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Psychotic major depression in older people: a systematicreview
Rossetos Gournellis1,2, Panagiotis Oulis3 and Robert Howard2
1SecondDepartment of Psychiatry, Psychogeriatric Unit, University of Athens,Medical School, University General Hospital “Attikon”, Athens, Greece2Institute of Psychiatry, King’s College, London SE5 8AF, UK3First Department of Psychiatry, University of Athens, Medical School, “Eginition” Hospital, Athens, GreeceCorrespondence to: R. Gournellis, E-mail: [email protected]
Objective: This study aimed to systematically review available evidence relevant to the following issues:(1) whether psychotic major depression (PMD) in older people differs in overall severity from non-PMD, besides the presence of psychotic symptoms; (2) whether it constitutes a distinct clinical entityfrom non-PMD; and (3) whether it differs from PMD in younger adults.
Design: A computerized MEDLINE, PsycINFO and the entire Cochrane Library search has beenperformed in June 2013 for prospective controlled studies investigating PMD features in older people.
Results: Thirty-five relevant studies were identified. PMD in older people compared with non-PMD hasbeen shown to present with overall more severe depressive symptomatology, more psychomotordisturbance, more guilt feelings, more depressive episodes with psychosis, worse prognosis, more severeexecutive dysfunction associated with frontal lobe atrophy, and lower serum dopamine β-hydroxylaseactivity. No differences in the efficacy of an antidepressant plus antipsychotic combination versusantidepressant monotherapy in the acute treatment as well as in the maintenance treatment were found.PMD in older patients is characterized by more somatic complaints and delusions of hypochondriacaland impending disaster content and by a lower comorbidity with anxiety disorders compared withPMD in younger adults.
Conclusions: Psychotic major depression in older people is associated with higher severity in mostclinically important key features than in non-PMD. However, available evidence is still insufficientfor the conclusive elucidation of its nosological status. Finally, the differences between PMD inolder and younger patients can be attributed to biological and psychosocial changes of old age.Copyright # 2014 John Wiley & Sons, Ltd.
Key words: psychotic; delusional; depression; elderly; old ageHistory: Received 19 April 2013; Accepted 21 November 2013; Published online 14 January 2014 in Wiley Online Library(wileyonlinelibrary.com)DOI: 10.1002/gps.4065
Introduction
Psychotic major depression (PMD) in patients under60years of age has been shown to have different clini-cal characteristics, neurobiological correlates, familyhistory, prognosis and treatment response comparedwith non-PMD patients. More precisely, youngerPMD patients exhibit more psychomotor disturbanceand guilt feelings; higher long-term morbidity andresidual impairment; more depressive episodes withpsychosis; higher rates of bipolar disorder in first-degree relatives; more severe cognitive impairment
in the domains of executive function, psychomotorspeed, attention and memory; more brain atrophy;higher serum glucocorticoid; and lower dopamineβ-hydroxylase (DBH) activity. Furthermore, an antide-pressant plus antipsychotic combinationmay be superiorto antidepressant monotherapy in their acute treatment(see Lykouras and Gournellis, 2009, for a review). Thesedifferences raise the issue of the nosological status ofPMD. In current psychiatric diagnostic systems,psychotic features in major depression are categorizedas a specifier of major depressive disorder (MDD).Accordingly, PMD is considered as a subtype of MDD
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
REVIEW ARTICLE
(WHO, 1992, APA, 2000, 2013). However, the degree ofdifferences from non-PMDhas led to the proposal that itmight even constitute an entity that is distinct fromMDD (see Schatzberg and Rotschild, 1992; Østergaardet al., 2012, for reviews).
Psychotic major depression in older people (≥60 years)is highly prevalent in inpatient settings, causes greatsuffering and disability and is a difficult-to-treat condi-tion as well. However, its differences from non-PMD inregard to the aforementioned key features and itspresumed nosological status have not been yet systemat-ically reviewed. A further issue pertains to the relation-ship between PMD in younger and older people.Finally, reviews on PMD in older people with oneexception date from the late 1990 (Meyers, 1992;Martinez et al., 1996; Baldwin, 1999; Gournellis andLykouras, 2006). Thus, a review of more recentlypublished studies is warranted in order to help addressthese issues.
Accordingly, the aim of the present systematicreview was threefold: first, to assess whether PMD inolder people exhibits higher severity in its clinicallyrelevant key features than non-PMD besides thepresence of psychotic features; second, to assesswhether the magnitude of these differences in severityjustifies its consideration as a distinct clinical entity;and third, to explore whether the differences betweenPMD in older and younger people warrant theirconsideration as different conditions.
Design
A computerized MEDLINE, PsycINFO and the entireCochrane Library search has been performed forpotentially relevant articles in June 2013 using the searchterms “psychotic depression,” “delusional depression”and “depression with psychotic features.” These werecombined with “old age,” “older people,” “elderly,” “latelife” and “geriatric.”
The studies that fulfilled our eligibility criteria werecross-sectional and prospectively controlled with aninvestigative focus on the features of PMD in adequatesamples of patients with age at index episode of60 years or over. We have also included cross-sectionalcomparative studies on older and younger PMDpatients. As a definition of PMD, we adopted thefollowing: coexistence of psychotic symptoms such asdelusions and/or hallucinations during a majordepressive episode in the context of MDD (unipolardepression). However, we have also included studiesthat define PMD according to the InternationalClassification of Diseases 10th revision criteria, a
broader definition allowing this diagnosis also inpatients with stupor, but we have indicated wherethis has been the case. Double-blind randomizedcontrolled studies were categorized as “high”-qualitystudies (++), open controlled trials as “medium”-quality studies (+), and studies that were either retro-spective, or with no control group, or with inadequatenumber of patients, or not focused on the comparisonbetween PMD and non-PMD patients, or withdoubtful relevance to our research questions as “low”-quality studies (�).
The effect sizes between groups in the high-qualityand medium-quality studies were calculated fromauthors’ published data by Cohen’s d for continuousand phi (φ) for categorical variables. The effect sizeswere grouped as “small” (0.20–0.40), “medium”(0.50–0.70) and “large” (0.80 or higher).
Results
The search in June 2013 yielded 9246 references, thetitles and abstracts of which were screened forrelevance. Independent screening of title and abstractof these studies by two authors resulted in 42potentially relevant articles on psychotic depression.Six studies were excluded because they were casereports (Chopra et al., 2002; Chiu et al., 2009; Ntatsakiet al., 2009; Ghio et al., 2011; Bar-Shai et al., 2011;Alvarez et al., 2012) and another one (Gournelliset al., 2008) because its findings are included in anotherstudy (Gournellis et al. 2011).
Thus, 35 studies were included. Four of them weredouble-blind randomized controlled studies and wererated as high-quality studies (Meyers et al., 2001;Mulsant et al., 2001; Meyers et al., 2009;Flint et al.,2013), whereas 19 were open prospective controlledones and were rated as medium-quality studies (Kivelaand Pahkala, 1989; Meyers et al., 1993; Baldwin, 1995;Zubenko et al., 1996; O’Brien et al., 1997; Flint andRifat, 1998a, 1998b; Kim et al., 1999; Simpson et al.,1999; Meyers et al., 1999; Gournellis et al., 2001;Ohayon and Schatzberg, 2002; Lykouras et al., 2002;Lee et al., 2003; Parker et al., 2003; Kessing,2006; Kok et al., 2010; Flint et al., 2010; Gournelliset al., 2011). Twelve were rated as low-quality studies—always in regard to our research questions—becausefour were retrospective (Baldwin and Jolley, 1986;Meyers and Greenberg, 1986; Baldwin, 1988; Nelsonet al., 1989), three had a small number of PMDpatients (Kunik et al., 1994, eight patients; Grierzet al., 1995, 10 patients; Politis et al., 2008, 11 patients),two (Murphy, 1983; Burvuil et al., 1991) did not directly
785Psychotic depression in older people
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
compare PMD and non-PMD patients, one (Gournelliset al., 2009) lacked a control group, one (Meyers et al.,2006) did not compare older and younger PMDpatients and one (Navaro et al., 2008) had doubtfulrelevance to our research questions (Table 1).
Differences between older psychotic major depressionand non-psychotic major depression patients
Epidemiological community studies. The study of Kivelaand Pahkala (1989) reported a 1% point prevalence ofPMD in older people of both sexes in a (Finish)community and a 2.7% prevalence of non-PMD (Kivelaet al., 1988). By contrast, Ohayon and Schatzberg(2002), in a study conducted in five European countries,reported a 0.3% point prevalence of PMD versus 1.3%of non-PMD in the older population.
Clinical studies. Four prospective cross-sectionalcontrolled studies (Baldwin, 1995; Gournellis et al.,2001; Lee et al., 2003; Parker et al., 2003) havereported significant clinical differences between PMDand non-PMD.
Parker et al. (2003) have compared 46 older PMDpatients with 46 non-PMD patients with melancholiausing the “CORE,” which provides a structuredbehavioral assessment of psychomotor disturbance(Parker and Hadzi-Pavlovic, 1996). The PMD groupexhibited significantly higher levels of psychomotordisturbance (agitation or retardation; effect size1.03). A study by the authors (Gournellis et al.,2001) also reported more severe psychomotorretardation in PMD patients, and this survivedadjustment for age, sex and melancholia symptoms.By contrast, Baldwin (1995) and Lee et al. (2003) didnot find such differences in psychomotor disturbance.Of note, in the Gournellis et al. (2001), Parker et al.(2003) and Lee et al. (2003) studies, the total HamiltonRating Scale for Depression (HRSD) scores werehigher than in Baldwin’s (1995) study. All four studiesfound higher levels of overall clinical depressiveseverity in PMD (with effect sizes ranging from 0.38to 1.27). Likewise, PMD patients exhibited higherrates of feelings of guilt or deserved punishment(with effect sizes ranging from 0.21 to 0.28). Onemajor limitation of these studies was the use of HRSD,which includes three items (guilt, hypochondriasisand insight) that assign higher scores to depressiveswith delusions.
Delusions of paranoid and somatic types were themost prevalent, followed by those of guilt (Baldwin,1995; Gournellis et al., 2001). About one third of
deluded patients experienced hallucinations, mainlyauditory (Gournellis et al., 2001).
A strong tendency of PMD patients to experiencemore psychotic depressive episodes was confirmed alsoin older-age PMD with effect sizes ranging from 0.76(Flint and Rifat, [1998a]) to 0.95 (Gournellis et al., 2001).
Suicidal behavior. One study in older-age PMD(Lykouras et al., 2002) failed to detect increased riskof attempted suicide during index or past depressiveepisodes and found no differences in the method used(violent or not). However, other similar studies foundhigher risk of attempted suicide (Lee et al., 2003) andmore severe suicidal ideation (Simpson et al., 1999).
Course and outcome. In one prospective follow-upstudy on the course and outcome of older-age PMD,Flint and Rifat (1998a) reported that PMD patientsexperienced more relapses and recurrences over a2-year period (effect size 0.33). However, their samplewas small (19 patients). Their findings are in line withthose of one large follow-up study in younger PMDpatients, which has reported fewer weeks withminimal symptoms and more psychological impair-ment at the end of a 10-year follow-up (Coryellet al., 1996). These findings overlap partially withthose of another study in younger PMD patients,which found a higher depressive morbidity, althoughnot a poorer outcome, in a 10-year follow-up study(Maj et al., 2007). All these studies attest to thetemporal stability of PMD in younger patients,although in one recent study, the 10-year diagnosticstability of young-age PMD inpatients was found tobe rather poor (Ruggero et al., 2011).
Murphy (1983) found that only 10% of olderpeople with PMD achieved full remission and almosta quarter died during a 1-year follow-up. By contrast,Baldwin (1988), in a 42- to 104-month retrospectivefollow-up study, failed to detect any differencesbetween older-age PMD and non-PMD patientsregarding clinical course, relapse rate or mortality.
Neuropsychological studies. Older-age PMD patientsdisplayed a worse performance on both the WisconsinCard Sorting (Kim et al., 1999; Simpson et al., 1999)and the Trail Making Tests (Simpson et al., 1999) thantheir non-PMD counterparts, even after correcting fordifferences in depression severity (Kim et al., 1999).Fleming et al. (2004) in a meta-analysis of thesestudies found a medium-to-large effect size (0.71)for the Wisconsin Card Sorting Test; however, overallsample sizes were small, with 32 PMD and 75 non-PMD patients.
786 R. Gournellis et al.
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
Table1
Maincharacteristicsof
theinclud
edstud
ies
Autho
rs(yea
r)/
qua
lityratin
gStudytype/
asse
ssmen
t/crite
riaAge
(yea
rs)
Sam
ple
Source
ofsa
mple
Stren
gths
Limita
tions
Key
findingsan
deffect
size
s
Studiesthat
inve
stigated
thefeatures
ofolder
PMD
patients(prese
nted
inthesa
meorder
asthey
appea
rin
theRes
ults
section)
Kivelaan
dPah
kala,
(198
9)/(+)
Epidem
iological,
ZSDS,HRSD,
clinical
interview,
DSM-III
≥60
1529
Commun
itysa
mple,
Finland
Scree
ning
and
clinical
asse
ssmen
tSmalln
umber
of
PMD
patients(12)
1%PMD
preva
lenc
eve
rsus
2.7%
of
non-PMD
Oha
yonan
dSch
atzb
erg,
(200
2)/(+)
Epidem
iological,
Sleep
-EVAL
system
interview,
DSM-IV
18–1
0018
980
Commun
itysa
mple,
German
y,Ita
ly,Spain,
Portug
al,UK
Largesa
mple
of
3487
≥65ye
ars
The
partic
ipan
tswereinterviewed
bytelepho
ne
0.3%
pointpreva
lenc
ein
subjects≥6
5ye
ars
versus
1.3%
of
non-PMD.
PMD:0.4–
0.5%
insu
bjects≤6
5ye
ars
Baldwin
(199
5)/(+)
Clinical,
HRSD,MMSE,
phy
sica
lhea
lthratin
gsc
ale,
DSM-III-R
65–9
613
4Inpatientsan
doutpatients,
older-age
service,
UK
Adeq
uate
sample,
34PMD
patients,
match
edsu
bgroup
Ran
geofclinical
mea
sureslim
ited
PMD
patientsco
mpared
with
non-PMD:↑
sing
le,
guilt,
anxiety,
less
insight,
delus
ions
ofperse
cutio
nan
dhy
poch
ond
riasis
preva
lent
Gourne
lliset
al.
(200
1)/(+)
Clinical,
SCID,HRSD,MMSE,
phy
sica
limpairm
ent
ratin
gsc
ale,
DSM-IV
≥60
118
Inpatients,
three
dep
artm
ents,
Greec
e
Adeq
uate
sample,
45PMD
patients,
match
edsu
bgroup
Ran
geofclinical
mea
sureslim
ited
PMD
patientsco
mpared
with
non-PMD:↑
ageat
ons
et,se
verityof
dep
ression(effec
tsize
1.27
),psych
omotorretardation,
pas
tpsych
otic
episodes
(effec
tsize
0.95
),perse
cutory
andso
matic
delus
ions
preva
lent
Leeet
al.
(200
3)/(+)
Clinical,
HRSD,MMSE,PSMS,
IADL,
DSM-IV
65–9
015
6Inpatients,
geriatric
psych
iatryward,
Taiwan
Adeq
uate
sample,
48with
PMD
Lack
ofa
match
edsu
bgroup
PMD
patientsco
mpared
with
non-PMD:↑
seve
redep
ression(effec
tsize
0.38
),guiltfeelings
(effec
tsize
0.21
),daily
func
tiona
land
cognitiv
eim
pairm
ent
Parke
ret
al.
(200
3)/(+)
Clinical,
semi-structured
interview,
CORE,MMSE,HRSD,
BAS,DSM-IIIR
≥65
123
Inpatientsan
doutpatients,
four
dep
artm
ents,Aus
tralia
Comparisons
betwee
nthreegroup
s:PMD
(46),
non-PMD
(46)
and
non-melan
cholic
(31)
patients,
robus
tas
sessmen
tofpsych
omotor
disturban
ces,
PCA,
LCA,clus
teran
alysis
Inclus
ionofnine
bipolarpatients
PMD
melan
cholia
patientsco
mpared
with
non-PMD
melan
cholia
patients:
↑psych
omotor
disturban
ce(effec
tsize
1.27
),se
verity
ofdep
ression(effec
tsize
0.57
),des
erve
dpun
ishm
ent
(effec
tsize
0.28
)an
dan
hedonia
Lyko
uras
etal.
(200
2)/(+)
Clinical,
SCID,MMSE,
HRSD,DSM-IV
≥60
104
Inpatients,
three
dep
artm
ents,
Greec
e
Adeq
uate
number
of
PMD
(40)
patients,
useofun
ivariate
and
multiv
ariate
analyses
Res
trictednu
mber
ofpatientswith
suicidal
attempt
(28patientswith
39attempts)
Nosignific
antdifferen
ces
orev
ensu
gges
tivetren
ds
betwee
ngroup
son
suicideattempts
duringprevious
orcu
rren
tdep
ressiveep
isode
(Con
tinue
s)
787Psychotic depression in older people
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
Table1.
(Con
tinued)
Autho
rs(yea
r)/
qua
lityratin
gStudytype/
asse
ssmen
t/crite
riaAge
(yea
rs)
Sam
ple
Source
ofsa
mple
Stren
gths
Limita
tions
Key
findingsan
deffect
size
s
Murphy
(198
3)/(�)
Follo
w-up(1ye
ar),
PSE,SPAS,
lifeev
ents
asse
ssmen
t,Feighn
ercrite
ria
65–8
912
4Outpatients,
older-agese
rvice
Onlyfirst
dep
ressive
episodeinclud
edNotfocu
sedon
thedifferen
ces
betwee
nPMD
(30)
andno
n-PMD
(94)
Only10
%ofPMD
had
reco
veredbytheen
dof1ye
arve
rsus
70%
ofno
n-PMD
patients;
almost
one
fourth
of
PMD
patientsdied
Baldwin
(198
8)/(+)
Follow-up(42–
104months
),HRSD,F
eighn
ercrite
ria≥6
548
Inpatients
Match
ingin
age,
sex,
leng
thoffollo
w-up
(24PMD
vs.24
non-PMD)
Retrosp
ectiv
eNodifferen
cesin
outco
meat
disch
arge
attheen
doffollo
w-up
Flintan
dRifa
t(199
8a)/(+)
Follo
w-up(2ye
ar),
SCID,HRSD,
Burvill’sphy
sica
lillne
sssc
ale
DSM-III-R
≥60
87Outpatients,
Can
ada
Adeq
uate
initial
asse
ssmen
t,group
smatch
edfor
nortrip
tylineplasm
aleve
ls
Open
nature
ofthestud
y,sm
alln
umber
ofPMD
patients
(19vs.68
non-PMD)
PMD
patientsco
mpared
with
non-PMD
atthe
endof2ye
ars:
↑rate
ofrelapse
or
recu
rren
ce(effec
tsize
0.33
)Kun
iket
al.
(199
4)/(�)
Neu
ropsych
ological,
WAIS,
BNT,H-R
TB,
COAT,TMTA-B
,DSM-III-R
≥60
14Inpatients,
USA
Adeq
uate
asse
ssmen
tSmalln
umber
of
patients(8
PMD
vs.
6no
n-PMD)
PMD
patientsco
mpared
with
non-PMD:
↓IQ,word
fluen
cy,
mem
ory
Lesser
etal.
(199
1)/(�)
Neu
roim
agingan
dne
uropsych
ological,
SCID,HRSD,MMSE,
WAIS,R-O
CFT,WCST,
STOOP,ACT,FASVerbal
Fluen
cy,RMT,
MRI,SPECT,
EEG,DSM-III-R
≥45
86Inpatientsan
doutpatients,
USA
Robus
tas
sessmen
t,ag
e,se
x,ed
ucation
match
ing
Inclus
ionof
youn
ger
patients,
lack
ofno
n-PMD
controls
PMD
patients(14)
compared
with
healthyco
ntrols
(72):
↑su
bco
rtical
white
matterlesions
,↓
frontal
lobe,
mem
ory
andvisu
alsp
atiala
ctivities
Kim
etal.
(199
9)/(+)
Neu
roim
agingan
dne
uropsych
ological,
semi-structured
interview,
MMSE,CRS,MADRS,
WCST,WMS-R
,VLT
,R-O
CFT,KBN
(BNT),
MRI,DSM-III-R
≥55
42Inpatients,
Korea
Robus
tas
sessmen
t,group
smatch
edforag
e,gen
der
and
seve
rityofdep
ression
Smalln
umber
ofpatients
(17PMD
vs.25
non-PMD
patients)
PMD
patients
compared
with
non-PMD:↓
volume
offrontal
lobe
(effec
tsize
0.64
),↑
unsa
tisfactory
exec
utiveperform
ance
Sim
pso
net
al.
(199
9)/(+)
Neu
roim
agingan
dne
uropsych
ological,
MADRS,phy
sica
lhe
alth
que
stionn
aire,
MMSE,DSST,RAVLT
,WCST,FASVF,TMTA-B
,R-O
CFT,MRI,DSM-III-R
65–8
566
Outpatients,
two
older-agepsych
iatry
services
,UK
Robus
tas
sessmen
tSmalln
umber
ofPMD
patients
(15vs.51
non-PMD)
PMD
patientsco
mpared
with
non-PMD:
↑phy
sica
lhea
lthproblems,
frontal
(effec
tsize
0.62
–0.83),
temporal,dienc
epha
lic,
brain-stem
atrophy
,retic
ular
activ
ating
system
lesions
,↑
unsa
tisfactory
exec
utiveperform
ance
and↓
proce
ssingsp
eed
O’Brie
net
al.
(199
7)/(+)
Neu
roim
agingan
dne
uroen
docrine,
HRSD,
MADRS,CAMCOG,
vasc
ular
risk
factors
asse
ssmen
t,MRI,DST,DSM-III-R
≥55
61Inpatients,
four
units
,UK
Docu
men
tatio
nof
vasc
ular
riskfactors,
adeq
uate
ove
rall
number
of
patients(61)
Smallg
roup
size
ofPMD
patients
(22),5bipolars
PMD
patientsco
mpared
with
non-PMD:
↑DSTno
n-su
ppressors
(effec
tsize
0.26
),↑
vasc
ular
risk
factors
(tren
d)
62–9
230
(Con
tinue
s)
788 R. Gournellis et al.
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
Table1.
(Con
tinued)
Autho
rs(yea
r)/
qua
lityratin
gStudytype/
asse
ssmen
t/crite
riaAge
(yea
rs)
Sam
ple
Source
ofsa
mple
Stren
gths
Limita
tions
Key
findingsan
deffect
size
s
Mey
erset
al.
(199
3)/(+)
Neu
roen
docrine,
SCID,SADS,HRSD,
MMSE,DST,DSM-III-R
Inpatients,
one
unit,
USA
Pretrea
tmen
tan
dposttrea
tmen
tDST
resu
ltsin
older
dep
ressives
Smalls
ample
size
(PMD
patients:16
)Nodifferen
ces
betwee
nPMD
and
non-PMD
on
non-su
ppressionrates
Zub
enko
etal.
(199
6)/(+)
Molecu
lar,
MMSE,gen
omic
DNAisolatio
nfrom
bloodce
lls,DSM-III-R
57–8
810
9Inpatients,
geriatric
service,
USA
Adeq
uate
asse
ssmen
tSmalln
umber
of
PMD
patients,
14vs.34
non-PMD
versus
61no
n-dem
entedhe
althy
controls
PMD
patientsco
mpared
with
non-PMD:
↑ap
olip
oprotein
Etype4allele
four
times
greater
(and
twotim
esgreater
than
healthyco
ntrols)
Mey
erset
al.
(199
9)/(+)
Enz
yme,
HRSD,MMSE,
DBH
serum
activ
ityas
sessmen
tDSM-III-R
≥60
57Inpatients,
geriatric
acutese
rvice,
USA
Adeq
uate
asse
ssmen
t,threegroup
sofsu
bjects
Smallg
roup
size
s(15PMD,20
non-PMD,
and22
healthyco
ntrols)
PMD
patientsco
mpared
with
both
controlg
roup
s:↓
DBH
activ
ityat
admission(effec
tsize
0.71
)and
aftera
course
oftrea
tmen
tKoket
al.
(201
0)/(+)
Open
12-w
eek
controlledtrial,MADRS,
HRSD,CAT,CGI-I,DSM-IV
≥60
81Inpatients,
four
units
,theNethe
rland
sPMD
andno
n-PMD
patientsmatch
edforHRSD
totals
core,
number
ofphy
sica
lillne
sses
,an
dve
nlafax
inean
dno
rtrip
tyline
plasm
aleve
ls
Open
non-rand
omized
trea
tmen
twith
antip
sych
otic
s,sm
allg
roup
size
s,16
PMD
and24
non-PMD
patients
rece
ivingve
nlafax
ine,
24PMD
and17
non-PMD
patients
rece
ivingno
rtrip
tyline
Nodifferen
cesbetwee
nPMD
andno
n-PMD
patientswith
regard
totrea
tmen
teffic
acy
Mulsa
ntet
al.
(200
1)/(++)
Doub
le-blind,rand
omized
9wee
ks(m
ean)
controlledtrial,
HRSD,BPRS,GAS,CIRS,
MMSE,ARSSE,GMDA,
SEPSS,BAS,AIM
S,
DSM-III-R
≥50
30Inpatients,
USA
Robus
tas
sessmen
t,group
smatch
edin
allc
linical
param
eters
andno
rtrip
tyline
plasm
aleve
ls
Smallg
roup
size
s(14PMD
patients
with
perphe
nazine
plusno
rtrip
tyline,
16with
nortrip
tyline
plusplace
bo),
asse
ssmen
tafter
only9wee
ks
Res
pons
erates:
50%
intheno
rtrip
tyline
+perphe
nazine
group
,44
%in
theno
rtrip
tyline
+place
bo,differen
ceno
tsignific
ant;both
trea
tmen
tswelltolerated
Mey
erset
al.
(200
9)/(++)
Doub
le-blind,rand
omized
,co
ntrolled12
-wee
ktrial
(STOP-P
Dstud
y),SCID,
DAS,HRSD,CGI-S,
BPRS,SPS,CIBS,AIM
S,UKU,
MMSE,DSM-IV
≥60
Inpatientsan
doutpatients,
four
sites,
Can
ada,
USA
Robus
tas
sessmen
t,stud
ydes
ign,
adeq
uate
duration,
largesa
mple
(142
older
patients)
Attritionrate
45.2%
↑Rem
issionrates
forolanz
apine
+se
rtralineove
rolanz
apine+place
bo,
signific
antmetab
olic
sideeffects
Flintan
dRifa
t(199
8b)/(+)
Open
,no
n-rand
omized
,8-wee
ktrial,HRSD,
MMSE,Burvill’sPhy
sica
lIllne
ssSca
le,HRSD,
DSM-III-R
≥60
25Inpatientsan
doutpatients,
Can
ada
Dire
ctco
mparison
betwee
nECTan
dpha
rmac
otherap
y,im
plemen
tatio
noffurthe
rtrea
tmen
tstep
s
Smallg
roup
size
:8PMD
patients
with
nortrip
tyline
andperphe
nazine
and
17with
ECT,
shorttriald
uration
Res
pons
eratesfor
PMD
patients:
88.2%
forECT,
25%
forno
rtrip
tyline
+perphe
nazine
,50
%forno
rtrip
tyline
+perphe
nazine
+lithium
Mey
erset
al.
(200
1)/(++)
Doub
le-blind,
rand
omized
26-w
eektrial,
SCID,SADS,RSD,
HRSD,MMSE,
CAS,DSM-IV
≥50
28Outpatients,
USA
Adeq
uate
asse
ssmen
tan
dtriald
uration
Smallg
roup
size
s,15
PMD
patientswith
nortrip
tylineplus
perphe
nazine
versus
13with
nortrip
tyline
plusplace
bo
Relap
serateseq
ual
betwee
nPMD
patients
under
combination
trea
tmen
tor
antid
epressan
tmono
therap
y;
(Con
tinue
s)
789Psychotic depression in older people
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
Table1.
(Con
tinued)
Autho
rs(yea
r)/
qua
lityratin
gStudytype/
asse
ssmen
t/crite
riaAge
(yea
rs)
Sam
ple
Source
ofsa
mple
Stren
gths
Limita
tions
Key
findingsan
deffect
size
s
↑ex
trap
yram
idal
symptoms,
↑inciden
ceoftardivedyskine
sia,
↑nu
mber
offalls
inthegroup
with
perphe
nazine
Nav
arro
etal.
(200
8)/(�)
Single-blindrand
omized
two-yea
rtrial,HRSD,
MMSE,UKU,
nortrip
tylineleve
ls,DSM-IV
≥60
33Inpatientsan
doutpatients,
Spain
Dire
ctco
mparisonof
continua
tionco
mbined
ECT+no
rtrip
tylineve
rsus
nortrip
tylinemono
therap
y
Smallg
roup
size
s(16PMD
under
ECT
+no
rtrip
tylineve
rsus
17PMD
patients
under
nortrip
tyline)
PMD
patients
under
ECT+no
rtrip
tyline
versus
PMD
under
nortrip
tylineha
dsignific
antly
long
ermea
nsu
rvival
time;
nodifferen
ces
intolerability
Studiesthat
compared
thefeatures
ofolder
PMD
patientswith
those
oftheiryo
unger
coun
terparts
(prese
nted
inthesa
meorder
asthey
appea
rin
theRes
ults
section)
Kes
sing
,(200
6)/(+)
Epidem
iological
stud
y,ICD-10
≥18
1819
2Inpatientsan
doutpatientsin
all
settingsin
Den
mark
Robus
tmetho
dology,
largesa
mple
Retrosp
ectiv
ena
ture
ofthestud
y,probab
ledim
inishe
ddiagno
stic
accu
racy
compared
with
rese
arch
acad
emic
centers
PMD
patientswith
alate-ons
et(>
65ye
ars)
first
dep
ressiveep
isode:
↑preva
lenc
ethan
theirea
rly-ons
et(≤65
)coun
terparts
Flintet
al.
(201
0)/(+)
Clinical
(STOP-P
D)
stud
y,SCID,DAS,
SADS,HRSD,
CIRS-G
,BPRS,
MMSE,DSM-IV
≥18
259
Inpatientsan
doutpatients,
four
sites,
Can
ada,
USA
Robus
tas
sessmen
t,largesa
mple
of
117PMD
patients
aged
18–5
9ye
ars
and14
2ag
ed60
yearsorove
r
Sub
synd
romal
anxiety
notas
sessed
,reca
llbias,
lack
ofOCD
preva
lenc
eas
sessmen
t
Older
PMD
patients:
↓leve
loffreq
uenc
ies
ofacu
rren
tan
dlifetim
epan
icdisorder,
social
anxietyan
dposttrau
matic
stress
disorder
Gourne
lliset
al.
(201
1)/(+)
Clinical
stud
y,SCID,HRSD,
MMSE,phy
sica
lim
pairm
entratin
gsc
ale,
DSM-IV
≥18
99Inpatients,
twodep
artm
ents,
Greec
e
Adeq
uate
asse
ssmen
t(sem
i-structured
interview
includ
ed),
comparisonbetwee
nyo
ung(30),older
early
-ons
et(34)
and
older
late-ons
et(35)
PMD
patients
Comparisons
did
not
includ
eco
ntrol
forhe
alth
status
The
late-ons
etPMD
patients,
compared
with
youn
ger:
↑totalH
RSD
scores,
hypoch
ond
riasis
(effec
tsize
0.99
),gas
trointestinal
symptoms,
phy
sica
limpairm
ent,
freq
uent
delus
ions
of
somatic
(effec
tsize
0.48
)an
dim
pen
dingdisas
ter
conten
ts(effec
tsize
0.28
)an
d↓
delus
ions
ofguilt
(effec
tsize
0.31
)and
paran
oid
conten
t(effec
tsize
0.29
).The
group
ofolder
early
-ons
etPMD
patientshe
ldan
interm
ediate
positio
nbetwee
ntheyo
ung
early
-ons
etan
dolder
late-ons
etPMD
patientswith
regard
(Con
tinue
s)
790 R. Gournellis et al.
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
Table1.
(Con
tinued)
Autho
rs(yea
r)/
qua
lityratin
gStudytype/
asse
ssmen
t/crite
riaAge
(yea
rs)
Sam
ple
Source
ofsa
mple
Stren
gths
Limita
tions
Key
findingsan
deffect
size
s
tohy
poch
ond
riaca
lidea
tion,
gas
trointestinal
symptomsan
ddelus
ions
ofso
matic,guiltan
dparan
oid
conten
tMey
erset
al.
(200
9)/(++)
Doub
le-blind,
rand
omized
,co
ntrolled12
-wee
k(STOP-P
D)tria
l,DSM-IV
≥18
259
Inpatientsan
doutpatients,
four
sites,
Can
ada,
USA
Robus
tas
sessmen
t,largesa
mplesof
117PMD
patients
aged
18–5
9ye
ars
and14
2ag
ed≥6
0ye
ars
Attritionrate
45.2%
Comparab
leeffic
acy,
tolerability
andmetab
olic
effectsac
ross
agegroup
s,↑
gluco
seincrea
sein
youn
ger
PMD
patients
Flintet
al.
(201
3)/(++)
Doub
le-blind,rand
omized
,co
ntrolled12
-wee
k(STOP-P
D)tria
l,DSM-IV
≥18
259
Inpatientsan
doutpatients,
four
sites,
Can
ada,
USA
Robus
tas
sessmen
t,largesa
mplesof
117PMD
patients
aged
18–5
9ye
ars
and14
2ag
ed≥6
0ye
ars
Smalln
umber
of
partic
ipan
tswho
fell
(14with
olanz
apine
+place
bo,18
with
olanz
apine+se
rtraline)
Older
PMD
patients
weresignific
antly
more
likelyto
fall
++,“
high
”qu
ality
;+,“
medium”qu
ality
;�,“
low”qu
ality
;ACT,A
udito
ryCon
sonant
Trigram
s;AIM
S,Abn
ormal
InvoluntaryMovem
entScale;
ARSS
E,A
sbergRatingScaleforSide
Effe
cts;BAS,
Brief
Assessm
entS
chedule;BAS,
Barne
sAkathisiaScale;BPRS,
Brief
PsychiatricRatingScale;BNT,B
ostonNam
ingTest;CAMCOG,C
ambridge
Cog
nitiv
eExamination
fortheElderly;C
AS,
Clin
ical
Anxiety
Scale;
CAT,C
linical
Assessm
entof
Tolerability
Score;
CIR
S-G,C
umulativeIllnessRatingScaleforGeriatrics;CIB
S,Cum
ulativeIllnessBurden
Scale;CGI-I,Clin
icalGlobalImpression
ofIm
provem
ent;CGI-S,
Clin
icalGlobalImpression
s,Se
verity
ofIllnessScale;COAT,C
ontrolledOralA
ssociatio
nTest;CORE,“CORE”mea-
sure
ofpsycho
motor
disturbance;CRS,
CarrollRatingScaleforDepression;
DAS,
DelusionalA
ssessm
entS
cale;D
BH,d
opam
ineβhy
droxylase;DSS
T,9
0-secDigitSy
mbo
lSub
stitu
tion
Test;DST
,Dexam
ethasone
Supp
ressionTest;ECT,E
lectroconv
ulsive
The
rapy
;EEG,E
lectroen
ceph
alog
raph
y;FA
SVF,
F.A.S
.VerbalF
luen
cy;G
AS,
GlobalA
ssessm
entS
cale;G
MDA,
Geriatric
Movem
entDisorderAssessm
ent;HRSD
,Ham
ilton
RatingScaleforDepression;
H-R
TB,H
alstead-ReitanTestBattery;IADL,Instrum
entalA
ctivities
ofDaily
Living;
KBN,
KoreanBostonNam
ingTest;LCA,laten
tclassanalysis;M
ADRS,
Mon
tgom
ery-AsbergDepressionRatingScale;
MMSE
,MiniM
entalS
tate
Examination;
MRI,Magne
ticReson
ance
Imaging;
OCD,O
bsessive
Com
pulsiveDisorder;PCA,p
rincipal
compo
nentsanalysis;P
D,P
sychotic
Depression;
PMD,p
sychotic
major
depression
;PSE
,Present
StateExamination;
PSM
S,Phy
sicalS
elf-Mainten
ance
Scale;
RAVLT,R
eyAud
itory
VerbalL
earningTest;R-O
CFT
,Rey-O
sterreith
Com
plex
Figu
reTest;RMT,W
arring
tonRecog
nitio
nMem
oryTest;
RSD
,RatingScaleforDelusions;S
ADS,
Sche
dule
forAffe
ctiveDisorders
andSchizoph
renia;SC
ID,S
tructuredClin
ical
InterviewforDSM
;SEPSS
,Sim
pson
Extrapy
ramidal
Symptom
Scale;
SPAS,
Survey
Psychiatric
Assessm
entSche
dule;S
PECT,S
inglePho
tonEmission
Com
putedTom
ograph
y;SP
S,ScaleforPositive
Symptom
s;TMT
A,B
,TrailMakingTestA
andB;U
KU,U
KU
Side
Effe
ctRatingScale;W
AIS,W
echslerAdu
ltIntelligenceScales;W
CST
,Wisconsin
CardSo
rtingTest;W
MS-R,W
echslerMem
oryScale-Revised;Z
SDS,
Zun
gSe
lf-RatingDepressionScale.
791Psychotic depression in older people
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
At any rate, these studies suggest a specific distur-bance in executive functioning, with impairment ofpsychomotor speed, which is indicative of a moreglobal neuropsychological impairment, associatedwith cortical atrophy in frontal and temporal regions(discussed later). Other comparative studies includingolder people with PMD (Kunik et al. 1994), or PMDpatients over 45 years old (Lesser et al., 1991), havefound a more global cognitive impairment in thedomains of general intelligence attention, memory,visuospatial abilities, language function, psychomotorspeed and executive function.
A review and meta-analysis of studies of all ageranges (Flemming et al., 2004) concluded that PMDpatients are more impaired in executive functioning,psychomotor speed and verbal memory, processes thatare largely mediated by the medial temporal lobe andprefrontal cortex.
Risk factors and neurobiological correlates
Family studies. Simpson et al. (1999) reported thattheir older PMD patients, compared with non-PMDones, had more family members with a history ofdepression. However, other studies have failed toconfirm this finding (O’Brien et al., 1997; Gournelliset al., 2001; Lee et al., 2003).
Genetic studies. Zubenko et al. (1996) reported thatthe apolipoprotein E4 allele frequency was nearly fourtimes higher in PMD patients than in those with noPMD. These authors have suggested that the E4 allelemight be a risk factor for the development of PMDas well as for Alzheimer’s disease. A limitation of thisstudy is the small number (14) of PMD patientsinvolved.
Enzyme studies. Serum DBH activity in older PMDpatients has been found to be significantly lower than innon-PMD patients, both before and after hospital treat-ment (Meyers et al., 1999) (with an effect size of 0.71 atbaseline). Diminished DBH activity, found also in youn-ger patients with PMD,might be a risk factor of psychosisthrough increased central dopaminergic activity.
Neuroendocrine studies. No differences were found inthe O’Brien et al. (1997) study between PMD andnon-PMD patients on the dexamethasone suppressiontest (DST) (effect size 0.22). These findings might beattributed to a “ceiling effect,” given the overall highrate of non-suppression in both groups of the study(54%). Meyers et al. (1993) have also found high and
comparable rates of non-suppression in both olderPMD and non-PMD patients (60%), which howevernormalized after treatment. In a meta-analysis ofstudies conducted in younger patients, Nelson andDavis (1997) concluded that PMD was the depressionsubtype most strongly associated with non-suppressionof cortisol on DST.
Neuroimaging studies. Two MRI studies (Kim et al.,1999; Simpson et al., 1999) have reported that olderpeople with PMD have smaller frontal lobe volumes(effect sizes: 0.64 in the Kim et al., 1999, study; 0.62[right] and 0.83 [left] in the Simpson et al., 1999,study), smaller temporal lobe volumes (Simpsonet al.1999), more brain-stem atrophy and a moreenlarged third ventricle (Simpson et al., 1999), alongwith more hyperintensities in the pontine reticularformation (Simpson et al., 1999) than their non-PMD counterparts. These differences were associatedwith more impaired frontal lobe function and mentalprocessing speed, poorer physical health (Simpsonet al., 1999) and more vascular risk factors (O’Brienet al., 1997, study, effect size 0.26).
Treatment studies
Treatment of the acute phase: antidepressantmonotherapy.In controlled studies of older-age PMD patients, treat-ment response rates to antidepressant monotherapy werepoor, ranging from 18% (Baldwin, 1988) and 23%(Simpson et al., 1999) to 44% (Mulsant. et al., 2001). Incontrast, response rates of older-age non-PMD patientswere higher, ranging from 45% to 60% (Baldwin, 1988;Flint and Rifat, 1998b; Simpson. et al., 1999).
Combination therapy versus monotherapy. Kok et al.(2010) found no differences between PMD and non-PMD patients with regard to efficacy or tolerabilityparameters of an antidepressant–antipsychotic combi-nation for PMD patients and an antidepressantmonotherapy for non-PMD patients. The antidepres-sants administered in a double-blind, randomizeddesign were venlafaxine (in 16 PMD and 24 non-PMD patients) and nortriptyline (in 24 PMD and 17non-PMD patients). The open-label administrationof antipsychotics (haloperidol or risperidone) in thePMD group, along with the small study sample,constitutes the main limitations of this 12-week trial.
In addition, two other high-quality double-blind,randomized controlled pharmacological trials haveinvestigated remission rates in samples of only PMDpatients: Mulsant et al. (2001) reported a higher, although
792 R. Gournellis et al.
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
non-significant, efficacy of a nortriptyline–perphenazinecombination compared with a nortriptyline–placebocombination (50% vs. 44%). The small size of patientgroups (14 vs. 16) and the rather short duration of thestudy (mean 9weeks) are its main limitations. Further-more, Meyers et al. (2009), in a 12-week study, havefound that an olanzapine–sertraline combination wassuperior to an olanzapine–placebo combination.
In another open, 8-week, non-randomized study ofonly PMD patients, Flint and Rifat (1998b) reported25% efficacy of a nortriptyline–perphenazine combina-tion, which rose to 50% after lithium co-administration.This study has also reported a favorable outcome withelectroconvulsive therapy (ECT) in up to 88% of olderpatients with PMD.
Maintenance/continuation treatment. Two high-qualityfollow-up studies have investigated the efficacy, safetyand tolerability of continuation therapy in older-agePMD patients who had achieved remission withECT. In the first randomized double-blind study(Meyers et al., 2001), relapse rates over 6months didnot differ between patients receiving nortriptyline plusperphenazine and those receiving nortriptyline plusplacebo. Patients receiving the active combinationsuffered from more extrapyramidal symptoms, fallsand tardive dyskinesia. The second study (Navarroet al., 2008) found that PMD patients receiving monthlymaintenance ECT plus nortriptyline had a lower risk ofrelapse and recurrence than the nortriptyline subgroupat the end of the first year and a significantly betteroutcome at the end of a 2-year follow-up.
To sum up, there is strong evidence that ECT inolder PMD patients is highly effective. Furthermore,two randomized double-blind trials have shown thata combination of a first-generation antipsychotic plusa tricyclic antidepressant and a tricyclic antidepressantmonotherapy are equally effective, although the latteroption has fewer adverse effects.
Differences between older and younger psychotic majordepression patients
Epidemiological studies in outpatient and inpatient set-tings. Kessing (2006), in a large epidemiological studyin Denmark in both outpatient and inpatient settings,has shown that patients with a late-onset (>65 years)first depressive episode had a higher prevalence ofpsychosis than their early-onset counterparts (28.2%vs. 20% in outpatient settings and 52.6% vs. 38.6% ininpatient settings). The Kessing (2006) study includeda total of 18 192 patients with a single depressive episode,
and patients’ age of onset and age at index episode wereidentical. Limitations of this study were patients’ assess-ment in non-academic setting and the use of the Interna-tional Classification of Diseases 10th revision (WHO,1992) diagnostic guidelines for PMD, which includestupor. Thus, the findings of this studymay be not com-parable with other studies that used the DSM criteria.
Clinical differences. Flint et al. (2010) in a large sample ofPMD patients found that patients over 60 years exhibitedsignificantly lower comorbidity with current or past panicdisorder, social anxiety or posttraumatic stress disorder.The sample of this study derives from the Study of Phar-macotherapy of Psychotic Depression, which is a double-blind randomized controlled pharmacological study.
Furthermore, in a study from our group (Gournelliset al., 2011) that compared younger (<60 years) witholder (≥60 years) and both early-onset and late-onsetPMD patients, we reported several substantial differ-ences between these three groups. More precisely,both groups of older patients exhibited higher severitylevels than the younger group of hypochondriasis(with effect sizes ranging from 0.41 to 0.99) andphysical impairment. Moreover, late-onset patients,compared with younger patients, had higher meantotal HRSD scores, higher scores on hypochondriasis(effect size 0.99), more gastrointestinal symptoms,physical impairment and more delusions of somatic(effect size 0.48) and impending disaster content(effect size 0.28) but less frequent delusions of guilt (effectsize 0.31) and paranoid content (effect size 0.29). Thegroup of older early-onset PMD patients was found tohold an intermediate position between the young andolder late-onset PMD patients with regard to hypo-chondriacal ideation, gastrointestinal symptoms anddelusions of somatic, guilt and paranoid content. Therecall bias in the assessment of age of onset wasminimized because young and late-onset patientswere suffering from their first depressive episode.However, the groups had not been controlled forphysical impairment.
Treatment of the acute phase. In the double-blindrandomized trial of Meyers et al. (2009), the combina-tion of olanzapine–sertraline was well tolerated andequally effective in both younger and older adults;moreover, it was more effective than the combinationolanzapine–placebo. However, both age groups expe-rienced important metabolic side effects (increases inweight, triglyceride and cholesterol levels), especiallythe younger group. Moreover, older patients weremore likely to fall, although the incidence of falls wassmall (Flint et al., 2013).
793Psychotic depression in older people
Copyright # 2014 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 784–796
Discussion
Our literature search revealed 35 relevant studies; how-ever, only four of them were double blind and random-ized (Meyers et al., 2001; Mulsant et al., 2001; Meyerset al., 2009; Flint et al., 2013). Among the main limita-tions of the primary studies were the small number ofPMDpatients inmany of them and the fact that patientsin the clinical psychopathological studies were medi-cated at the time of their assessment. Further, althoughwe assessed standardized mean differences (effect sizes)between PMD and non-PMD patient groups in severalprimary studies from authors’ published data acrossclinical, neuropsychological and biological keyfeatures, we did not perform a meta-analysis, whichconstitutes an additional important limitation.
Is PMD in older people different from non-PMD?Older-age PMD patients consistently exhibit an overallhigher clinical depressive severity than older-age non-PMD patients with more psychomotor disturbance(agitation and/or retardation), more guilt feelings and amore unfavorable 2-year outcome with more relapsesand recurrences. Furthermore, older-age PMD patientshave more severe cognitive dysfunction, in particular inexecutive function and psychomotor speed. Thisimpairment in executive functioning, which underminesthe integration of perceptions and cognitions requiredfor reasoning, self-evaluation and reality testing (Kimet al. 1999), is associated with greater prefrontal andfrontotemporal atrophy. The prefrontal cortex is the ma-jor executive center of cognitive function, controls thelimbic system’s dopamine activity and is connected withthe hypothalamus. The more pronounced hyperactivityof hypothalamic–pituitary–adrenal axis in older-agePMD may result in hypercortisolemia, dopaminedysregulation, cognitive executive dysfunction and brainatrophy, especially in those patients with repeated PMDepisodes. Moreover, central dopaminergic activity maybe enhanced by the lower serum DBH activity found inolder PMDpatients (Meyers et al., 1999) and thus furthercontribute to the formation of psychotic symptoms.
Brain atrophy and cognitive disturbance might beassociated with emerging dementia, or alternatively,they might be precursors of PMD. The findings ofZubenko et al. (1996) support the view that PMDmay be an early manifestation of dementia; however,extant follow-up studies do not support this hypothesis(Baldwin, 1988; Flint and Rifat, 1998a). In addition, nostudies are as yet available on the prevalence of PMD inpatients with mild cognitive impairment, which may bea precursor of Alzheimer disease. However, psychoticfeatures are rare among these patients (Ceda et al.,2008). Interestingly, Simpson et al. (1999) have found
that PMD patients with a family history of depressionhad greater lobar atrophy. Despite PMD patients’prominent executive dysfunction, their memoryimpairment is less pronounced and usually is notdetected by screening tests for dementia (Baldwin,1995; O’Brien et al., 1997; Gournellis et al., 2001).Cognitive impairment in PMD is likely a trait than statefeature. In particular, Jeste et al. (1996) found nodifferences in cognitive impairment between PMDpatients (over 45 years) undergoing a depressive episodeand those without a current episode but with a historyof past episodes, whereas Hill et al. (2009) found—inyounger PMD patients—that their neuropsychologicalimpairment remained rather stable 6weeks after treat-ment. Likewise, the Simpson et al. (1999) study pro-vided evidence that the cognitive impairment in PMDis more a trait than state marker. However, only long-term longitudinal follow-up studies could inform usconclusively on the stability of PMD patients’ cognitiveimpairment and/or their possibly stronger vulnerabilityto develop dementia than their non-PMD counterparts.
Although PMD is deemed resistant to antidepressantmonotherapy, two double-blind, randomized, con-trolled pharmacological trials (Mulsant et al., 2001;Meyers et al., 2001) found no differences in the efficacyof an antidepressant–antipsychotic combination versusantidepressant monotherapy in both the acute andmaintenance treatments. These findings are in line withthose of a recent review and meta-analysis (Farahaniand Correll, 2012) of PMD across the full age span,which found that a combination of a first-generationantipsychotic plus a tricyclic antidepressant had noadvantage over tricyclic antidepressant monotherapy.
Overall, PMD in older people exhibits a greaterseverity than non-PMD in most key features (clinicalpicture, prognosis, neuropsychological findings, neu-roimaging correlates and enzyme findings), althoughnot in all (treatment response and suicidal behavior).
Is PMD in older people a “distinct clinical entity”?Support for the hypothesis that PMD in older peopleis a distinct clinical entity from non-PMD comesmainlyfrom clinical psychopathological studies, not frompharmacological ones. In particular, PMD has, bydefinition, psychotic features; however, these are highlyrecurrent across successive episodes, which constitute arather qualitative difference from non-PMD. Moreover,older-age PMD patients exhibit an overall greaterdepressive severity than their non-PMD counterparts.This difference is limited to particular symptoms, suchas psychomotor disturbance, guilt feelings and lack ofinsight. Of note, the same particular symptoms discrim-inate PMD from non-PMD in younger patients (seeSchatzberg and Rotschild, 1992, for a review). In
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addition, older PMD patients exhibit more severe cog-nitive abnormalities, even after adjustment for clinicaldepressive severity, and these are associated with moresevere prefrontal and frontotemporal atrophy. Further-more, older PMD patients exhibit increased E4 allelefrequency and diminished serum DBH activity.
Medium to large standardized differences (effectsizes) between PMD and non-PMD in individualstudies were detected on the features of psychomotordisturbance, overall depressive severity, propensity toexperience recurrent psychotic depressive episodes,executive dysfunction, DBH activity and frontal lobevolumes. These findings establish perhaps conclusivelythe higher overall severity of older-age PMD in compar-ison with non-PMD. However, available evidence isbased on a small number of studies of often smallpatient samples. Moreover, to the extent that thesedifferences remainmainly quantitative and their magni-tude far from consistently large, they are compatible withboth the “specifier” and “distinct entity” hypotheses onthe nosological status of older-age PMD.
The lack of differential treatment response in tworecent pharmacological trials undermines the “distinctentity” hypothesis. However, the sample sizes of theseclinical pharmacological studies comparing the effi-cacy of an antipsychotic plus antidepressant combina-tion versus antidepressant monotherapy were small.Furthermore, relevant data are virtually lacking inregard to premorbid function, familial transmission,electroencephalographic, sleep and neurotransmitterstudies. Overall then, available evidence is still insuffi-cient to evaluate conclusively the two rival hypotheseson the nosological status of older-age PMD.
Is PMD in older people different from PMD in youngeradults? The finding that the prevalence of PMD mightincrease with age is intriguing. This finding might beattributed to biological factors such as marked (mainlyfrontal) brain atrophy coupled with vascular risk factorsand medical comorbidity. These factors might exerttheir influence alone or combined with psychologicaladversities of old age (Kumar et al. 2000). Nevertheless,given the lack of an age effect in the Ohayon andSchatzberg (2002) large epidemiological study, this in-creased prevalence in outpatient and inpatient (mainly)settings might be attributed to referral biases in that onlythe most severe and psychotic forms of depression in theelderly are referred for inpatient treatment.
Important clinical differences have also been foundbetween young and early-onset and late-onset PMDpatients. However, these clinical differences might beattributed to severe adverse biological and psychosocialfactors and conditions of old age, such as poor health,brain atrophy, prospect of the end of life, financial
problems, social and interpersonal isolation and dimin-ished activities. Of note, a recent meta-analysis of 11studies (Hegeman et al., 2012) found that older depres-sives exhibit more hypochondriasis, agitation andgeneral and gastrointestinal somatic symptoms but lessguilt feelings and sexual interest than their youngercounterparts; these differences parallel those observedin older PMD patients (Gournellis et al., 2001). Finally,the comparable efficacy of pharmacological treatmentin both younger and older patients favors the view ofthe diagnostic similarity of PMD across the full age span.
Although limited, available evidence from compara-tive studies in younger and older PMD patientssuggests that their differences might be attributable toconcomitant psychobiological and social changes of oldage. However, it remains unclear whether these changesmerely shape the symptomatic expression of PMD oralso strengthen older peoples’ vulnerability to de novodevelopment of PMD in old age. Thus, again, long-termlongitudinal comparative studies exploring the differen-tial clinical, neuropsychological, neurobiological andtreatment response correlates in young, early-onset andlate-onset PMD patients are clearly warranted.
Conflict of interest
None declared.
Key points
• Psychotic major depression (PMD), comparedwith non-PMD, in older people is characterizedby higher severity across most clinically importantkey features.
• Available evidence is compatible with bothcontending hypotheses, namely that PMD is amore severe subtype of major depressive disorder(MDD) (the specifier hypothesis) or, alternatively,that PMD constitutes a distinct form of MDDdisorder (the “distinct entity” hypothesis). Furtherevidence is required in order to adjudicatebetween these two nosological hypotheses.
• An antipsychotic–antidepressant combination orantidepressant monotherapy constitute the firsttreatment options for both the acute treatment andshort-term maintenance phases. Electroconvulsivetherapy is particularly effective in PMD.
• The number of comparative studies investigatingdifferences between PMD in younger and olderpeople is very small. However, the differencesfound may be attributable to the concomitantpsychobiological and social changes of old age.
795Psychotic depression in older people
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