Emotional Blunting in Depression in the PREDDICT Clinical Trial: Inflammation-Stratified Augmentation of Vortioxetine With Celecoxib.

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.

Unraveling phenotypic variance in metabolic syndrome through multi-omics.

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.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

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.

Exploratory Analysis of the Effects of Celecoxib on Cognitive Function in Vortioxetine-Treated Patients With Major Depressive Disorder in the PREDDICT Study: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

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.

Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder.

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.

General intelligence and executive functioning are overlapping but separable at genetic and molecular pathway levels: An analytical review of existing GWAS findings.

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.

Genome-wide interaction study with major depression identifies novel variants associated with cognitive function.

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.

No evidence for clinical efficacy of adjunctive celecoxib with vortioxetine in the treatment of depression: A 6-week double-blind placebo controlled randomized trial.

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).

Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol for a multicentre randomised controlled clinical trial.

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).

Clinical Switching Strategies of Various Antidepressants to Vortioxetine in the PREDDICT Trial.

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.

Review: Inflammation and anxiety-based disorders in children and adolescents - a systematic review and meta-analysis.

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.

Exploratory study of association between blood immune markers and cognitive symptom severity in major depressive disorder: Stratification by body mass index status.

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.

Contemporary methods of improving cognitive dysfunction in clinical depression.

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.

Cognitive Deficits in the THINC-Integrated Tool (THINC-it) Are Associated With Psychosocial Dysfunction in Patients With Major Depressive Disorder.

OBJECTIVE: To evaluate the extent to which cognitive measures in the recently developed THINC-integrated tool (THINC-it) are associated with global and domain specific psychosocial disability in patients with current and remitted major depressive disorder (MDD). METHODS: Cross-sectional data (N = 127) were obtained from participants with current (n = 105) or remitted (n = 22) MDD who completed the THINC-it between July 2014 and June 2018. Major depressive disorder was diagnostically assessed with DSM-IV and DSM-5 criteria. The THINC-it includes 4 objective cognitive tests: the Spotter (ie, Choice Reaction Time), Symbol Check (ie, n-back), CodeBreaker (ie, Digit Symbol Substitution), and Trails (ie, Trail Making Test part B), as well as a measure of self-perceived cognitive deficits, the Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D). Psychosocial dysfunction was assessed with the Functioning Assessment Short Test. RESULTS: The whole group analysis (ie, lifetime MDD) indicated that poor objective cognitive performance on the CodeBreaker (ß = 0.346, P = .002) and Trails tasks (ß = 0.232, P = .017) and greater self-reported cognitive deficits on the PDQ-5-D (ß = 0.596, P < .001) were associated with more severe global psychosocial disability. In addition, performance on the CodeBreaker and Trails tasks showed dissociable relationships with specific psychosocial deficits (eg, occupational functioning, daily autonomy). The relationship between cognitive and psychosocial deficits was stronger in participants with current compared to remitted MDD. CONCLUSIONS: Cognitive deficits identified by the THINC-it are associated with global and specific psychosocial deficits, highlighting the clinical value and utility of the THINC-it as a cognitive screening instrument in patients with MDD.

Anti-inflammatory treatment of depression: study protocol for a randomised controlled trial of vortioxetine augmented with celecoxib or placebo.

BACKGROUND: In patients with major depressive disorder (MDD), antidepressant response and remission rates are low, highlighting the need for new treatment approaches. Recently, the abundant literature linking inflammatory processes and depressive symptoms have led to the hypothesis that selecting treatment for MDD based on the patient's inflammatory status could be a promising strategy to improve outcomes in patients suffering from MDD. The aim of the randomised control trial we propose is to investigate the antidepressant efficacy of the combined treatment of MDD with antidepressant medication plus anti-inflammatory medication in individuals with raised inflammation levels. For the first time, this study will prospectively test the efficacy of an antidepressant plus anti-inflammatory augmentation based on baseline inflammatory maker levels in MDD using a randomised controlled trial design. METHODS: This study proposes to measure blood C-reactive protein (CRP) levels before the initiation of treatment in 200 participants with MDD. Study participants are then assigned into one of two study strata: either into the 'Depression with inflammation' stratum (CRP levels > 3 mg/L); or into the 'Depression without inflammation' stratum (CRP levels ≤ 3 mg/L). Within each of the two study strata, participants randomly receive either antidepressant medication alone (vortioxetine) plus anti-inflammatory medication (celecoxib) or vortioxetine plus placebo for six weeks. At the end of the treatment period, participants have the opportunity to continue vortioxetine alone for a six-month post-trial period. Clinical outcomes are measured at baseline, fortnightly during the treatment period and at the three-month and six-month post-trial visits. The primary outcome is change in MADRS score, with a primary endpoint of a score reduction by 50% from baseline to six weeks (end of augmentation treatment with celecoxib). Secondary clinical outcomes are changes in the cognitive dimensions of depression (cognitive function, emotion processing and social cognition). Biological outcome measures (levels of CRP and other inflammatory markers) are measured at baseline, after six weeks of treatment and at the six-month post-trial visit. DISCUSSION: The current study will generate novel evidence for biomarker-based personalised antidepressant treatment selection based on patient inflammatory status before treatment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p . Registered on 11 April 2017.

Investigating the relationship between iron and depression.

Lower levels of circulating iron have been associated with depression. Our objective was to investigate the phenotypic and genetic relationship between measures of circulating levels of iron (serum iron, transferrin, transferrin saturation, and ferritin) and depressive symptoms. Data were available from ongoing studies at QIMR Berghofer Medical Research Institute (QIMRB), including twin adolescents (mean age 15.1 years, standard deviation (SD) 3.2 years), and twin adults (mean age 23.2 years, SD 2.2 years). In the adolescent cohort, there were 3416 participants from 1688 families. In the adult cohort there were 9035 participants from 4533 families. We estimated heritabilities of, and phenotypic and genetic correlations between, traits. We conducted analyses that linked results from published large-scale genome-wide association studies (including iron and Major Depressive Disorder) with our study samples using single SNP and multi-SNP genetic risk score analyses, and LD score regression analyses. In both cohorts, measures of iron, transferrin, transferrin saturation, and log 10 of ferritin (L10Fer) were all highly heritable, while depressive measures were moderately heritable. In adolescents, depression measures were higher in those in the middle 10th versus top 10th percentile of transferrin saturation measures (p = 0.002). Genetic profile risk scores of the iron measures were not significantly associated with depression in study participants. LD score analyses showed no significant genetic relationship between iron and depression. Genetic factors strongly influence iron measures in adolescents and adults. Using several different strategies we find no evidence for a genetic contribution to the relationship between blood measures of iron and measures of depression.

Heritability of Transforming Growth Factor-ß1 and Tumor Necrosis Factor-Receptor Type 1 Expression and Vitamin D Levels in Healthy Adolescent Twins.

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.

Research review: the role of cytokines in depression in adolescents: a systematic review.

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.