Overcoming challenges in developing pharmacotherapies for NPS: - - PowerPoint PPT Presentation

▶

Feb 12, 2024 272 likes •386 views

Overcoming challenges in developing pharmacotherapies for NPS: apathy in Alzheimers disease K RISTA L. L ANCTT , P H D S ENIOR S CIENTIST , S UNNYBROOK R ESEARCH I NSTITUTE ; H EAD , N EUROPSYCHOPHARMACOLOGY ; P ROFESSOR OF P SYCHIATRY AND P

SLIDE 1

Overcoming challenges in developing pharmacotherapies for NPS: apathy in Alzheimer’s disease

KRISTA L. LANCTÔT, PHD SENIOR SCIENTIST, SUNNYBROOK RESEARCH INSTITUTE; HEAD, NEUROPSYCHOPHARMACOLOGY; PROFESSOR OF PSYCHIATRY AND PHARMACOLOGY, UNIVERSITY OF TORONTO

AAIC 2017 London, England

SLIDE 2

The possible role of DA

Dopaminergic pathways in the midbrain are

associated with reinforcement

Injury leads to decreased drive and poor

initiation

Apathy may be associated with dysfunction
f the Brain Reward System (BRS) (Mitchell,

Herrmann & Lanctôt 2010)

SLIDE 3

Optimizing treatment of apathy in Alzheimer’s disease

1. Neuroimaging
SPECT shows patients

with apathy have alterations in rCBF in crucial areas of the brain reward system

Lanctôt et al 2007

SLIDE 4

Optimizing treatment of apathy in Alzheimer’s disease

200 450

Baseline 60 min 120 min 180 min 240 min

ARCI Positive Effects Composite

Apathetic (n=13) Non-Apathetic (n=7)

2. Pharmacologic challenge—
Apathetic patients (n=20)

experience fewer positive effects following D-AMPH challenge

Suggests differences in the

DAergic system

Lanctôt, et al 2008 Supported by the American Health Assistance Foundation

SLIDE 5

Optimizing treatment of apathy in Alzheimer’s disease

2 AES Total NPI Total MMSE

Methylphenidate Placebo

3. Clinical trial
Pilot data show apathy

decreases following methlyphenidate

Supports larger RCT

Lanctôt, et al 2008 Supported by the American Health Assistance Foundation

SLIDE 6

Apathy in Dementia Methylphenidate Trial (ADMET)

Double blind, placebo-

controlled, 6-week, 3- centre* RCT in 60 patients with AD

efficacy and safety of

methylphenidate (20 mg/d) for clinically significant apathy in AD

*Mintzer, Lanctôt, Rosenberg, Scherer Supported by the National Institute for Aging R01 AG033032-01

SLIDE 7

ADMET Primary outcomes

Odds ratio (95% CI) for

improvement in CGI-C was 3.7 (1.3, 10.8) (p=0.02)

Rosenberg, et al J Clin Psychiatry 2013

0% 5% 10% 15% 20% 25%

methylphenidate placebo

% moderate or marked improvement on CGIC

Mean (SD) 6-week change

in AES scores was -1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (p=0.23)

SLIDE 8

ADMET Secondary outcomes

NPI Apathy score

improvement 1.8 points (95% CI 0.3, 3.4) greater in methylphenidate vs. placebo (p=0.02)

MMSE trend favouring

methylphenidate: estimated difference of 1.5 (95% C.I. -0.1, 3.1) (p=0.06)

5 10 15 baseline week 6 change

Mean (SE) NPI apathy score methylphenidate placebo

5 10 15 20 25 baseline week 6 change

Mean (SE) MMSE score methylphenidate placebo

Rosenberg, et al J Clin Psychiatry 2013

SLIDE 9

Attention in ADMET

change in DS forward

(selective attention) favoured MPH over placebo (δ=0.87 95% CI:

0.06-1.08, p=0.03)

change in DS total

(selective attention plus working memory) favoured MPH over placebo (δ=1.01 [0.09- 1.93], p=0.03)

0.2 0.4 0.6 0.8 1 1.2 1.4 2 4 6 Estimated Change Score Time (weeks) MPH PLB

Lanctôt et al Int Psychogeriatr Feb 2014

WAIS Digit Span forward

SLIDE 10

Apathy in Dementia Methylphenidate Trial 2

a phase III randomized multi-center placebo-controlled

trial of 6 months 20 mg methylphenidate versus placebo for apathy in Alzheimer’s disease  larger trial (n=200)  more sites (10)  longer duration (6 months)  evaluation of QoL and economic impact  improved cognitive battery

Mintzer, Lanctôt, Rosenberg, Scherer et al Supported by the National Institute for Aging