IPA Bulletin
Recent Advances - Volume 20, Number 4
By Professor John
O'Brien, Dr. Robert Barber, and Professor Robert Baldwin
ALZHEIMER’S DISEASE AND DEMENTIA
Treatment of Vascular dementia with donepezil: new findings New data from a 24-week RCT (Wilkinson et al Neurology 2003, 61:479-486 with commentary by Farlow
p429) found patients with vascular dementia (VaD) treated with donepezil demonstrated
significant improvements in cognition (ADAS-cog and MMSE) and global function (CIBIC-plus) compared with those on
placebo. Altogether 616 patients were recruited and 423 randomised to active treatment (donepezil 5mg n=208; 10mg
n=215). 76% of patients had probable VaD and 24% possible VaD using standardised
criteria. The primary efficacy measures were similar to those used in treatment studies
for Alzheimer’s disease (AD). Overall, the placebo group did not show cognitive
decline over 24 weeks. In contrast, patients on active treatment had on average an endpoint
treatment difference from baseline of 2 points on ADAS-cog. Improvements on
CIBIC-plus were 25% for placebo, 39% for 5mg and 32% for 10mg. Sub-analysis showed similar responses in patients with
probable and possible VaD. The magnitude of treatment effects was smaller than those
observed in AD, and the authors suggest that the lack of progression within the placebo group made it more difficult to
demonstrate drug-placebo differences. The proportion of patients with adverse events
and serious adverse events were similar among the three groups, but donepezil 10mg was associated with increased diarrhea,
vomiting, nausea, abnormal dreams, leg cramps and rhinitis. In the accompanying commentary, Farlow suggests donepezil may
have a narrower therapeutic window with a lower optimal dosage in VaD than for AD.
These results, in conjunction with similar findings from an RCT using galantamine in
VaD (reported in a previous Bulletin), add to a growing evidence base for supportingthe use of cholinesterase inhibitors in
VaD.
Wine-related polyphenols and Alzheimer's disease: could they be beneficial? Motivated by epidemiological evidence suggesting a protective effect of wine
consumption on Alzheimer's disease (AD), researchers from Japan (Ono et al J Neurochem
2003, 87:172-181) conducted a series of laboratory experiments to determine whether
wine-related polyphenols effected the formation and destabilization of beta-amyloid
fibrils. They found all polyphenols tested inhibited the formation of the fibrils and
destabilized preformed fibrils. Extrapolating from cell culture experiments to real life is
of course a complex business, but these preliminary findings offer insights into how
wine may protect against AD, and as the authors speculate, polyphenols may be key
molecules for the development of therapeutic interventions in AD.
Do patients with probable or possible Alzheimer’s disease have different clinical
outcomes? Probably not according to the findings from Villareal et al (Neurology 2003;
61:661-667). They followed up a large group of patients with either probable (n=432) or possible (n=208) AD for up to
11 years. Outcome was assessed using a range of cognitive measures supplemented by clinical endpoints such as nursing home
placement and death. Overall, they found no difference in outcome between the two
groups. Given that patients with possible AD are often excluded from studies, the
authors suggest that future studies would be more representative if these patients were
more readily included.
Head-to-head comparison of donepezil and galantamine in treatment of Alzheimer’s disease Results from the first long-term head-to-head trial of the efficacy of cholinesterase
inhibitors in Alzheimer’s disease (AD) was published by Wilcock et al (Drugs Aging
2003, 20:777-89). They compared the efficacy of donepezil (n=88; 5mg or 10mg depending on tolerance) and galantamine
(n=94; 16mg or 24mg depending on tolerance) over one year. It was a rater-blinded,
randomized, multicentre study with no placebo group. The primary endpoint was the Bristol Activities of Daily Living scale
and they found no differences between treatments. With respect to cognitive function, there was no significant
between group difference in MMSE change from baseline across the total study sample, though
in a sub-analysis of patients with MMSE scores of 12-18, significant group-differences
in MMSE change were observed in favor of galantamine compared to donepezil (-0.32 vs -2.00 respectively). Also, as a group
patients on galantamine maintained MMSE scores that were not significantly different
from baseline (-0.52 +/- 0.39), compared to a significant decline in the donepezil group
(-1.58 +/-0.42). Overall, both drugs had a similar adverse event profile and there was
no difference in their effects on noncognitive symptoms as measured by the Neuropsychiatric Inventory
(NPI). Janssen-Cilag and Shire Pharmaceuticals funded this study.
Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease The potential role of NSAIDs in reducing the risk of various degenerative diseases,
particularly Alzheimer’s disease, has been widely studied, often with conflicting findings.
Chen and colleagues (Arch Neurol 2003; 60:1059-64) were interested to determine
whether findings from animal models showing NSAIDs reduce dopamine neuronal degeneration would be replicated in human
studies and influence the natural history of Parkinson disease (PD). They followed up
two large prospective cohorts (n>142,000 in total) and found regular use of non-aspirin
NSAIDs was associated with a lower risk of PD than non-regular users (relative risk 0.55).
The authors conclude that NSAIDs may delay or prevent the onset of PD, though whether treatment with non-aspirin NSAIDS
will ever prove effective is unclear.
Sleep and insights into brain pathology Could alterations in sleep behavior be the “Royal Road” to neuropathology? Well,
possibly under certain circumstances. In a clinico-pathological study spanning 12 years,
Boeve et al from the Mayo Clinic, USA (Neurology 2003; 61:40-45) conducted
autopsies on all subjects (n=15) who were diagnosed with REM sleep behavior disorder (RBD) plus a neurodegenerative
disorder. Clinically, RBD is characterized by loss of muscle atonia during REM sleep with
prominent motor activity and dreaming. Patients may literally act out their dreams.
Based on previous case reports and their own experience, the central premise was that
RBD would be associated with synucleinopathy. In summary, they found 12 patients had
a neuropathological diagnosis of Lewy body disease (LBD) and 3 had multi-system atrophy
(MSA). LBD, MSA and indeed PD share a similar alpha-synucleinopathy. The authors
concluded that in the setting of degenerative dementia or parkinsonism, RBD often
reflects the presence of synucleinopathy. Interestingly, in their series RBD preceded
dementia or parkinsonism in 10 of the 15 patients by a median of 10 years (range 2 to
29). The findings suggest clinicians should have a greater awareness of RBD, its detection,
and implications for diagnosis and neuropathology.
Dementia, pain and depression Identifying and managing pain in someone with advanced dementia is difficult.
Frampton (Age and Ageing 2003; 32:248-251) reviewed the literature over a 10-year period.
She found that unidentified pain may lead to depression, possible inhibition of immune
function and declining medical health. Nonverbal pointers include agitation, shouting,
fluctuating cognition, withdrawal, unexpected decline in functional abilities, sweating
and tachycardia. The main factors in non-detection were the difficulty carers have in
identifying pain and the inappropriateness of many of the scales used to detect it.
Tranquilizers may mask pain. There is no consensus about how to manage suspected
pain in a person with dementia but some clinicians advocate a therapeutic trial of
non-opioid analgesia in people displaying non-verbal pain cues perhaps accompanied
by therapeutic massage.
Caregivers and their reasons not to treat a relative with Alzheimer's disease There are many influences on the journey a patient with Alzheimer’s disease (AD)
makes from diagnosis to treatment. Carers are often at the forefront of this journey and
can express a range of opinions, values and beliefs that effect therapeutic decisions. To
investigate carers’ attitudes to AD-slowing medicines Karlawish et al (J Am Geriatr Soc
2003; 51:1391-97) interviewed 102 carers of patients with mild to severe AD (52 patients
having severe dementia). Carers (17%) did not want their relative to receive medicine
that would slow AD, even if the drug was risk-free. Carers who would opt out or forgo
such treatments were older, more depressed, had relatives in nursing homes, and rated
their relative’s quality of life as poor. Patients were also more likely to be advanced to a
severe dementia. Overall, the authors conclude that there was a general willingness to
use medication to slow the illness, but there needs to be an awareness of the carer factors,
such as depression, that might influence whether to treat or not.
DEPRESSION
Prevalence and correlates of major depression Large epidemiological studies of the prevalence of depression in adult life are rare. Wilhelm and colleagues
(Journal of Affective Disorders 2003; 75:155-162) used the Australian National Survey of Mental
Health and Well-being database, which included 10,641 adults from 18 years to well into later life. Total rates for adults aged
over 65 were 1.2% compared to the overall population-weighted average of 3.2. Consistent
with other data, female rates were higher in every age period. The findings held true
whether DSMIV or ICD10 criteria were used. This will re-open the debate as to whether depression becomes less prevalent in
later life and especially the appropriateness of DSM and ICD to detect it among older
people. However, the authors also examined correlates for depression and found that
smoking and having a medical condition, especially heart disease or asthma, were
significant. Direction of causality cannot be ascertained but these findings are important
in the light of current interest in vascular depression.
Guidelines for depression Guidelines have a mixed record in terms of their ability to influence practice.
The UK Faculty of Old Age Psychiatry of the Royal College of Psychiatrists has attempted
to bring together in one document evidence on which to base the treatment of late-life
depression in primary care (Baldwin et al Int J Geriatr Psychiatry 2003; 18:829-838). The
good news is that there is reasonable quality evidence to support the use both of antidepressants
and psychological therapies in acute and continuation therapy but less encouragingly, there is little specific evidence
of efficacy in primary care as opposed to specialist care settings. There are obvious
gaps in the literature, such as how to classify and manage ‘minor’ depressions and what to
do with patients who do not get better with first line medication management. Regarding
the latter, the authors point out that augmentation treatment should now include an
option to prescribe a psychological therapy and not only antidepressants or mood
stabilizers. Of course the difficulty is that psychological treatments are often either not
available or only available after unacceptable waits. Some policy action is needed.
Drugs... Knowing how best to target antidepressants does not mean we can be sure who takes them. According to the Medical
Expenditure Survey (MEPS) sponsored by the Agency for Healthcare Research and Quality (AHRQ) 6 million
community dwelling older people were being prescribed antidepressants in 1996 (Aparasu et al
J Am Geri Soc 2003; 51:671-677). This amounted to about 1 in 5 of the older population.
Antidepressants, the most commonly prescribed psychotropic, were given to 9.1% and anxiolytics to 7.5%. The latter is a lower
figure than earlier surveys, suggesting a decline in use. Tricyclics were marginally
more prescribed than SSRIs although practice will have moved on in the intervening
7 years. Predictors of usage seemed largely to be non-clinical–race, geography, educational
status, access to health insurance. Self-perceived health status and reduction in
instrumental activities of daily living were strongly associated with psychotropic use.
Gender and marital status findings were quite striking. Elderly women were one and
a half times more likely to use antidepressants compared to men; and, elderly patients
who were married were four times more likely to take antidepressants than those who
were unmarried. But becoming a hermit does not help– elderly patients who lived
alone were three times more likely to be on antidepressants compared to those who did
not live alone.
…and psychotherapy? If psychological therapies are to gain ground in the management of late-life
mood disorder, more people need to be trained to deliver them. Acknowledging the
legacy of pessimism toward psychotherapy, Lee and colleagues (Age and Ageing 2003; 7:
133-141) sent a questionnaire to psychology trainees in the UK and received responses
from a little over a third. There were positive attitudes to working with older people and
respondents thought the tools of their trade were applicable to older adults, although
with some modification. It seems that negativity about working with older people
psychologically may be on the wane but of course those who did not return the questionnaire may be the sceptics.
Are we ’appy with apoE? Two papers in Biological Psychiatry shed new light on apoE. In the first, Murphy
et al. from the US (Biological Psychiatry, 2003; 54:665-673) showed that there may
be a biological basis to claims that some patients respond more quickly to certain
antidepressants. Of 246 older patients who were randomized either to mirtazapine or
paroxetine, a quarter carried an apoE4 allele and, in the mirtazapine group, this was associated
with a faster antidepressant response. Gender, race, side-effects, compliance and
severity of depression were not factors. Given that the apoE4 allele impairs recovery
from stress and trauma, these results are surprising. Paroxetine affects serotonergic
function whereas mirtazapine induces the release of noradrenaline too. The authors
speculate that in depressed older patients apoE4 affects brain-stem noradrenergic and
serotonergic neurones in some unknown way so that an antidepressant with a combined
affect has a quicker onset of action. The relationship between apoE4 and the vulnerability
to depression is less clear. Steffens and colleagues, also from the US (Biological
Psychiatry, 2003; 54:674-681), examined the relationship between the apoE4 gene
status and brain white and gray matter changes in older depressed patients compared
to control subjects. They found, in the depressed subjects, a significant association
between the apoE4 allele and volume of subcortical gray matter hyperintensities (but not
white matter) on neuroimaging. The authors argue that perhaps focal gray matter changes
are more specifically vascular in nature compared to white matter hyperintensities
that may be more heterogeneous. More support then for vascular depression.
John T. O’Brien, Robert Barber, and Robert Baldwin are the
Research Editors of the IPA Bulletin. They welcome readers’ comments via email
(J.T.O'Brien@ncl.ac.uk).
