,

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SPECIAL ARTICLE

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.

Methodology of 'Irearment
Studies in Geriatric Depression
George S. Alexopoulos, M.D.
Treatment studies of geriatric depression sbould focus
not only on recovery and remission but also on relapse,
recurrence. disability, quality of life, cognitive impairment, and exacerbation of medical morbidity. Each of
these outcomes appears to have different predictors.
Medical burden may influence geriatric depression, response 10 antidepressants, and overalldisability, as well
as specific conditions underlying geriatric depression
(e.g., Alzheimer's disease, stroke, orparkinsonism). Measures of medical morbidity, cognitive impairment, and
perhaps structural brain abnormalities should be considered as possible influences on treatment response. Studies
of geriatric depression associated with specific disease
entities are necessary, using instruments tbat avoid rating symptoms and signs that are part of a concurrent
dementia syndrome or result from a medica! illness.
However, there should also be ratings with an "all-inclusive" approach tbat disregards tbe origin of depressive
symptoms-nobetber from depression, dementia, or tbe
medical illness. This strategy will reduce tbe risk of underdiagnosing depression. (American Journal of Geriatric
Psychiatry 1995; 3:280-289)

T

he hypotheses and design of treatment studies in geriatric depression
depend on the rapidly developing clinical
and empirical knowledge base in this
area. Recognizing the clinical complexity
of late-life depression, treatment studies
have begun to extend their scope beyond
the outcomes of recovery or remission of
depression. Relapse, recurrence, disability, quality of life, cognitive dysfunction.

and even long-term outcome of coexisting medical or neurological disorders
have become important treatment targets. I Some of these outcomes may be
influenced by specific characteristics of
depression, as well as other clinical and
noncJinical factors. For example. in a
naturalistic treatment study of geriatric
depression, recovery was best predicted
by early age at depression onset and by

Recci\'W July 18. 1994; R:'\isc:d Nm'el11bc:r 21. 1994; accepted January 25. 1995. From Cornell Uni\'CI'Sity
Medical College, White Plains. NY 10605. Address correspondenee to Dr. Alexopoulos. Cornell Unn'CfSity
Medical Collr..-ge, Nr..-wYorkHospital-Comcll Medical Center. 21 Bloomingdale Rd., White Plains, NY 10605.
Copyright C 1995 American MsocialioR for Geriatric Psychiatry
280

VOLUME 3

• NUMBER of• FAll 1995

Alexopoulos
high intcnsityofantideprcssant treatment
(Alexopoulos. unpublished data). In contrast, over time. change in behavioral disability was predicted by disability,
cognitive impairment, severity and
chronicity of depression at cntry to the
study, and chronicity of depression (time
depressed prior to study entry).
Some outcomes require an observation period that is longer than can be
afforded by placebo-controlled drug trials. For example. cognitive dysfunction
may subside after remission of depression. However, a controlled study found
that 43% or depressed elderly patients
with an initially reversible dementia syndrome proceed to develop irreversible
dementia during an average follow-up of
34 months. l With few exceptions (notably. Sachdcv et al>'). most follow-up studies of elderly depressed patients with an
initially reversible dementia syndrome
noted that these patients develop irreversible dementia at the rate of 8% to
25% per year of follow-up.i'" For outcomes like dementia, naturalistic treatment studies are essential because they
can provide the required long-terrn observation.
Each treatment outcome may be influenced by a variety of patient-related
or treatment-related parameters. The
reciprocal relationships among characteristics of treatment, clinical, and biological parameters of the sample and
the nature of the outcome of interest
determine to a large extent the choice
of targets for research assessment. What
follows is a discussion of predictors of
various outcomes of geriatric depression and their potential impact on the
design of treatment trials. Because most
outcomes ofgeriatric depression arc influenced by medical and cognitive disorders, this article reviews approaches
used for systematic assessment of depression in medically and cognitivcly ill
patients and proposes avenues for future methodological improvement.

n IF.MtF.RICAN JOURNAl. OF CiHRJATRIC ~"YCIIIATRY

PATIENT-RElATED
PREDICTORS
OF OUTCOME
Historically, data on predictors of outcomes of depression have been derived
from treatment efficacy studies. Treatment efficacy studies as a rule rely on
cross-sectional evaluation for sample selection. As a consequence, most of the
clinical predictors of outcome are crosssectional clinical, social. and biological
parameters. These parameters have been
either dimensional measures or categorical entities, such as specific diseases or
syndromes.
The Dimensional Approach

Several studies suggest that dimensionally assessed medical burden,
cognitive impairment, disability, neuroradiological characteristics, or blood
chemistry parameters influence the
course of geriatric depression. In a naturalistic treatment study of older depressed patients, growth curve analysis
was used to observe the long-tenn course
of depressive symptomatology up to the
time or recove~ The strongest determlnants of depressive symptomatology in
this study were poor medical health, unfavorable living conditions, and high severity of depression at baseline.
In a sample of older depressed patients treated with a fixed-dose nortriptyline regimen, a positive association was
observed between nortriptyline plasma
concentrations and improvement of depressive symptomatology in cognitively
unimpaired patients. No such relationship could be identified in depressed.
cognitivcIy impaired patients." This study
suggests that cognitive Impairment may
influence the plasma concentration-efficacy relationships of some antidepressants.
Preliminary data suggest that the ven281

Treatment Studies ill Geriatric Depression
tricular-hraln ratio and third-ventriclewidth-to-cranial-width ratio of geriatric
depressed patients were negatively
associated with change in depressive
symptomatology after treatment with
nortriptyline.9 When the sample was divided at the median for ventricular-brain
ratio, a positive association between
plasma nortnptyltne concentration and
antidepressant response \\'3S observed
only in the group with smaller ventricles,
Finally, self-care deficits and low serum
albumin were found to predict poor response to nortriptyline in a nursing home
"old-old" population. l o Therefore, trials
of antidepressants need 10 consider
medical burden, disability. cognirive lmpalrment, and appropriate neuroradiological parameters in the inclusion
criteria for subjects and the selection of
dosage and plasma levels of antidepressants.
The Categorical Approach
There is some evidence that categorically defined geriatric depression syndromes may have distinct course and
treatment outcomes. This categorical approach has been predominantly applied
in psychotic depression and in depression occurring in the context of neurological brain disease,
Psychotic depression appears to run
through repeated episodes in both
younger and older depressed patients 11.12 and is associated with higher
morbid risk in the patients' families. U
1\vo meta-analyttc studies concluded that
35%-37% of patients with psychotic depression respond to treatment with tricydies alone, whereas 60%-77% respond to
combinations of tricyclics and neuroleptiCS. I -i . l !) Similarl}~ a controlled stud)'
showed that psychotic-depressed patients do not respond to placebo medication.1(1 At present, trtcyclic-neuroleptlc
combinations or electroconvulsive therapy (EO) are considered the treatment
282

of choice in psychotic depression. I':' In
elderly patients with psychotic depression, resistance to tricyclics has been confirmed by a retrospective study of
geriatric patients with psychotic depres17
sion. This study also showed that poor
response to tricyclics is not merely due to
the high severity ofdepressive symptomatology because elderly patients with severe yet non psychotic depression
responded favorably to antidepressants.'"
Nonetheless, prospective studies
need to examine the role of antidepressants in geriatric psychotic depression,
especially in patients with a first episode
in later life. Late-onset depression ap--

pears to include a large subgroup of
patients with neurological brain disor1H
dcrs. which can potentially influence
the overall efficacy of antidepressant
drugs,'> the drug plasma-level-efficacy
relationships,"·9 and the timing of anndepressant response.
The long-tenn course ofgeriatric psychotie depression is unclear. A prospective study of working-class British elderly
patients noted that 63%were depressed 1
year later and 23% were dead. 19 A retrospective study of elderly psychotic depressed patients reported a more
optimistic outcome. I 1 Approximately
80% of these patients recovered and only
50% had a subsequent relapse within
3.5-8 years of follow-up, Similar findings
were reported in an Australian sludy.ln
Sample selection, treatment intensity.
and design difference may account for
these differences. Although the long-term
outcome of geriatric psychotic depression is yet to be clarified, there is agreement that older psychotic depressed
patients have a poor short-term outcome
if treated with antidepressants alone.
In depression or Alzheimer's (AD) patients. open-label studies or tricyclics1 1
and monoamine oxidase inhibitors22 suggest a favorable treatment response.
However, controlled treatment studies
VOJ.UMF.3 • NUMBHR oj • FAU. 1995

Alexopoulos
arc sparse and difficult to interpret. An
8-week double-blind study compared
imipramine (mean total plasma level: 119
ng/ml) with placebo in AD patients who
met DSM-III criteria and in nondepressed
AD patients. 2 :\ Hamilton Depression Scale
(Ham-D) scores improved in both
groups. The efficacy of imipramine, however; was indistinguishable from that of
placebo. The above study used a categorically defined population of AD patients
with major depression.
Other studies have focused on depressive symptomatology of AD populations with a broad range of behavioral
disturbances. In patients with AD or vascular dementia, citalopram was more effective than placebo in reducing scores
on the Harn-D and the Montgomery Asberg depression rating scales. Z·i Citatopram is a selective serotonin reuptake
inhibitor with antidepressant and moodstabilizing properties. Another study used
depressed patients with mild-to-moderate dcmentia and noted that both small
doses of trazodone (100 mg daily) and
5-mclhyltetrahydrofolic acid significantly

of the dopaminergic and noradrenergic
systems. rr It has been proposed that depression in PD may be mediated by dysfunction in mesocortical prefrontal
reward, motivational, and stress-re2M
sponse systems. Despite the chronic
course and the degenerative nature ofthe
lesions of depressed PD patients, preliminary evidence suggests that nortriptyline,28 desipramine,29 imipramine,jO
and bupmpiorr'" may be effective in the
treatment of these patients.
In onc study. nortriptyline improved
depressed mood, helplessness, hopelessness, and anxiety but had minimal effect
on the movement disorder.2M Imipramine
and desipramine were found to have a
beneficial effect both on depressed mood
and motor disturbances of PD patients. 29...yJ Bupropion was observed to
ameliorate depression in almost ·50% of
PD patients and improve motor abnermalitics in about 30% of patients.3 1 ECt:
as a rule, improves tremors, bradykinesia,
and rigidity early in treatment, whereas
the antidepressant response occurs
later. rt Although in most cases both the

reduced depressive symptoms, 2; Com-

motor abnormalities and the depression
of PO patients improve. anecdotal evi-

plexity in the identification of depressive
symptomatology in patients with dementia as well as the presence of other behavioral manifestations can interfere with
systematic assessment of response to antidepressants. Combination of both categorical and dimensional approaches in
the selection of samples and use of depression rating scales as well as scales
rating a broad spectrum of behavioral all-normalities can therefore offcr the best
design for treatment trials of depressiondementia patients.
Some research experience exists on
the course and treatment ofdcpression in
patients with Parkinson's disease (PD).
Depression in patients with PD~ "J~ left
untreated. has a chronic course.- Depression is more likely to occur in PO
patients with pronounced frontal lobe
dysfunction and significant involvement
TIlE AMF.RlCAN JOURNALOF GERIATRIC PSYCHIATRY

dence suggests that some patients may
have an amelioration ofthe motor disturbance without a mood response or have
an improvement of depression without a
27
change in motor abnonnaUties.
The encouraging results of the initial
treatment studies should be followed by
investigations that focus on specific clinical characteristics of depressed patients
with PD. Instruments should be used that
can rate depression and other behavioral
abnormalities separately from bradykinesia, tremor, and rigidit}r. This task may be
complicated because there is symptom
overlap between depression and some of
the motor disturbances, cognitive impairment, and other behavioral abnonnalities
ofpatients with PD. However, assessment
of the motor abnormalities with electronic instruments may be of some help.
283

Treatment Studies in Geriatric Depression
Concomitantly administered antiparkinsonian drugs should be taken into
consideration in treatment studies of depression because these drugs may have
direct behavioral effects or interact with
antidepressants.
Particular attention to the relationship between antidepressant response
and cognitive impairment is needed. specifically with regard to frontal lobe dysfunction. because depressed patients
with PD have more marked frontal lobe
dysfunction compared with those who do
not experience mood changes.;r! Finally.
long and frequent observation is needed
because specific behavioral symptoms or
syndromes of patients with PD may have
a different timetable of response to antidepressants.
Similar to depression of PD. depressive syndromes of stroke patients appear
to be associated with the site of brain
lesion. Major depressive disorder was
found to be more frequent in patients
with lesions at the left frontal cortex and
the left head of the caudate.;\2 The site of
lesions appeared to be the most important factor in predicting development of
depression. whereas the degree of physical impainnent and severity of aphasia
played a minor role. Major depression in
stroke patients was associated with significant cognitive decline. but the clinical
presentation of poststroke depression is
similar to that of medically healthy patients. If left untreated, poststroke major
depression may last approximately 1 year.
whereas minor depression may last 2
years. 33 Two placebo-controlled studies
suggest that poststroke depression responds favorably to nonriptyline3.f and
trazodone.;\~i (· A retrospective treatment
..
study observed that poststroke depressian responded favorably to a variety of
antidepressants. 2M Although depression
does not appear to have a significant relationship with baseline motor disability or
behavioral competence. improvement of
depression appears to parallel improve-

ment in behavioral competence scores.3:'
The field of geriatric depression has
given linle attention to the identification
of subtypes defined according [0 the
course of the illness. Schizophrenia
researchers have divided patients into
"Kraepelinian" and "non-Kraepelinian.depending on whether or not they required at least 5 years ofcontinuous institution-like care. "Kraepelinian" patients
were found to have more negative ~1'01P­
toms. thought disorder. disorganized behavior. bizarre delusions, less severe
depressive symptoms, and worse prcmorbid adjustment than "non-Kraepellntan"
schizophrenic paticnts. 37 Poorer visuospatial working memory and asymmetry
of anterior horns were more prominent
in Kraepelinian patients. 3M A promising
strategy for geriatric depression research
may be the identification of depressive
syndromes with a characteristic course
and the study of their clinical and biological characteristics. For example. elderly
patients with chronic behavioral disability
or chronic somatic complaints occurring
in the context ofrelatively low-level mood
symptoms may be viewed as analogous to
the "Kraepelinian" subgroup. Cross-sectional studies of clinical and biological
characteristics of such patients may be
used to validate this entit}~

Treatment-Related
Predictors of Outcome
Pharmacologic studies suggest that
elderly depressed patients often require
longer exposure to antidepressants than
younger adults.:w It is unclear. however.
whether old age itself, or the medical and
neurological illnesses and disability that
accompany old age are responsible for
the delay in treatment response. There(ore, pharmacologic trials of geriatric
populations need to include measures of
disability. cognitive impairment. medical
burden. and specific medical conditions
and assess their effect on the latency of
VOI.UME

3 • NUMBf.R", • FAiJ. 199'5

Alexopoulos

response to antidepressant treatment,
Another complexity in geriatric drug
trials is the lack of knowledge of what
constitutes a therapeutic dosage or a
therapeutic drug plasma concentration in
elderly medically ill or dementia patients.
Preliminary evidence suggests that cognilively impaired depressed panents" or depressed patients with enlargement of
brain ventricles9 may not show drug
plasma concentration-efficacy relationships similar to those of younger adults.
Therefore. geriatric drug treatment studies should include not only clinical measures of medical illness and cognitive
dysfunction but should also consider
measures of specific brain structures as
marc infonnation becomes available.
Accurate definition of placebo response is important for the design of drug
treatment studies. The role of placebo
response in depressed patients treated
with antidepressant drugs was addressed
by an elegantly designed study comparing imipramine, phenelzinc, and placcbo:to In young adults who responded
to imipr:amine, the majority of early re[apses (7th to 12th week of treatment)
were due to loss of placebo response.
These findings suggest that a subgroup of
patients who respond to pharmacologic
treatment arc in fact placebo responders.
Identification of placebo responders appears to have clinical value because placebo response is associated with early
relapse.
Geriatric studies of placebo respondcrs and their long-term outcome are lacking. However there is some evidence that
placebo response may be frequent in
some populations of depressed elderly
patients. Early clinical literature suggests
that depressive symptoms arc transient
and recurrent in dementia patients•.j I A
recent study observed that almost 50% of
depressed AD patients responded to placebo, a percentage comparable to imi2
pramine rcsponse. ' Inclusion of
cognitive measures and perhaps identifi-

cation ofthe specific dementing disorder,
ifpresent. may be essential in antidepres-sant trials with geriatric depressed patients because these parameters may
influence placebo response.

TIlE A.MF.RlCAN Joua..'ltIALOf GERIATRIC ~'"YCllIATRY

Assessment of Geriatric
Mood Syndromes

The above discussion outlines how
medical and neurological disorders and
disabilities of elderly depressed patients
generate specific research goals for antidepressant treatment studies. However,
an overriding methodologic concern is
the difficulty in distinguishing symptoms
and signs ofmedical illness from behavioral manifestations of depression. Somatic
complaints are part of the depressive syndrome and depression itselfmay enhance
the symptoms of a medical iIInL-SS. It has
been observed that medically ill depressed patients have more somatic
symptoms than medically ill nondepressed patients. -j2 Moreover, depression
appears 10 have an additivc effect to
chronic medical illness in decreasing
functioning and well-being..j:\
Some neurological syndromes may
mimic the symptoms of depression. For
example, lesions ofthe medial orbital and
sagittal areas of the frontal lobes can impair drive and mouvanon, Lesions of the
posterior functional frontal lobe systems
can impair alertness, emotional tone, and
attcntion:H Overlap in symptomatology
may not permit accurate discrimination
of symptoms and signs of depression
from those originating from neurological
syndromes.
Instruments developed for the quantification of depressive symptoms in geriatric patients have traditionally used one
or more of the following approaches:
• avoidance of items in areas where
the symptoms and signs of depression overlap with those of medical
illness45 or dementia..j(j.....jS
285

Treatment Studies i" Geriatric Depression
• exclusive rating of depressive signs
(because symptoms may be unreliably reponed by patients with demcntia-deprcssion.j9
• reliance on informants- reE01tSas
well as patient evaluation ,-IS
• use of rather long periods of observatIon 37.38
A limitation of these approaches is
that they may fail co identify a significant
part of the depressive syndrome, for example. guilt, disturbances in concentration. or somatic complaints, and thus may
produce erroneously low scores. A second limitation is that the validity of some
of these scales may be compromised if
unreliable infonnants arc used. It should
be emphasized. however, that caregivers
as a group appeared to be more sensitive
than trained raters in identifYing depressive symptoms and signs in dementia paticnts.~)

Another approach to the assessment
of depressive syndromes in medically ill
or dementia patients is to be all-inclusive
and accept a broad range of depressive
symptoms and signs regardless of
whether they originate from medical illness. dementia, or depression. A study
using the Ham-D observed that depressed clderly patients (diagnosed according to DSM-III-R criteria of major
depression) with and without dementia
had higher Harn-D scores than nondepressed dementia patients and schizophrenic patients. 'lj,1 Moreover. there was
no significant association between patients' Ham-D scores and scores of medical burden or cognitive impairment..
The opposite of the all-inclusfve approach is the development of instruments that differentiate symptoms and
signs of depression from manifestations
of medical and neurological disorders. Although it is assumed that reliability and
validity may be difficult to establish. it is
likely that highly trained raters may meet
these requirements because experienced

clinicians often can differentiate depressive symptoms and signs from medical
and neurological symptomatology. Nonetheless. this approach may have practical
and conceptual problems. First, the usc
of experienced clinicians as raters is not
economical and may limit the research
application ofthese Instruments. Second,
distinction of depressive from nondepressive manifestations of medical and
neurological disorders introduces an arbitrary "dualism." Such dualism can only
be acceptable if it proves clinically useful;
that is. depression in medical and neurological patients may only include depressivc manifestations that predictably
subside after antidepressant treatment, If
validated through follow-up studies, such
definitions ofdepression may guide treatment and have prognostic significance.
However. treatment-reslstant and treatment-responsive depression often have
similar clinical presentations. Therefore,
it may prove difficult to address depressive symptomatology with a view 10 treatmcnt response.

CONCLUSIONS
Remission of depression. recovery, relapse, recurrence. disability. cognitive impairment. exacerbation of medical
morbidity, and poor quality of life have
been identified as clinically relevant outcomes of geriatric depression. Because
these outcomes may not have the same
predictors, treatment studies need to be
designed with a view ofthe characteristics
of outcomes of interest.
The number of treatment studies on
disease-speciflc depressive syndromes is
limited. However, there is inherent clinical and heuristic value in studying treatment outcomes of depression in patients
with AD. PD, cerebrovascular. and cardiovascular diseases.
Response to antidepressants depends on the usc of adequate dosages,
VOLUMF. 3

•

NUMBER -i • FAIJ. 1995

Alexopoulos
drug plasma concentrations, and lengths
of drug exposure. Preliminary evidence
suggests that advanced age, medical burden, and abnormallties in cognition and
brain structures may lengthen the duration of an "adequate" trial and interfere
with the plasma drug concentration-efficacy relationships. For this reason, age,
medical burden, cognitive measures, and
perhaps ncuroradiological measures
need to be taken into consideration in
sample selection or should be the focus
of studies of potential predictors of outcome.
A certain percentage of depressed patients who respond after drug treatment
have in fact a placebo response. Identification of elderly placebo responders is
important because placebo response may
lead to early relapse. Preliminary evidence suggests that AD patients have a
high response rate. For this reason, inclusion of cognitive measures and identification of specific dementing disorders may
be essential in studies of drug efficacy and
even prevention of relapse.
Longitudinal studies using a naturalistic treatment design are needed to identify elderly depressed patients at risk for
outcomes that require very long observa-

tion. Such studies can follow elderly patients for longer time periods than can
placebo-controlled drug studies and thus
can provide infonnation to guide sharply
focused treatment studies.
In cognitively impaired or medically
ill patients, depression should be assessed with instruments designed to
avoid rating of symptoms and signs that
may be part of the dementia syndrome or
result from medical illness, However,
these ratings should be complemented
with scales using an all-inclusive approach that disregards whether symptoms originate from the depressive
syndrome, the dementing disorder. or a
medical condition. Combining instruments may reduce the risk ofunderrating
depression in cognitively impaired patients.

This work was presented at the Mac·
Arthur-NIMH Workshop on Treatment of
late-Life Depression, Alexandria, VA,
January 24, 1994.
1bis study was supported by NIMH
grants, ROJMH42819, ROJMH51842, P20
MH49762, T32 MH11932, and by tbe
Xerox Foundation.

References
I. Alexopoulos GS. Chest"... jG: Outcomes ofgeri·
atrtc depression. Cltn Geriatr Med 1992:
8:363-376
2.Alc."Xopoulo5 GS. ML-ycrs as. Young RC. et OIl:
The COUr.iC of geriatric depression with "R."\'Cf50
Ible dementia": a contnJlIc.:d study. Am] Ps)'Chia.
tl'}' 19<)3:P;0:1693-1691-)
3.Sachdev ps. Smith JS, Angus-t.cpan H. et OIl:
Pseudodementla twelve )'C.-ars on. J Neuml
Neurosurg PS)'chiatry 1990; 53:254-259
4. Reding M. Ua)'Cox). Blass ]« Depression in patientl'O referred 10 a dementia clinic. Arch Neurol
1985: 42:894-896
S. Rc.")·notds CF III. Kupfc. DJ. Hoch Cc. et OIl:
...
Two..)'~ear follow-up of elderly patienL'i with
mlxcd depresslon and demenna. clinie:tJ and
elc.-ctrocnn-phalographic sleep findings. J Am
Gertatr Soc 1986: 34:793-799
6, Kral VA. Fornory OB: tong·tenn follow-up of de-

11 If. tUIF.RJCAN JOURNAl. OF GF.RJATRlC

~-YCIIiATRY

presslve psc:udodementia of the aged. Can J
PS)'Chiatry 1989; 34:445-i46
7. Copeland JRM. D;nidson lA. Dt:wc.:y ME, et at:
AI7.heimcr':o disease, other dementias, depression and pseudodementia: prevalence. intidence and thrc~yc:ar outcome in UVl.'t'pOO1. Or
J Psychiatry 1992; 161:230-239
8, Young Re. Mallis S. Alexopoulos GS. et 31:Verbal mL-moryand plasma drug ecncentranons in
cldLTly depressives treated with nonriptyline.
Ps)'Chopharmacol Bull 1991; 27:291-294
9. Young RC. Nambudiri D. Alc.."Xopoulos GS: Brain
morphology and response: to nonriptyline in
elderly depn.'Sscd patients (abstr:let). Annual
Mcc:ting. American Association of Geriatric Psychiatry. 1990
10. Katz Ill. Simpson GM. Curlik SM. et ah Pharmacologic treatment or major depression for elderly patients in n..-sidcntial can: senings.] Clin

Treatment Studies ill Geriatric Depression
~l"Chi;urr 1990; 51:-i1-17

It. Bald\\in Re: Delusional and nondelusional depresslon in late life:: e"\idence for distinct subl}'JX.'5. Or J Ps)'Chiatl')' 1988; 152:39-1-'
12. (i(xxl\\in fit Jamison KR: Manic Depressive
IIIne!'is. Ncw York. O"ford Uni\'Crsin' Pn-ss.
1990. p266
•
13, Wei~o;m:an M~t. PrusofTUA. Mcrikan~'t KR.et ;a.l:
~1'Chi::Uric illnr...~s in n:l:ni\"L"5 of pmbands with
ddu!oional depression, Paper pn..-sc:nced at ,\CNP
Annual l\h."t."ling. Pucno Rico, 1983
I-i.Chan ell. Janiak PG. D:I\'i."JM. et al: Rl'SpOnM:
of psychotic and nonpsycholic dl.. ressed pap
tienlS to 1rit.1"CUc anlidepn.-ssanb.J Clin Ps)'Chia.
tr}' 198i: -i8: 197-20n
15, Kn>t.-sslel" D: RcI.llh'c dliaC)' rates fur therapiLos
of delusion.1I depression. Cnn\' Ther 1985;
1:173-182
1(,. GIa..Oism:an All. ROOliC SP: Ilclusion:al depression:
a tlbtinet entity? Arch (ien Psychialry 1981;
3H:-i24-i27
17, Prien RF: Somatic treatment of unipolar depn.-sshoe disorder. in AmcriC3n Ps\'chialric Pn:~s Review uf ~l'chi3tr')·. Vol i. f~(liied b)' Francc..'SAl,
• [3k'S RE. "'3.'ihington.
Amt"ric:1n P:!l1'Chi:ltril.·
Pn.-ss. 19HX,pp 213-2;\01
tHoAIc.."XI)(1nulc~ (is: Clinic:d and hinln~.k;d finding...
in late-onset depresslun, in American Ps)·chiat·
ric Pn.~s Rt."\il,."\\' of Ps,"chi:ltn·. Vol 9. F.dited bv
Tasman A. (ioldlin~er·S~t. Kdufm;tnn CA.
ingtnn.I)C. 1990. pp 2-49-262
19. Murph)' E: The pmgnosi,. nf lk"n:l'i.<iion in old
age. IJr J 1~1'chiaU')' 19H3: 1-i2:111-119
lU,lJuo'i11 N'. lIull Ul1, Stampler JIG. et al: 1bc
pmgnnsis of depression in old age. Br J PsychiaIn' 19'-)1; 15H:(l-i-71
21. R~")'nulds CF. Perc) JM. Kupfer OJ, el 011: Opentrial response to antidepn.ossanl treatment in
eltlcrl)' pacicms with mixc.."lI depn.-s.c;ion :and cog·
nith'c impairment. Ps)'chialr)' Res 19M:;
21:III-J22
22,,\..hrlm.1 J\\'. I:nnl t.'V: u~ of MAO inhibicofS in
clderl)' patients. Am J Ps)'chialrr 1979:
I36:14(,(,...I·j(,!
23. Reincr BV.Teri 1 Ib.<tkindM. et al: I)ouble-hlind
..
crial of imipr.1mine in Ab:heimer's disc:L'l' pa.
ticnts with and without depn~si()n. Am J ~1'­
chiat[}' IlJHt); l-i6:-i5-i9
2·i. (ionfriL"S C'(i. Karlssun I. N)1h AI.: Tn.-alment of
dcpn.-ssinn in elderly Jl3tienlS "ith :md withuut
dementia di,.nrdcrs. 1m Clin PS)'chnph:lrm

nc.

"'3.,h.

1992: CJ(suppl 5):'iS4l-i
25, Pa..'''iCri ~t, Cucinutta 1>, Abate (j. ct al: Oml
.,.methyhclrah~·drnfulic acid in ~nile mpnic
mcmal disnnlcn; 'lilh dLlln."Ssion: n.~uhs
a
dnuhle-hlind multicenter slud~·. "gin~ Mil:lno
19'-).~: ,:6.:\-71
2(,. M:l)'eUlC R. Stem Y. S:lno )1. ct al: The relation!oohip nf M:nllunin In depn.-ssion in Parkinsnn's
disc..-a..;c. Mm' ()isonlI98H: 3:237-2·i-i
27. Cummin~ )1.: Oc.."n.."S."iinn :md Parkinson's dis-

or

casco a review, Am J ps)'chiatr)' 1992;
149:4,i3-iSi
2R.Andersen). Aahnt F Gulm.mn N. et al: AntidC'..
pn."Ss:lnl CR.-atmenc in P:lrkinson's diSL'3."iC: a
conln)IIL"d tri.:al of thc effect of n()nrip~'linc in
paticnts \\ilh Paool15On's disc:L'iC treated with

l-dopa. Acca Ncunll Scand 19Ho:62:210-219
29. bitincn I.: Dt.-sipr:lmine in treatment of Parkin·
son's disease. Acta Ncurol Scand 19(.9:
-45:109-113
3D, Stran~ RR: Imipt:lmine in rreatmem uf Parkin·
sonism: a double blind placebo studr. 81"~Icd J
19()5:2:33-34
3 J. Guet1. GG. Tanner CM. Kla\\,;&ns III.: Buprnpion
in Pa.rkinson·s disease. NeurohlJt)· 19tH:
34:t092-109-i
32. Robinson RG, Stark.. tc:in SE: Current research in
i
affective disoroers fc)lIowing SIRJkc.J Neumps)··
chb.. ')' Clin Neurosd 19C)O; 2:1-1-i
.33. Fc..'dcndTJP. Robinson RG: TriC)"Clic antidepn.-ssants in the 1n."3cmem ofposu..tnJke depn-s....iun.
.
) Clin Ps)"Chi:atl")' 1989~ 50:18-33
3-i.l.ipsey JR. Spencer \'(fe, Rabins P", et al:
Phenomenological l'umparison of poststrnke
d,,"pn.~si()n and functional dcprc..-s...ion.

chiatrv 1986; H3:527-529

,\mJ ~1··

.~.;;. Hc.'tling M). Ono loA. "1nter SW. et al: Antidepressant cherapy arler scnJke: a double-blind

trial. Arch

19tK",; 43:763-765
U"cintraub RJ. Karm3U7, N. et al:
Anlidepn.ossant drug treatment for pnstc;tmke
dc:pR.":'i."iinn: R"trnspc..'dh'C !'itud". Arch Ph}'S~Ic..'tl
Heh;dJiI 19tri: CtH:772-776
3'i.l\madur X. Flamm M. Gorman JM: The ":"illic)'
nf da., .ificalinn based on lon~·cerm deficits in
.
!iC:U-eare. American College
NcuroP~1'ch()..
ph:lrmacolog}' ,\hstr.tcts. 191)3. P 14
NCUR)I

36.I~inkebtein SP.

or

38. Kc..'Cfc Illoif Fn:cska f.. Da\id'l)Q M. et al: Validit)'
..
of Kl'3epclinian subt)'pc of schi;mphrcnia.
Amc..nr...":ln College: of Neumps)"Chnpharmacol.
o~' ,\bstraCL"i. 1993. p l-i
;\9. (icnrgnl:t.'li A. McCue RF.: Thc atldilion31 benefit

of ...
"'tcnding an

antidcpn.~Slnt

trial pa.. t !'en:n
..

wL'Cks in the depn."Sscd clderlr. In IL'I'I131i011:11
Journal of Geri;ltric P:o)"Chiatl")' 19H9: '1:191-195
-iO.Quitkin FM. Sll.·wartJN. Mc(iralh Pl. et OIl: l.. ss
o
ofdrugelfcct.o;;; durin~ c:ontinuatinn cherap)·. Am

J PS)'Chiau)' 1993: 1'j():563-')Ci.,
-i1. Roth :.,: The natur;al history ofmental disorders
in old age,) Ment Sci 195';: 1:281-301
.j2. Knc:nig IIG. Cohen IIJ. DI:I7.LT 00. ct 31: Pndile
ordcpn.-ssh'C 1oo1mptoms in )lJUngcr :mcl ulelcr
mc..'tJic.":d inpaticnls \\ith major depression, J Ant
Gcriatr Soc I9CJ3: -i I: 11&)-1176
.i3. "'clls KB, SIr...·wart A. 11:1)'5 RD. et ;11; lbe fune·
tioning and wen bcin~ of depn.osscd p:ltients:
R."Suhs from the Mr...·dkal(}utcumL'S Stud)'. Jr'L\L\
19K9: 262:9104-919
..-i. Benson I>F. Stus.~ [)T: Theuric..-s of fnlntal lobe
function. in Ncumlog)' and P!oo1"Chialr)": A :\lectin~

of the Minds.

l~ditt."lI

V()l.u~m.;\

b)'

~lucllcr

J.

D:L"iC1.

• NUMBER -i • FAil.. f91JS

Alexopoulos
Switzerland, K.:1tgl.'t'. 1989. pp 266-283
45. Yc:~'l\'age JA. Brink n .. Rose n.. et al: The geriatric rating scale. comparison with other self·report~ and psychtatrfc rating scales. in
A...K."S.
. ' sment in Geriatric Ps}'chophannacology.
f.ditl-d bv Crook T. Gem" S, Bartus R. NL""
Canaan, Cr. Mark Powk" A.;sod:J.lt."S. 1983. pp
153-165
-i6.Sundcrl.:and T. AhL'rnlan IS. Yound D. et al: A
nc.."" M:31e for the a...
. sessment of mood in demented patients. I\m J Psychiatry 1988;
145:955-959
47.Alexopoulos GS. Abrams Re. Young Re. er 011:
Cornell scale for dc.:pn.-:osion in dementia. Bioi
Psychi.:atf)·1988: 23:271-284

nIH AMf.RlCAN JOURNAl.OF GF.RIATRIC PSYCIIIATRY

.f8.Alexopoulos GS, Abrams RC. Young RC. et 011:
Usc of the Cornell Kale on nondemented patients. J Am Geri:ur Soc 1988; 36:230-236
49. K.:1tona CI.E. Aldridge CR: The dexamethasone
suppresston test and depressive signs in dementia. J Affect Dis 1985; 8:83-89
50, Alexopoulos GS. Abrams RC: Oc:prcssion in
Alzheimer's di.'iL":L"'C. Ps}-chi.:atr CUn Nonh Am

1991; 14:327-340
51. Mulsanl BU, Swt."Cl R. mfai AII. et at: The usc of
the Uamilton Rating Scale for Depression in
clderl)' patients with cognitive imp;linncnt and
ph)'Sical illness. American Journal of Geriatric
~l'chi01tl')'I994; 2:220-229

