IPA Bulletin
Recent Advances - Volume 21, Number 1
By Professor John
O'Brien, Dr. Robert Barber, and Professor Robert Baldwin
Donepezil and brain protection?
Could cholinesterase inhibitors influence the progression of Alzheimer’s disease?
Researchers from the US (Krishnan et al, Am J Psychiatry. 2003;160:2003-11) used
serial MRI scans to measure the effects of donepezil on hippocampal volumes in patients with Alzheimer’s disease. In this
study 67 patients with mild to moderate Alzheimer’s disease received 24 weeks of
treatment with donepezil or placebo. They found patients treated with donepezil had
smaller decreases in hippocampal volumes compared with the placebo group, suggesting
that donepezil may have a potentially protective effect in Alzheimer’s disease. The
authors conclude that larger, longer-term confirmatory studies of the medication’s
effects are now warranted.
Efficacy of donepezil in vascular dementia: results from a second RCT
It is perhaps not surprising that the therapeutic boundaries of cholinesterase inhibitors continue to be scrutinised and
tested. Readers may recall in the last edition of the IPA Bulletin, we reported the results
from the first randomised, double-blind trial of donepezil in vascular dementia
(VaD) (Wilkinson et al, Neurology 2003;61:479– 86). Results from a second study (Black et
al, Stroke. 2003;34:2323–30) are now available and by enlarge replicate those of
Wilkinson et al, This new study recruited just over 600 patients (mean age approximately
74 years) with probable (70.5%) or possible (29.5%) VaD. They were randomized to 24 weeks of treatment with donepezil
5 mg/d (n=198), donepezil 10 mg/d (5 mg/d for first 28 days; n=206), or placebo (n=199).
Compared to placebo, both donepezil groups showed statistically significant improvement in cognition (using
ADAS-cog and MMSE) and functioning, though improvements in patients’ global function
(as assessed by the CIBIC-Plus) were only observed for patients on donepezil 5 mg/d.
By the end of the study, the placebo arm showed no decline in cognition, and the
observed improvements in ADAS-cog from baseline in the donepezil groups was in the
order of 1 to 2 points. The authors concluded that donepezil was an effective and
well tolerated treatment for VaD.
Antipsychotics in late life psychosis: findings from recent clinical trials
The evidence base for the use of antipsychotic treatment of schizophrenia in later life is limited. To help redress this problem,
two recent studies have been published examining the efficacy of atypical antipsychotics
in older people with schizophrenia and related psychosis. The first study from Kennedy et al, (Int J Geriatr Psychiatry.
2003;18:1013–20) was a short six-week trial which compared olanzapine (OLZ) with
haloperidol (HAL). They used a doubleblind, randomized trial design and recruited
patients over the age of 60 years. Two treatment arms were set up, one receiving OLZ
(n=83, mean modal dose =11.9 mg/d) and the other HAL (n=34, mean modal dose = 9.4 mg/d). Overall, OLZ was superior to
HAL on the Positive and Negative Syndrome Scale (PANSS Total and PANSS Psychosis
Core total). OLZ was also less likely to be
associated with extrapyramidal signs. The authors conclude that in elderly patients with
schizophrenia, olanzapine is more efficacious and better tolerated than haloperidol.
In a second study from Lilly Research Laboratories (Feldman et al, J Clin Psychiatry.
2003;64:998–1004) the efficacy of risperidone and olanzapine in controlling negative
and positive symptoms of chronic psychosis in patients aged 50 to 65 years was compared.
The data was obtained by a post hoc assessment of a subset of risperidone-treated (N=
19) and olanzapine-treated (N= 20) older patients (aged 50 to 65 years) from a large multicenter, parallel, double-blind, 28-week
study of patients aged 18 to 65 years (N= 339). Patients were randomly assigned to
receive risperidone (4-12 mg/d) or olanzapine (10–20 mg/d). In summary, they found
that the two treatments had approximately equal efficacy in controlling positive symptoms,
but that olanzapine appeared to be more efficacious in maintaining control over negative symptoms.
How common is dementia with Lewy bodies?
Neuropathological series generally indicate that dementia with Lewy bodies (DLB) is the second most common
cause of degenerative dementia in older people, accounting for 20% of cases. Clinicians
often feel that in other settings, for example Memory Clinics, that the disorder is far less
frequent. Unfortunately, there are few epidemiological data pertaining to this, since
most studies were planned or ongoing before DLB Consensus Criteria were reached and published in 1996. Using subjects from the
Finnish “Kuopio 75 +” study Rahkonen et al (Journal of Neurology, Neurosurgery and Psychiatry
2003;74:720–24) examined 601 people and found a 23% prevalence of dementia. The prevalence of Alzheimer’s disease
was 47%, vascular dementia 23% and dementia with Lewy bodies 22%. Reasonably high rates of DLB might explain by
the fact that all subjects were examined by a trained Geriatrician and underwent a
physical examination looking for Parkinsonism. As with many disorders it seems that
the more you look the more you find!
Driving and Dementia
The thorny issue of how to assess and manage driving in patients with dementia continues to challenge clinicians. Duchek
et al (Journal of the American Geriatric Society 2003;51:1342–47) conducted a longitudinal
study of driving performance in a sample of healthy controls, participants with mild
Alzheimer’s disease (CDR 1.0) and with very mild (CDR 0.5) Alzheimer’s disease.
At baseline assessment 41% of those with mild Alzheimer’s disease, 14% with very
mild Alzheimer’s disease and 3% of controls were deemed unsafe, suggesting that while
driving clearly needs to be assessed in AD, a significant portion of patients even with
mild dementia might still be fit to drive. This study assessed patients longitudinally
over up to two years and found that decline in driving performance was apparent over
this period, particularly in those with mild AD. Although such results are not surprising
in a progressive degenerative disorder they do provide empirical support for the need to
reassess driving performance at regular intervals. Indeed, the authors conclude that their
findings support the Quality Standards Sub- Committee of the American Academy of
Neurology which recommends that driving evaluations be conducted every six months
for drivers with very mild and mild Alzheimer’s disease.
“He/She died from old age, doctor”
How many times does one hear this when taking a history? However, it seems that doctors as well as lay people sometimes feel
that old age is in itself reason enough for death. Hawley (Age and Ageing 2003;32:
484–86) examined the cause of death in 4,300 cases presenting to a crematorium
serving a population of around 250,000. 7% of deaths were recorded as associated
with “old age” as a contributing factor and
98 (2.3%) deaths were due to “old age” as the only listed cause. Further inquiry
showed that unrecorded comorbid medical conditions existed in at least two-thirds of
those certified as dying from old age alone. Is this perhaps yet another form of ageism?
Catching CJD from human pituitary growth hormone
The frequency of this was examined by Swerdlow and colleages (Neurology 2003; 61:783–91) who looked at data on a cohort
of 1,848 patients treated with human growth hormone in the UK between 1959 and 1985. CJD developed in 38 patients,
which represents 2% of those treated. Interestingly, risk was raised if the treatment was
administered between ages 8 and 10 and if a certain method of extraction (Wilhemli
method) was used. Peak rise was estimated to occur 20 years after first exposure,
confirming the long incubation period of this disorder.
MOOD DISORDERS
The bigger picture
The Depression And Bipolar Support Alliance Consensus Statement on the Unmet Needs In Diagnosis And Treatment
Of Mood Disorders In Late-Life. (Charney et al, Archives Of General Psychiatry 2003;60:
664–672) updates the National Institutes of Health Consensus Panel findings on late-life
depression first published in 1991 and further revised in 1997. Although there has
been considerable advance in the range of treatments available there are still large gaps
in knowledge especially regarding barriers to diagnosing depression (notably in primary
care); medical co-morbidity in depression (including treatment of depression in Alzheimer’s disease); ways of improving
concordance in treatment; ethnic elder minority groups and, in the US, problems with reimbursement for treatment. Evidence
about aetiology continues to advance as more information becomes available about
vascular and other biological risk factors. In contrast, relatively little is known about
psychodynamic issues in the causation of depression in later life. Using Medicare (free-for-service) data in a
nationally representative survey of community dwelling older people (65 and over), Crystal
and colleagues trawled the records of 20,966 individuals (Journal of the American Geriatrics
Society 2003;51:1718–28). Although the rate of depression diagnosis more than doubled
through the 1990s, with about two-thirds of those diagnosed received treatment in each
year, there were significant disparities. Older men, Latinos, and African Americans were
at particularly high risk for not receiving depression treatment, as were those without
additional coverage to supplement Medicare after controlling for other characteristics.
An accompanying editorial (Areán, PA, & Unützer, J. Journal of the American Geriatrics
Society 2003; 51:1808) highlights the complexities of understanding this data. For
example, Latinos may have a preference for medication over psychotherapy and African-Americans may prefer counselling, whereas
among those over 75 the “Fallacy of Good Reasons” may apply–because an older adult
has multiple reasons to be depressed (such as advanced medical illness, multiple losses,
or financial difficulties), treatment would not help.
Young and old
Fischer and colleagues (Journal of the American Geriatrics Society 2003; 51: 1554–62) set out to determine whether
depression is treated differently in older and younger patients in primary care clinics.
1,023 adult patients, aged 19 to 93 were divided into six age groups, from young
adult, under age 35, to old old, 75 or older. Providers were only 6% as likely to ask
old-old depressed patients about suicide risk,
about one-fourth as likely to referral them to a mental health therapist, about one-fifth as
likely to ask if they felt depressed, and one twentieth as likely to ask about a problem
with alcohol as they were with young-adult depressed patients. Interestingly, the old-old
were about one-third as likely to report improvement in depression symptoms after
three months as the young-adult patients. Failure to ask about suicide risk seems especially
concerning.
Predisposition
Does a history of depression induce a lasting increase in vulnerability, and thereby raise the risk of recurrence? Albertine
and colleagues from Holland (Depression and Anxiety 2003;18:67–75) studied 26 elderly people who had remitted from a
depressive episode and 96 control subjects. Several psychosocial vulnerability indicators
were assessed premorbidly, during the depressive episode and after remission. High
levels of psychological distress, low life satisfaction, chronic somatic diseases, high
neuroticism, and low scores on extraversion, mastery, and self-efficacy were predictors of
depression. However, there were no differences found between first and recurrent
episodes, and support for the vulnerability accumulation model was limited. On a similar note, several of the epidemiological
factors known to predispose to depression may be modifiable. In a postal survey using the Geriatric Depression Scale
Harris et al (Age and Ageing 2003; 32:510–18) found disability, poor physical health,
low social support and economic factors were, as expected, associated with depression
cross-sectionally. New though was the finding that having an internal health locus of
control was linked to lower depression scores. This is probably an aspect of personality but
may also suggest that learning new coping strategies rather than feeling helpless may
be beneficial.
Nursing home depression
Two papers, one a literature review (Snowden et al, 2003; Journal of the American Geriatric Society 51:1305–17) and
the other a consensus statement (American Geriatrics Society & American Association
for Geriatric Psychiatry, 2003; Journal of the American Geriatric Society 51:1287–98)
provide useful research summaries and recommendations for managing depression and
dementia in nursing homes. The evidence base for dementia is much larger than for
depression, for which the literature review could find only seven drug trials and eight
non-pharmacological studies. Antidepressants are probably effective in patients who are
relatively cognitively intact while both
specialist psychotherapies (eg, Cognitive Behaviour Therapy) and non-specialist psychological interventions (eg, recreational
activities) may help. It seems that nobody has put the two together to see what the
additive effects of antidepressants and psychological
input may be. The consensus document lists detailed assessment and management recommendations.
Comfort food?
Diet may affect mood and cognitive functions. Tryptophan has been implicated. In a study by Hakkarainen et al (Depression
and Anxiety 2003;18:89–94), 29,133 men aged 50–69 years were studied for 5–8
years in a population-based trial in Finland. Intake of amino acids was calculated from a
diet history questionnaire completed by 27,111 subjects at baseline. Self-reports of
depressed mood and hospital treatment
data were recorded three times a year. No association was found between the dietary
intake of amino acids and self-report of
depressed mood or risk of suicide. However, dietary intake of lysine and serine was associated
with risk of hospital treatment due to
major depressive disorder but these associations disappeared after excluding from
analysis participants who had reported depressed mood at study entry.
Pain and depression
In a US study (Journal of the American Geriatrics Society 2003; 51:1710–17) Carrington and colleagues found that of 744
older people aged 70 or over a fifth were depressed (on the CES-D) at baseline and
between one eighth and a quarter reported disabling back pain over the next 12 months.
After adjustment for potential confounders, the presence of depressive symptoms was independently
associated with the occurrence of disabling back pain with an odds ratio of 2.3 at one to two months and 7.8 for three
or more months. The authors conclude that
the presence of depressive symptoms is a strong, independent, and highly prevalent
risk factor for the occurrence of disabling back pain in community-dwelling older
persons. In the same vein Lin et al (JAMA 2003; 290:2428–29) tested an enhanced model of
care over usual management. Part of the widely known Improving Mood–Promoting Access to Collaborative Treatment (IMPACT)
trial, a large multi-site US RCT of depressed older adults ( 60 years) in primary care, the
researchers found that 56% of subjects reported both arthritis and depression at baseline.
Interventions included antidepressants and/or Problem-Solving Treatment. In addition
to reduction in depressive symptoms
pain in the intervention group was significantly reduced at 12 months. Importantly
this also seemed linked to improved function and quality of life. Commenting on the
findings in the BMJ (2003; 327:1185) Elizabeth Lin said that few patients were taking
either pain medications
or antidepressants. Another avenue for improved intervention.
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).
