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.

Corrigendum: Early Trauma and Cognitive Functions of Patients With Schizophrenia.

[This corrects the article DOI: 10.3389/fpsyt.2019.00261.].

Early Trauma and Cognitive Functions of Patients With Schizophrenia.

Aim: The following work aims to investigate the putative correlation between early trauma and cognitive functions, as well as psychotic symptoms and cognitive functions, in individuals diagnosed with schizophrenia. Methods: A quantitative assessment was performed with 20 individuals diagnosed with schizophrenia according to the 5th edition of the Diagnostic and Statistical Manual (DSM-5) criteria and who were in ongoing outpatient treatment in Psychosocial Care Centres in Brazil. Clinical measurements comprised a semistructured clinical interview, a screening questionnaire for common mental disorders, the Positive and Negative Syndrome Scale (PANSS), and the Early Trauma Inventory Self-Report-Short Form (ETISR-SF). Cognitive assessment included Beta III test, Concentrated Attention (CA) test, Color Trails Test (CTT), and Visual Face Memory (VFM) test. Results: Age-adjusted analysis showed a negative correlation between early trauma and visual memory performance (r = -0.585, p = 0.007) and negative symptoms and attention performance (r = -0.715, p = 0.000). Conclusion: Although a cause-effect relationship cannot be firmly stated, an association between early trauma experience and cognitive impairment such as visual memory, as well as a relationship between negative symptoms and attention domains, is suggested by our preliminary findings. Future studies with larger sample sizes and prospective design will clarify the long-term effects of early exposure to trauma and its clinical meaning in terms of developing psychotic-related illness.

Omega-3 Fatty Acids: Repurposing Opportunities for Cognition and Biobehavioral Disturbances in MCI and Dementia.

Neurodegenerative diseases may directly affect memory performance, thus leading to functional impairments. An increasing body of evidence suggests an association between dietary intake of omega-3 fatty acids and memory functioning in animal models as well as in human studies. Recent evidence supports a potential beneficial role of omega-3 fatty acid supplementation on psychopathological and cognitive symptoms, beside their established positive effects on cardiovascular health. OBJECTIVE: We summarize relevant and recent evidence from epidemiological, interventional and experimental studies investigating dietary consumption of omega-3 fatty acids and emphazing mechanisms of memory disorders, with a focus on mild cognitive impairment (MCI) and dementia. Omega-3 fatty acid could represent an affordable and accessible adjunctive treatment option to improve cognitive and non-cognitive function with a focus on MCI or dementia. However, apart from its translational promise, which is based on mechanistic models and evidence from animal studies, evidence for clinical benefits in humans is lacking. METHOD: To follow this research question, a search through electronic databases for the following search terms to identify relevant studies was conducted: 'omega 3 fatty acids', 'cognition', 'memory', ´Alzheimer´s Disease ´, ´dementia´, ´MCI`. Studies were included if they presented original data and were published in English between 1990 and 2015. RESULTS: To our the best of our knowledge, there are only 8 interventional studies that investigated the effects of n3-PUFAs in dementia patients, while 6 studies were conducted in healthy individuals, which in combination show equivocal results. CONCLUSION: This verifies the need for larger and (more) well designed clinical trials.

Integrated Biomarkers for Depression in Alzheimer's Disease: A Critical Review.

Depression is a common neuropsychiatric manifestation among Alzheimer's disease (AD) patients. It may compromise everyday activities and lead to a faster cognitive decline as well as worse quality of life. The identification of promising biomarkers may therefore help to timely initiate and improve the treatment of preclinical and clinical states of AD, and to improve the long-term functional outcome. In this narrative review, we report studies that investigated biomarkers for AD-related depression. Genetic findings state AD-related depression as a rather complex, multifactorial trait with relevant environmental and inherited contributors. However, one specific set of genes, the brain derived neurotrophic factor (BDNF), specifically the Val66Met polymorphism, may play a crucial role in AD-related depression. Regarding neuroimaging markers, the most promising findings reveal structural impairments in the cortico-subcortical networks that are related to affect regulation and reward / aversion control. Functional imaging studies reveal abnormalities in predominantly frontal and temporal regions. Furthermore, CSF based biomarkers are seen as potentially promising for the diagnostic process showing abnormalities in metabolic pathways that contribute to AD-related depression. However, there is a need for standardization of methodological issues and for replication of current evidence with larger cohorts and prospective studies.

Physical Exercise for the Treatment of Neuropsychiatric Disturbances in Alzheimer's Dementia: Possible Mechanisms, Current Evidence and Future Directions.

Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric or non-cognitive symptoms are common and often distressing features of Alzheimer's Dementia. BPSD significantly increase patient suffering, early institutionalization and caregiver's burden. The clinical management of BPSD is dominated by a pharmacological approach, although these medications often come with serious adverse side-effects. There are only few nonpharmacological treatment strategies for BPSD. A substantial amount of intervention studies that have investigated non-pharmacological treatment options for BPSD have focused on physical exercise. Although these studies are very heterogeneous in terms of type and severity of dementia, as well as type and duration of the exercise intervention, the overall picture shows a positive effect of physical exercise in alleviating BPSD. There is evidence that numerous mechanisms contribute to the positive effect of physical exercise on BPSD. No attempt has been undertaken so far to give an overview of the existing knowledge regarding these mechanisms. Therefore, the current review aims to integrate the existing evidence on psychological and neurobiological mechanisms that contribute to the beneficial effects of physical exercise in ameliorating BPSD in Alzheimer's dementia. A discussion of psychological mechanisms such as improved sleep and stress reduction will be followed by a discussion of neurobiological mechanisms including the exercise induced change in neurotransmitter concentrations, increased synthesis of neurotrophins and immune activation. The review closes with recommendations for future research to overcome the shortcomings of existing studies and broaden the current knowledge on the positive effects of physical exercise on BPSD.

Neuropsychiatric Disturbances in Mild Cognitive Impairment (MCI): A Systematic Review of Population-Based Studies.

Mild cognitive impairment (MCI) is a nosological entity associated with a higher risk of developing dementia. Previous evidence indicates that behavioral and psychological symptoms of dementia (BPSDs) frequently occur in individuals of MCI. These neuropsychiatric manifestations may predict conversion to dementia. However, no updated systematic review has been conducted aiming to investigate the prevalence of BPSDs in MCI in general population samples. We conducted a systematic review to summarize research results regarding the prevalence of any or specific BPSDs in MCI subjects out of the clinical setting, compared to subjects who are either cognitively intact and/or demented. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from January 1st, 1990 to January 3rd, 2015 for general population studies in which the prevalence of BPSDs in individuals with MCI was estimated. Twenty-one studies met inclusion criteria. Studies varied in overall methodological quality as evaluated with a modified version of the New Castle-Ottawa Scale for cross-sectional studies. Depression (median prevalence: 29.8%; range: 6.8-63.3%), sleep disturbances (median prevalence: 18.3%; range: 7.9-49.0%), and apathy (median prevalence: 15.2%; range: 2.3-18.5%) were the more frequent BPSDs across studies. The prevalence range for any BPSD was 12.8-66.0%. No consistent pattern for differences in the prevalence of BPSDs according to MCI subtype emerged. Studies considered different diagnostic criteria for MCI and used different instruments to assess BPSDs in this population. In conclusion, BPSDs are prevalent among communitydwelling individuals with MCI. However, consistent socio-demographic and clinical correlates for BPSDs in this population remains to be established.

White matter abnormalities in the fornix are linked to cognitive performance in SZ but not in BD disorder: An exploratory analysis with DTI deterministic tractography.

BACKGROUND: In psychosis, white matter (WM) microstructural changes have been detected previously; however, direct comparisons of findings between bipolar (BD) and schizophrenia (SZ) patients are scarce. In this study, we employed deterministic tractography to reconstruct WM tracts in BD and SZ patients. METHODS: Diffusion tensor imaging (DTI) data was carried out with n=32 euthymic BD type I patients, n=26 SZ patients and 30 matched healthy controls. Deterministic tractography using multiple indices of diffusion (fractional anisotropy (FA), tract volume (Vol), tract length (Le) and number of tracts (NofT)) were obtained from the fornix, the cingulum, the anterior thalamic radiation, and the corpus callosum bilaterally. RESULTS: We showed widespread WM microstructural changes in SZ, and changes in the corpus callosum, the left cingulum and the fornix in BD. Fornix fiber tracking scores were associated with cognitive performance in SZ, and with age and age at disease onset in the BD patient group. LIMITATIONS: Although the influence of psychopharmacological drugs as biasing variables on morphological alterations has been discussed for SZ and BD, we did not observe a clear influence of drug exposure on our findings. CONCLUSIONS: These results confirm the assumption that SZ patients have more severe WM changes than BD patients. The findings also suggest a major role of WM changes in the fornix as important fronto-limbic connections in the etiology of cognitive symptoms in SZ, but not in BD.

T helper 17 cells may drive neuroprogression in major depressive disorder: Proposal of an integrative model.

The exact pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) microglial activation, (ii) interactions with oxidative and nitrosative stress, (iii) increases of autoantibody production and the propensity for autoimmunity, (iv) disruption of the blood-brain barrier, and (v) dysregulation of the gut mucosa and microbiota. The clinical and research implications of this model are discussed.

Omega 3 Fatty Acids: Novel Neurotherapeutic Targets for Cognitive Dysfunction in Mood Disorders and Schizophrenia?

An increasing body of evidences from preclinical as well as epidemiological and clinical studies suggest a potential beneficial role of dietary intake of omega-3 fatty acids for cognitive functioning. In this narrative review, we will summarize and discuss recent findings from epidemiological, interventional and experimental studies linking dietary consumption of omega-3 fatty acids to cognitive function in healthy adults. Furthermore, affective disorders and schizophrenia (SZ) are characterized by cognitive dysfunction encompassing several domains. Cognitive dysfunction is closely related to impaired functioning and quality of life across these conditions. Therefore, the current review focues on the potential influence of omega-3 fatty acids on cognition in SZ and affective disorders. In sum, current data predominantly from mechanistic models and animal studies suggest that adjunctive omega-3 fatty acid supplementation could lead to improved cognitive functioning in SZ and affective disorders. However, besides its translational promise, evidence for clinical benefits in humans has been mixed. Notwithstanding evidences indicate that adjunctive omega-3 fatty acids may have benefit for affective symptoms in both unipolar and bipolar depression, to date no randomized controlled trial had evaluated omega-3 as cognitive enhancer for mood disorders, while a single published controlled trial suggested no therapeutic benefit for cognitive improvement in SZ. Considering the pleiotropic mechanisms of action of omega-3 fatty acids, the design of well-designed controlled trials of omega-3 supplementation as a novel, domain-specific, target for cognitive impairment in SZ and affective disorders is warranted.

Beyond Monoamines-Novel Targets for Treatment-Resistant Depression: A Comprehensive Review.

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

Religious coping and its influence on psychological distress, medication adherence, and quality of life in inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel disease (IBD) is associated with elevated levels of anxiety and depression and a reduction in health-related quality of life (HRQoL). Nonadherence to treatment is also frequent in IBD and compromises outcomes. Religious coping plays a role in the adaptation to several chronic diseases. However, the influence of religious coping on IBD-related psychological distress, HRQoL, and treatment adherence remains unknown. METHOD: This cross-sectional study recruited 147 consecutive patients with either Crohn's disease or ulcerative colitis. Sociodemographic data, disease-related variables, psychological distress (Hospital Anxiety and Depression Scale), religious coping (Brief RCOPE Scale), HRQoL (WHOQOL-Bref), and adherence (8-item Morisky Medication Adherence Scale) were assessed. Hierarchical multiple regression models were used to evaluate the effects of religious coping on IBD-related psychological distress, treatment adherence, and HRQoL. RESULTS: Positive RCOPE was negatively associated with anxiety (b = 0.256; p = 0.007) as well as with overall, physical, and mental health HRQoL. Religious struggle was significantly associated with depression (b = 0.307; p < 0.001) and self-reported adherence (b = 0.258; p = 0.009). Finally, anxiety symptoms fully mediated the effect of positive religious coping on overall HRQoL. CONCLUSION: Religious coping is significantly associated with psychological distress, HRQoL, and adherence in IBD.

Autobiographical Memory Disturbances in Depression: A Novel Therapeutic Target?

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.

Religious coping and its influence on psychological distress, medication adherence, and quality of life in inflammatory bowel disease

Objective:Inflammatory bowel disease (IBD) is associated with elevated levels of anxiety and depression and a reduction in health-related quality of life (HRQoL). Nonadherence to treatment is also frequent in IBD and compromises outcomes. Religious coping plays a role in the adaptation to several chronic diseases. However, the influence of religious coping on IBD-related psychological distress, HRQoL, and treatment adherence remains unknown.Method:This cross-sectional study recruited 147 consecutive patients with either Crohn’s disease or ulcerative colitis. Sociodemographic data, disease-related variables, psychological distress (Hospital Anxiety and Depression Scale), religious coping (Brief RCOPE Scale), HRQoL (WHOQOL-Bref), and adherence (8-item Morisky Medication Adherence Scale) were assessed. Hierarchical multiple regression models were used to evaluate the effects of religious coping on IBD-related psychological distress, treatment adherence, and HRQoL.Results:Positive RCOPE was negatively associated with anxiety (b = 0.256; p = 0.007) as well as with overall, physical, and mental health HRQoL. Religious struggle was significantly associated with depression (b = 0.307; p < 0.001) and self-reported adherence (b = 0.258; p = 0.009). Finally, anxiety symptoms fully mediated the effect of positive religious coping on overall HRQoL.Conclusion:Religious coping is significantly associated with psychological distress, HRQoL, and adherence in IBD.

Associations of sense of coherence with psychological distress and quality of life in inflammatory bowel disease.

AIM: To investigate the relationship between sense of coherence, psychological distress and health related quality of life in inflammatory bowel disease (IBD). METHODS: This cross-sectional study enrolled a consecutive sample of 147 IBD (aged 45.1 ± 14.1 years; 57.1% female) patients recruited from a tertiary gastroenterology service. Sixty-four participants met diagnostic criteria for Crohn's disease, while eighty-three patients had ulcerative colitis. Socio-demographic data (education, age, race, gender, gross monthly income and marital status), disease-related variables (illness activity, relapse rate in past 2 years, history of surgery and time since diagnosis), sense of coherence (Antonovsky's SOC scale), psychological distress symptoms (Hospital Anxiety and Depression Scale) and health-related quality of life (HRQoL; WHOQOL-Bref) were assessed. Hierarchical multiple regression analyses were performed to identify factors that are independently associated with psychological distress and HRQoL in patients with IBD and to provide indications for possible moderating or mediating effects. In addition, formal moderation and mediation analyses (Sobel tests) were performed to confirm potential moderators/mediators of the relationship between SOC, psychological distress symptoms and HRQoL. RESULTS: Lower SOC scores (std beta= -0.504; P < 0.001), female gender (std beta = 0.176; P = 0.021) and White race (std beta = 0.164; P = 0.033) were independently associated with higher levels of depressive symptoms, while lower levels of SOC (std beta = -0.438; P < 0.001) and higher relapse rate (std beta = 0.161; P = 0.033) were independently associated with more severe anxiety symptoms. A significant interaction between time since diagnosis and SOC was found with regard to the severity of depressive or anxiety symptoms, as the interaction term (time since diagnosis X SOC) had beta coefficients of -0.191 (P = 0.009) and -0.172 (P = 0.026), respectively. Lower levels of anxiety symptoms (std beta = -0.369; P < 0.001), higher levels of SOC (std beta = 0.231; P = 0.016) and non-White race (std beta = -0.229; P = 0.006), i.e., mixed-race, which represented the reference category, were independently associated with higher levels of overall HRQoL. Anxiety symptoms were the most potent independent correlate of most aspects of HRQoL. In addition, anxiety mediated the association between SOC and satisfaction with health, as well as its relationship with physical, mental, and social relations HRQoL. Depressive symptoms also mediated the association between SOC and mental HRQoL. CONCLUSION: Our data indicated that SOC is an important construct, as it influences psychological distress and has significant albeit indirect effects on several HRQoL domains in IBD.

Cognitive dysfunction in depression - pathophysiology and novel targets.

Major depressive disorder (MDD) is associated with cognitive dysfunction encompassing several domains, including memory, executive function, processing speed and attention. Cognitive deficits persist in a significant proportion of patients even in remission, compromising psychosocial functioning and workforce performance. While monoaminergic antidepressants may improve cognitive performance in MDD, most antidepressants have limited clinical efficacy. The overarching aims of this review were: (1) to synthesize extant literature on putative biological pathways related to cognitive dysfunction in MDD and (2) to review novel neurotherapeutic targets for cognitive enhancement in MDD. We found that reciprocal and overlapping biological pathways may contribute to cognitive dysfunction in MDD, including an hyperactive hypothalamic-pituitary-adrenal axis, an increase in oxidative and nitrosative stress, inflammation (e.g., enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins, anti-inflammatory compounds, N-acetylcysteine, omega-3 poliunsaturated fatty acids, erythropoietin, thiazolidinediones, glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium. Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients. Despite having preclinical and/or preliminary evidences from trials suggesting possible efficacy as novel cognitive enhancing agents for MDD, no RCT to date was performed for most of the other therapeutic targets reviewed herein. In conclusion, multiple biological pathways are involved in cognitive dysfunction in MDD. RCTs testing genuinely novel pro-cognitive compounds for MDD are warranted.

Structural neuroimaging findings in major depressive disorder throughout aging: a critical systematic review of prospective studies.

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