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1.
Hum Genet ; 143(1): 35-47, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38095720

RESUMO

Complex multi-omics effects drive the clustering of cardiometabolic risk factors, underscoring the imperative to comprehend how individual and combined omics shape phenotypic variation. Our study partitions phenotypic variance in metabolic syndrome (MetS), blood glucose (GLU), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and blood pressure through genome, transcriptome, metabolome, and exposome (i.e., lifestyle exposome) analyses. Our analysis included a cohort of 62,822 unrelated individuals with white British ancestry, sourced from the UK biobank. We employed linear mixed models to partition phenotypic variance using the restricted maximum likelihood (REML) method, implemented in MTG2 (v2.22). We initiated the analysis by individually modeling omics, followed by subsequent integration of pairwise omics in a joint model that also accounted for the covariance and interaction between omics layers. Finally, we estimated the correlations of various omics effects between the phenotypes using bivariate REML. Significant proportions of the MetS variance were attributed to distinct data sources: genome (9.47%), transcriptome (4.24%), metabolome (14.34%), and exposome (3.77%). The phenotypic variances explained by the genome, transcriptome, metabolome, and exposome ranged from 3.28% for GLU to 25.35% for HDL-C, 0% for GLU to 19.34% for HDL-C, 4.29% for systolic blood pressure (SBP) to 35.75% for TG, and 0.89% for GLU to 10.17% for HDL-C, respectively. Significant correlations were found between genomic and transcriptomic effects for TG and HDL-C. Furthermore, significant interaction effects between omics data were detected for both MetS and its components. Interestingly, significant correlation of omics effect between the phenotypes was found. This study underscores omics' roles, interaction effects, and random-effects covariance in unveiling phenotypic variation in multi-omics domains.


Assuntos
Síndrome Metabólica , Humanos , Síndrome Metabólica/genética , Multiômica , Fenótipo , Triglicerídeos/genética , HDL-Colesterol
2.
Int J Neuropsychopharmacol ; 27(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38441216

RESUMO

BACKGROUND: Emotional symptoms are recognized as a key feature in individuals with major depressive disorder. Previously, emotional blunting has been described both as a side effect of antidepressant treatment and as a symptom of depression. Little is known about the change of emotional blunting during antidepressant treatment. METHODS: The PREDDICT trial is a randomized, placebo-controlled, 6-week trial on the augmentation of vortioxetine with the anti-inflammatory agent celecoxib or placebo. Presently we report on exploratory secondary outcomes of changes in emotional blunting in depression assessed with the Oxford Depression Questionnaire (ODQ) total score and subscores from baseline to 8-week, 3-month, and 6-month follow-up assessments. RESULTS: In the whole group, there was a significant improvement in the ODQ total score and all subscores after 8 weeks. After stratification of participants into the treatment groups, the ODQ total score as well as subscores related to emotional blunting as a symptom of depression (reduction in positive emotions, not caring) improved between baseline and all follow-up time points in both treatment groups. Changes in subscores considered as a side effect of antidepressants (general reduction in emotions, emotional detachment) were inconclusive in both treatment groups. Overall, the placebo-augmented group showed slightly better results in changes of emotional blunting scores than the celecoxib group as did those with elevated inflammation at screening, regardless of treatment group. CONCLUSIONS: This analysis suggests favorable effects of vortioxetine on emotional blunting in both short- and long-term course. The beneficial impact of vortioxetine on emotional blunting was weaker in celecoxib-augmented patients compared with placebo, possibly due to pharmacokinetic interactions. Clinical Trials Registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.


Assuntos
Transtorno Depressivo Maior , Humanos , Vortioxetina/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Celecoxib/efeitos adversos , Depressão , Método Duplo-Cego , Austrália , Antidepressivos/efeitos adversos , Inflamação/induzido quimicamente
3.
J Neurochem ; 2023 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-37635396

RESUMO

Low-grade inflammation is considered as a pathophysiological mechanism in a subtype of patients with major depressive disorder (MDD). Anti-inflammatory drugs have shown efficacy in treating MDD. However, it remains unclear how to identify suitable patients for anti-inflammatory treatment of depression. This study investigates the predictive value of pre-treatment high-sensitivity C-Reactive Protein (hsCRP) stratification on the outcome of celecoxib augmentation of vortioxetine. The PREDDICT study was conducted as a randomized, double-blind, placebo-controlled 6-week trial on augmentation of vortioxetine with celecoxib between December 2017 and April 2020 at the University of Adelaide (Australia). The present analysis focusses on the question of whether the pre-treatment hsCRP measurement and stratification of patients to depression with inflammation (hsCRP >3 mg/L) or without inflammation (hsCRP ≤3 mg/L) has an impact on the outcome of anti-inflammatory treatment with celecoxib. A total of n = 119 mostly treatment-resistant MDD patients with moderate to severe symptomatology were recruited in the trial. There was no effect of treatment group (celecoxib or placebo), pre-treatment hsCRP strata (with/without inflammation), or interaction between the two terms on treatment outcome. The results of the current analysis do not support the hypothesis that pre-treatment hsCRP level is predictive for response to anti-inflammatory treatment with celecoxib in MDD patients. Further research is needed to identify appropriate biomarkers for the prediction of anti-inflammatory treatment outcome in depression. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.

4.
Br J Psychiatry ; 223(6): 533-541, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38108319

RESUMO

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.


Assuntos
Transtorno Depressivo Resistente a Tratamento , Ketamina , Humanos , Ketamina/efeitos adversos , Depressão , Midazolam/efeitos adversos , Austrália , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico
5.
Mol Psychiatry ; 27(2): 1111-1119, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34782712

RESUMO

Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from four large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA®). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development (REST), oligodendrocyte maturation (TNFRSF21), and myelination (ARFGEF1). IPA® identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions (MPO, FOXO1, PDE3A, TSLP, NLRP9, ADAMTS5, ROBO1, REST). Furthermore, IPA® identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.


Assuntos
Transtorno Depressivo Maior , Cognição , Depressão , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Herança Multifatorial/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Imunológicos
6.
Int J Neuropsychopharmacol ; 24(4): 314-321, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33269395

RESUMO

BACKGROUND: Partial response to antidepressant medication as well as relapse and treatment resistance are common in major depressive disorder (MDD). Therefore, for most patients with MDD, there will be a need to consider changing antidepressant medication at some stage during the course of the illness. The PREDDICT study investigates the efficacy of augmenting vortioxetine with celecoxib. METHODS: We describe the method used in the PREDDICT study to change participants, who were already taking antidepressant medication at the time of the screening visit, to vortioxetine. We used a cross-titration to change study participants to vortioxetine. RESULTS: Of a total of 122 study participants who were randomized to receive vortioxetine plus celecoxib or vortioxetine plus placebo at the study baseline visit, 82 were taking antidepressant medication (other than vortioxetine) prior to randomization. These medications were selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants, mirtazapine, or agomelatine. Eighty of these 82 participants completed the changeover to vortioxetine as well as the study baseline visit. We found side effects were generally mild during this changeover period. In addition, there was a reduction in mean total Montgomery-Åsberg Depression Rating Scale score of 2.5 (SD 6.0) from study baseline to week 2 and a further reduction in mean total Montgomery-Åsberg Depression Rating Scale of 2.5 (SD 5.9) from week 2 to week 4. CONCLUSION: Changing other antidepressants to vortioxetine can be done safely and was generally well-tolerated. However, there are some antidepressant classes, in particular monoamine oxidase inhibitors that require a washout period, which were not represented in this study. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR); ID number 12617000527369p; http://www.anzctr.org.au/ACTRN12617000527369p.aspx.


Assuntos
Antidepressivos/farmacologia , Substituição de Medicamentos , Vortioxetina/farmacologia , Adolescente , Adulto , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Transtorno Depressivo Maior , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Vortioxetina/administração & dosagem , Vortioxetina/efeitos adversos , Adulto Jovem
7.
Child Adolesc Ment Health ; 26(2): 143-156, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33200498

RESUMO

BACKGROUND: Anxiety-based disorders are common and are often chronic with an onset during childhood or adolescence. An emerging literature has examined the role of inflammation in these disorders by measuring blood concentrations of inflammatory markers such as cytokines, C-reactive protein (CRP) and immune markers such as white blood cell counts. However, existing results are inconsistent, with available meta-analyses only including adult populations. We believe this is the first systematic review and meta-analysis to investigate these inconsistencies among the population of children and adolescents. METHODS: A systematic search of five electronic databases was conducted to identify studies which compared inflammatory markers between individuals with an anxiety-based disorder and healthy controls. Study quality was assessed, and pooled effect sizes (Hedges' g) were calculated using random-effects meta-analyses. RESULTS: Nine independent studies were identified. The combined meta-analysis of 16 cytokines and CRP was approaching significance; however, no significant between-group difference was observed for meta-analyses of individual inflammatory or immune markers. Heterogeneity was high, and quality assessments identified important limitations; primarily, small sample sizes and a lack of control over confounding variables. CONCLUSIONS: Although no significant effects were observed, the small number of included studies and limitations in study or reporting quality render these findings provisional. Research in this area has the potential for important clinical implications in relation to therapeutic interventions. Important recommendations for further research are put forth.


Assuntos
Transtornos de Ansiedade , Inflamação , Adolescente , Ansiedade/epidemiologia , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Biomarcadores , Proteína C-Reativa , Criança , Humanos
8.
Brain Behav Immun ; 88: 242-251, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32526448

RESUMO

BACKGROUND: A subset of patients with Major Depressive Disorder (MDD) have shown differences relative to healthy controls in blood inflammatory and immune markers. Meanwhile, MDD and comorbid obesity appear to present with distinct biological and symptom characteristics, categorised as "atypical" or "immunometabolic" depression, although the relevant underlying biological mechanisms are still uncertain. Therefore, this exploratory study aimed to better characterise the relationship between peripheral blood immune markers and symptoms of MDD, as well as the extent to which body mass index (BMI) may alter this relationship. METHODS: Linear regression analyses were performed between selected baseline characteristics including clinical scales and blood inflammatory markers in participants with MDD (n = 119) enrolled in the PREDDICT randomised controlled trial (RCT), using age, sex and BMI as covariates, and then stratified by BMI status. Specifically, the Montgomery-Åsberg Depression Rating Scale (MADRS) for symptom severity, Clinical Global Impression scale (CGI) for functional impairment, Oxford Depression Questionnaire (ODQ) for emotional blunting, and THINC integrated tool (THINC-it) for cognitive function were considered as clinical measures. RESULTS: There was a significant association between basophil count and THINC-it Codebreaker mean response time (associated with complex attention, perceptual motor, executive function, and learning and memory abilities) in overweight individuals and with THINC-it Trails total response time (associated with executive function ability) in moderately obese individuals, when controlling for age, sex, and years of education. No correlation was found between any tested blood markers and MADRS, CGI or ODQ clinical measures, regardless of BMI. DISCUSSION: Although the present study is exploratory, the results suggest that targeting of the immune system and of metabolic parameters might confer benefits, specifically in patients with high BMI and experiencing cognitive impairment associated with MDD. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017.


Assuntos
Transtorno Depressivo Maior , Austrália , Biomarcadores , Índice de Massa Corporal , Cognição , Transtorno Depressivo Maior/complicações , Humanos
9.
Am J Med Genet B Neuropsychiatr Genet ; 177(1): 40-49, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29159863

RESUMO

Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impact on GxE in MDD using a common approach in 3944 subjects of European ancestry from the Psychiatric Genomics Consortium who had completed the Childhood Trauma Questionnaire. (3) We subsequently used the genome-wide SNP data for a genome-wide case-control GxE model and GxE case-only analyses testing for an enrichment of associated SNPs. No genome-wide significant hits and no consistency among the signals of the different analytic approaches could be observed. This is the largest study for systematic GxE interaction analysis in MDD in subjects of European ancestry to date. Most of the known candidate genes/variants could not be supported. Thus, their impact on GxE interaction in MDD may be questionable. Our results underscore the need for larger samples, more extensive assessment of environmental exposures, and greater efforts to investigate new methodological approaches in GxE models for MDD.


Assuntos
Depressão/genética , Transtorno Depressivo Maior/genética , Estudos de Casos e Controles , Depressão/etiologia , Transtorno Depressivo Maior/etiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Acontecimentos que Mudam a Vida , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , População Branca/genética
10.
Twin Res Hum Genet ; 18(1): 28-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25466434

RESUMO

Cytokines and vitamin D both have a role in modulating the immune system, and are also potentially useful biomarkers in mental illnesses such as major depressive disorder (MDD) and schizophrenia. Studying the variability of cytokines and vitamin D in a healthy population sample may add to understanding the association between these biomarkers and mental illness. To assess genetic and environmental contributions to variation in circulating levels of cytokines and vitamin D (25-hydroxy vitamin D: 25(OH)D3), we analyzed data from a healthy adolescent twin cohort (mean age 16.2 years; standard deviation 0.25). Plasma cytokine measures were available for 400 individuals (85 MZ, 115 DZ pairs), dried blood spot sample vitamin D measures were available for 378 individuals (70 MZ, 118 DZ pairs). Heritability estimates were moderate but significant for the cytokines transforming growth factor-ß1 (TGF-ß1), 0.57 (95% CI 0.26-0.80) and tumor necrosis factor-receptor type 1 (TNFR1), 0.50 (95% CI 0.11-0.63) respectively. Measures of 25(OH)D3 were within normal range and heritability was estimated to be high (0.86, 95% CI 0.61-0.94). Assays of other cytokines did not generate meaningful results. These potential biomarkers may be useful in mental illness, with further research warranted in larger sample sizes. They may be particularly important in adolescents with mental illness where diagnostic uncertainty poses a significant clinical challenge.


Assuntos
Interação Gene-Ambiente , Característica Quantitativa Herdável , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Crescimento Transformador beta1/genética , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Vitamina D/análogos & derivados , Adolescente , Biomarcadores/sangue , Estudos de Coortes , Citocinas/sangue , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Humanos , Mediadores da Inflamação/sangue , Masculino , Queensland , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Valores de Referência , Esquizofrenia/genética , Fatores Sexuais , Fator de Crescimento Transformador beta1/sangue , Vitamina D/sangue
11.
J Affect Disord ; 352: 163-170, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38378088

RESUMO

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.


Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Adulto , Humanos , Ketamina/efeitos adversos , Midazolam/efeitos adversos , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Método Duplo-Cego , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/psicologia , Cognição , Resultado do Tratamento
12.
J Child Psychol Psychiatry ; 54(8): 816-35, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24027786

RESUMO

BACKGROUND: While cytokines have been implicated in the pathophysiology of depression in adults, the potential role in younger age groups such as adolescents is less clear. This article therefore reviews the literature (a) to explore the relationship between cytokines and depression in adolescents, and (b) to examine how cytokines may be related to adolescent depression in the context of other neurobiological theories of depression. METHOD: A systematic review of the scientific literature on the subject was conducted in February 2013, searching the Web of Knowledge, PubMed (Medline), PsycInfo and Cochrane electronic databases. RESULTS: Eighteen studies were identified measuring both depression or depressive symptoms and cytokines or immune markers in adolescents. Adolescents with depression show age-specific characteristics of the immune and inflammatory system, specifically in NK cell activity and in pro-inflammatory cytokines (such as IL-1ß and TNF-α). In addition, the role of cytokines in adolescent depression is influenced by neurodevelopment, hormonal changes, stress and trauma. CONCLUSIONS: There may be differences in the neurobiology of adolescent major depressive disorder (MDD) compared with adult MDD. Increased understanding of the role of cytokines in adolescent MDD may lead to improved outcomes in the treatment of adolescent depression.


Assuntos
Desenvolvimento do Adolescente , Citocinas/fisiologia , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/patologia , Inflamação/imunologia , Inflamação/patologia , Adolescente , Desenvolvimento do Adolescente/fisiologia , Transtorno Depressivo Maior/metabolismo , Humanos , Inflamação/metabolismo
13.
J Clin Psychiatry ; 84(6)2023 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-37796652

RESUMO

Objective: Major depressive disorder (MDD) remains difficult to treat, with many patients resistant to existing treatments or experiencing relapse. Cognitive dysfunction is associated with more severe clinical outcomes. Vortioxetine has shown efficacy in remediating depression-associated cognitive impairment. Anti-inflammatory augmentation of antidepressants is a new strategy in treating depression and has not previously been assessed for effects on cognition in depression.Methods: Exploratory analyses were performed on secondary outcome cognitive data from the PREDDICT parallel-group, randomized, double-blind, placebo-controlled trial at the University of Adelaide (Australia). Participants (N = 119) with MDD (validated with Mini-International Neuropsychiatric Interview for DSM-IV) were treated with vortioxetine and celecoxib or vortioxetine and placebo for 6 weeks between December 2017 and April 2020. Measures included objective cognition composite scores (Choice Reaction Time, N-Back, Digit Symbol Substitution Test, Trail Making Task Part B), subjective cognition scores (Perceived Deficits Questionnaire), and global cognition composite scores (combined objective and subjective scores) derived from the THINC integrated tool (THINC-it). High-sensitivity C-reactive protein (hsCRP) measured at baseline and week 6 was tested for a predictive relationship with cognitive outcomes.Results: Cognition composite scores demonstrated improvement by week 6 in both treatment groups. However, there was no significant interaction between change over time and treatment group. HsCRP did not have a significant relationship with any tested cognition measures.Conclusions: Both treatment groups showed a reduction in depression-associated cognitive impairment. No superior clinical effect was reported for the add-on celecoxib group. HsCRP was modulated by neither vortioxetine nor add-on celecoxib.Trial Registration: ANZCTR identifier: ACTRN12617000527369.


Assuntos
Transtorno Depressivo Maior , Humanos , Vortioxetina/farmacologia , Vortioxetina/uso terapêutico , Transtorno Depressivo Maior/psicologia , Celecoxib/efeitos adversos , Proteína C-Reativa , Resultado do Tratamento , Cognição , Método Duplo-Cego
14.
PLoS One ; 17(10): e0272368, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36251633

RESUMO

Understanding the genomic architecture and molecular mechanisms of cognitive functioning in healthy individuals is critical for developing tailored interventions to enhance cognitive functioning, as well as for identifying targets for treating impaired cognition. There has been substantial progress in uncovering the genetic composition of the general cognitive ability (g). However, there is an ongoing debate whether executive functioning (EF)-another key predictor of cognitive health and performance, is separable from general g. To provide an analytical review on existing findings on genetic influences on the relationship between g and EF, we re-analysed a subset of genome-wide association studies (GWAS) from the GWAS catalogue that used measures of g and EF as outcomes in non-clinical populations. We identified two sets of single nucleotide polymorphisms (SNPs) associated with g (1,372 SNPs across 12 studies), and EF (300 SNPs across 5 studies) at p<5x10-6. A comparative analysis of GWAS-identified g and EF SNPs in high linkage disequilibrium (LD), followed by pathway enrichment analyses suggest that g and EF are overlapping but separable at genetic variant and molecular pathway levels, however more evidence is required to characterize the genetic overlap/distinction between the two constructs. While not without limitations, these findings may have implications for navigating further research towards translatable genetic findings for cognitive remediation, enhancement, and augmentation.


Assuntos
Função Executiva , Inteligência , Humanos , Estudo de Associação Genômica Ampla , Inteligência/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
15.
Eur Neuropsychopharmacol ; 53: 34-46, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34375789

RESUMO

Given the role of low-grade inflammation in the pathophysiology of major depressive disorder (MDD), anti-inflammatory strategies may improve treatment outcomes in some patients. However, it is controversial whether they can be used as adjunctive treatments and whether pre-treatment levels of inflammation can predict treatment outcomes. This study was conducted to measure the efficacy of anti-inflammatory augmentation of antidepressant treatment in MDD patients; and to investigate whether treatment response was dependent on baseline inflammation levels. This parallel-group randomised, double-blind, placebo-controlled trial was conducted at the University of Adelaide (Australia). Participants with MDD were randomised to receive vortioxetine with celecoxib or vortioxetine with placebo for six weeks, and baseline blood high sensitivity C reactive protein levels were measured. Primary outcome was change in depressive symptoms (Montgomery-Åsberg Depression Rating Scale) and secondary outcomes included change in cognition (THINC-integrated tool - Codebreaker task) and functioning (Functioning Assessment Short Test) over 6 weeks. There was no evidence of superior efficacy of celecoxib augmentation over placebo on depressive symptom severity, response and remission rates, cognition and psychosocial functioning. There was also no evidence that pre-treatment inflammation levels modified the effect of celecoxib augmentation versus placebo. This observed lack of efficacy of celecoxib add-on does not support the use of celecoxib augmentation of antidepressants in the treatment of MDD in a cohort that mostly comprises treatment-resistant individuals. Additionally, C-reactive protein may not be suitable to predict treatment selection and response in MDD. The study was registered on the Australian New Zealand Clinical Trials Registry: ACTRN12617000527369 (www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p).


Assuntos
Transtorno Depressivo Maior , Antidepressivos/farmacologia , Austrália , Proteína C-Reativa , Celecoxib/uso terapêutico , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Método Duplo-Cego , Humanos , Inflamação/tratamento farmacológico , Resultado do Tratamento , Vortioxetina/efeitos adversos , Vortioxetina/uso terapêutico
16.
BMJ Open ; 11(7): e046830, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233985

RESUMO

INTRODUCTION: There are no well-established biomedical treatments for the core symptoms of autism spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve clinical and cognitive outcomes in ASD. We describe here the protocol for a funded multicentre randomised controlled clinical trial to investigate whether a course of rTMS to the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain activation in ASD, can improve social communication in adolescents and young adults with ASD. METHODS AND ANALYSIS: This study will evaluate the safety and efficacy of a 4-week course of intermittent theta burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (n=150, aged 14-40 years) will receive 20 sessions of either active iTBS (600 pulses) or sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, and neurophysiological assessments before and at multiple time points up to 6 months after iTBS. Safety will be assessed via a structured questionnaire and adverse event reporting. The study will be conducted from November 2020 to October 2024. ETHICS AND DISSEMINATION: The study was approved by the Human Research Ethics Committee of Monash Health (Melbourne, Australia) under Australia's National Mutual Acceptance scheme. The trial will be conducted according to Good Clinical Practice, and findings will be written up for scholarly publication. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620000890932).


Assuntos
Transtorno do Espectro Autista , Estimulação Magnética Transcraniana , Adolescente , Austrália , Transtorno do Espectro Autista/terapia , Encéfalo , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
17.
Nurs Times ; 106(43): 22-4, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21155500

RESUMO

Maternity services must meet the demands of an increasingly diverse and rapidly growing population. Recent policy changes mean midwives are taking on roles formerly performed by doctors, leaving maternity support workers to undertake many traditional midwifery tasks. This article discusses how MSWs can facilitate choice by helping midwives deliver a flexible, personalised service to childbearing women and how the MSW role has developed.


Assuntos
Delegação Vertical de Responsabilidades Profissionais/organização & administração , Serviços de Saúde Materna/organização & administração , Enfermeiros Obstétricos , Assistentes de Enfermagem/organização & administração , Admissão e Escalonamento de Pessoal/organização & administração , Atitude do Pessoal de Saúde , Inglaterra , Necessidades e Demandas de Serviços de Saúde , Humanos , Enfermeiros Obstétricos/organização & administração , Enfermeiros Obstétricos/psicologia , Papel do Profissional de Enfermagem , Assistentes de Enfermagem/educação , Pesquisa em Avaliação de Enfermagem , Cuidado Pré-Natal , Medicina Estatal/organização & administração , Fatores de Tempo
18.
Expert Rev Neurother ; 19(5): 431-443, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31020872

RESUMO

INTRODUCTION: Cognitive dysfunction is prevalent in patients with major depressive disorder (MDD), with deficits observed across several domains (e.g., executive function, memory, attention). While depression alone is disabling, patients with cognitive deficits typically experience greater functional impairments, poorer clinical recovery, and reduced quality of life. Consequently, it is imperative to elucidate recent advances in our understanding of the treatment of cognitive dysfunction in MDD. Areas covered: This review spans psychological, physical, and pharmacological treatment approaches for cognitive dysfunction in depression. Where possible, the authors summarise where treatments have demonstrated efficacy in improving specific cognitive domains (e.g., attention), and highlight the differential mechanisms which underpin cognitive improvement. In addition, the roles of adjunctive cognitive treatments (e.g., exercise), and the possible side effects and drawbacks of specific treatments are explored. Expert opinion: Psychological treatments typically confer cognitive improvement alongside functional and/or clinical recovery; however, the efficacy of cognitive training and cognitive behavioral therapy to longitudinal cognitive improvement remains to be established. Recently developed pharmacological agents may improve cognition by reducing low-grade inflammation and promoting neurogenesis; however, the pro-cognitive effects of typical antidepressants are limited. Integrated approaches which emphasize cognitive recovery alongside clinical and functional improvement may be key to advancing patient outcomes.


Assuntos
Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/terapia , Humanos
19.
Sci Rep ; 9(1): 12041, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427629

RESUMO

Female reproductive behaviours have important implications for evolutionary fitness and health of offspring. Here we used the second release of UK Biobank data (N = 220,685) to evaluate the association between five female reproductive traits and polygenic risk scores (PRS) projected from genome-wide association study summary statistics of six psychiatric disorders (N = 429,178). We found that the PRS of attention-deficit/hyperactivity disorder (ADHD) were strongly associated with age at first birth (AFB) (genetic correlation of -0.68 ± 0.03), age at first sexual intercourse (AFS) (-0.56 ± 0.03), number of live births (NLB) (0.36 ± 0.04) and age at menopause (-0.27 ± 0.04). There were also robustly significant associations between the PRS of eating disorder (ED) and AFB (0.35 ± 0.06), ED and AFS (0.19 ± 0.06), major depressive disorder (MDD) and AFB (-0.27 ± 0.07), MDD and AFS (-0.27 ± 0.03) and schizophrenia and AFS (-0.10 ± 0.03). These associations were mostly explained by pleiotropic effects and there was little evidence of causal relationships. Our findings can potentially help improve reproductive health in women, hence better child outcomes. Our findings also lend partial support to the evolutionary hypothesis that causal mutations underlying psychiatric disorders have positive effects on reproductive success.


Assuntos
Predisposição Genética para Doença , Transtornos Mentais/etiologia , Característica Quantitativa Herdável , Reprodução , Adolescente , Adulto , Idoso , Bases de Dados Genéticas , Feminino , Estudos de Associação Genética , Humanos , Masculino , Transtornos Mentais/diagnóstico , Pessoa de Meia-Idade , Herança Multifatorial , Reprodução/genética , Fatores de Risco , Adulto Jovem
20.
Physiol Rep ; 6(16): e13838, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30156045

RESUMO

All three epithelial Na+ channel (ENaC) subunits (α, ß, and γ) and the mineralocorticoid receptor (MR), a known regulator of ENaC, are located in vasopressin (VP) synthesizing magnocellular neurons in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei. Our previous study showed that ENaC mediates a Na+ leak current that affects the steady-state membrane potential of VP neurons. This study was conducted in Dahl salt-sensitive (Dahl-SS) rats to determine if any abnormal responses in the expression of ENaC subunits and MR occur in the hypothalamus and kidney in response to a high dietary salt intake. After 21 days of high salt consumption, Dahl-SS rat resulted in a significant increase in γENaC expression and exhibited proteolytic cleavage of this subunit compared to Sprague-Dawley (SD) rats. Additionally, Dahl-SS rats had dense somato-dendritic γENaC immunoreactivity in VP neurons, which was absent in SD rats. In contrast, SD rats fed a high salt diet had significantly decreased αENaC subunit expression in the kidney and MR expression in the hypothalamus. Plasma osmolality measured daily for 22 days demonstrated that Dahl-SS rats fed a high salt diet had a steady increase in plasma osmolality, whereas SD rats had an initial increase that decreased to baseline levels. Findings from this study demonstrate that Dahl-SS rats lack a compensatory mechanism to down regulate ENaC during high dietary salt consumption, which may contribute to the development of hypertension.


Assuntos
Canais Epiteliais de Sódio/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Animais , Canais Epiteliais de Sódio/metabolismo , Hipertensão/metabolismo , Hipotálamo/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Concentração Osmolar , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/metabolismo , Núcleo Supraóptico/efeitos dos fármacos , Núcleo Supraóptico/metabolismo , Vasopressinas/metabolismo
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