Transcript Dementia: Use of Medications

Dementia: Use of Medications
Ross Dunne
Disclosure
• Research funded by HRB, post funded by NIHR
• No free lunches
• Not so much as a pen from big pharma
Contents
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Antidementia drugs
Treating BPSD
Anticholinergic side effects
DLB – special concerns
Depression in dementia
Above all else
• In dementia diagnosis, treatment and care;
medication comes last after
– Thorough Assessment
– Education of clients and carers including care
home staff / family
– Psychological interventions if possible
Why seek a pharmacological solution?
• Slow progression
– No Disease Modifiers in dementia yet
– Cholinergics + Memantine may increase duration
of independence
• Reduce distress
– Sufferer
• May also work for Family and Carers, but these are not
reasons to prescribe (remember that)
• Reduce risk
Prescribing context
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Cognitive impairment
Genetics
Medical history
Likely life span
Family
Polypharmacy
Genetics
• Sometimes the best thing to do is to remove a medication
Fig. 2: Projections from the nucleus basalis of Meynert and other cholinergic cell groups in
the septum pellucidum to the hippocampus and neocortex.
Gauthier S CMAJ 2002;166:616-623
©2002 by Canadian Medical Association
Why acetylcholine?
• Observation that scopolamine caused amnesia
much like Alzheimer dementia
• Trials of Tacrine and Physostigamine heralded
the “era” of Ach-based Alzheimer’s research
• The idea that these would be disease
modifying was based on the idea that Ach
deficit might cause atrophy
• This is not as mad as it might seem, but it
certainly isn’t the primary cause of atrophy
Nucleus Basalis of Meynert
• Marsel Mesulam
• Because cholinergic
neurons are in one area
and follow specific
trajectories to the
cortex, white matter
lesions may also be
important in their
interruption, even if the
nucleus is intact.
Memantine
Donepezil – cognitive outcomes
Donepezil – functional outcomes
Galantamine – functional outcomes
Rivastigamine – cognitive outcomes
Rivastigamine – functional
outcomes
NICE indications for anti-dementia drugs
• 2005 draft guidance suggested withdrawing
antidementia drugs altogether (not cost eff)
• TA 217 (2011):
– donepezil, galantamine and rivastigmine are now
recommended as options for managing mild as
well as moderate Alzheimer’s disease, and
– memantine is now recommended as an option for
managing moderate Alzheimer’s disease for
people who cannot take AChE inhibitors, and as an
option for managing severe Alzheimer’s disease.
Relative side effects - % suffering
nausea
diarrhoea
headache
insomnia
pain
dizziness
accident
muscle cramps
fatigue
vomiting
abdopain
anorexia
anxiety
asthenia
confusion
constipation
depression
dyspepsia
malase
somnolence
uti
weightloss
Donepezil
11
10
10
9
9
8
7
6
5
5
Rivastigamine
47
19
17
9
Rivastigamine Patch
7
6
Galantamine
24
9
8
5
Memantine
21
10
9
7
9
31
13
17
5
6
8
5
6
9
5
5
7
5
13
5
9
6
6
6
5
7
5
8
7
Cardiac conduction side effects
• We do ECGs before
instigating
Anticholinesterase
treatment, however,
these are a pretty poor
predictor of conduction
side effects. Especially
badly photocopied,
faxed and read by a
shrink!
Cardiac conduction side effects
DOMINO – 52 weeks
Community dwellers
5-13 MMSE score
Community dwellers with daily visitors
Been on Donepezil for 3 months and 10mg for 6
weeks
Doctor considering a change of meds, randomised:
1. Continue donepezil with placebo memantine
2. Continue donepezil with real memantine
3. Stop donepezil plus placebo memantine
4. Stop donepezil plus real memantine
DOMINO - AD
• Outcomes were MMSE and ADLS scores
• n=295
• Summary: Both Donepezil and D + M
Combination medication was better than
placebo in ADLS and cognition
• No benefit of changing to memantine
Take home
• Keeping people on donepezil is warranted
clinically.
• Adding Memantine may be warranted, but we
need another trial to be completely sure.
• Switching people to memantine is slightly
inferior to keeping them on Donepezil.
Behavioural and Psychological Symptoms
PHARMACOLOGICAL
MANAGEMENT OF BPSD
J Am Geriatr Soc. 1996 Sep;44(9):1078-81.
The evolution of psychiatric symptoms in Alzheimer's disease: a natural history study.
NPI 12-item Total: Moderate to Severe AD
NPI Individual Item Analysis
P = 0.0018
Clinical
improvement
P = 0.0128
P = 0.0166
Clinical decline
Gauthier S et al. Int J Psychogeriatr. 2002;14:389-404.
75
Memantine
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70
Placebo
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60
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55
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Percentage of patients showing
improvement at week 24/28 (LOCF)
NPI domains: improvement in baseline symptoms
Pooled data from six studies (MMSE <20), % of patients showing
improvement, NPI single items (LOCF)
*p<0.05
Gauthier et al. Int J Geriatr Psych 2008;23:537-45
Gauthier et al. Int J Geriatr Psych 2007
Agitation and aggression
Trials
Evidence
SE
Summary
ACHEIs
3 RCTs in clinically
significant agitation (of
total >30 trials)
Usual: GI, Flushing, N/V
Better results for anxiety
and apathy, = placebo for
agitation
Antidepressants
Trazodone: MetaAnalysis
of 2 trials
Citalopram: 1 small RCT
showed better than
placebo
Sertraline: Post-hoc RCT
better than placebo
Usual SSRI side effects:
GI++
Trazodone (MA):
Weak/No evidence
Citalopram: better
evidence
Sertraline: Best evidence
Memantine
6 RCTs of 3-6months
duration.
Well tolerated.
Hypertension in some
Meta-analysis showed
benefit in Lability,
Agitation, aggression and
psychosis
SGAs
18 PCRCTs 6-12wks, 3
PCRCTs >6/12
EPSEs, Pd sx, 1.5 – 1.7X
increased mortality, 3 x
CVA, accelerated
cognitive decline
Short term 6-12wks, good
outcome, longer term,
risks may outweigh
benefits
FGAs
11 PCRCTs
RR Mortality 1.37 v SGAs
+ usual FGA SE inc QTc
Don’t
Anticholinerigic medications
• There are more than you think
• Larry Tune 2000 – Atropine equivalents of
commonly used drugs in the elderly
• Becomes obvious why polypharmacy is a risk
• Link between multiple medical comorbidities
and confusion/delirium/cognitive
impairment/cholinergic deficit is sometimes
medication
ACB Scale
CFAS
Predictors of Anticholinergic
medication use
• Age >80 1.67 x more likely than Age 65-70
• Each additional comorbidity doubles odds of
being on at least one anticholinergic med
• After adjusting for all covariates including
number of health conditions, Each additional
anticholinergic point increased mortality by
26% at 2 years!
• Why no call to action on anticholinergic
medications?
True or False?
• Clomipramine has anticholinergic effects?
True or False?
• Clomipramine has anticholinergic effects?
• True – of course, as do all the TCAS
True or False?
• Paroxetine has worse anticholinergic effects
than Fluvoxamine?
• True – but how would you know?
Typical 65+
Cardiac patient Medication list
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Captopril
Diazepam
Warfarin
Furosemide
Paroxetine
Typical 65+
Cardiac patient Medication list
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Captopril
Diazepam
Warfarin
Furosemide
Paroxetine
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1
1
1
3
Priorities
• How would the priorities change if the patient
was a 95 year old nursing home resident with
advanced Alzheimer dementia whose chief
symptom was anxiety?
Antipsychotics in dementia 2
• We have already discussed the risks of using
antipsychotics in the treatment of BPSD
• However, what if your patent has genuine
psychotic symptoms?
• Think about the difference between auditory
and visual hallucinations
McKeith et al, BMJ 1992
Treating depression in dementia
• Systematic review – paucity of evidence –
Cochrane / Tom Dening 2002
• HTA-SADD: No benefit for either Mirtazapine or
Sertraline over placebo
• Lancet. 2011 Jul 30;378(9789):403-11. Epub 2011 Jul 19.
• DESEP: Patients who had a medication withdraw
worsened in terms of CSDD. However 37%
withdrew – unanalysable
• Why would this be the case?
T2 weighted magnetic resonance imaging of the brain of three patients illustrating different
degrees of severity of periventricular white matter lesions (left to right: severe, moderate,
mild).
Graham N L et al. J Neurol Neurosurg Psychiatry
2004;75:61-71
©2004 by BMJ Publishing Group Ltd
The nature of depression in dementia
• Vascular dementia – also the incidence of comorbid vascular pathology in AD and DLB is huge
– Vascular depression (Alexopoulos)
– Are we detecting slowed mentation and apathy?
• Locus Coeruleus undergoes early degeneration
• Median Raphe – 30-50% gone in
neuropathological studies of AD and DLB
(preserved in MSA)
Vascular depression
• Relationship between progression of brain white
matter changes and late-life depression: 3-year
results from the LADIS study.
– Progression of WMC was significantly associated with
incident depression during year 3 of the study (P =
0.002) and remained significant after controlling for
transition to disability, baseline WMC and baseline
history of depression. There was no significant
association between progression of WMC and GDS
score, and no significant relationship between
progression of WMC and history of depression at
baseline.