGF), brain-derived (BDNF), glial-cell line derived neurotrophic factor (GDNF), the interleukins (IL) IL-1s, IL-6, IL-8, IL-10, IL-12p70, IL-18, IL-33, tumor necrosis factor-alpha (TNF-alpha), and its soluble receptors sTNFr1 and sTNFr2. General linear models and mixed-models analyses of variance were used to respectively assess whether plasma levels of these molecules (1) predicted tDCS antidepressant improvement and (2) changed over time. Results After correction for multiple comparisons (false discovery rate method), NGF baseline levels predicted early depression improvement for tDCS vs. escitalopram, whilst other biomarkers did not significantly predict treatment improvement. The levels of IL12p70, IL10, IL-1s, IL-8 and sTNFr1 decreased over time, regardless of allocation group and clinical response. Conclusion In general, peripheral biomarkers were not associated with the outcome. The post-hoc finding of baseline NGF levels predicting early depression improvement for tDCS should be explored in further studies.

Major depressive disorder (MDD) has been conceived as a neuroprogressive illness in a subset of patients and is associated with progressive structural and functional brain abnormalities, due to reduced neurogenesis, dysfunction in neural plasticity, and increased apoptosis. Inflammatory cytokines and cell-mediated immunity may play a role in these abnormalities by activating microglial cells or modulating several pathways involved in neural physiology and homeostasis. Nevertheless, increasing evidence points out that depression is associated with peripheral immune activation in only a subset of patients. Moreover, the observations that immune activation can be involved in mood and cognitive symptoms across several psychiatric, neurological, and medical diseases warrant the need for a transdiagnostic dimensional approach, which is addressed by the Research Domain Criteria framework. Drugs with antiinflammatory activity may be efficacious for the treatment of depression in patients with elevated markers of peripheral inflammation and could also provide domain-specific treatment for specific symptoms. Further translational research is needed to identify new drug targets that may provide a pathway toward precision psychiatry.

BACKGROUND:\ud Stress in chronic conditions or multimorbidity (≥2 chronic conditions) has been reported to affect clinical outcomes but there are no studies on the association between stress and chronic conditions/multimorbidity among older adults in low- and middle-income countries (LMICs). Thus, we investigated this association among adults aged ≥50 years across six LMICs.\ud \ud METHODS:\ud A cross-sectional analysis using data from the World Health Organization's Study on Global Ageing and Adult Health (China, Ghana, India, Mexico, Russia, South Africa) was conducted. A perceived stress score [range 0 (lowest stress) -100 (highest stress)] was computed based on two questions from the Perceived Stress Scale. Thirteen chronic conditions were assessed. Multivariable linear regression analyses were conducted.\ud \ud RESULTS:\ud 34,129 adults with a mean age of 62.4 (SD=16.0)years (52.1% females) were included. Overall, 56.6% (95% CI=55.0%-58.2%) had multimorbidity. In the adjusted model including all countries, compared with those with no chronic conditions, higher numbers of chronic conditions were significantly associated with higher stress levels, dose dependently. In a countrywide meta-analysis, multimorbidity was associated with significantly higher stress levels in all countries (especially India and Ghana) although characterized by moderate heterogeneity (I2=54.6%). For single chronic conditions, notably high stress scores were observed for depression, stroke, and hearing problems.\ud \ud CONCLUSION:\ud Chronic conditions and multimorbidity are associated with higher levels of stress in older adults in LMICs. Given that perceived stress and chronic conditions are collectively associated with worse health outcomes, low-cost, population-level integrated interventions to address stress among those with chronic conditions are urgently needed.

The neurotrophic hypothesis of major depressive disorder (MDD) postulates that the pathology of this illness incorporates a down-regulation of neurotrophin signaling. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic mediator regarding the neurobiology of MDD. Nevertheless, emerging evidence has implicated the multi-competent angiogenic and neurogenic molecule - vascular endothelial growth factor (VEGF) - in hippocampal neurogenesis and depression pathophysiology.To compare peripheral levels of VEGF between individuals with MDD and healthy controls.We performed a systematic review and meta-analysis of original studies measuring peripheral levels of VEGF in participants with MDD compared to healthy controls. We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases for studies published in any language through December 16th, 2014.Fourteen studies met eligibility criteria (N=1633). VEGF levels were significantly elevated in individuals with MDD when compared to healthy controls (Hedges's g=0.343; 95% CI: 0.146-0.540; P0.01). Funnel plot inspection and the Egger's test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, sample for assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender emerged as significant sources of heterogeneity.Taken together, extant data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD.

Bipolar disorder (BD) is associated with a reduced life expectancy compared to the general population mainly due to a high prevalence of comorbid somatic illnesses. A model of accelerated aging has been proposed as a potential explanation to these epidemiological findings. Nevertheless, studies measuring telomere length (TL) in patients with BD compared to healthy controls have provided mixed results.To compare TL between BD patients and healthy controls, and to search for potential modePrators for observed differences.We performed a systematic review and meta-analysis of original studies comparing TL in patients with BD vs. healthy controls published up to February 24th, 2015 in main electronic databases. Heterogeneity was explored through meta-regression and subgroup analysis.Seven studies met inclusion criteria (N=1115). There was no difference in TL between participants with BD and healthy controls (Hedges's g=-0.012; 95% CI=-0.418 to 0.393, P=0.952). There was no evidence for publication bias. Heterogeneity was high (I(2)=89.65%). In meta-regression analyses, the percentage of females in healthy control samples (P=0.04) and the methodological quality of included studies (P0.001) emerged as significant moderators, while subgroup analyses suggest that the type of assay employed to measure TL and age- and gender-matching of BD and HC participants may contribute to heterogeneity.Telomere length does not differ between participants with BD vs. healthy controls; this finding does not support the view of BD as an illness associated with accelerated cellular aging. However, more studies controlling for potential confounders are necessary.

Activation of the brain angiotensin II type 1 receptor (AT1R) triggers pro-oxidant and pro-inflammatory mechanisms which are involved in the neurobiology of bipolar disorder (BD). Candesartan (CDS) is an AT1 receptor antagonist with potential neuroprotective properties. Herein we investigated CDS effects against oxidative, neurotrophic inflammatory and cognitive effects of amphetamine (AMPH)-induced mania. In the reversal protocol adult mice were given AMPH 2 mg/kg i.p. or saline and between days 8 and 14 received CDS 0.1, 0.3 or 1 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention treatment, mice were pretreated with CDS, Li or saline prior to AMPH. Locomotor activity and working memory performance were assessed. Glutathione (GSH), thiobarbituric acid-reactive substance (TBARS) and TNF-α levels were evaluated in the hippocampus (HC) and cerebellar vermis (CV). Brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase 3-beta (GSK-3beta) levels were measured in the HC. CDS and Li prevented and reversed the AMPH-induced increases in locomotor activity. Only CDS prevented and reversed AMPH-induced working memory deficits. CDS prevented AMPH-induced alterations in GSH (HC and CV), TBARS (HC and CV), TNF-α (HC and CV) and BDNF (HC) levels. Li prevented alterations in BDNF and phospho-Ser9-GSK3beta. CDS reversed AMPH-induced alterations in GSH (HC and CV), TBARS (HC), TNF-α (CV) and BDNF levels. Li reversed AMPH-induced alterations in TNF-α (HC and CV) and BDNF (HC) levels. CDS is effective in reversing and preventing AMPH-induced behavioral and biochemical alterations, providing a rationale for the design of clinical trials investigating CDS׳s possible therapeutic effects.

During the last decade, several meta-analytic studies employing different methodological approaches have had inconsistent conclusions regarding antidepressant efficacy. Herein, we aim to comment on methodological aspects that may have contributed to disparate findings. We initially discuss methodological inconsistencies and limitations related to the conduct of individual antidepressant randomized controlled trials (RCTs), including differences in allocated samples, limitations of psychometric scales, possible explanations for the heightened placebo response rates in antidepressant RCTs across the past two decades as well as the reporting of conflicts of interest. In the second part of this article, we briefly describe the various meta-analyses techniques (e.g., simple random effects meta-analysis and network meta-analysis) and the application of these methods to synthesize evidence related to antidepressant efficacy. Recently published antidepressant metaanalyses often provide discrepant results and similar results often lead to different interpretations. Finally, we propose strategies to improve methodology considering real-world clinical scenarios.

The current Review article provides a narrative review about the neurobiological underpinnings and treatment of treatment resistant late-life depression (TRLLD). The manuscript focuses on therapeutic targets of late-life depression, which include pharmacological, psychological, biophysical and exercise treatment approaches. Therefore, we summarize available evidences on that kind of therapies for patients suffering from late-life depression. The search for evidences of therapeutic options of late-life depression were done using searching websites as “pubmed”, and using the searching terms “depression”, “late-life depression”, “treatment”, “biophysical therapy”, “exercise therapy”, “pharmacological therapy” and “psychological therapy”. To the end, we summarize and discuss current data, providing some directions for further research. Treatment recommendations for elderly depressive patients favour a multimodal approach, containing psychological, pharmacological and secondary biophysical therapeutic options. Particularly, a combination of psychotherapy and antidepressant medication reflects the best therapeutic option. However, mostly accepted and used is the pharmacological treatment although evidence suggests that the drug therapy is not as effective as it is in younger depressive patients. Further studies employing larger samples and longer follow-up periods are necessary and may focus on comparability of study designs and involve novel approaches to establish the validity and reliability of multimodal treatment programs.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown.

Background Major Depressive Disorder (MDD) is frequent in the Accident and Emergency Department (AED) but is often unrecognized. We aimed to assess the prevalence of MDD and determine the psychometric properties of the PHQ-9 in diagnosing MDD in patients with long-term medical conditions attending an AED. Methods The PHQ-9 was administered to 349 patients with diabetes, COPD and chronic inflammatory rheumatic diseases, mainly rheumatoid arthritis and spondyloarthropathies, visiting an AED. The MINI interview was used as the criterion standard for MDD. Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal PHQ-9 cutpoint for MDD. Construct validators included psychological distress (SCL-90-R), illness perceptions (B-IPQ) and Health-Related Quality of Life (WHOQOL-BREF). Results The prevalence of MDD was 27.2%. At an optimal cutpoint of 8, PHQ-9 had a sensitivity of 90.5% and specificity of 89.4%. The area under the curve (0.96) was excellent. Convergent validity was established by the strong associations between PHQ-9 scores and functional status, SCL-90-R depression, illness perceptions and AED visits during the previous year. Limitations The sample consisted of multiple rather a single disease group, preventing us from accounting for illness severity using specific disease severity indices. Conclusion MDD is frequent in patients with long-term medical conditions attending the AED and the PHQ-9, at a cutpoint of 8, is an accurate, reliable and valid measure for MDD screening in this patient population.

Objectives Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1β, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). Methods Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1β, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. Results The present study showed that d-AMPH induced hyperactivity in rats (p

Background Bipolar spectrum disorders are frequently under-recognized and/or misdiagnosed in various settings. Several influential publications recommend the routine screening of bipolar disorder. A systematic review and meta-analysis of accuracy studies for the bipolar spectrum diagnostic scale (BSDS), the hypomania checklist (HCL-32) and the mood disorder questionnaire (MDQ) were performed. Methods The Pubmed, EMBASE, Cochrane, PsycINFO and SCOPUS databases were searched. Studies were included if the accuracy properties of the screening measures were determined against a DSM or ICD-10 structured diagnostic interview. The QUADAS-2 tool was used to rate bias. Results Fifty three original studies met inclusion criteria ( N =21,542). At recommended cutoffs, summary sensitivities were 81%, 66% and 69%, while specificities were 67%, 79% and 86% for the HCL-32, MDQ, and BSDS in psychiatric services, respectively. The HCL-32 was more accurate than the MDQ for the detection of type II bipolar disorder in mental health care centers ( P =0.018). At a cutoff of 7, the MDQ had a summary sensitivity of 43% and a summary specificity of 95% for detection of bipolar disorder in primary care or general population settings. Limitations Most studies were performed in mental health care settings. Several included studies had a high risk of bias. Conclusions Although accuracy properties of the three screening instruments did not consistently differ in mental health care services, the HCL-32 was more accurate than the MDQ for the detection of type II BD. More studies in other settings (for example, in primary care) are necessary.

A priority clinical and research agenda in mood and anxiety disorders is to identify determinants that influence illness trajectory and outcome. Over the past decade, studies have demonstrated a bidirectional relationship between the gut microbiome and brain function (i.e., the microbiota-gut-brain axis). Probiotic treatments and developmental analysis of the microbiome may provide potential treatments and preventative measures for depressive and anxiety disorders. This systematic literature review aims to identify original studies linking the gut microbiota to major depressive disorder and anxiety disorders. Furthermore, this review searched for original reports focusing on possible therapeutic and preventative effects of probiotics for these debilitating conditions. Accumulating data indicate that the gut microbiota communicates with the CNS through neural, endocrine and immune pathways. Studies in germ-free animals indicate that the microbiota is involved in the regulation of the stress response (e.g., hypothalamic-pituitary-adrenal axis) and in CNS development at critical stages. Probiotics attenuate anxiety and depressive-like behaviors in experimental animal models. Notwithstanding some inconsistencies and methodological limitations across trials, clinical studies suggest that probiotics may mitigate anxiety symptoms. However, future studies should investigate the anxiolytic and antidepressant effects of probiotics in more phenotypically homogeneous populations. In conclusion, the emerging concept of a gut microbiota-brain axis suggests that the modulation of the gut microbiota may provide a novel therapeutic target for the treatment and/or prevention of mood and anxiety disorders.

Background: Cognitive deficits differentially affect individuals with type 2 diabetes mellitus (T2DM) and mood disorders. Accumulating evidence implicates disturbances in metabolism as salient to cognitive function. Thus, the mitigation of metabolic disturbances may preserve or ameliorate cognitive function. This review aims to evaluate available evidence investigating the effects of metformin on cognitive function as well as summarize putative mechanistic properties related to these clinical effects. Methods: A PubMed search was conducted using the search words including, but not limited to: metformin, Major Depressive Disorder, type 2 diabetes mellitus, and cognitive dysfunction. All English language articles published from 1990 to July 2014 were reviewed. Results: Extant preclinical and clinical data have been mixed, wherein both cognitive disruption and pro-cognitive effects have been reported with the administration of metformin. Sound mechanistic evidence supports metformin as a treatment; however, the heterogeneity of study designs has contributed to an inability to arrive at an unequivocal conclusion regarding metformin effects upon cognition. Conclusion: Available evidence does not provide a robust signal for improvement in cognition in either mood disorder or T2DM samples. Notwithstanding, it is premature to label metformin as a “no-go” agent for further testing and development for cognitive dysfunction. A well designed, proof-of-concept trial of metformin investigating its possible cognitive effects in mood disorders is therefore warranted.

Clinical manifestations of major depressive disorder (MDD) have been linked to structural and functional alterations in fronto-limbic circuits and white matter microstructural abnormalities. However, little is known about how brain pathological changes in volume and microstructure are related to illness progression throughout aging, including course deterioration and treatment response. A comprehensive review of the literature regarding midlife- and late-onset MDD was performed through PubMed/Medline, ISI, and EMBASE electronic databases from January 2000 to May 2014. Eligible references included prospective studies in which structural neuroimaging assessments were performed in MDD samples. The course of MDD may be associated with brain aging modifications, including hippocampal, amigdalar and frontal volume reductions. White matter changes associated with MDD progression have been reported in the corpus callosum, frontal and temporal regions and may be associated with poorer response to treatment. The data suggest that both cortical and subcortical alterations may interact along the progression of MDD. Further knowledge brought by neuroimaging studies, through the integration of multimodal techniques, may help to improve the accuracy of diagnosis, disease monitoring and treatment response in MDD.

A growing body of evidence points toward an association between the glutamatergic system, as well as immune system dysregulation and major depression. So, the present study was aimed at evaluating the behavioral and molecular effects of the ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) receptor of glutamate in maternally deprived adult rats. In deprived rats treated with saline, we observed an increase in the immobility time; however, ketamine treatment reversed this effect, decreasing immobility time. In addition, maternal deprivation induced an increase in cytokines: TNF-α and IL-1 in serum, and in IL-6 in serum and cerebrospinal fluid (CSF). Interestingly, ketamine treatment reduced the levels of all the cytokines in deprived rats. In conclusion, these findings further support a relationship between immune activation and depression. Considering the action of ketamine, this study suggested that antagonists of the NMDA receptor, such as ketamine, could exert their effects by modulation of the immune system.

BackgroundDepression and pain are leading causes of global disability. However, there is a paucity of multinational population data assessing the association between depression and pain, particularly among low- and middle-income countries (LMICs) where both are common. Therefore, we investigated this association across 47 LMICs.MethodsCommunity-based data on 273 952 individuals from 47 LMICs were analysed. Multivariable logistic and linear regression analyses were performed to assess the association between the International Classification of Diseases, 10th Revision depression/depression subtypes (over the past 12 months) and pain in the previous 30 days based on self-reported data. Country-wide meta-analysis adjusting for age and sex was also conducted.ResultsThe prevalence of severe pain was 8.0, 28.2, 20.2, and 34.0% for no depression, subsyndromal depression, brief depressive episode, and depressive episode, respectively. Logistic regression adjusted for socio-demographic variables, anxiety and chronic medical conditions (arthritis, diabetes, angina, asthma) demonstrated that compared with no depression, subsyndromal depression, brief depressive episode, and depressive episode were associated with a 2.16 [95% confidence interval (CI) 1.83–2.55], 1.45 (95% CI 1.22–1.73), and 2.11 (95% CI 1.87–2.39) increase in odds of severe pain, respectively. Similar results were obtained when a continuous pain scale was used as the outcome. Depression was significantly associated with severe pain in 44/47 countries with a pooled odds ratio of 3.93 (95% CI 3.54–4.37).ConclusionDepression and severe pain are highly comorbid across LMICs, independent of anxiety and chronic medical conditions. Whether depression treatment or pain management in patients with comorbid pain and depression leads to better clinical outcome is an area for future research.

The depression, anxiety and physiosomatic symptoms (DAPS) of schizophrenia are associated with negative symptoms and changes in tryptophan catabolite (TRYCAT) patterning. The aim of this study is to delineate the associations between DAPS and psychosis, hostility, excitation, and mannerism (PHEM) symptoms, cognitive tests as measured using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and IgA/IgM responses to TRYCATs. We included 40 healthy controls and 80 participants with schizophrenia. Depression and anxiety symptoms were measured with The Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales, respectively. Physiosomatic symptoms were assessed with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF). Negative symptoms as well as CERAD tests, including Verbal Fluency Test (VFT), Mini-Mental State Examination (MMSE), Word List Memory (WLM), and WL Delayed Recall were measured, while ratios of IgA responses to noxious/protective TRYCATs (IgA NOX_PRO) were computed. Schizophrenia symptoms consisted of two dimensions, a first comprising PHEM and negative symptoms, and a second DAPS symptoms. A large part of the variance in DAPS was explained by psychotic symptoms and WLM. Of the variance in HAM-D, 58.9% was explained by the regression on excitement, IgA NOX_PRO ratio, WLM, and VFT; 29.9% of the variance in HAM-A by psychotic symptoms and IgA NOX/PRO; and 45.5% of the variance in FF score by psychotic symptoms, IgA NOX/PRO, and WLM. Neural network modeling shows that PHEM, IgA NOX_PRO, WLM, and MMSE are the dominant variables predicting DAPS. DAPS appear to be driven by PHEM and negative symptoms coupled with impairments in episodic memory, especially false memory creation, while all symptom dimension and cognitive impairments may be driven by an increased production of noxious TRYCATs, including picolinic, quinolinic, and xanthurenic acid.

Background Depression in tuberculosis increases the risk for adverse health outcomes. However, little is known about comorbid depression and tuberculosis in the general population. Thus, we assessed the association between depression and tuberculosis, and the decrements in health status associated with this comorbidity in 48 low- and middle-income countries. Methods Cross-sectional, community-based data from the World Health Survey on 242,952 individuals aged ≥ 18 years were analyzed. Based on the World Mental Health Survey version of the Composite International Diagnostic Interview, past 12-month depression was categorized into depressive episode, brief depressive episode, subsyndromal depression, and no depression. Health status across six domains (cognition, interpersonal activities, sleep/energy, self-care, mobility, pain/discomfort) was assessed. Multivariable logistic and linear regression analyses were performed to assess the associations. Results The prevalence of depressive episode among those with and without tuberculosis was 23.7% and 6.8%, respectively (P

Activation of immune-inflammatory and oxidative-nitrosative (IO&NS) stress pathways plays a role in major depression (MDD). Evidence suggests that curcumin (500–1000 mg/day), a polyphenol with strong anti-IO&NS properties, may have efficacy either as monotherapy or as an adjunctive treatment for depression. Further controlled trials with extended treatment periods (> 8 weeks) and higher curcumin doses are warranted. This 12-week study was carried out to examine the effects of adjunctive curcumin for the treatment of MDD. In this double-blind, placebo-controlled trial, 65 participants with MDD were randomized to receive either adjunctive curcumin (increasing dose from 500 to 1500 mg/day) or placebo for 12 weeks. Four weeks after the active treatment phase, a follow-up visit was conducted at week 16. Assessments of the primary, i.e., the Montgomery-Asberg Depression Rating Scale (MADRS), and secondary, i.e., the Hamilton Anxiety Rating Scale (HAM-A), outcome measures were rated at baseline and 2, 4, 8, 12, and 16 weeks later. Curcumin was more efficacious than placebo in improving MADRS scores with significant differences between curcumin and placebo emerging at weeks 12 and 16. The effects of curcumin were more pronounced in males compared to females. There were no statistically significant treatment-emerging adverse effects and no significant effects of curcumin on blood chemistry and ECG measurements. Adjunctive curcumin has significant antidepressant effects in participants with MDD as evidenced by significant benefits occurring 12 and 16 weeks after treatment initiation. Curcumin administration was safe and well-tolerated even when combined with antidepressants. Future trials should include treatment-by-sex interactions to examine putative antidepressant effects of immune-modifying compounds.