IPA Bulletin
Recent Advances - Volume 21, Number 2
By Professor John
O'Brien, Dr. Robert Barber, and Professor Robert Baldwin
Homocysteine and small vessel disease Interest in the possible links between diet and brain disease continues. Hassan et al (Brain 2004; 127:212-219) found subjects
with cerebral small vessel disease (defined as lacunar infarcts and more white matter diffuse
change - leukoaraiosis) had higher levels of homocysteine. The effects of homocysteine
could be mediated by damage to the endothelium, though the precise mechanisms are not known. Other studies have
found that a deficiency in folate and vitamin B12 can increase the level of
homocysteine, and that vitamin preparations or food enriched with folic acid, alone or in combination
with vitamin B12 and B6, can reduce plasma homocysteine levels. Ultimately, the outcome of both
prevention and treatment intervention focused on reducing homocysteine should help to clarify the clinical relevance
of elevated homocysteine in dementia.
Galantamine and Alzheimer’s disease: update
Cummings et al (Am J Psych 2004; 161:532-538) examined the effects of treatment with Galantamine in Alzheimer’s disease
on behaviour and carer distress. Data from a randomised study involving around 1,000 patients found subjects on active
treatment had no change in behavioural scores from baseline (as measured by the Neuropsychiatric Inventory), compared with
a decline in scores in the placebo group.
Subjects who were symptomatic at baseline improved by 29% to 48%. In addition, there was no difference in response from
16-24 mg/day while carer distress was also reduced in the active treatment group.
Data from a 3 year open-label extension of two RCT studies using Galantamine suggested that the cognitive benefits of
treatment can be sustained for at least 36 months (Raskind et al, Arch Neurol 2004;
61:252-256).
Paintings of an artist with Alzheimer’s disease Readers of the Bulletin may wish to reflect on a case study by Maurer and Prvulovic ( J Neurol Transm 2004; 111:235-245). The authors track the changes in the
artwork of the German artist Carolus Horn, who developed Alzheimer’s disease. The
description of the changes, which emerged as his illness progressed, offers insights into
a patient’s visual world and how this can become distorted.
How heritable is Alzheimer’s disease in late life? In an attempt to gauge the relative importance of genetic and environmental factors on the onset of Alzheimer’s disease in
late life, researchers from Sweden (Pedersen et al, Ann Neurol 2004; 55:180-185) followed
a dementia-free cohort of 662 pair of twins aged 52 to 98 years for 5 years. Around 6%
of the sample developed Alzheimer’s disease during the study. Using a form of statistical
modelling, 48% of the variation in liability to develop Alzheimer’s disease was attributed
to genetic variation. The authors conclude that genetic factors are indeed important
factors for liability to Alzheimer’s disease in later life.
Blood pressure and dementia The relationship between blood pressure and dementia appears to be complex, and
perhaps at times confusing. This putative link was subject of a further study by Verghese
and colleagues (Neurology 2003; 61:1667-1672). They followed up 488 community
dwelling, dementia-free elderly individuals for up to 21 years (the “Bronx Aging Study”)
and found low diastolic BP significantly influenced the risk of developing Alzheimer’s
disease, but not vascular dementia. The risk was highest in subjects with a persistently low
BP. To complicate matters, mildly to moderately raised systolic BP was associated with a
reduced risk of AD. Research continues!
Treatment and Alzheimer’s disease: a role for antibiotics? Loeb et al ( J Am Geriatr Soc 2004; 52:381-387) found subjects with Alzheimer’s
disease treated with a combination of antibiotics (doxycycline and rifampin) for
3 months showed less deterioration at 6 months compared to placebo, a difference
that was sustained at 12 months. The antibiotic group also showed less dysfunctional
behaviour at 3 months. The mechanism of action is not known.
Vitamins and Alzheimer’s disease The debate as to the nature of the relationship between AD and vitamins continues. Zandi et al (Arch Neurol 2004;
61:82-8) examined the relationship between vitamin use and the incidence and prevalence
of AD in 4700 participants from the Cache County Study. In summary, the use of vitamin E and C in combination was
associated with reduced AD, with a trend towards a lower risk in vitamin E and multivitamins combination. There was no
protection conferred by the use of vitamin E or C alone, with multivitamins alone, or
vitamin-B complex. The authors conclude that antioxidant supplements could have merit as a form of primary prevention subject
to further study.
Memantine and donepezil: a combination therapy for moderate to severe Alzheimer’s disease?
Following on reports that monotherapy with memantine could be effective in moderate to severe Alzheimer’s disease,
Tariot et al ( JAMA 2004; 291:317-324) conducted a trial to see whether patients
who were already receiving a cholinesterase inhibitor could benefit from the addition of
memantine. Just over 200 participants with advanced Alzheimer’s disease (MMSE 5–14)
who were on a stable dose of donepezil were randomised to either memantine or placebo for 24 weeks. In summary, patients receiving
combination therapy showed better outcomes in measures of cognition, activities of daily living, global outcome and behaviour. It was
also well tolerated. The authors conclude that memantine offers a new approach to
the treatment of patients with moderate to severe AD.
Hormonal treatment for depression
For women who have developed depression in later life the role of sex hormones, particularly estrogen, is of major
interest in terms of treatment. Therefore the study by Morrison et al (Biological Psychiatry,
2004; 55: 406-412) is interesting although somewhat disappointing. Here the population comprised out-patients at the
University of Pennsylvania between the ages of 50 and 90 who were biochemically postmenopausal.
The women had to meet criteria for major depression, dysthymia or minor depression with at least a months duration
of symptoms. After a run in phase they were randomly assigned to either eight weeks
with oestradiol or placebo and then two
weeks of open-label medroxyprogesterone. Neither treatment with oestradiol nor the
progesterone made any difference to mood.
The authors speculate that possibly different mechanisms apply to peri-menopausal as
opposed to post-menopausal women, the
former experiencing some benefit with estrogen in other studies. It is also possible that
combined estrogen-progesterone treatment
(perhaps including HRT) might benefit women with depressed mood who have vasomotor symptoms (e.g. hot flashes/flushes).
Lesion location and poststroke depression? The localisation-lateralisation hypothesis of poststroke depression (PSD) links
depression with left sided anterior/frontal lesions. However, there is considerable controversy
surrounding this hypothesis and findings are mixed. One explanation for the diversity of findings could well lie in
the hands of the investigators themselves, at least according to the meta-analysis
conducted by Bhogal et al (Stroke 2004;35: 794-802). Specifically, they found sampling
bias influences the direction of association between left sided hemispheric lesions and
PSD. The link was strongest in in-patients (OR, 1.36) compared to those from the
community (OR, 0.60), and the direction of association was more pronounced in those
with an acute stroke (OR, 2.14) as opposed to a chronic stroke (OR, 0.53). Other
methodological could also be influential, leading the authors to recommend greater
care in standardising studies.
TMS for post-stroke depression Repetitive transcranial magnetic stimulation (RTMS) is a promising treatment
for depression but has not quite made its mark yet. In a predominantly older patient
group (average age early to mid 60s) Jorge et al (Biological Psychiatry, 2004; 55: 398-
405) examined the effects of RTMS in 10 patients who had active treatment and 10
with sham treatment, all of whom suffered from post-stroke depression. Compared to
sham treatment, the active RTMS was associated with a significant reduction of depressive
symptoms as measured on the Hamilton Scale. This did not appear to be influenced
by age, type or location of the stroke or the volume of white matter change in the left
frontal area. Although not significant, there was a tendency for cognitive function to
improve in the active group. Consistent with other research, higher frontal volumes were
associated with more effective response. Although the numbers were small and the
overall response rate much less than that
associated with ECT, this is a promising area for further enquiry.
Jolly Fat
The “jolly fat” hypothesis proposes that individuals (mainly men) who are obese
tend to suffer from less depression. The opposite view is that obesity reduces positive
self-esteem and may increase depression. In an interesting study from China, Bin Li and
colleagues (International Journal of Geriatric Psychiatry 2004; 19: 68-74) over 55,000
individuals were screened for depression and also obesity. Depression was rated using the
Geriatric Depression Scale. Both men and women with an elevated Body Mass Index were 20% less likely to suffer from depressive
symptoms than those with normal weight adjusting for a variety of confounding factors.
That culture strongly affects this finding is indicated by the author’s description
of a Chinese saying. When a Chinese person meets a friend who has become fatter than
when previously seen the comment will be “you have acquired a good fortune recently.”
This may not go down well with current western preoccupations with the ill-effects
of obesity.
Atherosclerosis linked to depression It is known that across the lifespan women suffer more depression than men. In later
life interest is gaining in a vascular causation for depression. A paper by Jones et al
(Archives of General Psychiatry, 2003; 60: 153-60) is therefore interesting. This study,
part of the Women’s Health Around the Nation (Swan) study of middle aged women
found that arthrosclerosis, as measured by plaque formation in the common carotid
arteries, was twice as high in women with a lifetime history of major depression compared
to those without depressive disorder
and those with a single episode of depressive disorder. As the authors point out, associations
are not the same as causation but this
is an intriguing finding which, if replicated in post-menopausal elderly women (as opposed
to peri-menopausal women) would strengthen the need to elucidate which vascular mechanisms may predispose to
depression in later life.
Under-recognition of depression in those who commit suicide Older and younger people who attempt suicide have different co-morbidities and, crucially, among elderly attempters
contact with primary care is common before the act of self-harm. From Finland Suominen
and colleagues (International Journal of Geriatric Psychiatry 2004; 19: 35-40) found
that one of the main problems was that in the older age group depression was rarely
recognised. Only 4% of elderly suicide attempters
had received a diagnosis of mood disorder in primary health care in the 12 months before the attempt. After the attempt
over half of them were recognised as having depression. Various studies are currently
going on to evaluate the effects of screening for depression in suicide prevention (e.g.
“PROSPECT” in the US) and this study adds to the view that better screening and
more education in primary care about
depression could have an effect on suicide rates in older people.
Specialists may be of some use The role of specialists in assessment (as opposed to screening) of psychiatric
morbidity is reinforced in a study by Challis and colleagues (Age and Ageing 2004; 33:
25-34) in which 256 older people referred to Social Services in the UK and at risk of
entry to residential homes were allocated either to assessment by care manager versus
assessment by a psychiatrist or geriatrician. The clinician undertook a domiciliary consultation
attending to cognitive function, mood and activities of daily living using standardised scales. Half those assessed had
cognitive impairment and a fifth depression. Of the medical problems osteoarthrosis was
the most common major disorder. At 6 and 12 months there was no difference in outcome
as regards placement (42% of those assessed and 47% of a controlled group were in a care home at 6 months) but fewer of
those in the intervention group had died by 12 months and health costs were significantly
lower for the physician assessment group. In an attendant comment in the British
Medical Journal (328: 296), Columnist Minerva remarks that perhaps there is some
merit in re-establishing the role of specialist as opposed to the relentless pressure to put
everything back on generalists.
SSRI’s and clotting
It is well known that patients who have coronary events and who are depressed have higher mortality than those without
depression. But why should this be? Serebruany et al (Circulation, 2003;108: 939-944) examined 184 patients from the
“SADHART” trial and from a platelet substudy. Patients had been treated either with
a placebo or sertraline. These patients were on average in their late fifties, but included
some older people. Of eight biomarkers of platelet and endothelial function, two were
markedly different in the two groups. This suggested that those treated with sertraline
had reduced platelet aggregation, which was all the more surprising given that many of
the patients were on already on aspirin and/or anti-thrombotic treatment. The authors speculate that drugs such as
sertraline, and other SSRIs, exert their effect by influencing platelet 5HT binding and
possibly collagen-induced platelet secretion, an important component of the clotting
cascade. This is a different mechanism from drugs such as aspirin, dipyridamole and
clopidogrel. Importantly, SSRIs may now be the treatment of choice for mood disorders
in the setting of cardiovascular disease.
Is dysthymia just mild depression?
Little is known about dysthymic disorder compared to major depression in later life. Devanand et al (Journal of Affective
Disorders, 2004; 78: 259-267) examined a clinical sample of patients who met criteria
for either major depression or dysthymic disorder. They were all aged over 60. In
earlier work the same group had shown that dysthymia in later life has different
aetiological factors compared to dysthymia in early adulthood. This finding seemed to
confirm and expand this. As a whole the depressed group, both major depression and dysthymia, had more cardiovascular
risk factors when the onset was later in life. However the late onset dysthymic patients
seemed to have more in common with late onset major depression. Early onset dysthymia
(n=89) compared to late onset (n=70) was associated with greater anxiety disorders, a non-significant trend towards
a more family psychiatric history and reduced cardiovascular comorbidity. The authors speculate that perhaps late onset
depression is more of a spectrum disorder, of which dysthymic and major depression
are two points along the plot.
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).
