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Background: The definitions of treatment-resistant bipolar disorder (TRBD) have varied across studies. Additionally, its management is clinically challenging. An updated synthesis and appraisal of the available evidence is needed.Methods: A systematic search of major electronic databases from inception up to May 25th, 2020, was conducted to identify randomized controlled trials (RCTs) of pharmacological and non-pharmacological interventions for the management of TRBD. When sufficient evidence was available, a meta-analysis was conducted.Results: Seventeen studies (n = 928 patients) were included in the qualitative synthesis. Fourteen studies (n = 803) assessed treatment-resistant acute bipolar depression (TRBD-De), including five neuromodulatory and nine pharmacological trials. Rapid- vs. standard up-titration of clozapine showed promising efficacy for TRBD mania, without significant adverse events. Electroconvulsive therapy (ECT) was confirmed to be similarly effective for TRBD-De as for treatment-resistant unipolar depression: odd ratio, OR = 0.919 (95%C.I. = 0.44-1.917), I2 = 13.98, p = .822. TRBD-De patients exposed to ketamine at day one post-infusion had high odds of response: OR = 10.682 (95%C.I. = 2.142-53.272), I2 = 0, p = <.005. The pooled drop-out rate in the ketamine trials was 21.2%. Additional evidence is warranted to confirm the potential efficacy of pramipexole or stimulants for TRBD-De.Limitations: Publication/measurement bias; exploratory nature of the meta-analyses for interventions that included participants solely with TRBD-De.Conclusions: Overall, a few interventions are available for TRBD, including pramipexole, ECT, and clozapine, among others. Larger and better-designed trials for TRBD are warranted and should be based on more uniform operational definitions. PROSPERO registration number: CRD42018114567. [ABSTRACT FROM AUTHOR]

Objective: To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms. Methods: Forty women aged 18–45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle. Results: Significant changes in Δ (actual − 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase. Discussion: Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence points to the pathophysiological relevance between immune dysfunction and mood disorders. High rates of thyroid dysfunction have been found in patients with bipolar disorder (BD), compared to the general population. A systematic review of the relationship between BD and thyroid autoimmunity was performed.Methods: Pubmed, EMBASE and PsycINFO databases were searched up till January 28th, 2017. This review has been conducted according to the PRISMA statements. Observational studies clearly reporting data among BD patients and the frequency of autoimmune thyroid pathologies were included.Results: 11 original studies met inclusion criteria out of 340 titles first returned from the global search. There is evidence of increased prevalence of circulating thyroid autoantibodies in depressed and mixed BD patients, while there is no evidence showing a positive relationship between BD and specific autoimmune thyroid diseases. There is a controversy about the influence of lithium exposure on circulating thyroid autoantibodies, even if most of studies seem not to support this association. A study conducted on bipolar twins suggests that autoimmune thyroiditis is related to the genetic vulnerability to develop BD rather than to the disease process itself. Females are more likely to develop thyroid autoimmunity.Limitations: The samples, study design and outcomes were heterogeneous.Conclusion: Thyroid autoimmunity has been suggested to be an independent risk factor for bipolar disorder with no clear association with lithium exposure and it might serve as an endophenotype for BD. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is an emerging treatment target in bipolar disorder (BD). Several trials have assessed the efficacy of novel pharmacological and psychological treatments on cognition in BD but the findings are contradictory and unclear. A systematic search following the PRISMA guidelines was conducted on PubMed and PsychInfo. Eligible articles reported randomized, controlled or open-label trials investigating pharmacological or psychological treatments targeting cognitive dysfunction in BD. The quality of the identified randomized controlled trials (RCTs) was evaluated with the Cochrane Collaboration’s Risk of Bias tool. We identified 19 eligible studies of which 13 were RCTs and six were open-label or non-randomized studies. The findings regarding efficacy on cognition were overall disappointing or preliminary, possibly due to several methodological challenges. For the RCTs, the risk of bias was high in nine cases, unclear in one case and low in three cases. Key reasons for the high risk of bias were lack of details on the randomization process, suboptimal handling of missing data and lack of a priori priority between cognition outcomes. Other challenges were the lack of consensus on whether and how to screen for cognitive impairment and on how to assess efficacy on cognition. In conclusion, methodological problems are likely to impede the success rates of cognition trials in BD. We recommend adherence to the CONSORT guidelines for RCTs, screening for cognitive impairment before inclusion of trial participants and selection of one primary cognition outcome. Future implementation of a ‘neurocircuitry-based’ biomarker model to evaluate neural target engagement is warranted. [ABSTRACT FROM AUTHOR]

Newer generation antidepressant drugs (ADs) are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents. In this critical review, we evaluated the literature on adverse events, tolerability and safety of selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, bupropion, mirtazapine, trazodone, agomelatine, vilazodone, levomilnacipran and vortioxetine. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms (nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances (heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system disturbances (lowering of seizure threshold, extrapyramidal side effects, cognitive disturbances), sweating, sleep disturbances, affective disturbances (apathy, switches, paradoxical effects), ophthalmic manifestations (glaucoma, cataract) and hyperprolactinemia. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. Other areas of concern involve suicidality, safety in overdose, discontinuation syndromes, risks during pregnancy and breast feeding, as well as risk of malignancies. Thus, the rational selection of ADs should consider the potential benefits and risks, likelihood of responsiveness to the treatment option and vulnerability to adverse events. The findings of this review should alert the physician to carefully review the appropriateness of AD prescription on an individual basis and to consider alternative treatments if available. [ABSTRACT FROM AUTHOR]

Background: To aid in the differentiation of individuals with major depressive disorder (MDD) from healthy controls, numerous peripheral biomarkers have been proposed. To date, no comprehensive evaluation of the existence of bias favoring the publication of significant results or inflating effect sizes has been conducted.Methods: Here, we performed a comprehensive review of meta-analyses of peripheral nongenetic biomarkers that could discriminate individuals with MDD from nondepressed controls. PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched through April 10, 2015.Results: From 15 references, we obtained 31 eligible meta-analyses evaluating biomarkers in MDD (21,201 cases and 78,363 controls). Twenty meta-analyses reported statistically significant effect size estimates. Heterogeneity was high (I2 ≥ 50%) in 29 meta-analyses. We plausibly assumed that the true effect size for a meta-analysis would equal the one of its largest study. A significant summary effect size estimate was observed for 20 biomarkers. We observed an excess of statistically significant studies in 21 meta-analyses. The summary effect size of the meta-analysis was higher than the effect of its largest study in 25 meta-analyses, while 11 meta-analyses had evidence of small-study effects.Conclusions: Our findings suggest that there is an excess of studies with statistically significant results in the literature of peripheral biomarkers for MDD. The selective publication of 'positive studies' and the selective reporting of outcomes are possible mechanisms. Effect size estimates of meta-analyses may be inflated in this literature. [ABSTRACT FROM AUTHOR]

Background 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. Objective To compare peripheral levels of VEGF between individuals with MDD and healthy controls. Methods 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. Results 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; P < 0.01). 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, P < 0.001; 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is characterized by a dysfunctional processing of autobiographical memories. We review the following core domains of deficit: systematic biases favoring materials of negative emotional valence; diminished access and response to positive memories; a recollection of overgeneral memories in detriment of specific autobiographical memories; and the role of ruminative processes and avoidance when dealing with autobiographical memories. Furthermore, we review evidence from functional neuroimaging studies of neural circuits activated by the recollection of autobiographical memories in both healthy and depressive individuals. Disruptions in autobiographical memories predispose and portend onset and maintenance of depression. Thus, we discuss emerging therapeutics that target memory difficulties in those with depression. We review strategies for this clinical domain, including memory specificity training, method-of-loci, memory rescripting, and real-time fMRI neurofeedback training of amygdala activity in depression. We propose that the manipulation of the reconsolidation of autobiographical memories in depression might represent a novel yet largely unexplored, domain-specific, therapeutic opportunity for depression treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Adiponectin, leptin and resistin may play a role in the pathophysiology of major depressive disorder (MDD). However, differences in peripheral levels of these hormones are inconsistent across diagnostic and intervention studies. Therefore, we performed meta-analyses of diagnostic studies (i.e., MDD subjects versus healthy controls) and intervention investigations (i.e., pre-vs. post-antidepressant treatment) in MDD. Adiponectin (N = 1278; Hedge's g = −0.35; P = 0.16) and leptin (N = 893; Hedge's g = −0.018; P = 0.93) did not differ across diagnostic studies. Meta-regression analyses revealed that gender and depression severity explained the heterogeneity observed in adiponectin diagnostic studies, while BMI and the difference in BMI between MDD individuals and controls explained the heterogeneity of leptin diagnostic studies. Subgroup analyses revealed that adiponectin peripheral levels were significantly lower in MDD participants compared to controls when assayed with RIA, but not ELISA. Leptin levels were significantly higher in individuals with mild/moderate depression versus controls. Resistin serum levels were lower in MDD individuals compared to healthy controls (N = 298; Hedge's g = −0.25; P = 0.03). Leptin serum levels did not change after antidepressant treatment. However, heterogeneity was significant and sample size was low (N = 108); consequently meta-regression analysis could not be performed. Intervention meta-analyses could not be performed for adiponectin and resistin (i.e., few studies met inclusion criteria). In conclusion, this systematic review and meta-analysis underscored that relevant moderators/confounders (e.g., BMI, depression severity and type of assay) should be controlled for when considering the role of leptin and adiponectin as putative MDD diagnostic biomarkers. [ABSTRACT FROM AUTHOR]

Abstract: Background: Predominant polarity (PP) is a proposed course specifier for bipolar disorder, which was not incorporated in the DSM-5 as a descriptor for the nosology of bipolar disorder (BD). Here we perform a systematic review of original studies about PP. Methods: A computerized search of MEDLINE/Pubmed, EMBASE and Web of Science databases from inception to October 6th, 2013 was performed with keywords, including ‘bipolar disorder’, ‘polarity’ and ‘predominant polarity’. Results: A total of 19 studies met inclusion criteria. A unifying definition and conceptualization for PP is lacking. A PP is found in approximately half of BD patients. Most studies that included type I BD patients found the manic PP to be more prevalent, while studies that included type II BD participants found a higher prevalence of depressive PP. The depressive PP has been consistently associated with a depressive onset of illness, a delayed diagnosis of BD, type II BD and higher rates of suicidal acts. The manic PP is associated with a younger onset of illness, a first episode manic/psychotic and a higher rate of substance abuse. Evidence suggests that PP may influence responses to acute treatment for bipolar depression. Furthermore, evidences indicate that PP should be considered for the selection of maintenance treatments for BD. Limitations: There are few prospective studies on PP. There were disparate definitions for PP across studies. Conclusions: The concept of PP provides relevant information for clinicians. Future studies should investigate the genetic and biological underpinnings of PP. [Copyright &y& Elsevier]

Abstract: Background: To compare individuals in primary care (PC) who screen positive for bipolar depression to those who screened positive for unipolar depression on mental health care ouctomes, PC service utilization, medical comorbidities, suicidal ideation, health-related quality of life (HRQoL) and psychosocial functioning. Methods: In this cross-sectional study, participants (N=1197) answered self-reported measures of depressive symptoms (Center for epidemiologic studies depression scale), HRQoL (World Health Organization Quality of Life instrument-Abbreviated version), medical comorbidity (functional comorbidity index) and functioning (Functional Assessment Short test). Participants were partitioned into ‘bipolar’ and ‘unipolar’ depression groups based on a predefined cutoff on the Brazilian mood disorder questionnaire. Results: The prevalence of bipolar depression was in PC was 4.6% (95% CI: 3.4–5.8). Participants with bipolar depression were more likely to endorse suicidal ideation, present with more medical comorbidities, report a worse physical HRQoL and have a higher rate of PC services utilization as compared to participants who screened positive for unipolar depression. Only six (10.9%) participants were recognized by the general practitioner as having a diagnosis of bipolar depression. Limitations: The cross-sectional design prevents firm causal inferences from being drawn. A positive screen for BD does not substantiate the actual diagnosis. Co-morbid mental disorders were not accessed. Conclusions: Bipolar depression is common and under-recognized in Brazilian PC services. A positive screen for bipolar depression was associated with worse clinical outcomes and greater PC service utilization. [Copyright &y& Elsevier]

Preliminary data suggest that defensive profile of hemodialysis (HD) patients might influence adaptation to the disease. However, the association of defense mechanisms with health-related quality of life (HRQoL) of HD patients remains unknown. In this cross-sectional investigation, 170 HD patients and 170 age- and sex-matched healthy participants had their psychological profile assessed with the Defense Style Questionnaire-40 and the Hospital Anxiety and Depression Scale. Furthermore, the HD patients had their HRQoL measured with the World Health Organization Quality of Life instrument-abbreviated version. The HD patients had a more neurotic and immature defensive profile. Splitting, projection, reaction formation, and denial were significantly associated with impaired HRQoL, independent of psychological distress. Somatization was an independent correlate of worse overall and physical HRQoL. These findings suggest that, apart from the treatment of psychological distress symptoms, clinicians should also consider the defensive profile of HD patients because it is independently associated with HRQoL and may be amenable to treatment. [ABSTRACT FROM AUTHOR]

Abstract: Background: Affective temperaments may represent heritable subclinical manifestations of mood disorders. The concept of ego defense mechanisms also has provided a model for the comprehension of mood psychopathology. The relationships between affective temperaments, defense styles and depressive symptoms remain unknown. Methods: We obtained data from a subsample of the Brazilian Internet Study on Temperament and Psychopathology (BRAINSTEP). Socio-demographic information was collected and participants completed the Affective and Emotional Temperament Composite Scale (AFECTS), the defense style questionnaire (DSQ-40) and the Symptom Checklist-90-Revised (SCL-90-R). Results: Among 9937 participants (4472 male; 45%), individuals with hyperthymic or euthymic temperaments were more likely to present a mature defense style, whereas an immature defensive style was predominantly observed in individuals with cyclothymic, volatile, depressive, dysphoric, euphoric and disinhibited temperaments. Higher immature and lower mature defense style scores were independently associated with depressive symptoms. Participants with either euthymic or hyperthymic temperaments were less likely to endorse depressive symptoms. Euthymic and hyperthymic temperaments moderated the correlations of mature/immature defenses with depressive symptoms. Limitations: The data was collected from a convenience web-based sample. The study was cross-sectional. Conclusions: Affective temperaments are associated with distinct defense styles. These two personality theories provide distinct but interacting views for comprehension of depressive psychopathology. [Copyright &y& Elsevier]

Abstract: Escherichia coli heat-stable enterotoxin (STa), guanylin and uroguanylin are novel natriuretic and kaliuretic peptides that bind to and activate membrane guanylate cyclase (GC) receptors such as GC-C and OK-GC that are expressed in the kidney and intestine. Atrial natriuretic peptide (ANP) and its renal form (urodilatin, UROD) elicit natriuretic effects by activation of a different membrane guanylate cyclase, GC-A. Experiments were done in perfused rat kidneys to search for possible synergistic interactions between ANP, UROD, guanylin and uroguanylin on renal function. Pretreatment with ANP (0.03 nM) enhanced guanylin (0.19 μM) natriuretic activity (%ENa+; from 18.5±4.25 to 31.5±1.69, P <0.05, 120 min) and its kaliuretic activity (%EK+; from 24.5±4.43 to 50.6±3.84, P <0.05, 120 min). Furthermore, ANP increased the natriuretic (29.05±3.00 to 37.8±2.95, P <0.05, 120 min) and kaliuretic (from 33.2±3.52 to 42.83±2.45, P <0.05, 120 min) responses of perfused kidneys treated with low-dose (0.06 μM) uroguanylin. In contrast, ANP clearly inhibited the uroguanylin-induced (0.31 μM) increase in %ENa+ (from 35.9±2.37 to 14.8±1.93, P <0.05, 120 min), and in %EK+ (from 51.0±4.43 to 38.8±3.61, P <0.05, 120 min). UROD (0.03 nM) also enhanced the guanylin-induced natriuresis (to %ENa+ =31.0±1.93, P <0.05, 120 min) and kaliuresis (to %EK+ =54.2±3.61, P <0.05, 120 min), and inhibited the %ENa+ of uroguanylin (0.31 μM) to 17.9±1.67 as well as its %EK+ to 24.3±3.13 (both at 120 min, P <0.05). The synergism between ANP and UROD with either guanylin or uroguanylin at sub-threshold doses and the unexpected antagonism between ANP and UROD with uroguanylin at a pharmacological dose point to possible interactions between natriuretic peptide receptor (NPR) and uroguanylin/guanylin receptor signaling pathways. The interactions herein described may play a contributory role in the regulation of kidney function in many pathophysiological states, such as in the saliuresis following ingestion of salty meals. [Copyright &y& Elsevier]

Several evidences implicate that monoamines play a modulatory role in the brain mechanisms underlying encoding and retrieval of emotional memories. Recent experiments demonstrate that acute monoaminergic potentiation with the antidepressants bupropion or sertraline enhance the retrieval of longterm emotional memory in rodents. In the present study, we tested the hypothesis that acute monoaminergic re–uptake inhibition with these antidepressants might enhance retrieval of emotional memory in man. The central monoaminergic system was stimulated with either bupropion or sertraline in a doubleblind, randomized, placebo–controlled design with 105 healthy adult subjects divided in three groups (placebo, 150 mg–bupropion and 50 mg–sertraline). Memory was evaluated with a ‘surprise’ memory test 7 days after the presentation of an emotional story and with a wordcued autobiographical memory test. A total of 99 volunteers completed the experimental procedures. Contrasting to our prediction, we found no memory enhancing effect for either drug in both memory tests. All groups showed the expected heightened memory performance to the middle ‘emotive’phase of the story. Stimulation of the central monoaminergic system with the antidepressants bupropion and sertraline did not enhance the retrieval of long–term emotional memories in man. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that post-traumatic stress disorder (PTSD) may increase the risk of various types of dementia. Despite the large number of studies linking these critical conditions, the underlying mechanisms remain unclear. The past decade has witnessed an exponential increase in interest on brain imaging research to assess the neuroanatomical underpinnings of PTSD. This systematic review provides a critical assessment of available evidence of neuroimaging correlates linking PTSD to a higher risk of dementia. The EMBASE, PubMed/MEDLINE, and SCOPUS electronic databases were systematically searched from 1980 to May 22, 2021 for original references on neuroimaging correlates of PTSD and risk of dementia. Literature search, screening of references, methodological quality appraisal of included articles as well as data extractions were independently conducted by at least two investigators. Eligibility criteria included: 1) a clear PTSD definition; 2) a subset of included participants must have developed dementia or cognitive impairment at any time point after the diagnosis of PTSD through any diagnostic criteria; and 3) brain imaging protocols [structural, molecular or functional], including whole-brain morphologic and functional MRI, and PET imaging studies linking PTSD to a higher risk of cognitive impairment/dementia. Overall, seven articles met eligibility criteria, comprising findings from 366 participants with PTSD. Spatially convergent structural abnormalities in individuals with PTSD and co-occurring cognitive dysfunction involved primarily the bilateral frontal (e.g., prefrontal, orbitofrontal, cingulate cortices), temporal (particularly in those with damage to the hippocampi), and parietal (e.g., superior and precuneus) regions. A meta-analysis could not be performed due to heterogeneity and paucity of measurable data in the eligible studies. Our systematic review provides putative neuroimaging correlates associated with PTSD and co-occurring dementia/cognitive impairment particularly involving the hippocampi. Further research examining neuroimaging features linking PTSD to dementia are clearly an unmet need of the field. Future imaging studies should provide a better control for relevant confounders, such as the selection of more homogeneous samples (e.g., age, race, education), a proper control for co-occurring disorders (e.g., co-occurring major depressive and anxiety disorders) as well as the putative effects of psychotropic medication use. Furthermore, prospective studies examining imaging biomarkers associated with a higher rate of conversion from PTSD to dementia could aid in the stratification of people with PTSD at higher risk for developing dementia for whom putative preventative interventions could be especially beneficial. • Accumulating evidence suggests that PTSD may increase the risk of dementia. • The hippocampi were the most frequently represented regions in PTSD-related dementia. • The prefrontal, cingulate gyrus, and superior parietal regions were also frequently implicated. • PTSD-related dementia imaging findings considerably overlap with AD patterns. [ABSTRACT FROM AUTHOR]

Ferroptosis is a unique form of programmed death, characterised by cytosolic accumulation of iron, lipid hydroperoxides and their metabolites, and effected by the fatal peroxidation of polyunsaturated fatty acids in the plasma membrane. It is a major driver of cell death in neurodegenerative neurological diseases. Moreover, cascades underpinning ferroptosis could be active drivers of neuropathology in major psychiatric disorders. Oxidative and nitrosative stress can adversely affect mechanisms and proteins governing cellular iron homeostasis, such as the iron regulatory protein/iron response element system, and can ultimately be a source of abnormally high levels of iron and a source of lethal levels of lipid membrane peroxidation. Furthermore, neuroinflammation leads to the upregulation of divalent metal transporter1 on the surface of astrocytes, microglia and neurones, making them highly sensitive to iron overload in the presence of high levels of non-transferrin-bound iron, thereby affording such levels a dominant role in respect of the induction of iron-mediated neuropathology. Mechanisms governing systemic and cellular iron homeostasis, and the related roles of ferritin and mitochondria are detailed, as are mechanisms explaining the negative regulation of ferroptosis by glutathione, glutathione peroxidase 4, the cysteine/glutamate antiporter system, heat shock protein 27 and nuclear factor erythroid 2-related factor 2. The potential role of DJ-1 inactivation in the precipitation of ferroptosis and the assessment of lipid peroxidation are described. Finally, a rational approach to therapy is considered, with a discussion on the roles of coenzyme Q 10 , iron chelation therapy, in the form of deferiprone, deferoxamine (desferrioxamine) and deferasirox, and N -acetylcysteine. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the present study is to delineate the associations between body image dissatisfaction in pregnant women and immune-inflammatory biomarkers, i.e., C-reactive protein (CRP), zinc and IgA/IgM responses to tryptophan and tryptophan catabolites (TRYCATs).Methods: We assessed 49 pregnant and 24 non-pregnant females and assessed Body Image Satisfaction (BIS) scores at the end of term (T1), and 2-4 days (T2) and 4-6 weeks (T3) after delivery. Subjects were divided in those with a lowered BIS score (≤ 3) versus those with a higher score.Results: Logistic regression analysis showed that a lowered T1 BIS score was predicted by CRP levels and IgA responses to tryptophan (negative) and TRYCATs (positive), perinatal depression, body mass index (BMI) and age. The sum of quinolinic acid, kynurenine, 3-OH-kynurenine and 3-OH-anthranilic acid (reflecting brain quinolinic acid contents) was the single best predictor. In addition, a large part of the variance in the T1, T2 and T3 BIS scores was explained by IgA responses to tryptophan and TRYCATs, especially quinolinic acid.Conclusions: Body image dissatisfaction is strongly associated with inflammation and mucosa-derived IDO activation independently from depression, pregnancy, BMI and age. IgA responses to peripheral TRYCATs, which determine brain quinolinic acid concentrations, also predict body image dissatisfaction. [ABSTRACT FROM AUTHOR]

The aim of this study was to delineate the associations between the tryptophan catabolite (TRYCAT) pathway and affective symptoms in schizophrenia. Towards this end we measured immunoglobulin (Ig)A and IgM responses to relatively noxious TRYCATs, namely quinolinic (QA), xanthurenic (XA), picolinic (PA) acid and 3-OH-kynurenine (3HK), and generally protective TRYCATs, namely anthranilic (AA) and kynurenic (KA) acid in 80 patients with schizophrenia and 40 healthy controls. The Hamilton Rating Scale for Depression (HDRS) and anxiety (HAMA), Young Mania Rating Scale (YMRS) as well as the Positive and Negative Symptoms Scale of Schizophrenia (PANSS) were measured. Depression, anxiety and hypomanic as well as negative and positive symptoms were associated with increased IgA responses to PA. Increased IgA responses to XA were associated with anxiety, hypomanic and negative symptoms. Moreover, depressive, anxiety, hypomanic and negative symptoms were characterized by increased IgA responses to the noxious (XA + 3HK + QA + PA)/protective (AA + KA) TRYCAT ratio. All symptom dimensions were associated with increased IgM responses to QA, while depressive, anxiety, positive and negative symptoms were accompanied by lowered IgM responses to 3HK. Hypomanic symptoms were additionally accompanied by lowered IgM responses to AA, and negative symptoms by increased IgM responses to KA. In conclusion, both shared and distinct alterations in the activity of the TRYCAT pathway, as well as its regulatory factors and consequences, may underpin affective and classical psychotic symptoms of schizophrenia. Increased mucosa-generated production of noxious TRYCATs, especially PA, and specific changes in IgM-mediated regulatory activities may be associated with the different symptom dimensions of schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Frailty and pre-frailty are two common conditions in the older people, but whether these conditions could predict depression is still limited to a few longitudinal studies. In this paper, we aimed to investigate whether frailty and pre-frailty are associated with an increased risk of depression in a prospective cohort of community-dwelling older people.Methods: Four thousand seventy-seven community-dwelling men and women over 60 years without depression at baseline were included from the English Longitudinal Study of Ageing. Frailty status was defined according to modified Fried's criteria (weakness, weight loss, slow gait speed, low physical activity and exhaustion) and categorized as frailty (≥3 criteria), pre-frailty (1-2 criteria) or robustness (0 criterion). Depression was diagnosed as ≥4 out of 8 points of Center for Epidemiologic Studies Depression Scale, after 2 years of follow-up.Results: Over a 2-year follow-up, 360 individuals developed depression. In a logistic regression analysis, adjusted for 18 potential baseline confounders, pre-frailty (odds ratio (OR) = 0.89; 95% confidence interval (CI), 0.54-1.46; p = 0.64) and frailty (OR = 1.22; 95% CI, 0.90-1.64; p = 0.21) did not predict the onset of depression at follow-up. Among the criteria included in the frailty definition, only slow gait speed (OR = 1.82; 95% CI, 1.00-3.32; p = 0.05) appeared to predict a higher risk of depression.Conclusions: Among older community dwellers, frailty and pre-frailty did not predict the onset of depression during 2 years of follow-up, when accounting for potential confounders, whilst slow gait speed considered alone may predict depression in the older people. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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 < 0.001). Tuberculosis was associated with a 1.98 (95% CI 1.47-2.67), 1.75 (95% CI 1.26-2.42), and 3.68 (95% CI 3.01-4.50) times higher odds for subsyndromal depression, brief depressive episode, and depressive episode, respectively. Depressive episode co-occurring with tuberculosis was associated with significantly worse health status across all six domains compared to tuberculosis alone. Interaction analysis showed that depression significantly amplifies the association between TB and difficulties in self-care but not in other health domains.Conclusions: Depression is highly prevalent in adults with tuberculosis, and is associated with worse health status compared to tuberculosis without depression. Public health efforts directed to the recognition and management of depression in people with tuberculosis may lead to better outcomes. [ABSTRACT FROM AUTHOR]

Continuous monitoring of forest disturbance on tropical forests is a fundamental tool to support proactive preservation actions and to stop further destruction of native vegetation. Currently most of the monitoring systems in operation are based on optical imagery, and thus are flaw-prone on areas with frequent cloud cover. As this, several Synthetic Aperture Radar (SAR)-based systems have been developed recently, aiming all-weather disturbance detection. This article presents the main aspects and the results of the first year of operation of the SAR based Near Real-Time Deforestation Detection System (DETER-R), an automated deforestation detection system focused on the Brazilian Amazon. DETER-R uses the Google Earth Engine platform to preprocess and analyze Sentinel-1 SAR time series. New images are treated and analyzed daily. After the automated analysis, the system vectorizes clusters of deforested pixels and sends the corresponding polygons to the environmental enforcement agency. After 12 months of operational life, the system has produced 88,572 forest disturbance warnings. Human validation of the warning polygons showed a extremely low rate of misdetections, with less than 0.2% of the detected area corresponding to false positives. During the first year of operation, DETER-R provided 33,234 warnings of interest to national monitoring agencies which were not detected by its optical counterpart DETER in the same period, corresponding to an area of 105,238.5 ha, or approximately 5% of the total detections. During the rainy season, the rate of additional detections increased as expected, reaching 8.1%. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a highly prevalent, heterogeneous and systemic medical condition. Treatment options are limited, and recent studies have suggested that physical exercise can play an important role in the therapeutics of MDD. The aim of this study was to evaluate the antidepressant efficacy of adjunctive aerobic activity in association with pharmacotherapy (selective serotonin reuptake inhibitor) in symptomatic MDD as well as its association with physiological biomarkers. Methods: In this randomized, single-blind, add-on, controlled clinical trial, 57 patients (18–55 years of age) were followed-up for 28 days. All patients were drug-free, had been diagnosed with symptomatic MDD and received flexible dose of sertraline during the trial. Patients were randomized to either a 4-week program (4x/week) of add-on aerobic exercise (exercise group, N = 29) or no activity (control group, N = 28). Depression severity was assessed using the Hamilton Rating Scale for Depression (HAM-D) as the primary outcome. At baseline and endpoint, all patients underwent a comprehensive metabolic/cardiopulmonary exercise testing—including determination of maximal oxygen uptake (VO2max), VO2 at the second ventilatory threshold (VO2-VT2), and oxygen pulse (O2 pulse). Results: Depression scores significantly decreased in both groups after intervention. Importantly, patients in the aerobic exercise group required lower sertraline dose compared to the control group (sertraline monotherapy). The VO2max and O2 pulse parameters increased over time only in the exercise group and remained unchanged in the control group. Conclusions: The present findings suggest that a 4-week training of aerobic exercise significantly improves functional capacity in patients with MDD and may be associated with antidepressant efficacy. This approach may also decrease the need for higher doses of antidepressants to achieve response. Further studies in unmedicated and treatment-resistant MDD patients are needed in order to confirm the utility of short-term aerobic exercise as an alternative therapeutic approach in MDD. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: Homelessness has been associated with multiple detrimental health outcomes across observational studies. However, relatively few randomized controlled trials (RCTs) have been conducted on people who experience homelessness (PEH). Thus, this umbrella review ranked the credibility of evidence derived from systematic reviews (SRs) and meta-analyses (MAs) of observational studies investigating the associations between homelessness and any health outcome as well as RCTs targeting health needs in this population.Methods: Several databases were systematically searched from inception through April 28, 2021. Any SR and/or MA reporting quantitative data and providing a control group were eligible for inclusion. The credibility of the evidence derived from observational studies was appraised by considering the significance level of the association and the largest study, the degree of heterogeneity, the presence of small-study effects as well as excess significance bias. The credibility of evidence was then ranked in five classes. For SRs and/or MAs of RCTs, we considered the level of significance and whether the prediction interval crossed the null. The AMSTAR-2 and AMSTAR-plus instruments were adopted to further assess the methodological quality of SRs and/or MAs. The Newcastle-Ottawa Scale (NOS) was employed to further appraise the methodological quality of prospective cohort studies only; a sensitivity analysis limited to higher quality studies was conducted.Results: Out of 1549 references, 8 MAs and 2 SRs were included. Among those considering observational studies, 23 unique associations were appraised. Twelve of them were statistically significant at the p≤0.005 level. Included cases had worst health-related outcomes than controls, but only two associations reached a priori-defined criteria for convincing (class I) evidence namely hospitalization due to any cause among PEH diagnosed with HIV infection, and the occurrence of falls within the past year among PEH. According to the AMSTAR-2 instrument, the methodological quality of all included SRs and/or MAs was "critically low." Interventional studies were scant.Conclusion: While homelessness has been repeatedly associated with detrimental health outcomes, only two associations met the criteria for convincing evidence. Furthermore, few RCTs were appraised by SRs and/or MAs. Our umbrella review also highlights the need to standardize definitions of homelessness to be incorporated by forthcoming studies to improve the external validity of the findings in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Homelessness has been associated with multiple detrimental health outcomes across observational studies. However, relatively few randomized controlled trials (RCTs) have been conducted on people who experience homelessness (PEH). Thus, this umbrella review ranked the credibility of evidence derived from systematic reviews (SRs) and meta-analyses (MAs) of observational studies investigating the associations between homelessness and any health outcome as well as RCTs targeting health needs in this population. Methods: Several databases were systematically searched from inception through April 28, 2021. Any SR and/or MA reporting quantitative data and providing a control group were eligible for inclusion. The credibility of the evidence derived from observational studies was appraised by considering the significance level of the association and the largest study, the degree of heterogeneity, the presence of small-study effects as well as excess significance bias. The credibility of evidence was then ranked in five classes. For SRs and/or MAs of RCTs, we considered the level of significance and whether the prediction interval crossed the null. The AMSTAR-2 and AMSTAR-plus instruments were adopted to further assess the methodological quality of SRs and/or MAs. The Newcastle-Ottawa Scale (NOS) was employed to further appraise the methodological quality of prospective cohort studies only; a sensitivity analysis limited to higher quality studies was conducted. Results: Out of 1549 references, 8 MAs and 2 SRs were included. Among those considering observational studies, 23 unique associations were appraised. Twelve of them were statistically significant at the p≤0.005 level. Included cases had worst health-related outcomes than controls, but only two associations reached a priori-defined criteria for convincing (class I) evidence namely hospitalization due to any cause among PEH diagnosed with HIV infection, and the occurrence of falls within the past year among PEH. According to the AMSTAR-2 instrument, the methodological quality of all included SRs and/or MAs was "critically low." Interventional studies were scant. Conclusion: While homelessness has been repeatedly associated with detrimental health outcomes, only two associations met the criteria for convincing evidence. Furthermore, few RCTs were appraised by SRs and/or MAs. Our umbrella review also highlights the need to standardize definitions of homelessness to be incorporated by forthcoming studies to improve the external validity of the findings in this vulnerable population. [ABSTRACT FROM AUTHOR]

Guanylin and uroguanylin are two novel peptides that activate membrane-bound guanylate cyclases found in the kidney and intestine, influencing fluid and electrolyte homeostasis by cyclic GMP. Their natriuretic and kaliuretic activities are well documented. Since guanylin is inactivated by chymotrypsin in vitro , experiments were designed to evaluate the role of chymotrypsin-like proteases in renal metabolism of guanylin. Using the isolated perfused rat kidney, guanylin and a recombinant derivative containing a lysine residue in the N-terminus of the native peptide was tested. There were three experimental groups. In the first group, lys-guanylin (0.1–2.5 μg/ml) was placed into perfusate reservoir. In the second group, chymostatin (6 μg/ml), a chymotrypsin inhibitor, was placed into solution. In the third group, after 30 min. of perfusion with chymostatin (6 μg/ml), guanylin (0.3 μg/ml) was placed into solution. A maximal decrease in fractional Na + reabsorption (%TNa + ) was achieved at 1.0 μg/ml of lys-guanylin (from 73.25±2.29 to 54.97±0.10, P<0.05). Lys-guanylin (1.0 μg/ml) also decreased fractional K + reabsorption (%TK + ) from 59.26±3.93 to 30.75±0.78 (P<0.05). Chymostatin had no detectable effects in electrolyte reabsorption in this assay. When introduced after chymostatin, guanylin lowered %TNa + (from 81.2±1.86 to 72.6±2.45, P<0.05) and %TK + (from 69.4±4.12 to 65.8±2.81, P<0.05). At this subthreshold concentration, guanylin alone lacks effects in %TNa + or %TK +. Furthermore, the ability of both peptides to promote increases in intestinal fluid secretion was evaluated in the in vivo suckling mouse model. When administered per os , guanylin failed to stimulate intestinal secretion. When chymostatin was present in the test solution, guanylin induced intestinal secretion in this assay. In... [ABSTRACT FROM AUTHOR]

• Four clinical trajectories in non-affective first episode psychosis patients were identified, namely "excellent prognosis", "remitting course", "clinical worsening" and "chronic course". • The risk factors contributing towards a clinical worsening were low doses of antipsychotics, high depressive symptomatology and the presence of a positive family history. • The protective factors for a remitting course were a high cognitive reserve and better premorbid adjustment. The extreme variability in symptom presentation reveals that individuals diagnosed with a first-episode psychosis (FEP) may encompass different sub-populations with potentially different illness courses and, hence, different treatment needs. Previous studies have shown that sociodemographic and family environment factors are associated with more unfavorable symptom trajectories. The aim of this study was to examine the dimensional structure of symptoms and to identify individuals' trajectories at early stage of illness and potential risk factors associated with poor outcomes at follow-up in non-affective FEP. One hundred and forty-four non-affective FEP patients were assessed at baseline and at 2-year follow-up. A Principal component analysis has been conducted to identify dimensions, then an unsupervised machine learning technique (fuzzy clustering) was performed to identify clinical subgroups of patients. Six symptom factors were extracted (positive, negative, depressive, anxiety, disorganization and somatic/cognitive). Three distinct clinical clusters were determined at baseline: mild; negative and moderate; and positive and severe symptoms, and five at follow-up: minimal; mild; moderate; negative and depressive; and severe symptoms. Receiving a low-dose antipsychotic, having a more severe depressive symptomatology and a positive family history for psychiatric disorders were risk factors for poor recovery, whilst having a high cognitive reserve and better premorbid adjustment may confer a better prognosis. The current study provided a better understanding of the heterogeneous profile of FEP. Early identification of patients who could likely present poor outcomes may be an initial step for the development of targeted interventions to improve illness trajectories and preserve psychosocial functioning. [ABSTRACT FROM AUTHOR]

Objectives: This systematic review aimed at providing a critical, comprehensive synthesis of international guidelines' recommendations on the long‐term treatment of bipolar disorder type I (BD‐I). Methods: MEDLINE/PubMed and EMBASE databases were searched from inception to January 15th, 2019 following PRISMA and PICAR rules. International guidelines providing recommendations for the long‐term treatment of BD‐I were included. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation‐AGREE II. Results: The final selection yielded five international guidelines, with overall good quality. The evaluation of applicability was the weakest aspect across the guidelines. Differences in their updating strategies and the rating of the evidence, particularly for meta‐analyses, randomized clinical trials (RCTs) and observational studies, could be responsible of some level of heterogeneity among recommendations. Nonetheless, the guidelines recommended lithium as the 'gold standard' in the long‐term treatment of BD‐I. Quetiapine was another possible first‐line option as well as aripiprazole (for the prevention of mania). Long‐term treatment should contemplate monotherapy, at least initially. Clinicians should check regularly for efficacy and side effects and if necessary, switch to first‐line alternatives (i.e. Valproate), combine first‐line compounds with different mechanisms of action or switch to second‐line options or combinations. Conclusions: The possibility to monitor improvements in long‐term outcomes, namely relapse prevention and inter‐episode subthreshold depressive symptoms, based on the application of their recommendations is an unmet need of clinical guidelines. In terms of evidence of clinical guidelines, there is a need for more efficacious treatment strategies for the prevention of bipolar depression. [ABSTRACT FROM AUTHOR]

Gray matter and cortical thickness reductions have been documented in individuals at clinical high-risk for psychosis and may be more pronounced in those who transition to psychosis. However, these findings rely on small samples and are inconsistent across studies. In this review and meta-analysis we aimed to investigate neuroanatomical correlates of clinical high-risk for psychosis and potential predictors of transition, using a novel meta-analytic method (Seed-based d Mapping with Permutation of Subject Images) and cortical mask, combining data from surface-based and voxel-based morphometry studies. Individuals at clinical high-risk for psychosis who later transitioned to psychosis were compared to those who did not and to controls, and included three statistical maps. Overall, individuals at clinical high-risk for psychosis did not differ from controls, however, within the clinical high-risk for psychosis group, transition to psychosis was associated with less cortical gray matter in the right temporal lobe (Hedges' g = -0.377), anterior cingulate and paracingulate (Hedges' g = -0.391). These findings have the potential to help refine prognostic and etiopathological research in early psychosis. [ABSTRACT FROM AUTHOR]

Adherence to antidepressants is crucial for optimal treatment outcomes when treating depressive disorders. However, poor adherence is common among patients prescribed antidepressants. This targeted review summarizes the main factors associated with poor adherence, interventions that promote antidepressant adherence, pharmacological aspects related to antidepressant adherence, and formulates 10 clinical recommendations to optimize antidepressant adherence. Patient-related factors associated with antidepressant non-adherence include younger age, psychiatric and medical comorbidities, cognitive impairment, and substance use disorders. Prescriber behavior-related factors include neglecting medical and family histories, selecting poorly tolerated antidepressants, or complex antidepressant regimens. Multi-disciplinary interventions targeting both patient and prescriber, aimed at improving antidepressant adherence, include psychoeducation and providing the patient with clear behavioral interventions to prevent/minimize poor adherence. Regarding antidepressant choice, agents with individually tailored tolerability profile should be chosen. Ten clinical recommendations include four points focusing on the patient (therapeutic alliance, adequate history taking, measurement of depressive symptoms, and adverse effects improved access to clinical care), three focusing on prescribing practice (psychoeducation, individually tailored antidepressant choice, simplified regimen), two focusing on mental health services (improved access to mental health care, incentivized adherence promotion and monitoring), and one relating to adherence measurement (adherence measurement with scales and/or therapeutic drug monitoring). [ABSTRACT FROM AUTHOR]

Notwithstanding advances in understanding the pathophysiology of major depressive disorder (MDD), no single mechanism can explain all facets of this disorder. An expanding body of evidence indicates a putative role for the inflammatory response. Several meta-analyses showed an increase in systemic peripheral inflammatory markers in individuals with MDD. Numerous conditions and circumstances in the modern world may promote chronic systemic inflammation through mechanisms, including alterations in the gut microbiota. Peripheral cytokines may reach the brain and contribute to neuroinflammation through cellular, humoral, and neural pathways. On the other hand, antidepressant drugs may decrease peripheral levels of inflammatory markers. Anti-inflammatory drugs and nutritional strategies that reduce inflammation also could improve depressive symptoms. The present study provides a critical review of recent advances in the role of inflammation in the pathophysiology of MDD. Furthermore, this review discusses the role of glial cells and the main drivers of changes associated with neuroinflammation. Finally, we highlight possible novel neurotherapeutic targets for MDD that could exert antidepressant effects by modulating inflammation. • Stress situations can exacerbate neuroinflammation. • Inflammation from the periphery can access the brain. • In major depressive disorder there is an inflammation process involved. • Drugs with anti-inflammatory effects could be investigated to treat depression. [ABSTRACT FROM AUTHOR]

• Reports an umbrella review of potential diagnostic biomarkers in obsessive-compulsive disorder (OCD). • Several biomarkers showed convincing evidence of association with OCD. • None of the biomarkers seems to have diagnostic specificity. Obsessive-compulsive disorder (OCD) has been associated with a wide range of biological and neurocognitive findings, which could assist in the search for biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses to assess and grade the strength of the evidence of the association between OCD and several potential diagnostic biomarkers while controlling for several potential biases. Twenty-four systematic reviews and meta-analyses were included, comprising 352 individual studies, more than 10,000 individuals with OCD, and covering 73 potential biomarkers. OCD was significantly associated with several neurocognitive biomarkers, with varying degrees of evidence, ranging from weak to convincing. A number of biochemical, neurophysiological, and neuroimaging biomarkers also showed statistically significant, albeit weak, associations with OCD. Analyses in unmedicated samples (123 studies) weakened the strength of the evidence for most biomarkers or rendered them non-significant. None of the biomarkers seem to have sufficient sensitivity and specificity to become a diagnostic biomarker. A more promising avenue for future biomarker research in OCD might be the prediction of clinical outcomes rather than diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: There is evidence to suggest that tobacco use is associated with suicide attempts. However, it is unclear whether such an association can be extended to include secondhand smoke exposure. Using nationally representative data of school-attending adolescents from 33 countries, we examined the association of tobacco use and exposure to secondhand smoke with suicide attempts.Methods: We used data from the Global School-based Student Health Survey, a cross-sectional survey conducted among adolescents 12-15 years of age. We used logistic regression to estimate the country-specific associations. We then conducted random effect meta-analyses to obtain overall and country-income level pooled estimates. Lastly, we used logistic regression analyses to investigate a dose-response association of cigarette smoking and exposure to secondhand smoke with suicide attempts.Results: A positive association between tobacco use and suicide attempts among adolescents was present regardless of country-income level (low income: odds ratio 4.98, 95% CI: 3.11-7.96; lower middle income: 3.47, 2.91-4.15; upper middle income: 3.09, 2.75-3.47; and high income: 3.18, 2.63-3.84) and gender (boys: 3.28, 2.86-3.76; girls: 3.86, 3.30-4.51). Exposure to secondhand smoke was associated with suicide attempts, albeit weakly, among girls only (1.26, 1.14-1.39; boys: 1.00, 0.87-1.15). There was some evidence that a dose-response association of cigarette smoking and exposure to secondhand smoke with suicide attempts may only exist among girls.Conclusions: Adolescents who use tobacco, and adolescent girls exposed to secondhand smoke were found to be more likely to attempt suicide; however, future longitudinal studies are warranted to assess causality.Implications: Our findings indicate that routine screening of adolescents for tobacco use should be implemented globally, especially when assessing suicidal behaviors and risk. Future longitudinal and intervention studies are warranted to assess causality and whether prevention efforts such as tobacco control interventions and programmes targeting tobacco use and exposure to secondhand smoke among adolescents could ultimately lead to a reduction in the occurrence of suicide attempts. [ABSTRACT FROM AUTHOR]

Objectives: Stable-phase schizophrenia comprises two distinct entities namely Major Neuro-Cognitive Psychosis (MNP) and simple NP (SNP), which are defined by neuroimmune and neurocognitive abnormalities. Methods: This study investigates associations of psychomotor retardation (PMR), clinical and biomarker characteristics of schizophrenia. We recruited 40 healthy controls and 79 schizophrenia patients and measured IgA responses to tryptophan catabolites (TRYCATs), IgM to malondialdehyde and nitroso (NO)-cysteinyl, CCL-11, an immune activation index based on cytokine levels, and motor screening task (MOT) scores. Results: PMR differentiated schizophrenia from controls and MNP from SNP. In addition, PMR was strongly associated with impairments in executive functions and episodic and semantic memory, psychotic, hostility, excitation, mannerism and negative (PHEMN) symptoms. Around 50% of the variance in PMR was predicted by the cumulative effects of the immune activation index, CCL-11, TRYCATs, NO-Cysteinyl and natural IgM. PRM can reliably be combined with PHEMN symptoms, memory and executive impairments into one latent vector reflecting overall severity of schizophrenia. Conclusions: PMR is a key psychopathological feature of schizophrenia mainly MNP. In addition, PMR may be driven by deficits in the compensatory immune-regulatory system and increased production of neurotoxic immune products, namely TRYCATs, IgM to NO-cysteinyl, and CCL-11, an endogenous cognition deteriorating chemokine. [ABSTRACT FROM AUTHOR]

Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson's disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone-glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate-glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders. [ABSTRACT FROM AUTHOR]

Objective: Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring.Methods: The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018.Results: Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35-2.41; number needed to harm (NNH)=33, 95% CI=22-77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16-2.96; NNH=71, 95% CI=48-167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15-12.39; NNH=15, 95% CI=8-111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03-0.89; number needed to treat=3, 95% CI=1-12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations.Conclusions: The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. • Multiple predictors of recurrence in major depressive disorder have been identified. • Recurrence was associated with specific illness characteristics. • Predict recurrence may help clinicians to stratify patients who could benefit from more intensive maintenance treatments. [ABSTRACT FROM AUTHOR]

Objectives: 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).Methods: 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.Results: 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).Conclusion: 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. [ABSTRACT FROM AUTHOR]

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative-specific epitopes (OSEs), which are a first-line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls. Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all five Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the receiver operating characteristic curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the negative subscale score of the Positive and Negative Syndrome Scale was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the five enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini-Mental State Examination, Boston naming test, Verbal Fluency, and Word List Memory test scores. These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Social isolation is one of the main risk factors associated with suicidal outcomes. The aim of this narrative review was to provide an overview on the link between social isolation and suicidal thoughts and behaviors.Methods: We used the PubMed database to identify relevant articles published until April 13, 2018. We focused on: (a) systematic reviews, meta-analyses, and narrative reviews; (b) original observational studies with large samples (N ≥ 500); and (c) qualitative studies. We included all relevant suicidal outcomes: suicidal ideation (SI), suicidal planning, non-suicidal self-injury, deliberate self-harm, suicide attempt (SA), and suicide.Results: The main social constructs associated with suicidal outcomes were marital status (being single, separated, divorced, or widowed) and living alone, social isolation, loneliness, alienation, and belongingness. We included 40 original observational studies, the majority of them performed on adolescents and/or young adults (k = 23, 57.5%). Both the objective condition (e.g., living alone) and the subjective feeling of being alone (i.e., loneliness) were strongly associated with suicidal outcomes, in particular with SA and SI. However, loneliness, which was investigated in most studies (k = 24, 60%), had a major impact on both SI and SA. These associations were transculturally consistent.Limitations: Confounding factors can limit the weight of the results obtained in observational studies.Conclusions: Data from the observational studies suggest that both objective social isolation and the subjective feeling of loneliness should be incorporated in the risk assessment of suicide. Interventional studies targeting social isolation for suicide prevention are needed. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The re-emergence (i.e. 'breakthrough') of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre-clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non-adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid-cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub-threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic–pituitary–adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long-term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients. [ABSTRACT FROM AUTHOR]

Eotaxin is increased in neurodegenerative disorders and schizophrenia, and preclinical studies indicate that eotaxin may induce cognitive deficits. This study aims to examine whether peripheral levels of eotaxin impact cognitive functioning in healthy volunteers and formal thought disorder (FTD) and psychopathology in schizophrenia patients. Serum levels of eotaxin were assayed and cognitive tests were performed on a sample of 40 healthy participants and 80 schizophrenia patients. Among healthy participants, eotaxin levels were significantly associated with episodic/semantic memory, executive functions, Mini Mental State Examination, emotion recognition, and sustained attention. In addition, age-related effects on these cognitive measures were partly mediated by eotaxin. The super-variable "age-eotaxin" predicted a large part of the variance in cognitive functions among healthy participants, and hence, eotaxin may act as an "accelerated brain aging chemokine" (ABAC). In schizophrenia, eotaxin levels had a strong impact on formal thought disorders and psychopathology. In schizophrenia, increased eotaxin strongly impacts memory and sustained attention, which together to a large extent determine FTD. FTD together with memory deficits predicts around 92.5% of the variance in psychopathology. Moreover, the effects of eotaxin are partially mediated by executive functioning, while the effects of male sex on FTD and psychopathology are mediated by eotaxin. In healthy subjects, eotaxin strongly impacts executive functioning and multiple cognitive domains. In schizophrenia, peripheral levels of eotaxin strongly impact both negative symptoms and psychosis (hallucinations and delusions), and these eotaxin effects are mediated by impairments in frontal functioning, memory, sustained attention, and FTD. Eotaxin is an endogenous cognitive deteriorating chemokine (ECDC) and a novel therapeutic target for age-related cognitive decline and schizophrenia as well. [ABSTRACT FROM AUTHOR]

Background: Despite the potential importance of understanding violent criminal behavior (VCB) in individuals suffering from bipolar disorder (BD), previous findings are conflicting. The aims of the present study are to clarify the association of VCB and BD in comparison to general population and other psychiatric conditions.Methods: A systematic review of literature from January 1st, 1980 through January 16th, 2017 from 3 electronic databases (MEDLINE/PubMed, EMBASE and PsycInfo), following the PRISMA and the MOOSE statements. Original peer-reviewed studies reporting data on VCB in BD were included. A random-effects meta-analysis was performed. Potential sources of heterogeneity were examined through subgroup and meta-regression analyses. The protocol was registered in PROSPERO, CRD42017054070.Results: Twelve studies providing data from 58,475 BD participants. The prevalence of VCB in BD was 7.1% (95%CI = 3.0‒16.5%; k = 4). The association of BD and VCB compared to general population was not significant (OR = 2.784; 95% CI, 0.687‒11.287, P = .152). The association was significant only in cross-sectional studies, in studies in which VCB was assessed through self-reported measures, and in studies conducted in the USA. BD was more likely to be associated with VCB when BD patients were compared to controls with depressive disorders, whilst it was found to be less associated with VCB when BD was compared to psychotic disorders.Limitations: 1. the methodological heterogeneity across the included studies. 2. causal inferences were precluded by the inclusion of cross-sectional studies.Conclusions: These findings might provide a more balance portrait of the association between BD and VCB to clinicians, law enforcement and general public. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that nitro-oxidative pathways play an important role in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD) and maybe anxiety disorders. The current study aims to examine superoxide dismutase (SOD1), catalase, lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), malondialdehyde (MDA), glutathione (GSH), paraoxonase 1 (PON1), high-density lipoprotein cholesterol (HDL), and uric acid (UA) in participants with and without generalized anxiety disorder (GAD) co-occurring or not with BD, MDD, or tobacco use disorder. Z unit-weighted composite scores were computed as indices of nitro-oxidative stress driving lipid and protein oxidation. SOD1, LOOH, NOx, and uric acid were significantly higher and HDL and PON1 significantly lower in participants with GAD than in those without GAD. GAD was more adequately predicted by increased SOD + LOOH + NOx and lowered HDL + PON1 composite scores. Composite scores of nitro-oxidative stress coupled with aldehyde and AOPP production were significantly increased in participants with comorbid GAD + MDD as compared with all other study groups, namely MDD, GAD + BD, BD, GAD, and healthy controls. In conclusion, GAD is characterized by increased nitro-oxidative stress and lipid peroxidation and lowered lipid-associated antioxidant defenses, while increased uric acid levels in GAD may protect against aldehyde production and protein oxidation. This study suggests that increased nitro-oxidative stress and especially increased SOD1 activity, NO production, and lipid peroxidation as well as lowered HDL-cholesterol and PON1 activity could be novel drug targets for GAD especially when comorbid with MDD. [ABSTRACT FROM AUTHOR]

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. 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 sociodemographic 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. Results: Overall, 7,639 participants were included (71.3% females; age: 27.267.9 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. Conclusion: The Brazilian mYFAS 2.0 demonstrated adequate psychometric properties in our sample; however, future studies should further evaluate its discriminant validity. [ABSTRACT FROM AUTHOR]

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-1ß, 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-1ß, 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. [ABSTRACT FROM AUTHOR]