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.

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.

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.

Human monocyte-derived microglia-like cell models: A review of the benefits, limitations and recommendations.

In the last few decades, mounting evidence has highlighted that microglia have crucial roles in both health and disease. This has led to a growing interest in studying human microglia in disease-relevant models. However, current models present limitations that can make them unsuitable for moderate throughput studies in human cohorts. Primary human microglia are ethically and technically difficult to obtain and only allow low throughput studies; immortalized cell lines have been shown to differ too greatly from primary human microglia; and induced pluripotent stem cell-derived microglia, although physiologically relevant in most contexts, have limited potential for use in large cohorts of people or for personalised drug screening. In this review, we discuss monocyte-derived microglia-like (MDMi) cells, a model that has been developed and increasingly used in the last decade, using human monocytes isolated from blood samples. We describe the variety of protocols that have been used to develop MDMi cell models and highlight a need for standardization across protocols. We then summarize data that validate MDMi cells as an appropriate model to study human microglia in health and disease. We also present the benefits and limitations of using this approach to study human microglia compared with other microglial models, when used in combination with the relevant downstream applications and with cross-validation of findings in other systems. Finally, we summarize the paradigms in which MDMi models have been used to advance research on microglia in immune-related disease. This review is an important reference for scientists who seek to establish MDMi cells as a microglial model for the advancement of our understanding of microglia in human health and disease.

Comparison of chloroquine-like molecules for lysosomal inhibition and measurement of autophagic flux in the brain.

Measurement of autophagic flux in vivo is critical to understand how autophagy can be used to combat disease. Neurodegenerative diseases have a special relationship with autophagy, which makes measurement of autophagy in the brain a significant research priority. Currently, measurement of autophagic flux is possible through use of transgenic constructs, or application of a lysosomal inhibitor such as chloroquine. Unfortunately, chloroquine is not useful for measuring autophagic flux in the brain and the use of transgenic animals necessitates cross-breeding of transgenic strains and maintenance of lines, which is costly. To find a drug that could block lysosomal function in the brain for the measurement of autophagic flux, we selected compounds from the literature that appeared to have similar properties to chloroquine and tested their ability to inhibit autophagic flux in cell culture and in mice. These chemicals included chloroquine, quinacrine, mefloquine, promazine and trifluoperazine. As expected, chloroquine blocked lysosomal degradation of the autophagic protein LC3B-II in cell culture. Quinacrine also inhibited autophagic flux in cell culture. Other compounds tested were not effective. When injected into mice, chloroquine caused accumulation of LC3B-II in heart tissue, and quinacrine was effective at blocking LC3B-II degradation in male, but not female skeletal muscle. None of the compounds tested were useful for measuring autophagic flux in the brain. During this study we also noted that the vehicle DMSO powerfully up-regulated LC3B-II abundance in tissues. This study shows that chloroquine and quinacrine can both be used to measure autophagic flux in cells, and in some peripheral tissues. However, measurement of flux in the brain using lysosomal inhibitors remains an unresolved research challenge.

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.

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.

Rapeseed oil fortified with micronutrients improves cognitive alterations associated with metabolic syndrome.

Metabolic syndrome represents a major risk factor for severe comorbidities such as cardiovascular diseases or diabetes. It is also associated with an increased prevalence of emotional and cognitive alterations that in turn aggravate the disease and related outcomes. Identifying therapeutic strategies able to improve those alterations is therefore a major socioeconomical and public health challenge. We previously reported that both hippocampal inflammatory processes and neuronal plasticity contribute to the development of emotional and cognitive alterations in db/db mice, an experimental model of metabolic syndrome that displays most of the classical features of the syndrome. In that context, nutritional interventions with known impact on those neurobiological processes appear as a promising alternative to limit the development of neurobiological comorbidities of metabolic syndrome. We therefore tested here whether n-3 polyunsaturated fatty acids (n-3 PUFAs) associated with a cocktail of antioxidants can protect against the development of behavioral alterations that accompany the metabolic syndrome. Thus, this study aimed: 1) to evaluate if a diet supplemented with the plant-derived n-3 PUFA α-linolenic acid (ALA) and antioxidants (provided by n-3 PUFAs-rich rapeseed oil fortified with a mix of naturally constituting antioxidant micronutrients, including coenzyme Q10, tocopherol, and the phenolic compound canolol) improved behavioral alterations in db/db mice, and 2) to decipher the biological mechanisms underlying this behavioral effect. Although the supplemented diet did not improve anxiety-like behavior and inflammatory abnormalities, it reversed hippocampus-dependent spatial memory deficits displayed by db/db mice in a water maze task. It concomitantly changed subunit composition of glutamatergic AMPA and NMDA receptors in the hippocampus that has been shown to modulate synaptic function related to spatial memory. These data suggest that changes in local neuronal plasticity may underlie cognitive improvements in db/db mice fed the supplemented diet. The current findings might therefore provide valuable data for introducing new nutritional strategies for the treatment of behavioral complications associated with MetS.

Brain tumor necrosis factor-α mediates anxiety-like behavior in a mouse model of severe obesity.

Although the high prevalence of anxiety in obesity increasingly emerges as significant risk factor for related severe health complications, the underlying pathophysiological mechanisms remain poorly understood. Considering that chronic inflammation is a key component of obesity and is well known to impact brain function and emotional behavior, we hypothesized that it may similarly contribute to the development of obesity-related anxiety. This hypothesis was experimentally tested by measuring whether chronic food restriction, a procedure known to reduce inflammation, or chronic anti-inflammatory treatment with ibuprofen improved anxiety-like behavior and concomitantly decreased peripheral and/or hippocampal inflammation characterizing a model of severe obesity, the db/db mice. In both experiments, reduced anxiety-like behaviors in the open-field and/or elevated plus-maze were selectively associated with decreased hippocampal tumor necrosis factor-α (TNF-α) mRNA expression. Highlighting the causality of both events, chronic central infusion of the TNF-α blocker etanercept was then shown to be sufficient to improve anxiety-like behavior in db/db mice. Lastly, by measuring the impact of ex-vivo etanercept on hippocampal synaptic processes underlying anxiety-like behaviors, we showed that the anxiolytic effect of central TNF-α blockade likely involved modulation of synaptic transmission within the ventral hippocampus. Altogether, these results uphold the role of brain TNF-α in mediating obesity-related anxiety and provide important clues about how it may modulate brain function and behavior. They may therefore help to introduce novel therapeutic strategies to reduce anxiety associated with inflammatory conditions.

Neuroinflammation and cognition across psychiatric conditions.

Cognitive impairments reported across psychiatric conditions (ie, major depressive disorder, bipolar disorder, schizophrenia, and posttraumatic stress disorder) strongly impair the quality of life of patients and the recovery of those conditions. There is therefore a great need for consideration for cognitive dysfunction in the management of psychiatric disorders. The redundant pattern of cognitive impairments across such conditions suggests possible shared mechanisms potentially leading to their development. Here, we review for the first time the possible role of inflammation in cognitive dysfunctions across psychiatric disorders. Raised inflammatory processes (microglia activation and elevated cytokine levels) across diagnoses could therefore disrupt neurobiological mechanisms regulating cognition, including Hebbian and homeostatic plasticity, neurogenesis, neurotrophic factor, the HPA axis, and the kynurenine pathway. This redundant association between elevated inflammation and cognitive alterations across psychiatric disorders hence suggests that a cross-disorder approach using pharmacological and nonpharmacological (ie, physical activity and nutrition) anti-inflammatory/immunomodulatory strategies should be considered in the management of cognition in psychiatry.

Docosahexaenoic acid-containing choline phospholipid modulates LPS-induced neuroinflammation in vivo and in microglia in vitro.

BACKGROUND: Neuroinflammatory processes are considered a double-edged sword, having both protective and detrimental effects in the brain. Microglia, the brain's resident innate immune cells, are a key component of neuroinflammatory response. There is a growing interest in developing drugs to target microglia and control neuroinflammatory processes. In this regard, docosahexaenoic acid (DHA), the brain's n-3 polyunsaturated fatty acid, is a promising molecule to regulate pro-inflammatory microglia and cytokine production. Several works reported that the bioavailability of DHA to the brain is higher when DHA is acylated to phospholipid. In this work, we analyzed the anti-inflammatory activity of DHA-phospholipid, either acetylated at the sn-1 position (AceDoPC, a stable form thought to have superior access to the brain) or acylated with palmitic acid at the sn-1 position (PC-DHA) using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo. METHODS: In vivo, adult C57Bl6/J mice were injected intravenously (i.v.) with either AceDoPC or PC-DHA 24 h prior to LPS (i.p.). For in vitro studies, immortalized murine microglia cells BV-2 were co-incubated with DHA forms and LPS. AceDoPC and PC-DHA effect on brain or BV-2 PUFA content was assessed by gas chromatography. LPS-induced pro-inflammatory cytokines interleukin IL-1ß, IL-6, and tumor necrosis factor (TNF) α production were measured by quantitative PCR (qPCR) or multiplex. IL-6 receptors and associated signaling pathway STAT3 were assessed by FACS analysis and western-blot in vitro. RESULTS: In vivo, a single injection of AceDoPC or PC-DHA decreased LPS-induced IL-6 production in the hippocampus of mice. This effect could be linked to their direct effect on microglia, as revealed in vitro. In addition, AceDoPC or PC-DHA reduced IL-6 receptor while only AceDoPC decreased IL-6-induced STAT3 phosphorylation. CONCLUSIONS: These results highlight the potency of administered DHA-acetylated to phospholipids-to rapidly regulate LPS-induced neuroinflammatory processes through their effect on microglia. In particular, both IL-6 production and signaling are targeted by AceDoPC in microglia.

Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome.

Mounting evidence shows that the gut microbiota, an important player within the gut-brain communication axis, can affect metabolism, inflammation, brain function and behavior. Interestingly, gut microbiota composition is known to be altered in patients with metabolic syndrome (MetS), who also often display neuropsychiatric symptoms. The use of prebiotics, which beneficially alters the microbiota, may therefore be a promising way to potentially improve physical and mental health in MetS patients. This hypothesis was tested in a mouse model of MetS, namely the obese and type-2 diabetic db/db mice, which display emotional and cognitive alterations associated with changes in gut microbiota composition and hippocampal inflammation compared to their lean db/+ littermates. We assessed the impact of chronic administration (8weeks) of prebiotics (oligofructose) on both metabolic (body weight, food intake, glucose homeostasis) and behavioral (increased anxiety-like behavior and impaired spatial memory) alterations characterizing db/db mice, as well as related neurobiological correlates, with particular attention to neuroinflammatory processes. Prebiotic administration improved excessive food intake and glycemic dysregulations (glucose tolerance and insulin resistance) in db/db mice. This was accompanied by an increase of plasma anti-inflammatory cytokine IL-10 levels and hypothalamic mRNA expression of the anorexigenic cytokine IL-1ß, whereas unbalanced mRNA expression of hypothalamic orexigenic (NPY) and anorexigenic (CART, POMC) peptides was unchanged. We also detected signs of improved blood-brain-barrier integrity in the hypothalamus of oligofructose-treated db/db mice (normalized expression of tight junction proteins ZO-1 and occludin). On the contrary, prebiotic administration did not improve behavioral alterations and associated reduction of hippocampal neurogenesis displayed by db/db mice, despite normalization of increased hippocampal IL-6 mRNA expression. Of note, we found a relationship between the effect of treatment on dentate gyrus neurons and spatial memory. These findings may prove valuable for introducing novel approaches to treat some of the comorbidities associated with MetS.

Study protocol for two stepped-wedge interventional trials evaluating the effects of holistic information technology-based patient-oriented management in older multimorbid patients with cancer: The GERONTE trials.

INTRODUCTION: Current hospital-based care pathways are generally single-disease centred. As a result, coexisting morbidities are often suboptimally evaluated and managed, a deficiency becoming increasingly apparent among older patients who exhibit heterogeneity in health status, functional abilities, frailty, and other geriatric impairments. To address this issue, our study aims to assess a newly developed patient-centred care pathway for older patients with multimorbidity and cancer. The new care pathway was based on currently available evidence and co-designed by end-users including health care professionals, patients, and informal caregivers. Within this care pathway, all healthcare professionals involved in the care of older patients with multimorbidity and cancer will form a Health Professional Consortium (HPC). The role of the HPC will be to centralise oncologic and non-oncologic treatment recommendations in accordance with the patient's priorities. Moreover, an Advanced Practice Nurse will act as case-manager by being the primary point of contact for the patient, thus improving coordination between specialists, and by organising and leading the consortium. Patient monitoring and the HPC collaboration will be facilitated by digital communication tools designed specifically for this purpose, with the added benefit of being customisable for each patient. MATERIALS AND METHODS: The GERONTE study is a prospective international, multicentric study consisting of two stepped-wedge trials performed at 16 clinical sites across three European countries. Each trial will include 720 patients aged 70 years and over with a new or progressive cancer (breast, lung, colorectal, prostate) and at least one moderate or severe multimorbidity. The patients in the intervention group will receive the new care pathway whereas patients in the control group will receive usual oncologic care. DISCUSSION: GERONTE will evaluate whether this kind of holistic, patient-oriented healthcare management can improve quality of life (primary outcome) and other valuable endpoints in older patients with multimorbidity and cancer. An ancillary study will assess in depth the socio-economic impact of the intervention and deliver concrete implementation guidelines for the GERONTE intervention care pathway. TRIAL REGISTRATION: FRONE: NCT05720910 TWOBE: NCT05423808.

Basal autophagic flux measured in blood correlates positively with age in adults at increased risk of type 2 diabetes.

Preclinical data show that autophagy delays age-related disease. It has been postulated that age-related disease is-at least in part-caused by an age-related decline in autophagy. However, autophagic flux has never been measured in humans across a spectrum of aging in a physiologically relevant context. To address this critical gap in knowledge, the objective of this cross-sectional observational study was to measure basal autophagic flux in whole blood taken from people at elevated risk of developing type 2 diabetes and correlate it with chronological age. During this study, 119 people were recruited and five people were excluded during sample analysis such that 114 people were included in the final analysis. Basal autophagic flux measured in blood and correlations with parameters such as age, body weight, fat mass, AUSDRISK score, blood pressure, glycated hemoglobin HbA1c, blood glucose and insulin, blood lipids, high-sensitivity C-reactive protein, plasma protein carbonylation, and plasma ß-hexosaminidase activity were analysed. Despite general consensus in the literature that autophagy decreases with age, we found that basal autophagic flux increased with age in this human cohort. This is the first study to report measurement of basal autophagic flux in a human cohort and its correlation with age. This increase in basal autophagy could represent a stress response to age-related damage. These data are significant not only for their novelty but also because they will inform future clinical studies and show that measurement of basal autophagic flux in a human cohort is 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.

Cognitive improvement in patients with major depressive disorder after personalised multi domain training in the CERT-D study.

The CERT-D program offers a new treatment approach addressing disturbed cognitive and psychosocial functioning in major depressive disorder (MDD). The current analysis of a randomised controlled trial (RCT) comprises two objectives: Firstly, evaluating the program's efficacy of a personalised versus standard treatment and secondly, assessing the treatment's persistence longitudinally. Participants (N = 112) were randomised into a personalised or standard treatment group. Both groups received 8 weeks of cognitive training, followed by a three-month follow-up without additional training. The type of personalised training was determined by pre-treatment impairments in the domains of cognition, emotion-processing and social-cognition. Standard training addressed all three domains equivalent. Performance in these domains was assessed repeatedly during RCT and follow-up. Treatment comparisons during the RCT-period showed benefits of personalised versus standard treatment in certain aspects of social-cognition. Conversely, no benefits in the remaining domains were found, contradicting a general advantage of personalisation. Exploratory follow-up analysis on persistence of the program's effects indicated sustained intervention outcomes across the entire sample. A subsequent comparison of clinical outcomes between personalised versus standard treatment over a three-month follow-up period showed similar results. First evidence suggests that existing therapies for MDD could benefit from an adjunct administration of the CERT-D program.

The mTOR-lysosome axis at the centre of ageing.

Age-related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease-related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age-related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age-related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy-lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy-lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two-way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy-lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy-lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

The Break-Fast study protocol: a single arm pre-post study to measure the effect of a protein-rich breakfast on autophagic flux in fasting healthy individuals.

BACKGROUND: Autophagy is a cellular process that cleanses cells and is particularly important during ageing. Autophagy has been extensively studied in vitro and in animal models and is known to be sensitive to nutrition. However, human data are limited because autophagic flux (autophagic degradative activity) has been challenging to measure in humans. This protocol paper describes the Break-Fast study, in which autophagic flux will be measured using a recently developed blood test, before and after ingestion of whey protein. This aims to determine whether an acute nutritional intervention can change autophagy in humans. METHODS: A minimum of forty healthy participants (both male and female) aged 20-50 years, BMI 18.5-29.9 kg/m2 will be recruited into this single arm pre-post study. Participants will visit the clinic after an overnight fast for a first blood collection after which they will consume a whey protein-rich drink. A second blood collection will be performed 60 minutes after consumption of the drink. The primary outcome is the change in autophagic flux at 60 minutes post drink. Secondary outcomes include changes in blood glucose, autophagy-related proteins and mRNA, plasma hormones (e.g. insulin, C-peptide, adiponectin, GLP-1, GIP, ghrelin), cytokines, amino acids and lipids, protein synthesis, and correlation between molecular cell damage and autophagic flux. DISCUSSION: This study will provide information about whether autophagy responds to nutrients in humans, and if nutritional strategies could be used to treat or prevent autophagy-related diseases such as Alzheimer's disease or cancer. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), anzctr.org.au ACTRN12621001029886. Registered on 5 August 2021.

Lysosomal gene Hexb displays haploinsufficiency in a knock-in mouse model of Alzheimer's disease.

Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer's disease (AD), which appear early and are progressive in nature. Sandhoff disease and Tay-Sachs disease (neurological lysosomal storage diseases caused by mutations in genes that code for critical subunits of ß-hexosaminidase) result in accumulation of amyloid-ß (Aß) and related proteolytic fragments in the brain. However, experiments that determine whether mutations in genes that code for ß-hexosaminidase are risk factors for AD are currently lacking. To determine the relationship between ß-hexosaminidase and AD, we investigated whether a heterozygous deletion of Hexb, the gene that encodes the beta subunit of ß-hexosaminidase, modifies the behavioural phenotype and appearance of disease lesions in App NL-G-F/NL-G-F (App KI/KI ) mice. App KI/KI and Hexb +/- mice were crossed and evaluated in a behavioural test battery. Neuropathological hallmarks of AD and ganglioside levels in the brain were also examined. Heterozygosity of Hexb in App KI/KI mice reduced learning flexibility during the Reversal Phase of the Morris water maze. Contrary to expectation, heterozygosity of Hexb caused a small but significant decrease in amyloid beta deposition and an increase in the microglial marker IBA1 that was region- and age-specific. Hexb heterozygosity caused detectable changes in the brain and in the behaviour of an AD model mouse, consistent with previous reports that described a biochemical relationship between HEXB and AD. This study reveals that the lysosomal enzyme gene Hexb is not haplosufficient in the mouse AD brain.

Inhibiting mTOR activity using AZD2014 increases autophagy in the mouse cerebral cortex.

Autophagy is a catabolic process that collects and degrades damaged or unwanted cellular materials such as protein aggregates. Defective brain autophagy has been linked to diseases such as Alzheimer's disease. Autophagy is regulated by the protein kinase mTOR (mechanistic target of rapamycin). Although already demonstrated in vitro, it remains contentious whether inhibiting mTOR can enhance autophagy in the brain. To address this, mice were intraperitoneally injected with the mTOR inhibitor AZD2014 for seven days. mTOR complex 1 (mTORC1) activity was decreased in liver and brain. Autophagic activity was increased by AZD2014 in both organs, as measured by immunoblotting for LC3 (microtubule-associated proteins-1A/1B light chain 3B) and measurement of autophagic flux in the cerebral cortex of transgenic mice expressing the EGFP-mRFP-LC3B transgene. mTOR activity was shown to correlate with changes in LC3. Thus, we show it is possible to promote autophagy in the brain using AZD2014, which will be valuable in tackling conditions associated with defective autophagy, especially neurodegeneration.