Psychotic major depression in older people: a systematic review

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

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(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


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.


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)



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)



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)



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)



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.



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



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).



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



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.



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Psychotic major depression in older people: a systematic review