Bipolar symptoms, somatic burden and functioning in older-age bipolar disorder: A replication study from the global aging & geriatric experiments in bipolar disorder database (GAGE-BD) project.

OBJECTIVES: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset. DESIGN/METHODS: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601). RESULTS: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning. CONCLUSIONS: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning.

Cognition in older age bipolar disorder: An analysis of archival data across the globe.

BACKGROUND: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies. METHODS: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning. RESULTS: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning. LIMITATIONS: Cross-sectional design and loss of granularity due to harmonization. CONCLUSION: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD.

Higher IL-6 and IL-4 plasma levels in depressed elderly women are influenced by diabetes mellitus

Abstract Objective This study aimed at investigating a set of peripheral cytokines in elderly female patients with MDD, comparing them to controls, and assessing the potential influence of clinical comorbidities on inflammatory markers. Methods Twenty-five elderly female patients diagnosed with MDD and 19 age-matched female controls were enrolled on this study. Plasma levels of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were evaluated with commercially-available assays. Results Elderly female patients with MDD exhibited higher plasma IL-6 and IL-4 levels when compared to controls. In a logistic regression model taking cytokine levels, comorbidities, and age into account, only type 2 diabetes mellitus (DM2) remained associated with MDD. Conclusion Diabetes influences the association between MDD and higher levels of cytokines in elderly female patients. Future studies should take this evidence into account in order to mitigate confounding factors.

Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study protocol.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.

Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study Protocol.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5,000 richly-phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.

Essential data dimensions for prospective international data collection in older age bipolar disorder (OABD): Recommendations from the GAGE-BD group.

BACKGROUND: By 2030, over 50% of individuals living with bipolar disorder (BD) are expected to be aged ≥50 years. However, older age bipolar disorder (OABD) remains understudied. There are limited large-scale prospectively collected data organized in key dimensions capable of addressing several fundamental questions about BD affecting this subgroup of patients. METHODS: We developed initial recommendations for the essential dimensions for OABD data collection, based on (1) a systematic review of measures used in OABD studies, (2) a Delphi consensus of international OABD experts, (3) experience with harmonizing OABD data in the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD, n ≥ 4500 participants), and (4) critical feedback from 34 global experts in geriatric mental health. RESULTS: We identified 15 key dimensions and variables within each that are relevant for the investigation of OABD: (1) demographics, (2) core symptoms of depression and (3) mania, (4) cognition screening and subjective cognitive function, (5) elements for BD diagnosis, (6) descriptors of course of illness, (7) treatment, (8) suicidality, (9) current medication, (10) psychiatric comorbidity, (11) psychotic symptoms, (12) general medical comorbidities, (13) functioning, (14) family history, and (15) other. We also recommend particular instruments for capturing some of the dimensions and variables. CONCLUSION: The essential data dimensions we present should be of use to guide future international data collection in OABD and clinical practice. In the longer term, we aim to establish a prospective consortium using this core set of dimensions and associated variables to answer research questions relevant to OABD.

Cognitive impairment in hoarding disorder: a systematic review.

OBJECTIVE: In the present study, we aimed to perform a systematic review evaluating the cognitive performance of patients with hoarding disorder (HD) compared with controls. We hypothesized that HD patients would present greater cognitive impairment than controls. METHODS: A systematic search of the literature using the electronic databases MEDLINE, SCOPUS, and LILACS was conducted on May 2020, with no date limit. The search terms were "hoarding disorder," "cognition," "neuropsychology," "cognitive impairment," and "cognitive deficit." We included original studies assessing cognitive functioning in patients with HD. RESULTS: We retrieved 197 studies initially. Of those, 22 studies were included in the present study. We evaluated 1757 patients who were 41 to 72 years old. All selected studies comprised case-control studies and presented fair quality. Contrary to our hypothesis, HD patients showed impairment only in categorization skills in comparison with controls, particularly at confidence to complete categorization tasks. Regarding attention, episodic memory, working memory, information-processing speed, planning, decision-making, inhibitory control, mental flexibility, language, and visuospatial ability, HD patients did not show impairment when compared with controls. There is a paucity of studies on social cognition in HD patients, although they may show deficits. The impact of emotion in cognition is also understudied in HD patients. CONCLUSION: Except for categorization skills, the cognitive performance in HD patients does not seem to be impaired when compared with that in controls. Further work is needed to explore social cognition and the impact of emotion in cognitive performance in HD patients.

Depressive disorders in the elderly and dementia: An update.

The relationship between depressive disorders in the elderly and dementia, particularly Alzheimer's disease (AD), is highly complex. While the nature of this relationship is still a matter of debate, differential diagnosis and treatment remain a great clinical challenge. We review recent findings on the conundrum of depressive disorders in the elderly and AD. There is a biological continuum between depressive disorders in the elderly - or at least a subgroup of them - and AD. While elderly subjects with depression and patients with AD exhibit higher circulating levels of pro-inflammatory molecules and lower BDNF than matched controls, CSF levels of Aß42 can discriminate AD from depressive disorders in the elderly. The role of antidepressant treatment as a strategy to minimize the risk of AD remains to be established.

A relação entre transtornos depressivos em idosos e demência, particularmente a doença de Alzheimer (DA), é altamente complexa. Embora a natureza desse relacionamento ainda seja motivo de debate, o diagnóstico e o tratamento diferenciais continuam sendo um grande desafio clínico. Revisamos descobertas recentes sobre o dilema de transtornos depressivos em idosos e DA. Existe um contínuo biológico entre os transtornos depressivos em idosos ­ ou pelo menos um subgrupo deles ­ e a DA. Enquanto indivíduos idosos com depressão e pacientes com DA exibem níveis circulantes mais altos de moléculas pró-inflamatórias e menor BDNF do que os controles correspondentes, os níveis de Aß42 no LCR podem discriminar a DA de distúrbios depressivos em idosos. O papel do tratamento antidepressivo como estratégia para minimizar o risco de DA ainda precisa ser estabelecido.

Depressive disorders in the elderly and dementia: an update / Transtornos depressivos em idosos e demência: uma atualização

ABSTRACT. The relationship between depressive disorders in the elderly and dementia, particularly Alzheimer's disease (AD), is highly complex. While the nature of this relationship is still a matter of debate, differential diagnosis and treatment remain a great clinical challenge. We review recent findings on the conundrum of depressive disorders in the elderly and AD. There is a biological continuum between depressive disorders in the elderly ­ or at least a subgroup of them ­ and AD. While elderly subjects with depression and patients with AD exhibit higher circulating levels of pro-inflammatory molecules and lower BDNF than matched controls, CSF levels of Aß42 can discriminate AD from depressive disorders in the elderly. The role of antidepressant treatment as a strategy to minimize the risk of AD remains to be established.

RESUMO. A relação entre transtornos depressivos em idosos e demência, particularmente a doença de Alzheimer (DA), é altamente complexa. Embora a natureza desse relacionamento ainda seja motivo de debate, o diagnóstico e o tratamento diferenciais continuam sendo um grande desafio clínico. Revisamos descobertas recentes sobre o dilema de transtornos depressivos em idosos e DA. Existe um contínuo biológico entre os transtornos depressivos em idosos ­ ou pelo menos um subgrupo deles ­ e a DA. Enquanto indivíduos idosos com depressão e pacientes com DA exibem níveis circulantes mais altos de moléculas pró-inflamatórias e menor BDNF do que os controles correspondentes, os níveis de Aß42 no LCR podem discriminar a DA de distúrbios depressivos em idosos. O papel do tratamento antidepressivo como estratégia para minimizar o risco de DA ainda precisa ser estabelecido.

Decreased percentage of CD4+ lymphocytes expressing chemokine receptors in bipolar disorder.

OBJECTIVE: Although accumulating evidence supports the hypothesis that immune/inflammatory mechanisms are associated with the pathophysiology of bipolar disorder (BD), data about the profile of chemokines (chemotactic cytokines) and chemokine receptors are still scarce. The current study was designed to evaluate the expression of chemokine receptors on lymphocytes of patients with BD in comparison with controls. METHODS: Thirty-three patients with type I BD (N = 21 in euthymia; N = 6 in mania/hypomania; N = 6 in depression) and 22 age- and sex-matched controls were subjected to clinical evaluation and peripheral blood draw. The expression of chemokine receptors CCR3, CCR5, CXCR4, and CXCR3 on CD4+ and CD8+ lymphocytes was assessed by flow cytometry. RESULTS: Patients with BD had decreased percentage of CD4+CXCR3+ (p = 0.024), CD4+CCR3+ (p = 0.042), and CD4+CCR5+ (0.013) lymphocytes in comparison with controls. The percentage of both CD4+ and CD8+ lymphocytes expressing the chemokine receptor CXCR4 was similar in patients with BD and controls. Likewise, the percentages of CD8+CXCR3+, CD8+CCR3+, and CD8+CCR5+ lymphocytes were similar in patients with BD and controls. CONCLUSION: Our findings reinforce the hypothesis that immune pathways, especially involving CD4+ lymphocytes, are involved in the physiopathology of BD.

Lower circulating levels of angiotensin-converting enzyme (ACE) in patients with schizophrenia.

This study aimed at evaluating changes in the renin-angiotensin system (RAS) in patients with schizophrenia in comparison with controls. Plasma levels of angiotensin-converting enzyme (ACE), ACE2, angiotensin (Ang)-(1-7) and Ang II were assessed in 25 patients with schizophrenia and 20 controls. Patients with schizophrenia presented decreased levels of ACE compared to controls [median (25th-75th percentiles) = 434.79 (341.15-524.02) vs. 508.49 (396.34-608.72); p < 0.05]. No significant differences were found regarding ACE2, Ang-(1-7) and Ang II levels. There were no associations between the measured molecules and clinical parameters. Our results corroborate the hypothesis that the RAS is involved in the pathophysiology of schizophrenia.

The effect of insulin-induced hypoglycemia on inflammatory markers: A systematic review.

INTRODUCTION: The effects of acute hypoglycemia on markers of inflammation have been investigated, but the results have been heterogeneous. OBJECTIVE: We aimed to perform a systematic review about the acute effects of insulin-induced hypoglycemia on inflammatory markers in patients with diabetes as well as non-diabetic subjects. METHODS: A systematic search of the literature using the electronic databases MEDLINE and SCOPUS was conducted through September 2017. Search terms included: "hypoglycemia"," insulin", "cytokines", and "inflammation". We included original studies assessing peripheral inflammatory markers during insulin-induced hypoglycemia in humans. RESULTS: Two hundred twenty-two citations were initially retrieved. Eleven studies were included in our systematic review. Acute hypoglycemia increases total leukocyte number and several pro-inflammatory markers. Elevation in pro-inflammatory markers in response to insulin-induced acute hypoglycemia appears to be of similar magnitude in non-diabetic subjects and in type-1 diabetic patients with intact awareness of hypoglycemia. Adrenaline rises in response to acute hypoglycemia correlates with the increase of pro-inflammatory markers. CONCLUSION: Acute hypoglycemia induces a pro-inflammatory state in both type-1 diabetic and non-diabetic subjects with no apparent significant difference between these two populations. Activation of the sympathetic nervous system is a likely mediator of these effects.

Further Evidence of Accelerated Aging in Bipolar Disorder: Focus on GDF-15.

BACKGROUND: Bipolar disorder (BD) is a mood disorder associated with cardiovascular and metabolic diseases and premature aging. Growth differentiation factor 15 (GDF-15) has emerged as a biomarker for cardiovascular risk and aging. Our aim was to compare plasma levels of GDF-15 between BD patients and controls, and to evaluate whether they were associated with clinical parameters. METHODS: Forty-six patients with type I BD (23 in euthymia and 23 in mania) and 33 healthy controls were recruited for this study. Plasma levels of GDF-15 were measured by immunoassay. RESULTS: The levels of GDF-15 were significantly higher (p < 0.001) in patients with BD in comparison with controls. In patients, GDF-15 levels correlated with age (rho = 0.434; p = 0.003) and illness duration (rho = 0.502; p = 0.001). CONCLUSION: Our findings corroborate the view that BD is an illness associated with accelerated aging.

Inflammatory molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates: A Systematic Review.

OBJECTIVE: To provide a systematic review investigating the role of inflammatory molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates. DATA SOURCE: Databases including PubMed, BIREME, and Scopus were systematically searched. Observational studies, as well as transversal, and cohort studies using human subjects published from 1990 to September 2017 were eligible for inclusion. Two authors independently identified eligible studies and analyzed their characteristics, quality, and accuracy in depth. DATA SYNTHESIS: 11 eligible studies clearly investigated the association between peripheral inflammation and motor and/or cognitive development in preterm infants. However, the selected populations differed in relation to the events associated with prematurity and the risk factors to abnormal motor and/or cognitive development. These studies measured circulating levels of cytokines, chemokines, adhesion molecules, acute phase proteins, and growth factors. The most commonly analyzed proteins were IL-1ß, IL-6, TNF, CCL5/RANTES, CXCL8/IL-8, IGFBP-1, and VEGF. In seven of the eligible studies, plasma levels of IL-6 correlated with development delay. Two studies reported correlation between CXCL8/IL-8 plasma levels with cognitive and motor delay. In one study, higher levels of MCP-1/CCL2 were associated with better cognitive and motor outcome. CONCLUSION: There is preliminary evidence indicating that circulating inflammatory molecules are associated with motor and cognitive development in preterm neonates, even considering different populations.

Plasma Levels of Tumor Necrosis Factor Superfamily Molecules Are Increased in Bipolar Disorder.

OBJECTIVE: Patients with bipolar disorder (BD) exhibit peripheral low-grade inflammation. The aim of the current study was to investigate the involvement of hitherto unexplored components of the tumor necrosis factor (TNF) superfamily in BD. METHODS: Eighty patients with type I BD and 50 healthy controls matched for age and gender were enrolled in this study. All subjects were assessed with the Mini-Plus to evaluate psychiatric comorbidities; the Young Mania Rating Scale and the Hamilton Depression Rating Scale to evaluate manic and depressive symptoms severity, respectively. TNF superfamily molecules (TNF, TNF-related weak inducer of apoptosis [TWEAK], TNF-related apoptosis-inducing ligand [TRAIL], soluble TNF receptor type 1 [sTNFR1], and soluble TNF receptor type 2 [sTNFR2]) levels were measured by ELISA. RESULTS: Patients with BD, regardless of mood state, presented increased plasma levels of sTNFR1 and TWEAK in comparison with controls. CONCLUSION: These findings corroborate the view that TNF superfamily may play a role in BD pathophysiology.

Update on bipolar disorder biomarker candidates.

INTRODUCTION: Bipolar disorder is a chronic and disabling mood disorder with a complex pathophysiological basis. A significant percentage of patients do not receive correct diagnosis which directly influences therapeutic response, rendering recovery troublesome. There is a long-standing need for proper non-clinically based tools for diagnosis, treatment selection and follow-up of such patients. Areas covered: In the past decade, the scientific community has shown a great interest in biomarker development. Here, we highlight the different potential biomarkers and we discuss their feasibility and their possible clinical relevance. Expert commentary: To date, despite the major ongoing trials and consortia with promising future perspectives, no reliable biomarker of bipolar disorder has been fully defined.

Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression.

Coronary heart disease (CHD) and depression are very common and often co-existing disorders. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients. Inflammation has been proposed as one of the mechanisms involved in the association between these two debilitating diseases. Therefore, the present study aimed to evaluate inflammatory responses as well as to investigate the pathophysiological mechanisms underlying the putative inflammatory activation in CHD patients with and without depression, by assessing the function of two important biological factors regulating inflammation, the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid receptor (GR). Eighty-three CHD patients with (n=28) and without (n=55) comorbid depression were recruited from primary care services in South London. Depression status was assessed by means of Clinical Interview Schedule Revised for diagnosis of depression, and Beck Depression Inventory for the presence of depressive symptoms. Serum C-reactive protein (CRP), plasma vascular endothelial growth factor (VEGF), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and interleukin-6 (IL-6) were conducted via qPCR. GR sensitivity was evaluated in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Serum levels of kynurenine pathway metabolites were measured using high performance liquid chromatography. Our results show that CHD patients with depression had higher levels of CRP, IL-6 gene expression, and VEGF compared with CHD non-depressed, as well as lower plasma and saliva cortisol levels. The CHD depressed group also exhibited a reduction in GR expression and sensitivity. Finally, tryptophan levels were significantly lower in patients with depression, who also showed an increased kynurenine/tryptophan ratio. In conclusion, CHD patients with depression had elevated levels of inflammation in the context of HPA axis hypoactivity, GR resistance, and increased activation of the kynurenine pathway. Reduced cortisol bioavailability and attenuated glucocorticoid responsiveness due to decreased expression and sensitivity of GR may lead to insufficient glucocorticoid signaling and thus elevation of inflammation in these patients.