Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group.

BACKGROUND: Apathy is a very common behavioural and psychological symptom across brain disorders. In the last decade, there have been considerable advances in research on apathy and motivation. It is thus important to revise the apathy diagnostic criteria published in 2009. The main objectives were to: a) revise the definition of apathy; b) update the list of apathy dimensions; c) operationalise the diagnostic criteria; and d) suggest appropriate assessment tools including new technologies. METHODS: The expert panel (N = 23) included researchers and health care professionals working on brain disorders and apathy, a representative of a regulatory body, and a representative of the pharmaceutical industry. The revised diagnostic criteria for apathy were developed in a two-step process. First, following the standard Delphi methodology, the experts were asked to answer questions via web-survey in two rounds. Second, all the collected information was discussed on the occasion of the 26th European Congress of Psychiatry held in Nice (France). RESULTS: Apathy was defined as a quantitative reduction of goal-directed activity in comparison to the patient's previous level of functioning (criterion A). Symptoms must persist for at least four weeks, and affect at least two of the three apathy dimensions (behaviour/cognition; emotion; social interaction; criterion B). Apathy should cause identifiable functional impairments (criterion C), and should not be fully explained by other factors, such as effects of a substance or major changes in the patient's environment (Criterion D). CONCLUSIONS: The new diagnostic criteria for apathy provide a clinical and scientific framework to increase the validity of apathy as a clinical construct. This should also help to pave the path for apathy in brain disorders to be an interventional target.

Switching from other antipsychotics to once-daily extended release quetiapine fumarate in patients with schizophrenia.

OBJECTIVE: To evaluate the clinical benefit, efficacy and tolerability of switching patients experiencing suboptimal efficacy or tolerability with their current antipsychotic to once-daily extended release quetiapine fumarate (quetiapine XR). RESEARCH DESIGN AND METHODS: 12-week, multicenter, open-label study in adult, in- or outpatients with schizophrenia. Quetiapine XR (mg/day) was initiated during a 4-day cross-titration phase (day 1: 300; day 2: 600; days 4-84: 400-800 [flexible-dosing]). The primary endpoint was the percentage of patients achieving clinical benefit (improvement on the Clinical Global Impression-Clinical Benefit [CGI-CB] scale). Secondary endpoints included CGI-Improvement (CGI-I) and Positive and Negative Syndrome Scale (PANSS) total scores. Tolerability was assessed by adverse events (AEs), Simpson-Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) scores. Changes in rating scale scores were analyzed using analysis of covariance and are presented as least squares mean (LSM) changes using the baseline level as a covariate. RESULTS: Of 477 patients switched to quetiapine XR, 77.6% completed treatment. Following switching, 295 of 470 patients adequate for evaluation (62.8%) achieved a clinical benefit (95% confidence interval [CI] 58.4, 67.1; p < 0.0001). Significant improvements in LSM (95% CI) CGI-I of 2.88 (2.67, 3.08) and the LSM change in PANSS total scores of -12.3 (-14.95, -9.58) were observed (both p < 0.001). Common AEs included somnolence (17.8%), sedation (15.1%), dizziness and dry mouth (14.0% each). The incidence of extrapyramidal symptoms (EPS) was 8.0%. Mean improvements from baseline in SAS and BARS scores were -2.1 and -0.4, respectively (both p < 0.001). CONCLUSIONS: Switching to quetiapine XR was associated with clinical benefit and good efficacy and tolerability.

A multicentre, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate Alzheimer's disease: the MALT study.

BACKGROUND: Metrifonate is a long-lasting acetylcholinesterase inhibitor being developed for the symptomatic treatment of Alzheimer's disease (AD). OBJECTIVES: This study compared the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate AD, over a 26-week treatment period. METHODS: Six hundred and five patients were randomized to placebo (n=208), a 40/50 mg dose (40 or 50 mg by weight; n=200) or a 60/80 mg dose (60 or 80 mg by weight; n=197) metrifonate. Patients randomized to receive metrifonate were administered a once-daily loading dose of 80 or 120 mg based on weight for 2 weeks, followed by the relevant maintenance dose for 24 weeks. Four main clinical domains of AD were assessed: cognition (ADAS-cog and MMSE), psychiatric and behavioural symptoms (ADAS-noncog and NPI), instrumental and basic activities of daily living (DAD) and global functioning (CIBIC-plus, CIBIS-plus and GDS). RESULTS: ADAS-cog performance was significantly improved in the 60/80 mg and 40/50 mg dose groups, compared with placebo, in the intention-to-treat (ITT) population. In addition, statistically significant treatment differences were demonstrated between the 60/80 mg dose group and placebo on MMSE, ADAS-noncog, the NPI subitems of hallucinations and apathy, DAD, CIBIC-plus, CIBIS-plus and the GDS. The performance of the 40/50 mg dose group was also significantly superior to placebo on the CIBIS-plus and the NPI subitem aberrant motor behaviour. CONCLUSIONS: Metrifonate significantly improved a wide range of symptoms across all four clinical domains of AD in a dose-dependent manner, and was safe and well tolerated at both doses studied.

Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex.

The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE epsilon3 allele, an increased risk associated with the APOE epsilon4 allele (odds ratio [OR] [epsilon4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE epsilon2 allele (OR[epsilon2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the epsilon4 allele dosage on susceptibility was confirmed (OR[epsilon4/epsilon4] vs. the epsilon3/epsilon3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[epsilon3/epsilon4] vs. the epsilon3/epsilon3 genotype = 2.2 [95% CI = 1.5-3.5]). The frequency of the epsilon4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the epsilon4 allele versus the epsilon3 allele, OR(epsilon4), were not equal in all age classes: OR(epsilon4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In epsilon3/epsilon4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women.