Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

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.

The Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder.

BACKGROUND: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD). METHODS: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes. DISCUSSION: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 .

Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

The relationship between inflammatory markers and voxel-based gray matter volumes in nondemented older adults.

Ageing is characterized by chronically elevated inflammatory markers (IMs). Peripheral IM levels have been found in negative correlations with brain structural measures including global and lobar volumes and the hippocampus. This study investigated the relationship between 10 peripheral IMs and voxel-based gray matter (GM) volumes in nondemented older adults (n = 463). Two proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-1ß) and 2 vascular IMs (vascular cellular adhesion molecule-1 and plasminogen activator inhibitor-1) were negatively correlated with regional GM volumes. TNF-α and interleukin-1ß were both significantly correlated with GM volumes in the left occipitotemporal area, left superior occipital gyrus, and left inferior parietal lobule; TNF-α was also significantly correlated with the bilateral medial prefrontal cortices and approached significance for the correlations with the bilateral hippocampi. Significant GM correlations with vascular cellular adhesion molecule-1 were located in the bilateral anterior cingulate cortices, and with plasminogen activator inhibitor-1 in the cerebellum and right hippocampus. The neuroanatomical correlation patterns of 2 proinflammatory cytokines and 2 vascular IMs might be reflective of the effects of neurodegenerative and vascular pathological processes in the ageing brain.

Graded Resistance Exercise And Type 2 Diabetes in Older adults (The GREAT2DO study): methods and baseline cohort characteristics of a randomized controlled trial.

BACKGROUND: Type 2 diabetes (T2D) is projected to affect 439 million people by 2030. Medical management focuses on controlling blood glucose levels pharmacologically in a disease that is closely related to lifestyle factors such as diet and inactivity. Physical activity guidelines include aerobic exercise at intensities or volumes potentially unreachable for older adults limited by many co-morbidities. We aim to show for the first time the efficacy of a novel exercise modality, power training (high-velocity, high-intensity progressive resistance training or PRT), in older adults with T2D as a means for improving glycemic control and targeting many associated metabolic and physiological outcomes. Eligibility criteria included community-dwelling men and women previously diagnosed with T2D who met the current definition of metabolic syndrome according to the International Diabetes Federation. Participants were randomized to a fully supervised power training intervention or sham exercise control group for 12 months. Intervention group participants performed whole body machine-based power training at 80%1RM, 3 days per week. The control group undertook the same volume of non-progressive, low-intensity training. Participants were assessed at baseline, 6 months and 12 months and followed for a further 5 years, during which time participants were advised to exercise at moderate-high intensity. Glycemic control (HbA1c) and insulin resistance as measured by the homeostatic model assessment 2 (HOMA2-IR) were the primary outcomes of the trial. Outcome assessors were blinded to group assignment and participants were blinded to the investigators' hypothesis regarding the most effective intervention. RESULTS: We recruited 103 participants (48.5 % women, 71.6 ± 5.6 years). Participants had 5.1 ± 1.8 chronic diseases, had been diagnosed with T2D for 8 ± 6 years and had a body mass index (BMI) of 31.6 ± 4.0 kg/m(2). Fasting glucose and insulin were 7.3 ± 2.4 mmol/L and 10.6 ± 6.3 mU/L, respectively. HbA1c was 54 ± 12 mmol/mol. Eighty-six participants completed the 12-month assessment and follow-up is ongoing. This cohort had a lower-than-expected dropout (n = 14, 14 %) over the 12-month intervention period. CONCLUSIONS: Power training may be a feasible adjunctive therapy for improving glycemic control for the growing epidemic of T2D in older adults. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12606000436572 (24 September 2006).

The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study.

Type 2 diabetes predicts accelerated cognitive decline and brain atrophy. We hypothesized that impaired fasting glucose (IFG) and incident glucose disorders have detrimental effects on global cognition and brain volume. We further hypothesized that metabolic and inflammatory derangements accompanying hyperglycaemia contribute to change in brain structure and function. This was a longitudinal study of a community-dwelling elderly cohort with neuropsychological testing (n = 880) and brain volumes by magnetic resonance imaging (n = 312) measured at baseline and 2 years. Primary outcomes were global cognition and total brain volume. Secondary outcomes were cognitive domains (processing speed, memory, language, visuospatial and executive function) and brain volumes (hippocampal, parahippocampal, precuneus and frontal lobe). Participants were categorised as normal, impaired fasting glucose at both assessments (stable IFG), baseline diabetes or incident glucose disorders (incident diabetes or IFG at 2 years). Measures included inflammatory cytokines and oxidative metabolites. Covariates were age, sex, education, non-English speaking background, smoking, blood pressure, lipid-lowering or antihypertensive medications, mood score, apolipoprotein E genotype and baseline cognition or brain volume. Participants with incident glucose disorders had greater decline in global cognition and visuospatial function compared to normal, similar to that observed in baseline diabetes. Homocysteine was independently associated with the observed effect of diabetes on executive function. Apolipoprotein E genotype did not influence the observed effects of diabetes on cognition. Incident glucose disorders and diabetes were also associated with greater 2-year decline in total brain volume, compared to normal (40.0 ± 4.2 vs. 46.7 ± 5.7 mm(3) vs. 18.1 ± 6.2, respectively, p < 0.005). Stable IFG did not show greater decline in global cognition or brain volumes compared to normal. Incident glucose disorders, like diabetes, are associated with accelerated decline in global cognition and brain volumes in non-demented elderly, whereas stable IFG is not. Preventing deterioration in glucose metabolism in the elderly may help preserve brain structure and function.

The value of the metabolic syndrome concept in elderly adults: is it worth less than the sum of its parts?

OBJECTIVES: To determine whether the metabolic syndrome (MetS) or its components were more closely associated with disease states and inflammation in elderly adults. DESIGN: Sydney Memory and Ageing Study. Cross-sectional, observational cohort. SETTING: Population-derived, community-dwelling elderly adults. PARTICIPANTS: Nine hundred thirty individuals aged 70 to 90. MEASUREMENTS: Age- and sex-adjusted odds ratios (ORs) for disease states; fasting circulating inflammatory markers and oxidative metabolism byproducts. RESULTS: MetS was associated with diabetes mellitus (OR = 4.1, P < .001) and bowel cancer (OR = 9.1, P = .03) but not in analyses that controlled for component conditions. Models containing component conditions had the strongest associations with heart disease. Disease associations were improved after addition of component conditions to the MetS model. The reverse did not hold: disease associations were not improved when MetS was added to the components model. Low high-density lipoprotein cholesterol (HDL-C) was independently associated with myocardial infarction (OR = 2.32) and angina pectoris (OR = 2.59) (both P < .008). Waist circumference was independently associated with cancer (OR = 1.82, P = .008). Although MetS was associated with higher C-reactive protein, vascular cell adhesion molecule, interleukin-6, amyloid A, homocysteine, and malondialdehyde, it explained less than half of the variance of models containing its components. CONCLUSION: The observation that MetS is associated with disease states and markers of circulating inflammation in the elderly is explained mainly by abdominal obesity and low HDL-C. Longitudinal data will further clarify these cross-sectional findings that MetS appears to be less than the sum of its parts in elderly adults.

Single and combined effects of cerebral white matter lesions and lacunar infarctions on cognitive function in an elderly population.

BACKGROUND: This study is to investigate the association between single and combined vascular brain changes (white matter lesions [WMLs], lacunar infarctions) and the cognitive domains of memory, processing speed, and motor function in the elderly adults. METHODS: In a sample of 268 participants aged 65-83 years of the MEMO (Memory and Morbidity in Augsburg Elderly) population-based study in Augsburg, Germany, cerebral magnetic resonance imaging (MRI) was performed and a detailed neuropsychological test battery applied. Analysis of covariance determined the effects of vascular brain changes on domains of cognitive functioning. RESULTS: Strong associations of large WMLs and of MRI-defined lacunar infarction with three different domains of cognitive function even after adjustment for age, gender, and education were found. The combined occurrence of both lesions affected about one in 10 participants and was associated with a strong decrease in cognitive function in all domains. The difference between the groups with only one lesion type (either large WMLs or MRI-defined infarction) and participants affected by both was significant in the domains of processing speed and memory, even after adjustment for important confounders such as age, gender, education, and comorbidities. The effects of both lesion types on cognitive function were not more than additive. CONCLUSIONS: Our study shows that both large WMLs and MRI-defined lacunar infarction contribute to impairments in different cognitive domains. The results suggest that their combined occurrence is associated with stronger reductions in cognitive function than each of the two brain lesion types alone.