Deferiprone in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. Objective: To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. Design, Setting, and Participants: This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Interventions: Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months. Main Outcomes and Measures: The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis). Results: Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (ß for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; ß for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%). Conclusions: These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03234686.

Operationalising the Family-Friendly Medical Workplace and the Development of FAM-MED, a Family-Friendly Self-Audit Tool for Medical Systems: A Delphi Consensus.

Globally, the call for Family-Friendly (FF) workplaces is loud and clear. However, this call is inaudible in medical workplaces, despite both well-established benefits of FF workplaces across businesses and well-known effects of work-family conflict on the well-being and practice of doctors. We aimed to use the Delphi consensus methodology to: (i) operationalise the Family-Friendly medical workplace and (ii) develop a Family-Friendly Self-Audit tool for medical workplaces. The expert medical Delphi panel was deliberatively recruited to capture a breadth of professional, personal, and academic expertise, diversity of age (35-81), life stage, family contexts and lived experience of dual commitments to work and family, and diversity of work settings and positions. Results reflected the inclusive and dynamic nature of the doctor's family and the need to adopt a family life cycle approach to FF medical workplaces. Key processes for implementation include holding firms to zero discrimination; flexibility and openness to dialogue and feedback; and a mutual commitment between the doctor and the department lead to best meet the doctor's individualised needs while still ensuring optimal patient care and team support and cohesion. We hypothesise that the Department Head may be the key to implementation but recognise the workforce constraints to realising these aspirational systemic shifts. It is time we acknowledge that doctors have families, to narrow the gap between identifying as a partner, mother, father, daughter, son, grandparent, and identifying as a doctor. We affirm the right to be both good doctors and good family members.

Pilot dose-response trial of i.v. ketamine in treatment-resistant depression.

OBJECTIVES: Research studies have reported impressive antidepressant effects with ketamine but significant knowledge gaps remain over the best method of administering ketamine, and the relationships between dose, antidepressant response and adverse effects. METHODS: In this pilot dose-finding study, the efficacy and tolerability of ketamine given by rapid intravenous (i.v.) infusion were assessed in a double-blind, placebo-controlled, crossover design, in four subjects with treatment- resistant depression. Each subject received up to four i.v. doses of ketamine (0.1, 0.2, 0.3, 0.4 mg/kg), given over 2-5 min, 1 week apart, and one randomly inserted placebo treatment. RESULTS: Three of four subjects achieved antidepressant response (≥ 50% decrease in Montgomery-Asberg Depression Rating Scale scores), two at the minimum 0.1 mg/kg dose, though all relapsed within a week. For two subjects, the greatest improvement occurred at the highest dose received. Rapid infusion over 2 min led to significant adverse psychotomimetic effects which also increased proportionately with ketamine dosage. CONCLUSIONS: This is the first trial to present dose-response data of ketamine efficacy and psychomimetic effects in depressed subjects. Antidepressant efficacy may be dose-related. Psychotomimetic effects were dose-related. Rapid infusion over 2 min may not be a feasible clinical approach to treatment, given poor tolerability.

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects.

OBJECTIVE: Narrative review of the literature on the efficacy and safety of subanaesthetic doses of ketamine for the treatment of depression. METHOD: Medline and PubMed databases were searched up to October 2012 using appropriate keywords. RESULTS: The studies consistently report substantial efficacy with high response and remission rates from 4 to 72 hours (averages 77% and 43%, respectively) from single doses, though not all patients respond to ketamine. Early relapse is common. While the usual procedure involves the administration of intravenous ketamine at a dose of 0.5 mg/kg over 40 minutes, some preliminary evidence suggests other dosing regimens and routes of administration may be useful or even better. Repeated doses and maintenance pharmacological treatments have been investigated in order to prolong the antidepressant effects, with only modest success. CONCLUSIONS: Current research on the antidepressant effects of ketamine has consistently shown rapid and substantial improvement in mood in the majority of patients. However, these effects have often been found to be short-lived. Future research should focus on identifying predictors of response (e.g. clinical, genetic, pharmacokinetic, environmental), examining different dosing regimens and routes of administration, and strategies to maintain the antidepressant response.