ORCID Profile
0000-0002-0794-6363
Current Organisation
Deakin University
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Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.JAD.2014.02.018
Abstract: Major depression and bipolar disorder are accompanied by the activation of immune-inflammatory and Oxidative and Nitrosative Stress (O&NS) pathways and lowered levels of antioxidants. Paraoxonase (PON)1 (EC 3.1.8.1) is an antioxidant bound to High Density Lipoprotein (HDL). Polymorphisms in the PON1 Q192R coding sequence determine three functional genotypes, i.e. 192QQ, 192QR and 192RR. This study was carried out to delineate the associations of plasma PON1 activity and functional PON1 Q192R genotypes in major depression and bipolar disorder. PON1 status that is plasma PON1 abundance and three functional PON1 Q192R genotypes were assayed in 91 major depressed and 45 bipolar patients and compared to 199 normal controls. Major depression, but not bipolar disorder, was accompanied by lowered PON1 activity. PON1 activity was decreased by smoking and a diagnosis by genotype interaction (i.e. lower PON1 in major depression with the QQ genotype). Logistic regression showed that smoking by QQ genotype significantly increased the odds of bipolar disorder and that major depression was predicted by plasma PON1 activity, serum HDL cholesterol and interactions between genotype×smoking. The results suggest that lowered plasma PON1 activity is a trait marker of major depression and that PONQ192R gene-environment (smoking) interactions differentially predict the odds of depression and bipolar disorder. Association studies are prone to a risk of false positive findings and replication is essential. The findings suggest that there are differential PON1 Q192R functional genotype×environment interactions in major depression and bipolar disorder. The effects of lowered PON1 activity may contribute to increased O&NS and immune-inflammatory burden in depression. PON1 status may contribute to the comorbidity between depression and other immune- and O&NS-related disorders, e.g. cardiovascular disorder.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.NEULET.2016.02.011
Abstract: There is evidence that immune-inflammatory, stress of reactive oxygen and nitrogen species (IO&NS) processes play a role in the neurodegenerative processes observed in Parkinson's disease (PD). The aim of the present study was to investigate peripheral IO&NS biomarkers in PD. We included 56 healthy in iduals and 56 PD patients ided in two groups: early PD stage and late PD stage. Plasma lipid hydroperoxides (LOOH), malondialdehyde (MDA), nitric oxide metabolites (NOx), sulfhydryl (SH) groups, catalase (CAT) activity, superoxide dismutase (SOD) activity, paraoxonase (PON)1 activity, total radical trapping antioxidant parameter (TRAP) and C-reactive protein (CRP) were measured. PD is characterized by increased LOOH, MDA and SOD activity and lowered CAT activity. A combination of five O&NS biomarkers highly significantly predicts PD with a sensitivity of 94.5% and a specificity of 86.8% (i.e., MDA, SOD activity, TRAP, SH-groups and CAT activity). The single best biomarker of PD is MDA, while LOOH and SOD activity are significantly associated with late PD stage, but not early PD stage. Antiparkinson drugs did not affect O&NS biomarkers, but levodopa+carbidopa significantly increased CRP. It is suggested that MDA may serve as a disease biomarker, while LOOH and SOD activity are associated with late PD stage characteristic. New treatments for PD should not only target dopamine but also lipid peroxidation.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2021
DOI: 10.1007/S41999-021-00490-8
Abstract: To investigate the association between serum interleukin-6 (IL-6) and frailty. Participants were 581 men aged 60-90 yr (median (IQR): 74 yr (67-83 yr)) from the Geelong Osteoporosis Study. Tallies of ≥ 3, 1-2 and 0 for weight loss/exhaustion hysical-inactivity/slowness/weakness indicated frailty, pre-frailty and robustness, respectively. Anthropometry, lower-limb muscle strength and physical performance were measured and health behaviours self-reported. Serum IL-6 was measured using an enzyme-linked immunosorbent assay and log-transformed (ln-IL-6). Total antioxidant capacity (TAC) was also measured using quantitative colorimetric determination. Multivariable ordinal logistic regression models tested associations between ln-IL-6 and frailty while considering age, anthropometry, comorbidities, TAC, medications that affect inflammatory processes, lifestyle and socioeconomic status. There were 49(8.4%) frail and 315(54.2%) pre-fail men. A relationship was evident between ln-IL-6 and frailty before and after accounting for age (adjusted OR = 1.24, 95%CI 1.01-1.53). Adjusting for medications attenuated the association (OR = 1.20, 95%CI 0.98-1.48). No other confounders were identified. These data suggest that IL-6 is positively associated with frailty in men, partly explained by advancing age and medications known to affect inflammation.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2022
DOI: 10.1007/S00198-022-06602-9
Abstract: We aimed to investigate the association between serum lipopolysaccharide-binding protein (LBP) and bone health in men. LBP was associated with lower bone density at the mid-forearm and the quantitative heel ultrasound measure, broadband ultrasound attenuation, for heavier participants. Data do not support clear associations between serum LBP and bone health. The objective of this study was to investigate the association between serum lipopolysaccharide-binding protein (LBP) and potential downstream effects on skeletal density, quality, and turnover in a population-based s le of men. This cross-sectional study utilised data from 1149 men (aged 20-96 year) enrolled in the Geelong Osteoporosis Study. Blood s les were obtained and lipopolysaccharide-binding protein (LBP), bone resorption marker, C-telopeptide (CTx), and formation marker, type 1 procollagen amino-terminal-propeptide (P1NP), were measured. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Stiffness Index (SI), broadband ultrasound attenuation (BUA), and speed of sound (SOS) were derived from quantitative heel ultrasound (QUS). Linear regression models were developed to test associations between log-transformed LBP (ln-LBP), BMD, QUS, and bone turnover, after adjusting for potential covariates. Serum LBP ranged from 1.07-208.53 ng/mL (median 16.53 ng/mL). Those with higher levels were older, less mobile, and had lower BMD at the mid-forearm, otherwise, groups were similar. Before and after adjustment for age, ln-LBP was associated with lower BMD at the spine, total body, and mid-forearm. Further adjustment for weight attenuated associations at the spine and total body, yet the relationship at the mid-forearm was sustained (β - 0.014 ± 0.004, p = 0.001). SOS and SI were not associated with ln-LBP either before or after adjustment for age however, weight was identified as an effect modifier in the relationship between ln-LBP and BUA. An association was observed for those weighing greater than 82.7 kg (β 3.366 ± 0.929, p < 0.001), after adjustment for potential covariates. Neither bone turnover marker was associated with ln-LBP. Our data do not support a clear association between serum LBP and measures of bone health in this s le of men.
Publisher: Cambridge University Press (CUP)
Date: 30-06-2020
DOI: 10.1017/NEU.2020.25
Abstract: The aims of this study were to evaluate changes in inflammatory and oxidative stress levels following treatment with N -acetylcysteine (NAC) or mitochondrial-enhancing agents (CT), and to assess the how these changes may predict and/or moderate clinical outcomes primarily the Montgomery-Åsberg Depression Rating Scale (MADRS). This study involved secondary analysis of a placebo-controlled randomised trial ( n = 163). Serum s les were collected at baseline and week 16 of the clinical trial to determine changes in Interleukin-6 (IL-6) and total antioxidant capacity (TAC) following adjunctive CT and/or NAC treatment, and to explore the predictability of the outcome or moderator effects of these markers. In the NAC-treated group, no difference was observed in serum IL-6 and TAC levels after 16 weeks of treatment with NAC or CT. However, results from a moderator analysis showed that in the CT group, lower IL-6 levels at baseline was a significant moderator of MADRS χ 2 (df) = 4.90, p = 0.027) and Clinical Global Impression-Improvement (CGI-I, χ 2 (df) = 6.28 p = 0.012). In addition, IL-6 was a non-specific but significant predictor of functioning (based on the Social and Occupational Functioning Assessment Scale (SOFAS)), indicating that in iduals with higher IL-6 levels at baseline had a greater improvement on SOFAS regardless of their treatment ( p = 0.023). Participants with lower IL-6 levels at baseline had a better response to the adjunctive treatment with the mitochondrial-enhancing agents in terms of improvements in MADRS and CGI-I outcomes.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.JAD.2015.03.041
Abstract: This study examines the effects of malondialdehyde (MDA) and uric acid on insulin resistance and atherogenicity in subjects with and without mood disorders, the metabolic syndrome (MetS) and tobacco use disorder (TUD). We included 314 subjects with depression and bipolar depression, with and without the MetS and TUD and computed insulin resistance using the updated homeostasis model assessment (HOMA2IR) and atherogenicity using the atherogenic index of plasma (AIP), that is log10 (triglycerides/high density lipoprotein (HDL) cholesterol. HOMA2IR is correlated with body mass index (BMI) and uric acid levels, but not with mood disorders and TUD, while the AIP is positively associated with BMI, mood disorders, TUD, uric acid, MDA and male sex. Uric acid is positively associated with insulin and triglycerides and negatively with HDL cholesterol. MDA is positively associated with triglyceride levels. Comorbid mood disorders and TUD further increase AIP but not insulin resistance. Glucose is positively associated with increasing age, male gender and BMI. The results show that mood disorders, TUD and BMI together with elevated levels of uric acid and MDA independently contribute to increased atherogenic potential, while BMI and uric acid are risk factors for insulin resistance. The findings show that mood disorders and TUD are closely related to an increased atherogenic potential but not to insulin resistance or the MetS. Increased uric acid is a highly significant risk factor for insulin resistance and increased atherogenic potential. MDA, a marker of lipid peroxidation, further contributes to different aspects of the atherogenic potential. Mood disorders and TUD increase triglyceride levels, lower HDL cholesterol and are strongly associated with the atherogenic, but not insulin resistance, component of the MetS.
Publisher: Cambridge University Press (CUP)
Date: 18-12-2018
DOI: 10.1017/S0033291718003690
Abstract: Elevated levels of pro-inflammatory cytokines are consistently reported in schizophrenia (SZ) and bipolar-I disorder (BD), as well as among in iduals who have been exposed to childhood trauma. However, higher levels of inflammatory markers in these disorders are yet to be investigated with respect to levels of exposure to different types of childhood trauma. Participants were 68 cases with a diagnosis of schizophrenia/schizoaffective disorder (SZ), 69 cases with a diagnosis of psychotic BD and 72 healthy controls (HC). Serum levels of interleukin 6 (IL-6), tumour necrosis factor- α (TNF- α ) and C-reactive protein (CRP) were quantified, and childhood trauma exposure was assessed with the Childhood Trauma Questionnaire. The SZ group had significantly higher levels of IL-6, TNF- α and CRP when compared with the HC group (all p 0.05, d = 0.41–0.63), as well as higher levels of TNF- α when compared with the BD group ( p = 0.014, d = 0.50) there were no differences between the BD and HC groups for any markers. Exposure to sexual abuse was positively associated (standardised β = 0.326, t = 2.459, p = 0.018) with levels of CRP in the SZ group, but there were no significant associations between any form of trauma exposure and cytokine levels in the HC or BD groups. These results contribute to the evidence for a chronic state of inflammation in SZ but not BD cases. Differential associations between trauma exposure and levels of pro-inflammatory cytokines across the diagnostic categories suggest that trauma may impact biological (stress and immune) systems differently in these patient groups.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.NEULET.2013.03.059
Abstract: To determine if oxidative stress and inflammation are linked with major depressive disorder, nicotine dependence and both disorders combined. This study comprised 150 smokers and 191 never smokers. The instruments were: a socio-demographic questionnaire, diagnoses of mood disorder and nicotine dependence according to DSM-IV, (SCID-IV), and the Alcohol, Smoking and Substance Involvement Screening Test. Laboratory assessments included: nitric oxide metabolites (NOx), lipid hydroperoxides, malondialdehyde (MDA), total reactive antioxidant potential (TRAP), advanced oxidation protein products (AOPP), fibrinogen concentrations, homocysteine, erythrocytes sedimentation rate (ESR) and high-sensitivity C-reactive protein (hs-CRP) were assayed from blood specimens. Statistically significant differences were found among depressed smokers who had more severe depressive symptoms, a higher risk of alcohol consumption, more suicide attempts, and more disability for work than non-depressed never smokers. Depressed smokers had significantly higher levels of NOx, fibrinogen, hs-CRP, AOPP, ESR and lower levels of TRAP compared to non-depressed never smokers. Depressed smokers had significant levels of oxidative stress and inflammatory biomarkers after adjusting for gender, age, years of education, disability for work, and laboratory measures. The levels of NOx, lipid hydroperoxides, AOPP, and fibrinogen were substantially higher, whereas levels of TRAP were lower in depressed smokers compared to non-depressed never smokers. (1) Depressed smokers exhibited altered concentrations of NOx, lipid hydroperoxides, AOPP, TRAP, and fibrinogen. (2) Depressed smokers were more unable to work, showed more severe depressive symptoms and attempted suicide more frequently.
Publisher: Wiley
Date: 28-08-2013
DOI: 10.1111/J.1542-4758.2012.00736.X
Abstract: Premature atherosclerosis represents the main cause of mortality among end-stage renal disease patients (ESRD). Increased inflammation and oxidative stress are involved in initiation and progression of the atherosclerotic plaque. As foam cells are capable of producing significant amounts of inflammatory mediators and free radicals, we hypothesized that foam cells from uremic patients could produce more inflammation and oxidative stress than foam cells from normal people and be, somehow, involved in the accelerated atherosclerosis of uremia. To test this hypothesis, the levels of a few markers of inflammation and oxidative stress: Tumor necrosis factor-α, inducible nitric oxide synthase, malondialdehyde, nitric oxide by-products were measured in the supernatants of macrophage-derived foam cells cultures from 18 hemodialysis patients and 18 apparently healthy in iduals controls. Malondialdehyde levels in the supernatant of cell cultures (macrophages stimulated or not with native and oxidized lipoprotein) were significantly increased in uremic patients no statistically significant difference was found between the supernatant concentrations of nitric oxide by-products, inducible nitric oxide synthase activity, and tumor necrosis factor-α between patients and controls. Our results, obtained with human macrophages and macrophage-derived foam cells, are compatible with the theory that increased cellular oxidative stress and inflammatory activity in ESRD patients could accelerate the atherosclerotic process. The present culture protocol showed it is possible to use human mononuclear cells to evaluate the oxidative metabolism of foam cells, which are considered to be the initial step of atherosclerotic lesions.
Publisher: Oxford University Press (OUP)
Date: 19-02-2018
DOI: 10.1093/IJNP/PYY014
Publisher: SAGE Publications
Date: 08-01-2020
Abstract: The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is h ered by the paucity of knowledge of the pathophysiology of this disease. This study aims to explore the role of microRNAs in bipolar disorder and understand the molecular mechanisms of action of commonly used bipolar disorder drugs. The transcriptional effects of bipolar disorder drug combination (lithium, valproate, lamotrigine and quetiapine) in cultured human neuronal cells were studied using next generation sequencing. Differential expression of genes ( n=20) and microRNAs ( n=6) was assessed and the differentially expressed microRNAs were confirmed with TaqMan MicroRNA Assays. The expression of the differentially expressed microRNAs were inhibited to determine bipolar disorder drug effects on their target genes ( n=8). Independent s les t-test was used for normally distributed data and Kruskal-Wallis/Mann-Whitney U test was used for data not distributed normally. Significance levels were set at p .05. We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 ( p .05). Putative target genes of these microRNAs targeted pathways including those identified as “neuron projection development” and “axonogenesis”. Many of the target genes are inhibitors of neurite outgrowth and neurogenesis and were downregulated following bipolar disorder drug combination treatment (all p .05). The bipolar disorder drug combination tended to decrease the expression of the target genes ( NOVA1, GRIN3A, and VIM), however this effect could be reversed by the application of microRNA inhibitors. We conclude that at a transcriptional level, bipolar disorder drugs affect several genes in concert that would increase neurite outgrowth and neurogenesis and hence neural plasticity, and that this effect is mediated (at least in part) by modulation of the expression of these two key microRNAs.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Informa UK Limited
Date: 29-04-2020
Publisher: Elsevier BV
Date: 08-2021
Publisher: MDPI AG
Date: 06-11-2020
DOI: 10.3390/IJMS21218333
Abstract: Although neurogenesis is affected in several psychiatric diseases, the effects and mechanisms of action of psychoactive drugs on neurogenesis remain unknown and/or controversial. This study aims to evaluate the effects of psychoactive drugs on the expression of genes involved in neurogenesis. Neuronal-like cells (NT2-N) were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), or valproate (0.5 mM) for 24 h. Genome wide mRNA expression was quantified and analysed using gene set enrichment analysis, with the neurogenesis gene set retrieved from the Gene Ontology database and the Mammalian Adult Neurogenesis Gene Ontology (MANGO) database. Transcription factors that are more likely to regulate these genes were investigated to better understand the biological processes driving neurogenesis. Targeted metabolomics were performed using gas chromatography-mass spectrometry. Six of the eight drugs decreased the expression of genes involved in neurogenesis in both databases. This suggests that acute treatment with these psychoactive drugs negatively regulates the expression of genes involved in neurogenesis in vitro. SOX2 and three of its target genes (CCND1, BMP4, and DKK1) were also decreased after treatment with quetiapine. This can, at least in part, explain the mechanisms by which these drugs decrease neurogenesis at a transcriptional level in vitro. These results were supported by the finding of increased metabolite markers of mature neurons following treatment with most of the drugs tested, suggesting increased proportions of mature relative to immature neurons consistent with reduced neurogenesis.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.JAD.2013.05.016
Abstract: There is evidence that depression is accompanied by inflammation, oxidative and nitrosative stress (O&NS) and metabolic disorders. However links between oxidative stress and suicide attempts in depressed patients are poorly understood. This study examines whether a history of suicide attempts is associated with inflammation, O&NS and metabolic disorders. Blood specimens were collected from study participants aged 18-60 (N=342) recruited at the State University of Londrina, Brazil, and measured for oxidative stress biomarkers: nitric oxide metabolites (NOx), lipid hydroperoxides, malondialdehyde, advanced oxidation protein products and plasma total antioxidant potential (TRAP) inflammatory biomarkers: fibrinogen, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, interleukin-6 and tumor necrosis factor-α and metabolic variables. Subjects were ided into those with (n=141) and without (n=201) a history of suicidal attempts. In iduals with a history of suicide attempts had significantly higher levels of NOx and lipid hydroperoxides and lowered TRAP as compared to in iduals without suicide attempts. There were no significant associations between a history of suicide attempts and inflammatory and metabolic biomarkers and metabolic syndrome. Logistic regression showed that both unipolar and bipolar disorder, female gender, smoking behavior and lipid hydroperoxides were significantly associated with a history of suicide attempts. The combined effects of oxidative stress, smoking, depression, female gender were independent from classical risk factors, including marital status, years of education and anxiety. O&NS as well as lowered antioxidant levels may play a role in the pathophysiology of suicidal behavior independently from the effects of depression and smoking, both of which are associated with increased O&NS, and classical suicide predictors, such as years of education and marital status.
Publisher: Cambridge University Press (CUP)
Date: 16-07-2018
DOI: 10.1017/NEU.2018.13
Abstract: This study aimed to explore effects of adjunctive treatment with N -acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression. This is a secondary analysis of a placebo-controlled randomised trial. Serum s les were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers. Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters. The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.EURONEURO.2021.10.002
Abstract: Smoking represents a significant health threat to the population, however there remains a core group of consistent smokers that are largely unable to break the addiction. Novel therapies are required to assist this group with cessation. N-acetylcysteine (NAC) is a nutraceutical supplement that has shown efficacy compared to placebo in previous pilot studies for assisting smokers to quit or reduce their consumption of cigarettes. A double-blind, randomised trial with a treatment period of 16 weeks and a final follow-up at 42 weeks was conducted comparing 1.8g of effervescent NAC per day (n=47) with placebo (n=47) as an aide to smoking cessation. Both study arms received adjunctive online support through the QuitCoach program. Participants reported smoking at each timepoint (baseline and weeks 8, 16 & 42), which was confirmed through salivary cotinine and exhaled carbon monoxide testing. Primary and secondary analyses were undertaken using a modified intent-to-treat basis, including all participants with at least one valid post baseline outcome, regardless of treatment received or their withdrawal from the study. There was no significant difference in smoking outcomes between intervention groups among the 24 participants that competed follow-up. There were no significant differences in age, gender, or body mass index (BMI) between the groups lost to follow-up or recorded at follow-up. This study found no evidence to support NAC as a therapy for smoking cessation. The negative outcome could be the result of lack of treatment efficacy, or alternatively, small s le size, participant retention difficulties, dose, or duration of follow-up. Trial Registration: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303. Registered on 19 October 2017.
Publisher: Informa UK Limited
Date: 18-06-2022
DOI: 10.1080/15622975.2021.1925152
Abstract: This study examined cognition-immune interactions, specifically executive function, working memory, peripheral levels of tumour necrosis factor-alpha (TNF-α), and soluble tumour necrosis factor receptors-1 and -2 (sTNFR1 and 2) levels in bipolar disorder (BD) patients in comparison with controls. Thirty-one BD participants and twenty-seven controls participated in the study. The neurocognitive assessment was performed through three of CogState Research Battery BD presented a significantly worse performance in the working memory task ( TNF-α and its receptors might be an important variable in cognitive impairment in BD. Future studies might focus on the development of anti-inflammatory therapeutic targets for cognitive dysfunction in BD.
Publisher: Cambridge University Press (CUP)
Date: 20-03-2017
DOI: 10.1017/NEU.2017.2
Abstract: This study aimed to explore effects of adjunctive N -acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression. We embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum s les at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment. NAC treatment significantly improved depressive symptoms on the Montgomery–Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment. Overall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.JAD.2018.08.041
Abstract: There is evidence that substance use disorders and other mental disorders may have shared biological mechanisms. However, the neurobiological basis of this comorbidity remains only partially explained. This review describes the historical evolution of the dual disorders concept and approach, and reviews the existing literature on neurobiological findings specifically regarding comorbid substance use and mood disorders. Searches were conducted using PubMed and Scopus in December 2017. A Boolean search was performed using combinations of "dual diagnosis" or "dual disorder" or "depression" or "bipolar" or "affective disorder" or "mood disorder" and "substance use" or "substance abuse" and "neurobiology" or "functional neuroimaging" or "genetics" or "neurotransmitters" or "neuroendocrinology" in the title or abstract, or as keywords, using no language restriction. 32 studies met the inclusion criteria. We found robust evidence for involvement of the neurotransmitters dopamine, GABA and glutamate and their receptors, as well as by the central corticotrophin-releasing hormone, hypothalamic-pituitary-adrenal axis activation, oxidative stress and inflammation. Recent studies focusing on neuroimaging and genetics have not shown consistent results. Only two search tools were used most identified studies excluded the population of interest (comorbid mood and substance abuse disorders). The neurobiological relevance for the occurrence of comorbid mood and substance abuse disorders has not been fully elucidated. Considering the high levels of in iduals who experience comorbidity in these areas as well as the negative associated outcomes, this is clearly an area that requires further in-depth investigation. Furthermore, findings from this area can help to inform drug abuse prevention and intervention efforts, and especially how they relate to populations with psychiatric symptoms.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PNPBP.2019.109708
Abstract: Major antioxidant responses to increased levels of inflammatory, oxidative and nitrosative stress (ONS) are detailed. In response to increasing levels of nitric oxide, S-nitrosylation of cysteine thiol groups leads to post-transcriptional modification of many cellular proteins and thereby regulates their activity and allows cellular adaptation to increased levels of ONS. S-nitrosylation inhibits the function of nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor-mediated signalling and the activity of several mitogen-activated protein kinases, while activating nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2) in turn, the redox-regulated activation of Nrf2 leads to increased levels and/or activity of key enzymes and transporter systems involved in the glutathione system. The Nrf2/Kelch-like ECH-associated protein-1 axis is associated with upregulation of NAD(P)H:quinone oxidoreductase 1, which in turn has anti-inflammatory effects. Increased Nrf2 transcriptional activity also leads to activation of haem oxygenase-1, which is associated with upregulation of bilirubin, biliverdin and biliverdin reductase as well as increased carbon monoxide signalling, anti-inflammatory and antioxidant activity. Associated transcriptional responses, which may be mediated by retrograde signalling owing to elevated hydrogen peroxide, include the unfolded protein response (UPR), mitohormesis and the mitochondrial UPR the UPR also results from increasing levels of mitochondrial and cytosolic reactive oxygen species and reactive nitrogen species leading to nitrosylation, glutathionylation, oxidation and nitration of crucial cysteine and tyrosine causing protein misfolding and the development of endoplasmic reticulum stress. It is shown how these mechanisms co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system.
Publisher: Frontiers Media SA
Date: 13-03-2019
Publisher: Bentham Science Publishers Ltd.
Date: 05-07-2017
DOI: 10.2174/1871527316666170223161004
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a complex interplay between peripheral and central inflammatory and oxidative stress pathways. To investigate immune-inflammatory and oxidative stress pathways in relation to iron metabolism in peripheral blood of PD patients and healthy controls. We recruited 56 healthy in iduals and 56 PD patients in stages 1-3 of Hoehn and Yahr Scale. Plasma haptoglobin (Hp), homocysteine, interleukin 6, soluble interleukin 6 receptor, iron (Fe), ferritin, total iron binding capacity, transferrin (Tf), soluble transferrin receptor (sTfR), malondialdehyde (MDA) and paraoxonase 1 (PON1) were measured. PD was associated with significant changes in Tf (lowered), sTfR, ferritin, Hp, interleukin 6 and MDA (all increased) levels, while there was a trend towards a negative association with PON1. Logistic regression showed that the most significant biomarkers of PD were MDA, sTfR, Hp and ferritin. Moreover, Fe levels were negatively associated with Hp and positively with PON1, total iron binding capacity and Tf, while ferritin and sTfR were positively associated with MDA levels. Our study indicates a state of systemic inflammation and oxidative stress in PD patients coupled with alterations in Fe metabolism. Chronic inflammation and oxidative pathways in PD may in part determine changes in iron metabolism. New drug treatments for PD should target inflammatory and oxidative stress pathways and iron metabolism as well.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.NEULET.2014.11.002
Abstract: There is evidence that genetic factors influence the probability of comorbidity of tobacco use disorder (TUD) with mood disorders. This study was carried out to examine whether both TUD and mood disorders are associated with genetic biomarkers particularly paraoxonase 1 (PON1) status, polymorphisms of glutathione S-transferases (GSTs), such as GSTM1 and GSTT1, and the STIn 2 polymorphism of the serotonin transporter. PON1 status (Q192R polymorphism and PON1 plasmatic activity), GSTM1, GSTT1, and STin.2 genotypes and alleles were assayed in 4 mutually exclusive study groups, i.e., comorbid mood disorder and TUD (n=95) TUD without mood disorders (n=90) mood disorders but no TUD (n=62) and controls (never-smokers without mood disorders n=113). Logistic regression analyses showed that comorbid mood disorders and TUD were associated with significantly lower PON1 activity, the STin2.10/10 genotype (protective) or the Stin2.12 allele (risk factor) and the GSTM1 and GSTT1 null genotypes (protective). These results show that comorbid mood disorders and TUD are associated with specific biomarkers related to oxidative stress and serotonin pathways.
Publisher: Informa UK Limited
Date: 03-08-2020
DOI: 10.1080/15622975.2018.1492734
Abstract: To create a gene expression signature (GES) to represent the biological effects of a combination of known drugs for bipolar disorder (BD) on cultured human neuronal cells (NT2-N) and rat brains, which also has evidence of differential expression in in iduals with BD. To use the GES to identify new drugs for BD using Connectivity Map (CMap).
Publisher: BMJ
Date: 03-2020
DOI: 10.1136/BMJOPEN-2019-035080
Abstract: Due to the anti-inflammatory, antioxidant and anti-apoptotic properties of minocycline, clinical trials have evaluated the potential of this drug to treat several psychiatric and neurological disorders, including major depressive disorder, schizophrenia, bipolar disorder, stroke and amyotrophic lateral sclerosis. This protocol proposes a systematic review (and potential meta-analysis) that aims to identify and critically evaluate randomised controlled trials of minocycline for treating psychiatric and neurological disorders. PubMed, Embase, Cochrane Central Register of Controlled Clinical Trials, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be used to identify randomised controlled trials that used minocycline to treat psychiatric and neurological disorders. Double-blind, randomised, controlled, clinical trials of participants aged 18 years or older and written in English will be included in the review. Data will be extracted by two independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed and the Cochrane Collaboration’s ‘Risk of Bias’ tool will be used to assess the risk of bias in all studies included in the systematic review. The Grading of Recommendations, Assessment, Development and Evaluation system will be used to access the overall quality of the level of evidence of the studies. If sufficient evidence is identified, a meta-analysis will be conducted using the standardised mean difference approach and reported with 95% CIs. Heterogeneity of evidence will be evaluated using the I 2 model. This systematic review will evaluate only published data therefore, ethical approval is not required. The systematic review will be published in a peer-reviewed journal and presented at relevant research conferences. CRD42020153292.
Publisher: MDPI AG
Date: 10-09-2021
DOI: 10.3390/JCM10184095
Abstract: Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs’ propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs’ propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2019
DOI: 10.1186/S13063-019-3786-5
Abstract: First-episode psychosis (FEP) may lead to a progressive, potentially disabling and lifelong chronic illness however, evidence suggests that the illness course can be improved if appropriate treatments are given at the early stages. Nonetheless, the efficacy of antipsychotic medications is suboptimal, particularly for negative and cognitive symptoms, and more efficacious and benign treatments are needed. Previous studies have shown that the antioxidant amino acid N -acetylcysteine (NAC) reduces negative symptoms and improves functioning in chronic schizophrenia and bipolar disorder. Research is scarce as to whether NAC is beneficial earlier in the course of illness. The primary aim of this study is to determine the efficacy of treatment with adjunctive NAC (2 g/day for 26 weeks) compared with placebo to improve psychiatric symptoms in young people experiencing FEP. Secondary aims are to explore the neurobiological mechanisms underpinning NAC and how they relate to various clinical and functional outcomes at 26- and 52-week follow-ups. ENACT is a 26-week, randomised controlled trial of adjunctive NAC versus placebo, with a 26-week non-treatment follow-up period, for FEP. We will be recruiting 162 young people aged 15–25 years who have recently presented to, and are being treated at, the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The primary outcome is the Total Score on the Positive and Negative Syndrome Scale which will be administered at baseline, and weeks 4, 8, 12, 26 (primary endpoint), and 52 (end of study). Secondary outcomes include: symptomatology, functioning, quality of life, neurocognition, blood-derived measures of: inflammation, oxidative and nitrosative stress, and magnetic resonance spectroscopy measures of glutathione concentration. Targeted drug development for FEP to date has generally not involved the exploration of neuroprotective agents. This study has the potential to offer a new, safe, and efficacious treatment for people with FEP, leading to better treatment outcomes. Additionally, the neuroprotective dimension of this study may lead to a better long-term prognosis for people with FEP. It has the potential to uncover a novel treatment that targets the neurobiological mechanisms of FEP and, if successful, will be a major advance for psychiatry. Australian New Zealand Clinical Trials Registry, ID: ACTR N12618000413224 . Registered on 21 March 2018.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.JPSYCHIRES.2022.03.025
Abstract: The molecular mechanism(s) underpinning the clinical efficacy of the current drugs for bipolar disorder (BD) are largely unknown. This study evaluated the transcriptional perturbations potentially playing roles in the therapeutic efficacy of four commonly prescribed psychotropic drugs used to treat BD. NT2-N cells were treated with lamotrigine, lithium, quetiapine, valproate or vehicle control for 24 h. Genome-wide mRNA expression was quantified by RNA-sequencing. Incorporating drug-induced gene expression profiles with BD-associated transcriptional changes from post-mortem brains, we identified potential therapeutic-relevant genes associated with both drug treatments and BD pathophysiology and focused on expression quantitative trait loci (eQTL) genes with genome-wide association with BD. Each eQTL gene was ranked based on its potential role in the therapeutic effect across multiple drugs. The expression of highest-ranked eQTL genes were measured by RT-qPCR to confirm their transcriptional changes observed in RNA-seq. We found 775 genes for which at least 2 drugs reversed expression levels relative to the differential expression in post-mortem brains. Pathway analysis identified enriched biological processes highlighting mitochondrial and endoplasmic reticulum function. Differential expression of SRPK2 and CHDH was confirmed by RT-qPCR following multiple-dose treatments. We pinpointed potential genes involved in the beneficial effects of drugs used for BD and their main associated biological pathways. CHDH, which encodes a mitochondrial protein, had a significant dose-responsive downregulation following treatment with increasing doses of quetiapine and lamotrigine, which in combination with the enriched mitochondrial pathways suggests potential therapeutic roles and demand more studies on mitochondrial involvement in BD to identify novel treatment targets.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 10-09-2019
DOI: 10.1186/S13063-019-3628-5
Abstract: Tobacco smoking is a highly prevalent, addictive behaviour and a key public health priority. However available cessation therapies have low quit and high relapse rates, indicating an urgent need for more effective treatments. Predicated on promising preclinical and pilot clinical data, this paper presents a rationale and protocol for the trial of N-acetylcysteine (NAC) as a novel anti-craving smoking cessation aid. Current smokers ( n = 120) of at least 10 cigarettes a day are recruited through online advertisements, print publications and dissemination of flyers. Participants are randomised on a 1:1 ratio to receive either 16-week treatment of 1.8 g/day of NAC or placebo with all participants receiving quit support from the online QuitCoach tool. Participants are attending visits at baseline, 8 and 16 weeks with a 42-week post-discontinuation follow-up. The primary outcome measure is sustained abstinence at six months after treatment based on self-reported rating scales and confirmed by exhaled carbon monoxide and salivary cotinine levels. Secondary outcomes are timing of the first lapse and relapse, between-group cigarette consumption, withdrawal symptoms, general wellbeing and mood/anxiety symptoms. Between-group differences in adverse events and subgroup analyses for variables including gender and Diagnostic Statistics Manual 5 diagnostics will also be investigated. The planned trial addresses an issue of major importance to human health and, if an effect is shown, may result in substantial changes to the management of smoking and nicotine addiction with overt public health implications. Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303 . Registered on 19 October 2017.
Publisher: FapUNIFESP (SciELO)
Date: 2016
DOI: 10.5935/0101-2800.20160045
Abstract: Patients at end stage renal disease have higher levels of inflammation and oxidative stress than the general population. Many factors contribute to these issues, and the parathyroid hormone (PTH) is also implicated. The study was conducted in order to assess the relationship between PTH levels and inflammation and oxidative stress in hemodialysis patients. Cross-sectional study with patients of two hemodialysis facilities in Londrina, Brazil. Patients with other conditions known to generate oxidative stress and inflammation were excluded. Blood levels of PTH and biochemical parameters of inflammation (interleukins 1 and 6, tumor necrosis factor-alpha) and oxidative stress (total plasma antioxidant capacity, malonic dialdehyde, lipid hydroperoxidation, advanced oxidation protein products, quantification of nitric oxide metabolites, and 8-isoprostane) were measured before a dialysis session. Then, we made correlation analyses between PTH levels - either as the continuous variable or categorized into tertiles-, and inflammatory and oxidative stress biomarkers. PTH did not show any correlation with the tested inflammation and oxidative stress parameters, nor as continuous variable neither as categorical variable. In this descriptive study, the results suggest that the inflammation and oxidative stress of hemodialysis patients probably arise from mechanisms other than secondary hyperparathyroidism. Pacientes com doença renal em estágio terminal têm níveis de inflamação e estresse oxidativo maiores do que a população geral. Muitos fatores contribuem para isso, e o hormônio paratireoidiano (PTH) é um deles. Estudo foi realizado para avaliar a relação entre os níveis de PTH e níveis de inflamação e estresse oxidativo em pacientes em hemodiálise. estudo transversal com pacientes de duas unidades de hemodiálise de Londrina, Brasil. Pacientes com condições causadoras de inflamação e estresse oxidativo foram exclusos. Níveis plasmáticos de PTH e parâmetros bioquímicos de inflamação (interleucina 1 e 6, fator de necrose tumoral alfa) e estresse oxidativo (capacidade antioxidante plasmática total, dialdeído malônico, hidroperoxidação lipídica, produtos avançados da degradação proteica, quantificação de metabólitos de óxido nítrico e 8-isoprostano) foram dosados antes da sessão de hemodiálise. Realizou-se análise de correlação entre os níveis de PTH - tanto como variável continua como variável categórica em tercis - e os parâmetros de inflamação e estresse oxidativo. Não houve correlação do PTH com nenhum dos parâmetros testados, nem como variável contínua, nem como categórica. Neste estudo descritivo, os resultados sugerem que a inflamação e o estresse oxidativo em pacientes em hemodiálise provavelmente tem origem em mecanismos que não incluem o hiperparatireoidismo secundário.
Publisher: MDPI AG
Date: 28-06-2022
DOI: 10.3390/IJMS23137180
Abstract: Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.NEULET.2014.08.020
Abstract: The measurement of the total radical trapping antioxidant potential (TRAP) is a general marker of peripheral blood antioxidant defenses. Paraoxonase 1 (PON1) is a potent antioxidant, which protects against lipid peroxidation. The study aimed to examine the relation between TRAP levels and PON1 activity, PON1 Q192R functional genotypes, smoking, interactions between PON1 genotypes and smoking, and mood disorders, while adjusting for effects of ethnicity, marital status, body mass index (BMI) and gender. The analyses were performed in 197 controls and 136 subjects with mood disorders. TRAP levels were significantly associated with higher plasma PON1 activity, the RR functional genotype, non smoking by RR carriers, male gender and a higher BMI. TRAP levels were significantly lower in patients with mood disorders than in controls, but this association was no longer significant after considering the effects of the above predictors. The risk in the subgroup with low TRAP levels is increased by a smoking X RR genotype interaction and decreased by male gender, the RR genotype, and higher BMI and PON1 activity. Plasma PON1 activity, the PON1 Q192R functional genotypes and specific interactions between this genotype and smoking contribute significantly to TRAP levels. Gender and BMI also appear to influence TRAP levels.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.NEUBIOREV.2019.09.025
Abstract: Activated immune-inflammatory, oxidative and nitrosative stress (IO&NS) pathways and consequent mitochondrial aberrations are involved in the pathophysiology of psychiatric disorders including major depression, bipolar disorder and schizophrenia. They offer independent and shared contributions to pathways underpinning medical comorbidities including insulin resistance, metabolic syndrome, obesity and cardiovascular disease - herein conceptualized as somatoprogression. This narrative review of human studies aims to summarize relationships between IO&NS pathways, neuroprogression and somatoprogression. Activated IO&NS pathways, implicated in the neuroprogression of psychiatric disorders, affect the pathogenesis of comorbidities including insulin resistance, dyslipidaemia, obesity and hypertension, and by inference, metabolic syndrome. These conditions activate IO&NS pathways, exacerbating neuroprogression in psychiatric disorders. The processes whereby proinflammatory cytokines, nitrosative and endoplasmic reticulum stress, NADPH oxidase isoforms, PPARγ inactivation, SIRT1 deficiency and intracellular signalling pathways impact lipid metabolism and storage are considered. Through associations between body mass index, chronic neuroinflammation and FTO expression, activation of IO&NS pathways arising from somatoprogression may contribute to neuroprogression. Early evidence highlights the potential of adjuvants targeting IO&NS pathways for treating somatoprogression and neuroprogression.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.PSYCHRES.2017.03.038
Abstract: There is evidence that the acute phase of schizophrenia (SCZ) is accompanied by specific changes in oxidative and nitrosative stress (O&NS) biomarkers. There are, however, no firm data regarding these biomarkers in chronic SCZ. Therefore, this study aimed to delineate O&NS biomarkers in patients with chronic SCZ. 125 outpatients with SCZ and 118 controls were enrolled. The markers included lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP) and paraoxonase 1 (PON-1) activity. Immune-inflammatory markers known to be altered in SCZ were also measured: leptin, IL-6, soluble TNF receptors (sTNF-Rs) and the chemokines CCL-11 and CCL-3. There were no significant associations between chronic SCZ and the O&NS markers (AOPP, NOx, LOOH) and the anti-oxidants PON-1 and TRAP. Leptin, sTNF-R, CCL-3 and CCL-11 were significantly higher in SCZ. There were significant associations between pro-inflammatory and O&NS biomarkers (leptin/CCL-8 and AOPP IL-6 and NOx CCL-3 and LOOH CCL-3/IL-6/NOx and TRAP). In conclusion, there were significant intercorrelations between inflammatory and O&NS pathways, which play a role in the pathophysiology of chronic SCZ. O&NS markers and the enzyme PON-1 are not useful as biomarkers in chronic stable polymedicated SCZ patients.
Publisher: Informa UK Limited
Date: 16-10-2019
Publisher: Elsevier BV
Date: 10-2021
Publisher: American Medical Association (AMA)
Date: 07-2017
Publisher: Informa UK Limited
Date: 18-07-2014
No related grants have been discovered for Chiara Bortolasci.