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Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19.
Yang, CP, Chang, CM, Yang, CC, Pariante, CM, Su, KP
Brain, behavior, and immunity. 2022;:19-27
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Abstract
The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the "long COVID." The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus-pituitaryadrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis. Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.
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Mediators and moderators in the relationship between maternal childhood adversity and children's emotional and behavioural development: a systematic review and meta-analysis.
Ma, X, Biaggi, A, Sacchi, C, Lawrence, AJ, Chen, PJ, Pollard, R, Matter, M, Mackes, N, Hazelgrove, K, Morgan, C, et al
Psychological medicine. 2022;(10):1817-1837
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Abstract
Maternal experiences of childhood adversity can increase the risk of emotional and behavioural problems in their children. This systematic review and meta-analysis provide the first narrative and quantitative synthesis of the mediators and moderators involved in the link between maternal childhood adversity and children's emotional and behavioural development. We searched EMBASE, PsycINFO, Medline, Cochrane Library, grey literature and reference lists. Studies published up to February 2021 were included if they explored mediators or moderators between maternal childhood adversity and their children's emotional and behavioural development. Data were synthesised narratively and quantitatively by meta-analytic approaches. The search yielded 781 articles, with 74 full-text articles reviewed, and 41 studies meeting inclusion criteria. Maternal mental health was a significant individual-level mediator, while child traumatic experiences and insecure maternal-child attachment were consistent family-level mediators. However, the evidence for community-level mediators was limited. A meta-analysis of nine single-mediating analyses from five studies indicated three mediating pathways: maternal depression, negative parenting practices and maternal insecure attachment, with pooled indirect standardised effects of 0.10 [95% CI (0.03-0.17)), 0.01 (95% CI (-0.02 to 0.04)] and 0.07 [95% CI (0.01-0.12)], respectively. Research studies on moderators were few and identified some individual-level factors, such as child sex (e.g. the mediating role of parenting practices being only significant in girls), biological factors (e.g. maternal cortisol level) and genetic factors (e.g. child's serotonin-transporter genotype). In conclusion, maternal depression and maternal insecure attachment are two established mediating pathways that can explain the link between maternal childhood adversity and their children's emotional and behavioural development and offer opportunities for intervention.
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Understanding treatment-resistant depression using "omics" techniques: A systematic review.
Amasi-Hartoonian, N, Pariante, CM, Cattaneo, A, Sforzini, L
Journal of affective disorders. 2022;:423-455
Abstract
BACKGROUND Treatment-resistant depression (TRD) results in huge healthcare costs and poor patient clinical outcomes. Most studies have adopted a "candidate mechanism" approach to investigate TRD pathogenesis, however this is made more challenging due to the complex and heterogeneous nature of this condition. High-throughput "omics" technologies can provide a more holistic view and further insight into the underlying mechanisms involved in TRD development, expanding knowledge beyond already-identified mechanisms. This systematic review assessed the information from studies that examined TRD using hypothesis-free omics techniques. METHODS PubMed, MEDLINE, Embase, APA PsycInfo, Scopus and Web of Science databases were searched on July 2022. 37 human studies met the eligibility criteria, totalling 17,518 TRD patients, 571,402 healthy controls and 62,279 non-TRD depressed patients (including antidepressant responders and untreated MDD patients). RESULTS Significant findings were reported that implicate the role in TRD of various molecules, including polymorphisms, genes, mRNAs and microRNAs. The pathways most commonly reported by the identified studies were involved in immune system and inflammation, neuroplasticity, calcium signalling and neurotransmitters. LIMITATIONS Small sample sizes, variability in defining TRD, and heterogeneity in study design and methodology. CONCLUSIONS These findings provide insight into TRD pathophysiology, proposing future research directions for novel drug targets and potential biomarkers for clinical staging and response to antidepressants (citalopram/escitalopram in particular) and electroconvulsive therapy (ECT). Further validation is warranted in large prospective studies using standardised TRD criteria. A multi-omics and systems biology strategy with a collaborative effort will likely deliver robust findings for translation into the clinic.
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A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.
Sforzini, L, Worrell, C, Kose, M, Anderson, IM, Aouizerate, B, Arolt, V, Bauer, M, Baune, BT, Blier, P, Cleare, AJ, et al
Molecular psychiatry. 2022;(3):1286-1299
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Abstract
Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.
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Associations of Dietary Intake on Biological Markers of Inflammation in Children and Adolescents: A Systematic Review.
Bujtor, M, Turner, AI, Torres, SJ, Esteban-Gonzalo, L, Pariante, CM, Borsini, A
Nutrients. 2021;13(2)
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Inflammation is the normal physiological response to injury in the body and is designed to protect the host. However, in children and adolescents, chronic low-grade inflammation has been linked to a wide range of conditions. Certain markers in the blood can be measured and used to determine levels of inflammation in the body. This review of 53 studies provides the first evidence for the association between dietary intake and biological markers of inflammation in children and adolescents. Results show that adhering to a healthy way of eating such as the Mediterranean diet, are associated with decreased levels of pro-inflammatory biomarkers. The Western Dietary pattern, as well as intake of ultra-processed foods is associated with higher levels of the same pro-inflammatory markers. A good quality diet, high in fruit and vegetables, wholegrains, fibre and healthy fats ameliorates low-grade inflammation, and therefore represents a potential therapeutic approach. It is also an important element for disease prevention in both children and adolescents.
Abstract
BACKGROUND In children and adolescents, chronic low-grade inflammation has been implicated in the pathogenesis of co- and multi-morbid conditions to mental health disorders. Diet quality is a potential mechanism of action that can exacerbate or ameliorate low-grade inflammation; however, the exact way dietary intake can regulate the immune response in children and adolescents is still to be fully understood. METHODS Studies that measured dietary intake (patterns of diet, indices, food groups, nutrients) and any inflammatory biomarkers in children and adolescents aged 2 to19 years and published until November 2020 were included in this systematic review, and were selected in line with PRISMA guidelines through the following databases: Academic Search Complete, CINAHL, Global Health, Medline COMPLETE and Web of Science-Core Collection. A total of 53 articles were identified. RESULTS Results show that adequate adherence to healthful dietary patterns such as the Mediterranean diet, or food groups such as vegetables and fruit, or macro/micro nutrients such as fibre or vitamin C and E, are associated with decreased levels of pro-inflammatory biomarkers, mainly c-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), whereas adherence to a Western dietary pattern, as well as intake of food groups such as added sugars, macro-nutrients such as saturated fatty acids or ultra-processed foods, is associated with higher levels of the same pro-inflammatory biomarkers. CONCLUSIONS This is the first systematic review examining dietary intake and biological markers of inflammation in both children and adolescents. A good quality diet, high in vegetable and fruit intake, wholegrains, fibre and healthy fats ameliorates low-grade inflammation, and therefore represents a promising therapeutic approach, as well as an important element for disease prevention in both children and adolescents.
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Neurogenic and anti-inflammatory effects of probiotics in Parkinson's disease: A systematic review of preclinical and clinical evidence.
Leta, V, Ray Chaudhuri, K, Milner, O, Chung-Faye, G, Metta, V, Pariante, CM, Borsini, A
Brain, behavior, and immunity. 2021;:59-73
Abstract
There is increasing evidence highlighting the potential role of the gut-brain axis in the pathogenesis of Parkinson's disease (PD) and on the use of probiotics as a therapeutic strategy for this neurodegenerative disorder. While several studies have been published on the topic in recent years, there is still a lack of a comprehensive understanding of the effects of probiotics in PD and their possible underlying mechanisms. Through this systematic review, we collected a total of 17 articles, consisting of preclinical and clinical models of PD investigating the effect of probiotics on (1) energy metabolism, (2) inflammation and oxidative stress, (3) neurodegeneration, as well as (4) motor and (5) non-motor function. Articles were obtained from PubMed/Medline, Scopus, Web of Science and Embase databases. Findings from preclinical studies suggest that treatment with probiotics increases glucose metabolism (increased secretion of glucagon-like peptide-1), reduces peripheral and central inflammation (reduced interleukin-6 and tumor necrosis factor-α (TNF-α)), reduces peripheral and central oxidative stress (reduced peripheral superoxide anion levels and increased central antioxidant glutathione levels), decreases neurodegeneration (increased numbers of tyrosine hydroxylase dopaminergic neurons and levels of brain-derived neurotrophic factor), increases motor function (increased motor agility) and non-motor function (decreased memory deficits). Similarly, findings from clinical studies suggest that probiotics increase glucose metabolism (reduced insulin resistance), reduce peripheral inflammation (reduced peripheral TNF-α expression and C-reactive protein levels), and increase motor and non-motor function (decreased overall PD symptomatology and constipation); however, findings on oxidative stress were inconclusive across studies. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of probiotics on molecular and cellular mechanisms, as well as behavioural phenotypes, in either preclinical or clinical studies in PD. However, additional and more robust studies are still needed to confirm these outcomes, and should aim to focus more on bench-to-bedside approaches, in order to address the existing gaps between preclinical and clinical findings in this field.
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Omega-3 fatty acids in the psychological and physiological resilience against COVID-19.
Chang, JP, Pariante, CM, Su, KP
Prostaglandins, leukotrienes, and essential fatty acids. 2020;:102177
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Abstract
As the infected cases of COVID-19 reach more than 20 million with more than 778,000 deaths globally, an increase in psychiatric disorders including anxiety and depression has been reported. Scientists globally have been searching for novel therapies and vaccines to fight against COVID-19. Improving innate immunity has been suggested to block progression of COVID-19 at early stages, while omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have immunomodulation effects. Moreover, n-3 PUFAs have also been shown to improve mood disorders, thus, future research is warranted to test if n-3 PUFAs may have the potential to improve our immunity to counteract both physical and mental impact of COVID-19.
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Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: A meta-analysis.
Lombardo, G, Enache, D, Gianotti, L, Schatzberg, AF, Young, AH, Pariante, CM, Mondelli, V
Psychoneuroendocrinology. 2019;:104420
Abstract
INTRODUCTION Hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis and high cortisol levels have been widely reported in patients with mood disorders but previous clinical trials investigating the efficacy of antiglucocorticoid treatment in this population have reported inconsistent findings. The inconsistencies among these studies may be because not all patients with mood disorders have increased HPA axis activity and therefore might not benefit from antiglucocorticoid treatment. The aim of this meta-analysis was to investigate whether baseline cortisol levels influence the efficacy of antiglucocorticoid drugs in patients with mood disorders. METHODS PubMed and Scopus databases were searched systematically up to October 2018. We included studies using metyrapone, ketoconazole or mifepristone in patients with major depressive disorder, bipolar disorder and major depressive disorder with psychotic symptoms. We tested for a difference in cortisol levels between responders (a reduction equal to or greater than 30% on depression scales following antiglucocorticoid treatment) and non-responders (a reduction of less than 30% on depression scales). We performed a meta-analysis to look specifically at differences in cortisol levels in the sample of patients treated with cortisol synthesis inhibitors (metyrapone and ketoconazole) and in those treated with glucocorticoid receptor (GR) antagonist (mifepristone). RESULTS We were able to retrieve data from 11 of the 16 selected studies and to include 9 studies in the meta-analysis. In the overall sample (N = 846), responders had similar baseline cortisol levels compared with non-responders (standardised mean difference, SMD = -0.03, 95% CI [-0.17, 0.12], p = 0.75). In the group of patients treated with cortisol synthesis inhibitors, responders (N = 109) had significantly higher peripheral baseline cortisol levels compared with non-responders (SMD = 0.42, 95% CI [0.01, 0.83], p = 0.047). In the group of patients treated with a GR antagonist (N = 737), both responders and non-responders had similar baseline cortisol levels (SMD = -0.09, 95% CI [-0.25, 0.07], p = 0.26). CONCLUSION Our data suggest that only patients with higher cortisol levels at baseline benefit from treatment with cortisol synthesis inhibitors and support a potential role for cortisol as a predictive biomarker for treatment with cortisol synthesis inhibitors in patients with mood disorders.
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High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels.
Chang, JP, Su, KP, Mondelli, V, Satyanarayanan, SK, Yang, HT, Chiang, YJ, Chen, HT, Pariante, CM
Translational psychiatry. 2019;(1):303
Abstract
No studies have examined the relationship between endogenous polyunsaturated fatty acids (PUFAs) levels and treatment response to PUFAs. We conducted a 12-week, double-blind, placebo-controlled trial comparing the effects of high-dose eicosapentaenoic acid (EPA, 1.2 g) and placebo on cognitive function (continuous performance test) in n = 92 youth (age 6-18-years-old) with Attention Deficit Hyperactivity Disorder (ADHD). Blood erythrocytes PUFAs were measured before and after treatment, to examine the effects of baseline endogenous EPA levels on treatment response and the effects of EPA treatment on PUFAs levels. Secondary measures included other ADHD symptoms, emotional symptoms, and levels of plasma high-sensitivity c-reactive protein (hs-CRP) and brain-derived neurotrophic factor (BDNF). Overall, EPA group improved more than placebo group on focused attention (variability, Effect size (ES) = 0.38, p = 0.041); moreover, within youth with the lowest baseline endogenous EPA levels, EPA group improved more than placebo group in another measure of focused attention (hit reaction time, HRT, ES = 0.89, p = 0.015) and in vigilance (HRT interstimulus interval changes, HRTISIC, ES = 0.83, p = 0.036). Interestingly, EPA group improved less than placebo group in impulsivity (commission errors), both overall and in youth with the highest baseline EPA levels, who also showed less improvement in other ADHD and emotional symptoms. EPA increased blood erythrocytes EPA by 1.6-fold but not DHA levels, and did not affect hs-CRP and BDNF plasma levels. In conclusion, EPA treatment improves cognitive symptoms in ADHD youth, especially if they have a low baseline endogenous EPA level, while youth with high EPA levels may be negatively affected by this treatment.
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Metabolic-inflammatory status as predictor of clinical outcome at 1-year follow-up in patients with first episode psychosis.
Nettis, MA, Pergola, G, Kolliakou, A, O'Connor, J, Bonaccorso, S, David, A, Gaughran, F, Di Forti, M, Murray, RM, Marques, TR, et al
Psychoneuroendocrinology. 2019;:145-153
Abstract
BACKGROUND Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at the onset of psychosis and associated with important physical health disorders and increased mortality. However, the impact of an abnormal metabolic-inflammatory status on the psychiatric outcome of these patients has not yet been investigated. OBJECTIVES The aims of this study were 1) to explore whether, in a sample of patients at their first episode of psychosis (FEP), an overall metabolic-inflammatory status may be measured, by combining metabolic and inflammatory variables in metabolic-inflammatory factors; 2) to explore the association between these factors and clinical outcome at 1-year follow-up (FU), in terms of symptoms severity and treatment response. METHODS In this longitudinal study we recruited 42 FEP patients and 46 healthy controls (HC) matched with patients for age, gender and ethnicity. At baseline (T1) we measured high sensitivity C-reactive protein (hsCRP) as biomarker of inflammation, and body mass index (BMI), lipid profile and gluco-metabolic parameters (glycated hemoglobin (HbA1c) and fasting glucose) as metabolic variables. A principal component analysis (PCA) was then used to reduce the dimensionality of the dataset accounting for both inflammation and metabolic status. In FEP patients, we assessed symptoms severity at T1 and at 1-year FU (T2) as well as treatment response to antipsychotics at T2. RESULTS at T1, FEP showed higher HbA1c (p = 0.034), triglycerides (TG) (p = 0.045) and BMI (p = 0.026) than HC. PCA identified 3 factors: factor 1 accounting for hsCRP, TG and BMI, factor 2 accounting for LDL and cholesterol, and factor 3 accounting for fasting glucose and HbA1c. Factor 1 was associated with T1 negative symptoms severity (p = 0.021) and predicted T2 positive (p = 0.004) and overall symptoms severity (0.001), as well as general psychopathology (p < 0.001) and T2 treatment response (p = 0.007). CONCLUSION In this sample of FEP patients, inflammation and metabolism, closely correlated at the onset of psychosis, proved to play a key role as predictors of the clinical course of psychosis when combined in a single factor. These findings offer an important potential target for early screening and interventions.