The Course of Geriatric
Depression
“Reversible
Dementia”:
A Controlled
With
George
C. Young,
Robert
Objective:
The
ment
of irreversible
subsided
demented
goals ofthis
dementia
after improvement
patients.
Method:
f or major
depression.
longitudinal
in elderly
At
entry
reversible
dementia
than
at entry
versible
dementia
clusions:
These
that
the
findings
suggest
1993;
were
that
ofpatients
dementia
in order
the
study,
in the group
the follow-up
a group
reversible
follow-ups
Psychiatry
study
during
includes
tification
ofa
and frequent
(Am-”J
into
found
period
geriatric
with
syndrome
to identify
Received
Oct. 26, 1992;
revision
received
March
9, 1993; accepted
March
25, 1993.
From
the Department
of Psychiatry,
Cornell
University
Medical
College
and the New York Hospital-Cornell
Medical
Center,
Westchester
Division.
Address
reprint
requests
to Dr. Alexopoulos,
Department
of Psychiatry,
New York
Hospital-Cornell
Mcdical Center,
21 Bloomingdale
Rd., White
Plains,
NY 10605.
Supported
by NIMH
grants
MH-42819,
MH-19132,
and MH49762
and by the Xerox
Foundation.
Copyright
© 1993
American
Psychiatric
Association.
150:1
1, November
23
subjects
also
met
criteria
for
“reversible
with
depression
alone
had a 4.69-times
with depression
to discriminate
from
depression
early-stage
those
the
who
with
dementing
(1 2%).
Survival
analysis
higher
chance
of having
alone.
No clinical
characsubjects
who
remained
reversible
developed
irre-
nondemented.
dementia
disorders.
is a clinical
Therefore,
is an indication
for a thorough
diagnostic
treatable
neurological
disorders.
idenworkup
150:1693-1699)
sizable
proportion
of elderly
persons
with dcprcssion-18%-57%-pncscnt
a syndrome
of dementia that subsides
after remission
of the depressive
symptoms (1 ). This “reversible
dementia”
syndrome
has been
the focus of considerable
clinical
and heuristic
interest.
Clinical
studies
have
sought
to identify
symptoms
and signs that could
be used in the differential
diagnosis
of reversible
and irreversible
dementia.
However,
the
clinical
presentation
of reversible
dementia
is variable
and depends
on the age of the patient,
the underlying
psychiatric
disorder,
and the setting
in which
the patient is treated
(2-6).
Early observations
suggested
that
patients
with
reversible
dementia
express
excessive
complaints
and distress
about
their cognitive
loss and
often claim
that they are unable
to find the correct
answens
during
a mental
status
examination
(3). These
J Psychiatry
Ph.D.
After a systematic
clinical
evaluation,
the subjects
intervals
for an average
of 33.8 months.
Results:
more
frequently
in the depressed
group
with
dementia
the patients
A
Am
Kakuma,
and 2) to compare
it with that ofdepressed,
neverwere 57 elderly
patients
consecutively
hospitalized
dementia.
yearly
significantly
that the group
with
reversible
dementia
at follow-up
than
teristics
entity
(43 %)
into
M.D.,
investigation
were 1) to study
the rate of developdepressed
patients
with a dementia
syndrome
that
ofdepression
The subjects
dementia,
“ while
34 were without
were followed
up at approximately
Irreversible
dementia
developed
showed
developed
M.D.,
Barnett
S. Meyers,
Mattis,
Ph.D.,
and Tatsuyuki
S. Alexopoulos,
M.D.,
Steven
Study
1993
findings
were
based
on a series
of middle-aged
on
“young-old”
patients
treated
in a consultation-liaison
setting
for diverse
psychiatric
conditions,
but mainly
for personality,
posttraumatic,
or neurotic
disorders.
Subsequent
studies
did not observe
excessive
cognitive
complaints
on “I don’t know”
responses
by elderly
depressed
subjects
(1, 7-9),
and therefore
this clinical
presentation
may not be characteristic
of elderly
depressed
populations.
The depressive
syndrome
of eldenly patients
with reversible
dementia
is usually
severe
(10). These patients
suffer
from more intense
motor
mctardation,
hopelessness,
helplessness,
and anxiety
than
cognitivcly
unimpaired
elderly
depressed
patients
and
are more
likely to demonstrate
delusions
(10-12).
The
dementia
syndrome,
on the other
hand,
tends
to be of
mild severity
and consists
principally
of impairment
in
attention,
free recall,
motor
speed,
spontaneous
elaboration
of detail
(1 0, 1 3), word
fluency,
and syntactic
complexity
( I , 5).
Despite
these observations,
clinical
examination
alone
does
not permit
reliable
identification
of depressed
patients
in whom
the dementia
syndrome
will subside
after effective
antidepressant
treatment.
Similarly,
biological
studies,
including
the dcxamcthasone
suppncssion test (14), investigation
of platelet
monoamine
oxi-
1693
GERIATRIC
DEPRESSION
AND
DEMENTIA
dase activity
(15), brain computerized
tomography
(16,
17), EEG (18), and sleep EEG studies
(12, 19), do not
appear
to help in the differential
diagnosis
of reversible
dementia.
However,
some
of these
tests have demonstrated
differences
between
groups
with depression
and
reversible
dementia,
irreversible
dementia,
and geriatric
depression
without
dementia.
From
the heuristic
point
of view, the clinical
and biological
variability
of geriatric
depression
with reversible
dementia
suggests
that this syndrome
represents
a hetenogencous
group
of disorders
(20). Cognitive
impairment
is frequently
pant of the depressive
syndrome,
especially
in the elderly.
However,
it is unclear
why some
elderly
depressed
patients
develop
severe
cognitive
dysfunction,
on even a transient
dementia,
and others
do
not. One reason
may be that at least some of these patients
have an underlying
dcmcnting
disorder.
This is
supported
by the observation
that many
patients
with
reversible
dementia
do not achieve
complete
cognitive
recovery
even when their intellectual
function
improves
following
remission
of depression
(21).
Moreover,
it
has been
found
that
some
elderly
depressed
patients
with reversible
dementia
develop
irreversible
dementia
during
follow-up.
However,
the reported
percentages
vary widely
(S%-89%)
depending
on the criteria
applied and the length
of follow-up
(6, 22-26).
Taken
together,
the findings
we have mentioned
suggest that geriatric
depression
with reversible
dementia
includes
a subgroup
of patients
with
early-stage
dcmenting
disorders.
Since
early-stage
dementing
disondens are difficult
to diagnose
through
clinical
examination,
the course
of illness
offers
a better
method
for
studying
the relation
between
reversible
and
inrcvensible
dementias
in elderly
depressed
patients.
We
conducted
a controlled
follow-up
study
to test the hypothesis
that elderly
depressed
subjects
with reversible
dementia
develop
irreversible
dementia
at a greater
rate
than nondemented
elderly
depressed
subjects.
the DSM-III-R
mission
and
criteria
for major
depression
and
had a remission
of their
dementia
for dementia
at adsyndrome
after
im-
provement
of depression.
In addition
to meeting
the DSM-III-R
criteria
for dementia,
the depressed
subjects
with
reversible
dementia
were
required
to have
a Mini-Mental
State
score
lower
than
24 at
admission
(Mini-Mental
State scores
below
24 have been reported
to
be associated
with
irreversible
dementia
[291).
Improvement
of depression
was defined
as a reduction
of the Hamilton
depression
scale
score
to less than
12. Remission
of the dementia
syndrome
was defined as a clinical
state that no longer
met the DSM-III-R
criteria
for
dementia
and a Mini-Mental
State score greater
than 23. Twenty-five
consecutive
subjects
who met the criteria
for depression
with reversible dementia
were identified
for the follow-up
study.
The depressed
patients
with
reversible
dementia
were compared
with a group
of 35 consecutively
admitted
elderly
depressed,
nondemented
patients
whose
depression
improved
during
hospitalization.
At admission
the nondemented
depressed
subjects
met the DSM-III-R
criteria
for major
depression
but did not meet the criteria
for dementia and had Mini-Mental
State scores
greater
than 23. Improvement
of depression
was defined
as a reduction
of the Hamilton
depression
scale score
to below
12. Improvement
of depressive
symptoms
was
required
of the nondemented
depressed
patients
because
the depressed
patients
with reversible
dementia
had to accomplish
a similar
remission
of depression
in order
to meet
the criteria
for reversible
dementia.
Follow-up
consisted
of interviews
of both
the subject
and an informant
conducted
at approximately
yearly
intervals.
The informant
was selected
on the basis of his or her ability
to provide
reliable
information
and willingness
to participate
in the study.
If there
was
considerable
change
in the subject’s
cognitive
function,
the subject
and the informant
were
instructed
to contact
the investigators,
and
an interview
was arranged
sooner
than
the usual
annual
follow-up
interview.
Follow-up
examinations
sought
to identify
symptoms
and signs of
depression
or dementia.
For this purpose,
the Hamilton
depression
scale and the Mini-Mental
State examination
were readministered,
as
well as the parts
of the SCID-P
that are relevant
to the diagnosis
of
depression
and dementia.
The DSM-III-R
criteria
were used to classify depression
or dementia
at follow-up.
Irreversible
dementia
was
considered
a syndrome
that met the DSM-III-R
for criteria
for dementia but not for depression;
a Mini-Mental
State score
lower
than 24
and a Hamilton
depression
scale score
lower
than
12 were required.
DSM-III-R
criteria
were
applied
to classify
the type of dementia
in
subjects
who became
irreversibly
demented
during
follow-up.
Statistical
analysis
of the data was conducted
with Student’s
t test
for groups
with
unequal
variance,
chi-square
tests,
and
survival
analysis
that used
the Cox
proportional
hazard
model
(30).
Twotailed
tests of significance
are reported.
METHOD
RESULTS
The
subjects
were
elderly
persons
consecutively
admitted
to an
acute inpatient
geriatric
psychiatry
service.
Symptoms
were recorded
with the use of the Structured
Clinical
Interview
for DSM-III-R-Patient
Version
(SCID-P)
(27), and diagnoses
were made
according
to
DSM-III-R.
Depressive
symptoms
were rated
with the 24-item
Hamilton
Depression
Rating
Scale
(28),
and cognitive
dysfunction
was
quantified
with
the Mini-Mental
State examination
(29). Each
subject had a medical
and neurological
examination
and underwent
a
laboratory
test battery:
CBC
and differential
counts,
BUN,
VDRL
test, urinalysis,
chest
X-ray,
ECG,
and determination
of creatinine,
T3, T4, thyrotropin,
and serum
B,2 and folate
levels.
All subjects
were required
to meet the DSM-III-R
criteria
for major
depression.
The exclusion
criteria
were
1 ) a history
of psychiatric
disorders
other
than
major
depression
or dementia,
2) a history
of
dementia
prior
to the index
depressive
episode,
and 3) conditions
associated
with
dementias,
i.e., parkinsonism,
alcoholism,
drug
abuse,
Huntington’s
chorea,
CNS space-occupying
lesions,
B12 or folate deficiency,
CNS
infection,
renal
failure,
hepatic
failure,
severe
heart
failure,
and collagen
disease.
By using
these criteria
we sought
to exclude
subjects
with
dementias
secondary
to conditions
that
could
be diagnosed
by means
of a cross-sectional
clinical
evaluation.
The elderly
subjects
with depression
and reversible
dementia
met
1694
Sixty subjects
were initially
recruited.
Three
of these
subjects,
two depressed
patients
with
reversible
dementia
and one patient
with
major
depression
alone,
were
lost to follow-up.
Data
are reported
for 23 subjects
with
major
depression
and reversible
dementia
and 34 nondcmentcd
subjects
with
major
depression
who were evaluated
at least once after discharge
(table
1). The duration
of follow-up
was comparable
for the
two groups.
The group
of depressed
patients
with a reversible
dementia
syndrome
was similar
in age and gender
distnibution
to the group
with depression
alone.
However,
the severity
of depression
of the subjects
with reversible
dementia
was higher
than that of the subjects
with depnession
alone,
as shown
by the Hamilton
depression
scale scones
at admission
(table
1). The group
with mcvemsible
dementia
had a higher
percentage
of psychotic
Am
J Psychiatry
150:1
1, November
1993
ALEXOPOULOS,
TABLE
Reversible
1. Data on Elderly
Dementia
Depressed
Inpatients
With and Without
Depressed
Patients
Reversible
Dementia
(N=23)
Age (years)
Hamilton
depression
Admissiona
Discharge
Mini-Mental
State
Admissionb
Dischargc’
Length
offollow-up
scale
Mean
SD
Mean
73.7
6.8
74.2
8.7
3.7
18.6
26.4
32.7
3.9
2.4
11.7
SD
6.7
27.3
7.4
2.3
2.6
27.3
27.6
34.6
2.2
1.8
12.5
score
(months)
aSignificant
difference
between
groups
(t=3.SO,
bSignificant
difference
between
groups
(t=9.49,
CNcarly
significant
difference
between
groups(t=i.75,
df=23.9,
p<O.0O2).
df=32,
p<O.OOl).
df=37.9,
p-<0.09).
depression
syndrome
(39%,
N=9)
than
the never-dcmented
depressed
patients
(21 %, N=7)
df=1,
pzO.lS).
In addition,
a greater
proportion
of the group
with reversible
dementia
(78%,
N=18)
than of the patients
with
depression
alone
(62%,
N=21)
had recurrent
major
depression.
The subjects
with
depression
and reversible
dementia
had significantly
lower
MiniMental
State scones at admission
than the nondemented
depressed
subjects
(table
1).
Treatment
was not controlled.
The patients
with mevemsible
dementia
were successfully
treated
for depression with
tnicyclic
secondary
amines
(N=10),
imipnamine
(N=2),
phenelzine
(N=2),
an antidepressant
plus
a neuroleptic
(N=4),
or ECT (N=S);
the subjects
with
major
depression
alone
achieved
remission
after
the
same
treatments:
tnicyclic
secondary
amines
(N=1 1),
imipnaminc
(N=1 ), phenelzine
(N=2),
an antidepressant
plus a ncuroleptic
(N=7),
or ECT (N=13).
After memission
of depression,
the Hamilton
depression
scale
scores
of the two groups
were statistically
indistinguishable, and the Mini-Mental
State scones
of the subjects
with reversible
dementia
approached
those
of the nondemented
depressed
subjects
(table
1).
During
the follow-up
period,
eight
(35%)
of the 23
depressed
patients
with reversible
dementia
and eight
(24%)
of the 34 initially
classified
as having
depression
without
dementia
died. There
was no significant
differcnce in the death
rate between
the two groups
(2=O.86,
df=1,
n.s.). The causes
of death
for the eight
subjects
with
reversible
dementia
were
cardiovascular
disease
(N=4),
malignancies
(N=2),
and chronic
obstructive
pulmonary
disease
(N=1 ); in one case the cause of death
could
not be ascertained.
The causes
of death
for the
eight subjects
with depression
alone
were cardiovasculam disease
(N=3),
malignancies
(N=2),
cerebrovascular
disease
(N=1 ), respiratory
infection
(N=1 ), and septicemia (N=1).
During
the follow-up
period,
14 subjects
developed
irreversible
dementia.
When
first seen at follow-up,
two
J Psychiatry
1 50:1
I
I
0
0
1, November
1993
0.6
-
Depression
---
Depression
Dementia
0
ci)
Alone
With
(N=23)
‘5
(N=34)
‘5
I
Reversible
I
0.5
>
E
0
(x2=2.34
Am
ET AL.
I
>
score
36.6
6.9
YOUNG,
FIGURE 1. Estimates of the Cumulative Probability of Development
of Irreversible Dementia by Elderly Inpatients Originally Diagnosed as
Having Depression Alone or Depression With Reversible Dementiaa
Depressed
Patients
Without
Dementia
(N=34)
With
Variable
MEYERS,
0.4
-
0.3
-
0.2
-
0.1
-
I
I
I
‘5
‘4
‘.4
‘.4
0.C
I
I
I
5
10
15
I
and
I
I
I
I
I
2025303540455055
Months
aAgc
I
-
0
cognitive
status
at entry
to Dementia
into
the
study
arc
taken
into
con-
sideration.
of these
14 subjects
had symptoms
and signs of both
dementia
and depression
(Hamilton
depression
scale
score
>1 1 ). However,
reexamination
of both
of these
subjects
after
remission
of depression
(Hamilton
depnession
scale scone <12) revealed
irreversible
dementia. Irreversible
dementia
developed
more frequently
in
the group
originally
diagnosed
as having
reversible
dementia,
occurring
in 43%
(N=10
of 23) in that group
and in 12% (N=4 of 34) of the group
initially
classified
as having
depression
alone
(x2=7.4S
df=1, p<O.Ol).
In addition
to studying
the frequency
of irreversible
dementia
at the end of the follow-up
period,
we used
survival
analysis
to compare
the occurrence
of dementia in the two groups
of depressed
patients.
In this
analysis,
age and Mini-Mental
State score at discharge
were the covaniates,
since advanced
age and cognitive
dysfunction
remaining
after
recovery
from
depression
may be associated
with development
of dementia.
Sunvival analysis
using the Cox proportional
hazard
model
indicated
that the depressed
subjects
with reversible
dementia
had higher
rates of development
of irreversible
dementia
than the subjects
with depression
alone
(likelihood
ratio,
24.44,
df=1, p<O.O4) when the effect of
group
as well as the effects
of age and Mini-Mental
State scone at discharge
were taken
into consideration
(figure
1 ). Calculation
of the risk ratio
indicated
that
the patients
with reversible
dementia
had a 4.69-times
higher
chance
of developing
irreversible
dementia
duning the follow-up
period
than the patients
with depres-
1695
GERIATRIC
DEPRESSION
AND
DEMENTIA
x2=
sion alone.
This difference
was significant
(Wald
4.19, df=1, p<O.O4).
When
all of the subjects
who developed
irreversible
dementia
(N=14)
were
compared
with
the subjects
whose
dementia
had improved
or who remained
nondemented
throughout
the study
(N=43),
there were no
significant
differences
in age, length
of follow-up,
MiniMental
State total score at discharge,
and total Hamilton depression
scale score
at admission
and discharge.
There
were no significant
differences
in these variables
among
subjects
in the reversible
dementia
group
who
later
developed
dementia
(N=10)
and those
who
did
not develop
dementia
(N=13).
Similarly,
there were no
significant
differences
between
patients
who developed
dementia
in the depression-alone
group
(N=4)
and
those who remained
nondemented
at the end of followup (N=30).
There
were no significant
differences
in the diagnostic
types
of irreversible
dementia
between
the group
of
subjects
with reversible
dementia
and the group
with
depression
alone.
In the group
originally
diagnosed
as
having
depression
with reversible
dementia,
the diagnoscs of the 10 subjects
who
developed
irreversible
dementia
were primary
degenerative
dementia
(N=6)
and
multi-infarct
dementia
(N=2);
for two patients
the diagnosis of dementia
could
not be determined.
These
two
patients
had an insidious
onset and a slowly
detenionating course,
but both
had hypertension
and coronary
artery
disease.
From
the depression-alone
group,
four
patients
developed
irreversible
dementia
during
followup. Two of these patients
met the DSM-III-R
criteria
for
primary
degenerative
dementia;
the other
two patients
had a dementia
syndrome
with
slow onset
and progressive
course
but also had hypertension.
One of these
two patients
also developed
hypothyroidism
and was
treated
with L-thyroxinc,
after which
thyroid
function
became
normal.
DISCUSSION
The principal
finding
of this investigation
was that
elderly
depressed
patients
with
reversible
dementia
were more
likely to develop
irreversible
dementia
duning follow-up
than nondemented
elderly
depressed
patients.
To our knowledge,
this was the first controlled
study
to use survival
analysis
to evaluate
the outcome
of depression
with reversible
dementia.
The advantage
of these methods
is that they evaluate
data throughout
the observation
period
rather
than confining
analysis
to
cross-sectional
examination
of the final
event.
Thus,
survival
analysis
can result
in findings
of clinical
usefulness, i.e., estimates
of the probability
that patients
will
develop
a certain
outcome
oven a given time period.
The limitations
of this study
include
the use of a
group
of severely
depressed
elderly
inpatients
and the
absence
of a detailed
neunopsychological
assessment.
The conclusions
of this study
cannot
be generalized
to
outpatients
with mild depressive
syndromes.
The use of
the Mini-Mental
State examination,
a rather
insensitive
1696
method
for the evaluation
of cognitive
abnormalities,
may have resulted
in identification
of a small
number
of dementia
cases at follow-up
and our reporting
of an
erroneously
optimistic
outcome.
Conversely,
if a highly
sensitive
cognitive
examination
had been used at entry
into the study,
the group
of subjects
left with very mild
cognitive
deficits
after
improvement
of depression
would
have
been excluded
from
participation.
Such a
selection
strategy
might
have resulted
in a lower
nate of
dementia
development
than
we arc reporting.
In this
study,
the assessment
instruments
and subject
selection
criteria
were
guided
by methods
that clinicians
often
use to evaluate
elderly
patients,
and thus the findings
of
the study
may be relevant
for clinical
practice.
The subjects
of the study did not have a drug washout
period
when
they entered
the study
and received
a vamicty of antidepressant
treatments
during
their
hospitalization.
Therefore,
cognitive
dysfunction
attnibutable to antidepressant
treatment
may possibly
have led
to an erroneously
high number
of depressed
patients
with
reversible
dementia.
Another
potential
methodologic
limitation
may
be the high
mortality
rate
among
the subjects
during
the follow-up
period,
probably a result of the high initial
medical
morbidity
of the
study
group.
Treatment-induced
cognitive
dysfunction
at admission
and high mortality
at follow-up
may have
reduced
the probability
of observing
development
of inreversible
dementia
in our study group
and thus would
have worked
against
the hypothesis
of the study.
Nonethclcss,
a rather
high percentage
(43%)
of depressed
subjects
with
reversible
dementia
developed
an imnevemsible
dementia
syndrome.
Three
uncontrolled
studies
observed
development
of
irreversible
dementia
at rates similar
to those
reported
here.
In a group
of 27 depressed
elderly
outpatients
who sought
evaluation
of memory
complaints
at a dementia
clinic,
irreversible
dementia
developed
in 57%
of the subjects
over 3 years
(24). Although
the clinical
characteristics
of that group
may have
been
different
from those of the subjects
in this study,
the percentages
of subjects
who developed
irreversible
dementia
were
rather
similar
(57%
oven 36 months
and 43%
over 34
months,
respectively).
In a 2-year
follow-up
study of 16
hospitalized
elderly
subjects
with
mixed
symptoms
of
depression
and dementia
(23), 50%
showed
improvement
of cognitive
function,
and 50%
showed
further
cognitive
deterioration.
Finally,
in an 8-year
prospective follow-up
study,
Kral and Emery
(22) observed
that
89% of 44 elderly
patients
who initially
had been diagnosed
as depressed
and “pseudodemented”
proceeded
to develop
dementia
of the Alzheimen
type. That
study
did not use systematic
clinical
ratings,
formal
inclusion
criteria,
or a control
group.
Instead,
its population
was
a combination
of two groups
of patients
who were independently
evaluated
and followed
up every 6 months
by two experienced
clinical
investigators.
Despite
the
anecdotal
nature
of the Knal and Emery
study,
its mesults have the value of observations
made
by senior
clinicians
about
patients
followed
for long
periods
of
time. In this study we used inclusion
criteria
that sought
Am
J Psychiatry
150:1
1, November
1993
ALEXOPOULOS,
to openationalize
the clinical
concept
of depressive
pseudodementia;
therefore,
our study
group
may be
somewhat
similar
to Knal and Emery’s
group.
While
definitive
comparisons
between
the two studies
cannot
be
made,
the rate of development
of dementia
in elderly
depressed
patients
with
reversible
dementia
was memarkably
similar
(89%
over 8 years
versus
43%
over
2.8 years).
A recent
study
(26) followed
21 patients
with dcpnessive pseudodementia
from
a large community
sample.
Oven a period
of 3 years,
24%
became
demented,
and
28%
developed
cognitive
dysfunction
but did not fully
meet criteria
for dementia.
Three
studies
reported
rates of irreversible
dementia
lower
than the rate observed
in this study.
In a 2-year
longitudinal
study
of 1 8 elderly
subjects
who initially
met criteria
for both depression
and dementia
(6), three
(17%)
remained
demented
during
the follow-up
period
despite
improvement
of depression.
Another
study (16)
showed
that only one (9%)
of 1 1 elderly
patients
with
a reversible
dementia
syndrome
developed
irreversible
dementia
over a 2-year
follow-up.
In addition
to a low
rate of dementia
in depressed
patients
with reversible
dementia,
both
studies
found
that more
of the elderly
patients
with depression
alone developed
dementia
duning 2 years.
The third
study
(25) noted
that only one
(5%) of 19 elderly
patients
originally
diagnosed
as haying depression
with
reversible
dementia
developed
an
irreversible
dementia
syndrome
within
12 years.
Follow-up
in that study
consisted
of a single evaluation
of
subjects
12 years after their recruitment.
However,
10.5%
of the subjects
refused
in-person
evaluation,
and 42%
died during
the study period.
For the subjects
who died,
information
on development
of dementia
was derived
from medical
records,
autopsy
reports,
or interviews
with
relatives.
These
methodologic
limitations
compromise
the conclusions
of that
study.
Nonetheless,
taken
together,
the three studies
suggest
that there exists among
elderly
depressed
patients
with
reversible
dementia
a
group
that remains
cognitively
intact,
at least for a few
years after resolution
of the dementia
syndrome.
The findings
of the present
study,
viewed
in the context of the existing
literature,
suggest
that geriatric
depression
with reversible
dementia
is a clinical
entity that
includes
patients
with early-stage
neurological
dementing disorders.
Assessment
with the Mini-Mental
State
examination,
an instrument
that rates cognitive
symptoms
and signs observed
during
a usual
clinical
evaluation,
failed to identify
the subjects
who later developed
irreversible
dementia.
Cognitive
dysfunction
at baseline
may be viewed
as an expression
of decreased
reserve
capacity
of the brain
that is uncovered
by the disturbances
of the depressive
syndrome.
Therefore,
some depressed
patients
with reversible
dementia
may already
be suffering
from
a dementing
disorder.
Depression
in
some
of these cases may be the first manifestation
of a
coarse
brain
disease
leading
to dementia.
This suggestion is supported
by the observation
that the most frequent
dementing
disorders,
such as Alzheimer’s
disease,
multi-infarct
dementia,
and parkinsonism,
have a high
Am
J Psychiatry
1 50:1 1, November
1993
MEYERS,
YOUNG,
ET AL.
rate of comonbidity
with depression,
ranging
from 17%
to 50%
(31-33).
Therefore,
reversible
dementia
in the
context
of geriatric
depression
should
be viewed
as a
risk factor
for development
of a progressive
dementing
disorder
rather
than as a benign
entity.
Another
possibility
may be that depressive
disorders
predispose
to development
of Alzhcimcn’s
disease
and
other
dementing
disorders.
This theory
is supported
by
observations
suggesting
high mates of previous
psychiatnc illness in patients
with Alzheimen’s
disease.
Appnoximately
30%
of depressed
patients
who
have
Alzhcimer’s
disease
have
histories
of previous
psychiatric
illness
(34), and 18%
of all patients
with Alzhcimer’s
disease
in one study were found
to have histories
of dcpression
on paranoia
(35). Furthermore,
the percentage
of demented
patients
in study groups
of elderly
persons
with major
depression
is approximately
10 times higher
than that of the elderly
population
in general
(21, 31,
33). However,
medically
ill patients
have
depression
(36) at a rate comparable
to that of demented
patients.
This observation
challenges
the specificity
of the association
between
depressive
and dementing
disorders.
Moreover,
follow-up
studies
show
that cognitively
intact elderly
persons
with depression
have only a slightly
higher
probability
of developing
dementia
than the general population
(37).
Finally,
the study
reported
here
shows
that
nondemented
geriatric
depressed
patients
develop
dementia
at the mate of 12%
oven appnoximately
3 years,
which
is only slightly
higher
than
the
rate for the general
population
(2%-3%
per year) (37).
While
some
cases
of depression
with
reversible
dementia
develop
against
a background
of subclinical
dcmenting
disorders,
other
cases
do not progress
into
irreversible
dementia.
The transient
cognitive
dysfunction that
these
patients
demonstrate
when
depressed
may
be attributed
to various
factors.
In our study
group,
the subjects
with reversible
dementia
had more
severe depression
than the nondemented
depressed
subjects and frequently
had psychotic
depression.
Severely
depressed
and,
often,
psychotically
depressed
elderly
patients
may be unable
to participate
fully in tests of
cognitive
function
and thus may appear
impaired
to the
point
of meeting
criteria
for dementia.
Another
possibility may be that severe
cognitive
dysfunction
is an integral
part of severe
geriatric
depression.
Theme is cvidence suggesting
that cognitive
dysfunction
is a primary
sign in depression
rather
than
an indirect
behavioral
consequence
of the affective
symptoms
of depression.
Improvement
in memory
appears
to correlate
with
amelioration
of depressive
symptoms
and signs
(38).
Pharmacologic
interventions
may selectively
affect cognitive
function
on affective
state.
It has been reported
that L-dopa
and L-tryptophan
improve
memory
without significantly
changing
affective
symptoms
(39); in
contrast,
it was found
that lithium
and imipramine
disproportionately
improved
depressive
manifestations
over memory.
These
pharmacologic
findings
raise the
question
of whether
cognitive
and affective
manifestations of depression
are mediated
by related
yet distinct
neurobiological
mechanisms.
1697
GERIATRIC
DEPRESSION
AND
DEMENTIA
Manifestations
of depression
may not be limited
to
affective
and memory
disturbances
but may also indude
neurological
and neuropsychological
signs.
Leftside hemiparesis
with
increased
deep
tendon
reflexes
and extensor
plantam
reflexes
has been reported
in some
depressed
patients
(40). In addition,
neunopsychological and physiological
experiments
have given
evidence
of right hemisphere
dysfunction
in depression
(20). Inability
to remember
names
has been
noted
in elderly
depressed
patients
compared
with control
subjects
(41).
The naming
ability
of elderly
depressed
patients
with
“reversible
cognitive
dysfunction”
appears
to be comparable
to that
of cognitively
unimpaired
elderly
depressed
patients
(42). However,
in another
study,
depressed
subjects
with
reversible
dementia
had naming
abnormalities
similar
to those
of patients
with
irreversible
dementia
(43). Positron
emission
tomography
(PET)
studies
showed
reduced
glucose
metabolism
in
the basal ganglia
and the prefrontal
areas of depressed
patients
(44, 45), while
magnetic
resonance
imaging
studies
observed
reduced
volumes
of the putamen
(46)
and the caudate
(47) in depressed
patients
who were
compared
to normal
subjects.
These
observations
suggest that the spectrum
of clinical
manifestations
of depression
may be quite broad
and may include
a considenable
cognitive
component
that
could
account
for
some
of the subjects
with reversible
dementia
who did
not deteriorate
during
follow-up.
Finally,
there
exists
the possibility
that the cognitive
dysfunction
of depression
may
be particularly
pronounced
in patients
with
asymptomatic,
nonprogressive brain
lesions,
leading
to a dementia
syndrome
that
is evident
only when
the depressive
manifestations
arc
present.
The concept
of an interaction
between
depression and lesion
is supported
by the observation
that
neurological
symptoms
and signs arc exacerbated
when
patients
become
depressed
(48).
A recent
PET study
showed
that depressed
subjects
with reversible
dementia had a characteristic
profile
of regional
cerebral
blood
flow abnormalities
consisting
of decreases
in the
left anterior
prefrontal
cortex
and increases
in the cenebellar
venmis
(49).
These
changes
were
distinct
from
those
of neurodegenerative
dementia.
While
a larger
number
of subjects
must
be studied,
it appears
that
some patients
with depression
and reversible
dementia
have a dysfunction
of neural
systems
distinct
from that
of depression
alone
on of neurodegenerative
dcmentias.
Our study
group
was small and does not permit
conclusions
about
the heterogeneity
of depression
with meversible
dementia.
Transient
cognitive
dysfunction
in
the elderly
may be caused
by a metabolic
on drug-induced
delirium
or side effects
of somatic
treatments.
The impact
of these
conditions
may be heightened
by
the high
sensitivity
of this population
to metabolic,
pharmacologic,
and
environmental
changes.
One
would
expect
that
patients
with
delirium
on drug-induced
cognitive
side effects
would
have
a favorable
long-term
outcome,
but specific
studies
arc lacking.
Patients who develop
depression
with reversible
dementia
in the absence
of metabolic
on drug-induced
distum-
1698
bances
can be viewed
along a continuum.
At one end of
the continuum
are patients
in whom
the cognitive
disturbance
results
primarily
from
the depressive
syndrome
itself. At the opposite
extreme
of the continuum
are those
in whom
the intellectual
impairment
omiginates
from
a progressive,
subclinical
dementing
disorden, with a rather
mild contribution
by the depressive
syndrome.
Between
the two extremes
lie cases in which
reversible
dementia
results
from varying
degrees
of interaction
between
depression
and brain
disorders
with
a progressive
on nonprogressive
course.
This
conceptualization
suggests
that
terms
such
as
reversible
dementia,
“
“ pseudodementia,
“
and “ depmcssion
of dementia”
cannot
be accurately
used at the
time of recovery
from
depression.
In this study,
cognitive dysfunction
at baseline
did not distinguish
patients
who
later
developed
irreversible
dementia
from
patients
who
remained
cognitively
unimpaired.
Clinical
examination
alone,
or use of insensitive
instruments
like the Mini-Mental
State
examination,
is not sufficient for prediction
of long-term
outcome.
Studies
arc
needed
to examine
whether
more
sensitive
assessment
of neuropsychological
dysfunction
can reliably
identify
patients
who proceed
to develop
irreversible
dementia.
Potential
neuropsychological
predictors
may
include
disturbances
in semantic
encoding
and retrieval
(SO),
naming
(43), visuospatial
tasks
(1, 51), and “automatic” cognitive
processes
(52) that do not require
effort.
Neuropsychological
abnormalities
in these
areas
have
distinguished
geriatric
depressed
patients
from
mildly
demented
patients.
Similarly,
imaging
measures
associated with
dementing
disorders
may be investigated
as
predictors
of irreversible
dementia.
These
may include
measures
of brain
atrophy
(10, 16, 17) or metabolic
disturbances
in selected
areas
(44, 45, 49).
The clinical
significance
of this conceptualization
is
that reversible
dementia
is an indication
for a thorough
diagnostic
workup
and frequent
follow-ups
in order
to
identify
treatable
neurological
disorders.
Studies
using
neunopsychological
assignment
and
structural
and
functional
imaging
may characterize
specific
interactions
between
lesions
and depression
or neurological
disease
and depression
that lead to reversible
dementia.
“
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