IPA Bulletin
Recent Advances - Volume 16, Number 2
John O'Brien and Bob Barber
The notion that depression in Alzheimer’s disease (AD) is associated with
neurobiological changes in brain stem nuclei is challenged by Hoogendijk et
al. (Archives of General Psychiatry 1999; 56: 45-51). They performed
computerized image analysis looking at neuronal counts in locus coeruleus in 6
depressed, 6 transiently depressed, and 6 non-depressed AD patients, as well
as control subjects. Before death, subjects had been followed longitudinally
every 6 months and assessed with standardized depression rating scales. Cell
counts in locus coeruleus were reduced by 50% or more in all subjects with AD,
regardless of whether subjects were depressed, transiently depressed, or
non-depressed. The authors consider that previous studies which found
differences in locus coeruleus counts may have been confounded by the
inclusion of patients with neurological disease or associated behavioral
problems.
Depression after bereavement is common, with over 30% of the elderly
bereaved meeting DSM criteria for major depression within a year following
bereavement. There is sometimes a tendency among health professionals to
regard such depressions as “normal” or “understandable” and so not offer
pharmacotherapy. A study by Reynolds et al. (American Journal of
Psychiatry 1999; 156: 202-208) included 80 subjects over the age of 50
with major depressive episodes (MDEs) that began around the time of
bereavement. They were randomized to a 16-week double-blind trial of
nortriptyline plus medication clinic, nortriptyline plus interpersonal
psychotherapy, placebo plus medication clinic, and placebo plus interpersonal
psychotherapy. Rates of remission for those treated with nortriptyline and
interpersonal therapy were 69%, for nortriptyline and medication clinic 56%,
for placebo and interpersonal psychotherapy 29%, and for placebo and
medication clinic 45%. Overall there was a significant effect of nortriptyline
over placebo but, surprisingly, no effect of interpersonal psychotherapy
either on its own or in addition to medication, though the combination of
medication and psychotherapy was associated with the highest rate of treatment
completion. Results provide further support for the idea that pharmacological
treatment of MDEs in older people is efficacious, even when such depressions
may be seen as “understandable” in the wake of serious life stresses such as
bereavement.
A study by Mori et al. (American Journal of Psychiatry 1999; 156:
212-222) suggests that the amygdala plays an important role in emotional
memory (the memory of events which arouse strong emotions). The authors used
MRI scanning to document amygdala and hippocampal volumes in 36 patients with
probable AD who experienced a highly emotional event, the 1995 earthquake in
Kobe, Japan. Findings were that, irrespective of generalized brain atrophy and
level of cognitive impairment, emotional memory for the earthquake showed a
higher correlation with amygdala volume than with hippocampal volume. These
results suggest that memory for emotional events may be anatomically separate
from learning other types of information and may, perhaps, explain why some
patients with AD remember emotionally charged memories (e.g. bereavement) to a
greater extent than may be expected on the basis of their level of generalized
cognitive decline.
The finding of increased platelet membrane fluidity in patients with AD
was described by Zubenko 15 years ago. However, its role as a putative risk
factor for AD has not been established. Zubenko et al. (American Journal of
Psychiatry 1999; 156: 50-57) studied 330 initially asymptomatic first
degree relatives of AD subjects over a 7-year follow-up period. Nine cases
developed AD; significant independent predictors of this were increased age,
increased platelet membrane fluidity, and possession of the ApoE-4 allele.
There was some evidence that these risk factors operated over different age
ranges, as increased membrane fluidity made the greatest contribution in those
under the age of 70, while the ApoE-4 allele was associated with AD from ages
64 to 80. Relative risks for developing AD were 11.4 for carrying an ApoE-4
allele and 6.7 for increased membrane fluidity. Although based on small
numbers, and requiring confirmation, the study suggests another factor which
may be a marker for those at risk of AD.
Further evidence for the gloomy prognosis of untreated depression in old
age comes from a 5-year follow-up of community dwelling sample in Liverpool
(Sharma et al., Psychological
Medicine 1998; 28: 1329-1337). A 3-year follow-up of this sample has
already been reported. This study reports a 5-year follow-up of 120 index
cases of depression as defined by the AGECAT program based on the Geriatric
Mental State (GMS) examination. Of 43 subjects who were still cases at year 3,
16 were still cases at year 5 and 9 had died. yes"> Of cases who had
recovered by year 3 (36), 9 had become cases again by year 5. Overall, 5-year
mortality was 34%. Of cases followed up, only 22% completely recovered from
their symptoms at all time points during the 5-year study. Fifteen percent
developed organic disorders. As the majority of subjects were not known to
services or on antidepressant treatment, this study serves to reinforce the
poor outcome in terms of increased mortality and persistence or recurrence of
depressive symptoms in untreated elderly depressed subjects.
The possible benefits of treating AD patients with D-cycloserine, an
antibiotic traditionally used in the treatment of tuberculosis, were reported
in the American Journal of Psychiatry (Tsai et al., 1999; 156:
467-469). Seventeen patients were randomly assigned, under double-blind
conditions, to receive three 4-week trials of 50mg/day of D-cycloserine,
100mg/day of D-cycloserine, and placebo in random order. Despite the short
duration of intervention and small number of subjects, D-cycloserine
significantly improved cognitive function, though no overall improvement in
functioning was seen. The therapeutic effects on cognition, equivalent in size
to that observed with acetylcholinesterase inhibitors, may result from
increased activity at the N-methyl-D-aspartate glutamate receptor.
Both patient and physician can take encouragement from the findings of a
study examining the benefits of low dose clozapine for the treatment of
drug-induced psychosis in Parkinson’s disease (The Parkinson Study Group, New England Journal of Medicine 1999; 340: 757-763). Using a
randomized, double-blind, placebo-controlled design, 60 patients (mean age 72)
were treated with clozapine (6.25mg to 50mg per day). Clozapine improved
psychosis despite the fact that patients continued taking antiparkinsonian
medication. This gain was achieved without deleterious effect on motor
function, though one person developed agranulocytosis which resolved after
clozapine withdrawal.
Optimizing maintenance treatment for late-life depression was the subject
of a recent study in Journal of the American Medical Association
(Reynolds et al., 1999; 281: 39-45). A total of 187 patients with recurrent
unipolar depression (mean age 67) were randomly allocated to one of 4
maintenance therapies: combined medication and psychotherapy (nortriptyline
and interpersonal psychotherapy), medication alone, psychotherapy alone and
placebo. All 3 active treatments were significantly better than placebo.
Overall, combined treatments appeared to offer the best clinical strategy for
preserving recovery.
The treatment of insomnia was also the subject of a combined medication
and psychological controlled trial (Morin et al., Journal of the American
Medical Association 1999; 281: 991-999). In this case, the drug was
temazepam and the psychotherapy was cognitive-behavior therapy. Again,
subjects (n=78, mean age 65) were randomly allocated to these therapies,
singly and combined, and compared to placebo. The 3 active interventions were
more effective than placebo with a trend for greater improvement with the
combined treatments. Compared to medication the improvements seen with
behavioral treatments were more likely to persist.
Delirium is associated with well-known poor outcomes. Inouye and
colleagues (New England Journal of Medicine 1999; 340: 669-676)
designed and tested a risk-factor intervention strategy to see if they could
prevent delirium. Studying 852 patients over 70 years of age who had been
admitted to a general medical hospital service, they found their intervention
reduced the number and duration of delirium episodes. The intervention had no
effect on delirium severity or on recurrence rates. The authors suggest that
initial prevention is probably the most effective treatment strategy, as once
delirium has occurred it proved more difficult to positively influence
outcome.
Perhaps one of the most contentious issues in neuroimaging relates to the
clinical significance of white matter changes. Kramer-Ginsberg et al.
attempted to throw some light on this issue by examining cognitive function in
older depressed subjects with and without white matter changes on MRI
(American Journal of Psychiatry 1999; 156: 438-444). Not only did
depressed patients have evidence of greater cognitive impairment than healthy
controls, but depressed subjects with moderate-to-severe deep white matter
changes demonstrated worse performance on a range of neuropsychological tests
than those without lesions. Quite how these lesions affect brain function
(e.g. by disruption of frontal-subcortical circuits) is still a matter for
debate.
The growing recognition of mixed pathologies in late onset dementias was
the focus of a post-mortem study from Finland (Irina et al., Stroke
1999; 30: 613-618). The authors examined a large series of non-demented and
demented subjects to analyze the association between cardiovascular risk
factor calculated at autopsy, apolipoprotein status and Alzheimer’s-type
pathology. They found no association between cardiovascular disease and
Alzheimer-type pathology in either group. In contrast, ApoE-4 allele
influenced the extent of Alzheimer’s lesions in demented as well asymptomatic
controls. These findings run counter to recent epidemiological studies
reporting a link between AD and atherosclerosis.
Drs. John O'Brien and Bob Barber are the IPA Bulletin's
research editors. They welcome comments via (fax) +44 191 219 5040 or (e-mail)J.T.O'Brien@ncl.ac.uk
Drs. John O'Brien and Bob Barber are the Research
Editors of the IPA Bulletin. They welcome readers' comments via
e-mail (J.T.O'Brien@ncl.ac.uk) or
fax (+44 191 219 5040). John O’Brien
also is Deputy Editor of the IPA Bulletin.
