IPA Bulletin
Recent Advances - Volume 23, Number 1
By Professor John
O'Brien, Dr. Robert Barber, and Professor Robert Baldwin
Neuropsychiatric symptoms in Alzheimer’s disease
The importance of neuropsychiatric
symptoms in dementia was underlined
by a study from Wilson et al (Am J Geriatr
Psychiatry. 2005:13:984–90). They followed
up just over 400 patients with Alzheimer’s
disease (AD) for a mean of 3.7
years and found higher mortality rates in
those with hallucinations. Indeed controlling
for any obvious confounding factors,
the risk of death was more than doubled in
those with both auditory and visual hallucinations,
but there was no association between
delusions and mortality.
But how stable are neuropsychiatric
symptoms in AD? Ryu et al studied 224
patients and found, taking the group as
a whole, there were no changes in mean
scores for any symptom over the 6 months
of the study (Am J Geriatr Psychiatry. 2005;
13:976–83). However, many individuals
became either better or worse; for example
just over 60% of those with at least one
significant baseline symptom in any domain
improved. Patients with more severe symptoms
from the beginning were more likely
to continue to experience symptoms, and
patients with deteriorating cognitive function
were also more likely to experience deterioration
in neuropsychiatric symptoms.
In a separate study, the overall burden
of neuropsychiatric symptoms in subjects
with AD were found to be lower than those
with vascular dementia (VaD), with sleep
disturbance and apathy being particularly
more problematic in VaD (Fuh et al,
J Neurol Neurosurg Psychiatry. 2005;76:
1337–41). The epidemiology of and risk
factors for psychosis of Alzheimer’s disease
are reviewed by Ropacki and Jeste (Am J
Psychiatry. 2005;162:2022–30).
Risk of death with atypical antipsychotic drug treatment for dementia
A meta-analysis of pooled data from
published and unpublished randomised
controlled trials indicates that use
of atypical antipsychotics in older individuals
with dementia (AD, VaD or mixed
dementia) is associated with an increased
mortality (placebo 2.3% vs drug 3.5%)
(Schneider et al, JAMA. 2005; 19;294:
1934–43). The analysis was based on fifteen
trials (n= 3,353; 9 unpublished) using
aripiprazole, olanzapine, quetiapine or risperidone.
The increase in mortality was observed
despite the relatively short duration
of the trials (10 to 12 weeks on average).
The FDA (US Food and Drug Administration)
published similar results (Public
Health Advisory for Antipsychotic Drugs
used for Treatment of Behavioral Disorders
in Elderly Patients April 2005 — available
via http://www.fda.gov/). In their analysis
of seventeen placebo-controlled studies
using atypical antipsychotics, the rate of
death for elderly patients with dementia
was about 1.6 to 1.7 times that of placebo.
The causes of death were variable, but most
often were related to either heart disease
(such as heart failure or sudden death) or
from infections (pneumonia). Overall,
the risk appears to be a class rather than
individual drug effect.
Randomised controlled trial of realityorientation therapy combined with
cholinesterase inhibitors in Alzheimer’s disease
The principle of augmenting pharmacological
intervention with psychological
therapies is well established in depression,
but are there parallels with the treatment
of Alzheimer’s disease? Onder and colleagues
reporting in the British Journal of
Psychiatry (2005;187:450–5.) combined a
cholinesterase inhibitor (donepezil) with a
programme of reality orientation (administrated
by caregivers for 30 min/day for
25 weeks plus encouragement to stimulate
and involve patients in reality-based communication).
They found the group receiving
both treatments showed a slight improvement
in MMSE scores (mean change
+0.2) compared with a decline in the drug
only group (mean change -1.1; P=0.02).
The benefits were observed in both subjects
with mild and moderate impairment, but
there were no effects on behavioural and
functional outcomes. The authors conclude
that reality orientation enhances the effects
of donepezil on cognition in Alzheimer’s
disease.
Relevance of butyrylcholinesterase activity in Alzheimer’s disease?
A major advantage of newer neuroimaging
techniques lies in their ability
to investigate the pathogenesis of diseases
like Alzheimer’s disease as they unfold in
life. Kuhl et al (Ann Neurol. 2006;59:13–
20) used positron emission tomography in
individuals with AD (n=15) and control
subjects (n=12) to measure the activity of
both butyrylcholinesterase (BuChE) and
acetylcholinesterase (AChE) in the cerebral
cortex. They found that, as expected, AChE
activity in AD was decreased to 75 ±13%
of normal (p =0.00001) but contrary to predictions,
BuChE activity was also decreased
to 82 ±14% of normal (p =0.001). The authors
conclude that their findings do not
support the premise that inhibitor therapy
should target BuChE so as to prevent increased
levels of BuChE from hydrolyzing
acetylcholine in Alzheimer’s disease.
Vitamins and Alzheimer’s disease: are there benefits?
By following a cohort of dementia free,
community dwelling subjects (n=616;
aged 65–105 years) from 1986–87 to 2000
Fillenbaum et al examined the relationship
between the use of vitamins C and/or E and
the prevention of Alzheimer’s disease (Ann
Pharmacother. 2005;39:2009–14). During
the period of the study 141 subjects developed
dementia, of whom 93 had AD. Vitamin
supplements were used infrequently
(around 8%). Despite their antioxidant effects,
the use of vitamins C and/or E did
not delay the incidence of dementia or AD.
In a review of the literature published in the
same edition of the journal (39:2073–9.)
Boothby and Doering conclude that “in the
absence of prospective, randomized, controlled
clinical trials documenting benefits
that outweigh recently documented morbidity
and mortality risks, vitamin E supplements
should not be recommended for
primary or secondary prevention of AD.
Although the risks of taking high doses of
16 IPA Bulletin • February 2006
vitamin C are lower than those with vitamin
E, the lack of consistent efficacy data
for vitamin C in preventing or treating AD
should discourage its routine use for this
purpose.”
Cholinesterase inhibitors: do they have a role in delirium? — Findings from a
randomized, double-blind, placebo-controlled trial
Abnormalities in cholinergic neurotransmission
could contribute to
the onset of delirium, raising the possibility
that cholinesterase inhibitors could improve
the natural history and/or symptoms
of this syndrome. To evaluate this hypothesis,
Liptzin et al compared the impact of
donepezil versus placebo on the prevention
and treatment of postoperative delirium
in older subjects (Am J Geriatr Psychiatry.
2005;13(12):1100–6). The patients (n=80)
were undergoing elective total joint-replacement
surgery and did not have dementia.
Participants received donepezil or placebo
for 14 days before surgery and 14 days afterwards.
Just under 20% of patients experienced
a delirium, but on average it lasted
only one day. Overall there was no difference
in the prevention and treatment of
delirium between drug vs. placebo in this
group of elder patients (who were relatively
young and cognitively-intact).
Does Divalproex sodium reduce agitation in nursing home residents with
Alzheimer Disease?
Using a randomized, double-blind,
placebo-controlled clinical trial design,
Tariot et al (Am J Geriatr Psychiatry.
2005;13(11):942–9) assessed the efficacy
and safety of divalproex sodium for the
treatment of agitation associated with dementia.
153 nursing home residents were
recruited with 72% completing the study.
A mean dose of 800mg/day was used over
the six weeks of the trial. Overall they
found no benefit of divalproex sodium for
treatment for agitation, leading the authors
to conclude that the results do not support
findings from previous trials indicating
possible benefits.
Moderate alcohol consumption reduces
risk of ischemic stroke
To assess the relationship between alcohol
consumption and ischemic stroke,
researchers from Manhattan, United States
conducted a prospective study of 3,176 participants
recruited between 1993–2001
(Elkind et al, Stroke 2006;37:13–19). The
mean age of the sample was 69 years. Compared
to those who did not drink in the past
year, they found moderate drinkers had a
reduced risk of ischemic stroke (0.67; 95%
CI, 0.46 to 0.99) and death related to ischemic
stroke, myocardial infarction, or vascular
death (0.74; 95% CI, 0.59 to 0.94).
There are parallels here with the other studies
that show moderate alcohol consumption
could be protective against coronary
disease.
Can MRI help predict patients who are likely to benefit from cholinesterase
inhibitors?
Possibly “yes” according to a recent MRI
study (Csernansky JG et al, Arch Neurol.
2005;62:1718–22). Although the number
of subjects was relatively small (n=37),
they were able to demonstrate that subjects
with smaller hippocampi (as well as changes
in the lateral and inferomedial portions of
the hippocampal surface) had the poorer response
to donepezil (10mg/d).
Do antidepressants work in post-stroke depression?
Post-stroke depression is a common
clinical problem in geriatric psychiatry.
What is the evidence of efficacy of antidepressants?
Bhogal and colleagues ( Journal
of the American Geriatric Society, 2005;
53:1051–57) conducted a literature review
and found 9 studies that met criteria for
satisfactory trials. This represented 599
patients. Six studies investigated the effects
of heterocyclic antidepressants or SSRIs
on the treatment of post-stroke depression
and three investigated the effect of antidepressant
on the prevention of post-stroke
depression. All the antidepressants save
fluoxetine (for which there may have been
problems with dosaging) were effective but
heterocyclic antidepressants were associated
with more side-effects and drop outs than
the SSRIs. One study showed that sertraline
had a significantly better prophylactic
effect than placebo in stroke prevention but
this area is very poorly researched — most
of these studies were a very small scale and
much more work is needed.
When do psychiatric disorders start?
The lifetime prevalence of DSM IV
disorders was assessed in a large US
sample (the National Co-morbidity Survey
Replication, Kessler et al, Archives of General
Psychiatry, 2005;62:593–602). The median
age of onset was much earlier for anxiety
disorders and impulse control disorders
than for substance misuse (which averaged
20 years) and mood disorders (which were
commoner in the 18–43 year old group).
For the cohort aged over 60, the lifetime
prevalence of the most common disorders
was 10.6% compared to 16.6% overall but
with the highest rates in 30-44 year olds
(19.8%) and 45–59 year olds (18.8%). The
authors suggest that, unlike physical illnesses,
mental disorders most often develop earlier
in life and then become chronic. Clearly
in Geriatric Psychiatry there will be a much
greater prevalence of mood disorders combined
with physical co-morbidity but the
latter was not studied and the survey did
not include psychotic disorders or dementia.
Kennedy and colleagues (Psychological
Medicine 2005, 35:855–63) examined the
incidence by age or age of onset over a period
of 35 years, of first episode mania. This
included all patients who contacted the
psychiatric services of a London Borough,
UK. Of almost 1,500 case notes that were
examined, 10% had an onset of mania
age 60 or over. On the whole though, in
later life, there appears to be a declining
incidence of mania. The peak incidence
was in the age group 21–25 but there was a
second peak in middle life, around the age
of 50. The earlier onset was distinguished
by a strong family history, substance misuse
and a very abrupt florid onset whereas the
later group tended to be characterised by
symptoms suggestive of an organic aetiology
such as visual hallucinations. However,
patients with a clear organic cause for their
symptoms were excluded.
Homocysteine, folate, B12, vascular risk and depression
It is known that homocystine , folic acid
and B12 are associated with depression.
However different mechanisms may apply
for each. Sachdev and colleagues (Psychological
Medicine 2005; 35:529–38) studied
the relationship between homocystine,
folic acid and Vitamin B12 in a group of
patients with major depression, mean age
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February 2006 • IPA Bulletin 17
62.5 years. Analyses were carried out using
a depressive symptoms score checklist as
the dependent variable. Homocystine levels
had a significant linear relationship with
the depressive symptom score in men but
not women. Lower homocystine level was
associated with fewer depressive symptoms.
On the other hand, lower folic acid was associated
with an increased number of depressive
symptoms. Vitamin B12 levels,
however, did not have any significant association
with depressive symptoms. The authors
explored a number of possible models
that might explain the relationship including
whether brain atrophy and white matter
lesions might be mediating factors, with the
suggestion in their study that greater prevalence
of deep white matter lesions might
be such a factor. Alternatively, different but
overlapping biochemical pathways might be
involved.
Hyperhomocysteinaemia is associated
with vascular risk and can be corrected
by dietary supplementation with Vitamin
B12 and/or Folic Acid. Hickie and colleagues
from Australia ( Journal of Affective
Disorders, 2005; 85:327–32) studied 21
healthy volunteers and 47 patients with
major depression (mean age 53). White
matter lesions were closely correlated with
the advancing age which is not surprising
given the width of the age span in the study.
In patients, lower B12 levels were associated
with increased lesions of the deep white
matter. Also, white matter lesions were
linked to markers of small vessel disease
(here defined as hypertension and/or diabetes)
rather than the overall vascular risk
score. The authors suggest that the risk of
white matter lesions in patients with major
depression may be limited largely to those
with concurrent vascular, dietary or genetic
risk factors.
Depression in dementia predicts institutionalisation
Depression in dementia is common.
Does it alter clinical outcomes?
Dorenlot and colleagues from France (International
Journal of Geriatric Psychiatry,
2005; 20:471–8) studied 348 dementia outpatients
with a mean age of 81. Alzheimer’s
disease predominated, mostly of mild to
moderate severity. Using a physician-rated
assessment of depression, 25% met criteria
for major depression. At one year follow up
earlier institutionalisation was predicted by
older age, living alone, greater dementia severity,
greater functional impairment and
major depression at baseline. With regression,
the only factor which remained significantly
associated with institutionalisation at
one year was major depression. Most of the
patients who had depression did not receive
antidepressant medication, ie it was either
unrecognised or not deemed to be worth
treating.
Depression and dementia
Does depression lead to cognitive
impairment or dementia? This muchdebated
issue remains unresolved although
evidence increasingly points towards depression
as an independent predictor of
cognitive impairment and dementia. Sach-
Ericksson and colleagues provide more
evidence (American Journal of Geriatric
Psychiatry, 2005, 13:402–8). Using the Epidemiologic
Studies of the Elderly (EPESE)
(n=4,162) database they showed a significant
association between depressive symptoms
and cognitive errors measured three
years apart. This was so even allowing for
baseline cognitive status. This is therefore
different from other studies in which an association
has been shown but mediated by
baseline cognitive score. The use of a continuous
measure of depression and the possibility
of overlooking early, mild cognitive
impairment are possible methodological
weaknesses.
Are there symptomatic differences between subtypes of depression based on
presumed aetiology?
There are concerns that the all embracing
term “major depression” (enshrined
within DSM and ICD) inhibits research.
An approach which some advocate is to
look at subtypes and symptoms profiles
which may relate more pragmatically to aetiology
and outcome. Naarding and colleagues
( Journal of Affective Disorders, 2005;
88:155–62) examined 4,051 subjects from
the Amstel epidemiological study of elderly
people (65–84). Depression was diagnosed
using a structured algorithm (GMS). The
total population was subdivided as to
whether they were ‘vascular’ (15%), ‘inflammatory’
(17%) or ‘degenerative’ (6%),
all defined by clinical criteria. Depression
was subdivided by mood symptoms or motivational
symptoms. Each of the three risk
factor groups substantially increased the
odds of developing depression. However
there were differences across the category of
symptoms. For motivational symptoms (e.g.
psychomotor change or loss of energy) there
was a stronger association with vascular and
degenerative risk indicators than with inflammatory
ones. Mood symptoms were
more strongly associated with inflammatory
risk as opposed to degenerative or vascular
risks. This study is limited by the fairly
basic evaluation of the three risk factors, but
it represents a step forward the regarding
the debate about the usefulness of the term
‘major depression’ (see also Parker, G, Psychological
Medicine, 2005; 35:467–74).
Informant reported depression
Given that older people tend to underreport
a complaint of depression,
might it be the case that an informant depression
rating scale could help? This was
the approach by Brown and Shinka (International
Journal of Geriatric Psychiatry,
2005;20:911–18). The authors, aware that
there had been a prototypic 30 item informant
version of the Geriatric Depression
Scale, interviewed the spouses, relatives,
friends or care givers (18 years and above)
of 147 patients aged 65 and older from a
Veterans’ Centre in the United States. Although
performing less effectively than the
longer 30 item version, a 15 item GDS informant
scale showed reasonable internal
consistency and retest reliability. The GDS
15 informant version therefore holds promise
although this sample was 94% Caucasian
and therefore may not represent other
ethnic groups.
Symptom changes with antidepressant treatment
Which symptoms change most with
treatment of major depression? This
was addressed by Nelson and colleagues
(American Journal of Geriatric Psychiatry,
2005;13:520–6) in a study of patients recruited
for an 8-week placebo controlled
trial of sertraline. All met DSM IV criteria
for non-psychotic major depression with a
score of at least 18 on the Hamilton Rating
Scale for Depression (17 item). The authors
found 9 symptoms that best described depression
in these older patients (mean age
70 years). They were: depression mood, loss
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18 IPA Bulletin • February 2006
of interest in work and activities, psychic
anxiety, lack of energy, guilt, middle or late
insomnia, somatic anxiety and suicidal ideation.
These accounted for 92% of the variance
and showed at least frequent or moderate
change during treatment. Interestingly,
these symptoms also appear to be relatively
age independent.
Does personality influence response to antidepressants?
In a secondary analysis of The Maintenance
Therapies in Late-life Depression
Study, Morse and colleagues from Pittsburgh
(American Journal of Geriatric Psychiatry,
2005;13:808–14) examined the effect
of particular personality types termed
“Cluster C” (meaning avoidance, dependent,
perfectionist and/or self-defeating in
nature) on the outcome of depressive disorder
in patients aged 60 and above. 187
elderly patients were included, all with recurrent
non-psychotic unipolar major depressions.
Compared to patients with “non-
Cluster C” personality, those with the traits
were as likely to respond to treatment but
did so more slowly and experienced greater
functional impairment in instrumental activities
of daily living. This is an interesting
pointer, as the authors themselves mention,
to identifying which patients might benefit
more from a psychotherapeutic approach
in addition to an antidepressant, a question
which has resource implications.
Depression and mortality
There is quite a lot of evidence about the
effects of combined morbidity, from
depression plus physical comorbidity, on
mortality. Gallo and colleagues (American
Journal of Geriatric Psychiatry, 2005;13:
748–55) examined data from 20 primary
care practices across three sites in the United
States. Using a two-stage and age-stratified
(60–74, 75 plus) model, they calculated
population-attributable fraction (PAF)
estimates for the risk of death. Important
covariates were diabetes, myocardial infarction
and other cardiovascular disease.
Of 598 patients depressed at baseline, at
two years 64 had died. After allowing for
the above covariates, patients with depression
were 1.75 times likely to die than those
not depressed. The PAF estimates shows
that if depression were to be removed from
the population from which the sample was
drawn, a 13% reduction in death at two
years could be expected, which is comparable
to the PAF for both cardiovascular disease
and diabetes. This well designed study
is one of few specifically accessing primary
health care setting. It provides useful data
regarding health care delivery, not least the
need for better alignment of primary care
and psychiatry services in order to provide
better integrated treatment for mental
health and chronic medical disorders.
Access to psychotherapy for older people
Participants in the PROSPECT Study
w ere lucky in that they had a choice
between antidepressants and psychotherapy.
On the whole though, psychological
interventions and psychotherapy are used
little in the treatment of older depressed
adults. Wei and colleagues (American Journal
of Psychiatry, 2005;162:711–17) examined
the Medicare Current Beneficiary Survey
(MCBS) data to explore the frequency
of psychotherapy usage in older adults with
depression. The study comprised 1,542
community dwelling Medicare beneficiaries.
Depression was defined with ICD 9/
DSM IV criteria and broader criteria using
Physicians’ Current Procedural Terminology
(CPT-4). Factors associated with the
use of psychotherapy included the “young”
elderly, higher income, college education.
Those who received medication management
during the episode were also more
likely to receive psychotherapy than those
who did not. Surprisingly most of the psychotherapy
was given by psychiatrists but
their delivery was inconsistent compared to
other mental health professionals. The authors
comment that the use of psychotherapy,
based on their Medicare claims, appears
to have altered little between 1992 and 1999
although antidepressant use has increased
substantially. Particulars of financial reimbursement
in the United States may have
affected the results, but the authors’ comment
that a significant barrier in accessing
psychotherapy is the limited availability of
qualified providers will not come as a surprise
elsewhere in the world.
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).
Robert Baldwin