Outcome of Schizophrenia in Relation to Brain Abnormalities

Outcome of Schizophrenia in Relation toBrain Abnormalities

by Wouter Q. Stool, HUleke E. HtdshoffPol, and Rene S. Kahn

AbstractThis article reviews the 21 studies that investigatedpossible relationships between structural brain abnor-malities and outcome in schizophrenia. Fifteen studiesused computer tomography to visualize brain mor-phology. In these studies, images were obtained of theventricles but not of specific brain regions. Theremaining six studies used magnetic resonance imag-ing, examining possible relationships between out-come, ventricular size, and specific brain regions. Oneout of two studies found relationships between brainstructure and outcome. The data suggest that theextent of ventricular enlargement in patients withschizophrenia may be related to outcome. No clearrelationship between outcome and changes in specificbrain regions was found. Apart from considerationsabout the methodology of measuring different brainregions, the procedure used to measure outcome isimportant Outcome, as it is assessed at various pointsduring the course of illness, may be variable and seemsto fluctuate during the first 10 to 15 years of disease.Significantly, to date no studies relating outcome tobrain structure have used patient samples with a dura-tion of illness longer than 15 years.

Key words: Outcome, course, neuroimaging.Schizophrenia Bulletin, 25(2):337-348,1999.

Although the cause of schizophrenia is unknown, cumula-tive evidence from structural Imaging studies using com-puted tomography (CT) and magnetic resonance imaging(MRI) suggests that brain abnormalities play an importantrole in the pathology of schizophrenia. The early echoen-cephalographic (Huber et al. 1979) and CT studiesreported ventricle volume enlargement (e.g., Johnstone etal. 1976). More recent studies found regional brain abnor-malities such as basal ganglia volume enlargement(Young et al. 1991; Chakos et al. 1994) and volumedecreases in frontal lobe areas (Williamson et al. 1991;

Raine et al. 1992; Buchanan et al. 1993; Harvey et al.1993; Seidman et al. 1994; Wible et al. 1995; Winn 1994),the temporal lobes, the hippocampus, amygdala, and thesuperior temporal gyms (Dauphinais et al. 1990; Suddathet al. 1990; Di Michele et al. 1992; Shenton et al. 1992;Bogerts et al. 1993; Shapiro 1993; Marsh et al. 1994;Rossi et al. 1994; Menon et al. 1995; Petty et al. 1995).

Some prodromal phase, with a slow increase of signsand symptoms, can be observed in most patients withschizophrenia (Yung and McGorry 1996). After onset,patients will usually display some continuing or intermit-ting symptoms that lead to social or occupational dysfunc-tion for the rest of their lives (Aro et al. 1995). However,the course of disease varies among individual patients.Some patients display a relatively stable course, whereasothers show a progressive increase of disability.Interestingly, the data from some followup studies suggestthat patients with schizophrenia have largely poor out-comes (Strauss and Carpenter 1972; Bland et al. 1976),while other studies suggest that outcome is relativelygood (Tsuang et al. 1979; Engelhardt et al. 1982;McGlashan 1984). The inconsistency of results may bedue to differences in study design and the large number offactors related to outcome, such as early age at onset andinsidious onset of disease (Remschmidt et al. 1994), malegender (Beiser et al. 1994), family history of schizophre-nia (Kendler et al. 1994), history of drug abuse and lackof compliance with medication (DeQuardo et al. 1994;Martinez Arevalo et al. 1994), and profound negativesymptomatology (Deister andJMarneros 1994; Fenton andMcGlashan 1994; Mayerhoff et al. 1994). Despite theprognostic value of some of these factors, the questionwhy some schizophrenia patients display a poor outcomeand other patients do not has not been resolved.

A combination of social and biological factors may

Reprint requests should be sent to Dr. W.G. Staal, Department ofPsychiatry, University Hospital Utrecht, Heidelberglaan 100, 3584 CX,Utrecht, The Netherlands, fax 0031-30-2505443.

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Schizophrenia Bulletin, Vol. 25, No. 2, 1999 W.G. Staal et al.

be involved in the explanation for the differences in out-come among patients with schizophrenia. In a number ofstudies, abnormalities in the biochemistry (homovanillicacid [HVA]/5-hydroxyindoleacetic acid [5-HIAA]) of thecerebrospinal fluid (CSF) have been found that may berelated to outcome (Szymanski et al. 1991; Lindstrom1996). The extent of morphological brain abnormalitiesalso may be related to outcome in schizophrenia. Indeed,results from a meta-analysis suggest that ventricularenlargement in patients with "major psychosis" may berelated to the cumulative duration of hospitalization (Razand Raz 1990). That review included 16 structural imag-ing studies examining ventricular volume. Apart fromcumulative duration of hospitalization, no other outcomemeasure was used. The ventricles were the only regions ofthe brain included in that meta-analysis and no specificbrain structure was investigated. This article reviews theEnglish-language literature on structural brain abnormali-ties in schizophrenia in relation to outcome. It includes allstudies that related any outcome measure to brain mor-phology, even those in which association between brainstructure and outcome was not the main topic. In case offollowup studies or other publications involving the samepatient sample, only the most recent published study wasincluded. Studies that used the number of hospitalizationsor the length of time in hospital as outcome measureswere included only when these measures were controlledfor duration of illness. The broad inclusion criteria used inthis article were chosen for two reasons. First, thatapproach permits an evaluation of studies that used differ-ent outcome measures and not only cumulative durationof hospitalization. Second, it includes studies measuring avariety of brain regions apart from the ventricles.

Studies Investigating Outcome andNeuroanatomy

Outcome Measurements. Different methods to mea-sure outcome have been used. Some studies used a singleitem such as duration of hospitalization, marital status, orwork history as an outcome measure. Other studies usedoutcome scales such as the Disability AssessmentSchedule (DAS), the Life Skills Profile (LSP), theStrauss-Carpenter outcome scales, the Global AssessmentScale (GAS), and the Quality of Life Scale (QLS).

The DAS (Jablensky et al. 1988) consists of fiveparts: overall behavior, social role performance, patient ina hospital (for hospitalized patients only), modifying fac-tors, and a global evaluation. The scores are based onfunctioning over die past month. The LSP (Rosen et al.1989; Parker and Hadzi-Pavlovic 1995) is a 39-item inter-

view, divided over five scales, assessing general outcomeover the past 3 months. The scales developed by Straussand Carpenter (1972, 1974) result from an analysis of sin-gle outcome predictors. The most reliable outcome pre-dictors, such as social functioning, employment, and timespent in a hospital, were selected to develop differentscales. These scales evaluate functioning over the past 12months of patients suffering from psychosis. GAS(Endicott et al. 1976) differs from die other scales becauseit uses a single rating scale with values that range from 1,representing the hypothetically sickest individual, to 100,the hypothetically healthiest individual. The QLS(Heinrichs et al. 1984) is specifically designed to addressdeficit symptoms in patients and assesses patients' func-tioning during the preceding 4 weeks. The scale focuseson patients outside institutions.

Brain Structure and Outcome. Twenty-one structuralimaging studies (see tables 1 and 2) investigated a rela-tionship between neuroanatomical changes and variousmeasurements of outcome in schizophrenia patients.Fifteen of these studies used CT to visualize the brainanatomy; the remainder employed MRI. hi the CT stud-ies, after selection of a reference line (e.g., the orbito-meatal line), a series of slices at intervals varying from 8to 13 mm was obtained. Usually one slice was selected inwhich die lateral and sometimes the third ventricle weremeasured. The slice demonstrating the ventricular systemat its largest was the one assessed for analysis. Two-dimensional data were obtained either by manually outlin-ing the ventricles or by measuring the distance betweentwo reference points in the ventricles.

Each of the six MRI studies used different imagingacquisition methods. Scanners included those operatingwith 0.5 T, 1.0 T, and 1.5 T magnets. Some of the MRIstudies used Tl-weighted images, which are best for visu-alizing anatomical structures, whereas others used T2-weighted images, which are more sensitive for detectingsubde tissue abnormalities such as tumors. Some studiesused a combination of Tl- and T2-weighted images. Inaddition to differences in slice thickness the planes usedfor analysis also varied in the MRI studies. Coronal,transaxial, and sagittal planes have been used. The post-processing in the MRI studies was accomplished usingsemiautomatic and automatic operations, thus allowingvolume measurements of the selected brain regions.

A relationship between outcome and brain morphol-ogy was found in 50 percent of the studies reviewed. Pooroutcome was usually related to more pronounced enlarge-ment of the ventricles and not to morphological changesof other brain regions. This is not surprising because moststudies used CT to visualize die brain. These CT studies

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Tab

le 1

. C

T s

tud

ies

an

d o

utc

om

e I

n s

ch

izo

ph

ren

ia

Au

tho

r

Wei

nber

ger

et a

l. 1979

And

reas

en e

t al.

1982

De

Lis

ieta

l. 1983

Bo

ron

ow

eta

l. 1985

Kol

akow

ska

et a

l. 1985

Loso

nczy

et a

l. 1986

Ka

nb

ae

tal.

1987

Kem

alie

tal.

1987

Gat

taze

t'al.

1988

Gro

up

s

— Larg

e V

BR

(n

=1

6)

Sm

all V

BR

(n

- 16)

Larg

e V

BR

(n -

7)S

mal

l VB

R (n

= 2

2)

— Poo

r ou

tcom

e(n

-20

)In

term

edia

te o

ut-

com

e (

n -

32)

Goo

d o

utco

me

(n-2

5)

Poo

r out

com

e(n

-9)

Goo

d ou

tcom

e(n

-19

)— La

rge

VB

R (

n=

13)

Sm

all V

BR

(n

o 3

7)

—

N

58 52 29 20 m

ale

10 fe

mal

e

49 m

ale

28 f

emal

e

28 m

ale

21 m

ale

16 fe

mal

e

22 m

ale

28 f

emal

e

12 m

ale

18 fe

mal

e

Ag

e

< 3

0 y

ears

{n =

30)

30

-40

year

s (n

= 1

5)4

0-5

0 ye

ars

(n =

13)

Larg

e V

BR

: 36.

69 ±

13.4

4 ye

ars

Sm

all V

BR

: 25.

31 ±

4.7

year

s

23.7

± 7

.3 y

ears

24.9

± 4

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ears

Poo

r ou

tcom

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yea

rsIn

term

edia

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ut-

com

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4.6

± 1

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year

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ood

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ome:

36.0

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Du

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Larg

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Poo

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Inte

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No

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Larg

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cor

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Tab

le 1

. C

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ies

an

d o

utc

om

e I

n s

ch

izo

ph

ren

ia (

Co

nti

nu

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Poo

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1)

Larg

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4)

Sm

all V

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Atr

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1)

127

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11 m

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Cul

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dman

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ber

of

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ase

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hang

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bra

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orph

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egio

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= G

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com

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d to

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raph

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ent

Sch

edul

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LS -

Qua

lity

of

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le.

q in

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Tab

le 2

. M

RI

stu

die

s a

nd

ou

tco

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In

sc

hiz

op

hre

nia

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tho

rG

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ps

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ge

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on o

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rain

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ion

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easu

reC

on

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ns

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mm

ent

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03 S. > (T Q o

And

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t al.

1990

—

Deg

reef

eta

l. 1992

—

Har

vey

et a

l. 1993

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e(n

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)In

term

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teou

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e

37 m

ale

18 fe

mal

e

25 m

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15 fe

mal

e

37 m

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11 fe

mal

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De

LJs

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l. 19

95

Tur

etsk

y e

tal.

1995

—

Bec

ker

eta

l. 1996

—

Mal

es 3

2.46

±8.

59 y

ears

Fem

ales

35 ±

10.7

5 ye

ars

24.1

±5

.7 y

ears

31.1

yea

rs(r

ange

18

-^8

)

Mal

es 1

0.3

year

sF

emal

es 1

3.1

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s

1.7

yea

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year

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mus

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ral v

entr

icle

sT

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le

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entr

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sT

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leF

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ntric

le

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erio

r ce

rebr

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lum

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ral t

obes

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hite

and

gre

ym

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pus/

amyg

dala

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cort

ical

nuc

lei

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ral v

entr

icle

s

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th o

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spita

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tion

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DA

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nem

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ent

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sign

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tric

ular

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rgem

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rela

ted

to G

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res

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29.7

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ears

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4.7

yea

rs

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rs (

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Cha

nge

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e of:

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l ven

tric

les

Cor

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sum

Sup

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r te

mpo

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gyru

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myg

dala

/hip

poca

mpu

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auda

te

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ci C

SF

Ven

tric

les

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l lob

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icle

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No

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ut-

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e

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f I- Co p

Not

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bal A

sses

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t S

cale

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Dis

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ched

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MR

I = m

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investigated outcome in relation to the size of the ventri-cles or sometimes the amount of sulcal fluid, but not inrelation to specific brain regions.

In contrast, five of the six MRI studies examined apossible relationship between outcome and specific brainregions. The single MRI study that did not investigatespecific brain regions (Degreef et al. 1992) involved 40first-episode schizophrenia patients diagnosed accordingto the Research Diagnostic Criteria (RDC; Spitzer et al.1978). By means of a 1.0 T scanner, Tl-weighted imageswere obtained from 3.1 mm thick contiguous slices.Ventricular size was related to outcome scores on theGAS.

The MRI studies that measured volumes of specificbrain regions and related these measures to outcome showdiffering results. One of these studies (Andreasen et al.1990) measured the volume of the frontal lobes and thethalamus by means of a 0.5 T scanner producing Tl- andT2-weighted 1 cm thick contiguous cuts. The patient sam-ple consisted of 55 DSM-IH-R (American PsychiatricAssociation 1987) schizophrenia patients. No relationshipwas found between these specific regions and outcome,which was expressed as cumulative duration of hospital-ization. Another study (DeLisi et al. 1995) obtained thevolume of the temporal lobes, the superior temporalgyrus, the hippocampus and amygdala, the caudatenucleus, and the corpus callosum in 20 first-episodepatients after 4 years. This study was specifically designedto repeatedly measure changes in brain structure duringthe course of schizophrenia. Scans were made at time ofthe first episode, up to 4 years after onset. Ten patientswere diagnosed with schizophrenia, one patient withschizophreniform disorder, and the others with schizo-affective or affective disorder, according to DSM-HI-R.In this study, 5 mm thick slices at 2 mm intervals weregenerated by means of a 1.5 T scanner, 4 years after onsetof psychosis. Thus, Tl- and T2-weighted images of thebrain were obtained. An exploratory data analysis re-vealed a significant negative correlation between left hip-pocampus/amygdala volume decrease and the GAS, andbetween duration of hospitalization and right ventricularvolume. When corrected for the number of tests per-formed, however, none of the correlations found remainedsignificant. Interestingly, in the 2-year followup study ofthis patient sample (DeLisi et al. 1992), a relationshipbetween outcome and ventricular size was found.

A third such MRI study (Turetsky et al. 1995) foundno relationship between outcome, measured by theStrauss-Carpenter scale (Strauss and Carpenter 1974), andthe frontal and temporal lobes. The patients in that studywere 71 DSM-III-R diagnosed schizophrenia patients.T2-weighted images of the brain were acquired on a 1.5 Tscanner producing 5 mm slices with no interslice gaps. In

another MRI study (Harvey et al. 1993), volume of thetemporal lobes, the hippocampus and amygdala, the ante-rior cerebral region, the subcortical nuclei, die ventricles,and the sulcal fluid was measured. A 0.5 T scanner pro-duced contiguous 5 mm thick slices. Using patients' DASscores, the study compared three groups of DSM-III-Rschizophrenia patients with favorable (n = 14), intermedi-ate (n - 20), and poor outcome (n = 14). Decreased ante-rior cortical volume and increased sulcal fluid wererelated to poor outcome patients. Finally, the most recentMRI study investigating the temporal lobes, the hip-pocampus/amygdala, and the lateral and third ventriclesfound a relationship between the GAS and enlargement ofthe third ventricle (Becker et al. 1996). Tl-weightedimages of the brain were obtained for 20 DSM-III-Rschizophrenia patients using a 1.5 T scanner that provided4 mm contiguous slices.

In summary, MRI technique, as compared with CT-scanning, allows more detailed measurements of the brainand makes it possible to measure specific brain regions.However, regional brain abnormalities were related tooutcome in only one of the MRI studies (Harvey et al.1993), whereas ventricular enlargement and increased sul-cal fluid were related to outcome in three of the six MRIstudies (Degreef et al. 1992; Harvey et al. 1993; Becker etal. 1996).

Subgroups of Patients. Some studies created sub-groups of patients. In four studies, the patient groupswere based on differences in ventricular size (Andreasenet al. 1982; DeLisi et al. 1983; Kemali et al. 1987; Vita etal. 1991); in other studies they were based on differencesin outcome, for example, a poor, an intermediate, and agood outcome group (Kolakowska et al. 1985; Losonczyet al. 1986; Keefe et al. 1991; Harvey et al. 1993).

The four studies using subgroups with different ven-tricular size all used the same procedures to create thesesubgroups. First, they calculated the mean from a controlgroup of normal subjects. Next, they created groups thatvaried in the number of standard deviations from themean. Thus, groups with small ventricles could be com-pared with groups with larger ventricles. Three of the fourstudies found that die groups with the most pronouncedenlargement showed decreased scores on outcome scales(DeLisi et al. 1983; Kemali et al. 1987; Vita et al. 1991).In addition to creating large and small ventricular brainregion (VBR) groups, Vita et al. created two groups withdifferences in cortical atrophy. CT scans were obtainedfor 18 patients diagnosed with schizophrenia accordingDSM-III-R. Cortical atrophy was determined with refer-ence to a 4-point scale (from 0 = no atrophy to 3 = severeatrophy) in 17 patients. Outcome was measured 2 yearsafter scanning using the Strauss-Carpenter outcome scale.

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Patients with ventricular enlargement were more oftenunemployed. Moreover, cortical atrophy was significantlyrelated to poor outcome scores on the Strauss-Carpenterscale. Kemali et al. obtained CT scans with 10 mm slicesfrom a sample of 50 DSM-lII (American PsychiatricAssociation 1980) schizophrenia patients. They measurethe patients' outcome with the DAS. The study by DeLisiet al. included 29 DSA/-///-diagnosed schizophreniapatients followed up for more than 4 years after their firstepisode. CT was performed with 8 mm slices, and theStrauss-Carpenter outcome scale and the GAS were usedto measure outcome. The one study (Andreasen et al.1982) that did not find a poor outcome in the large VBRgroup included 52 DSM-III schizophrenia patients. Slicethickness was 8 mm. The only finding was mat patients inthe small VBR group were less often married. However,the small VBR group in this study is relatively youngcompared to the large VBR group. This finding, therefore,could also be a result of age.

Among the studies investigating brain morphology ingroups with differing outcome, tfiree (Kolakowska et al.1985; Losonczy et al. 1986; Keefe et al. 1991) of four(Harvey et al. 1993) showed that the poor outcome groupdisplayed more extensive enlargement of the lateral ven-tricles. Keefe et al. assessed scans producing 10 mmslices in 127 patients with schizophrenia according toRDC or Feighner diagnostic criteria. The patient samplewas divided into one group that fulfilled Kraepelinian cri-teria and one that did not. The Kraepelinian group met thefollowing criteria for the past 5 years: continuous hospi-talization, no useful work, and no remission of symptoms.These criteria were also used in the study by Losonczy etal. to divide 28 schizophrenia patients into a severelydeteriorated group (n - 9) and a group with no severedeterioration (n = 19). Using a three-point scale to esti-mate patients' functioning, Kolakowska et al. formed poor(n - 20), intermediate (n = 32), and good (n = 25) out-come groups from a sample of 77 schizophrenia patientsdiagnosed according to RDC. CT slices were taken at 13mm intervals. In the one study where no difference inVBR outcome groups was demonstrated (Harvey et al.1993), unemployment as single item was related todecreased anterior cortical volume and increased amountof sulcal fluid.

In 75 percent of the studies that used subgroups ofpatients, a relationship between brain morphology andoutcome is found. The studies used at least two single out-come measures, such as duration of hospitalization andmarital status, or a scale to measure outcome.

Remaining Studies. The remaining eight CT studiesdid not create subgroups of patients, but investigated apossible correlation between VBR of the whole patient

sample and outcome. Seven of the eight studies(Weinberger et al. 1979; Boronow et al. 1985; Gattaz etal. 1988; Kanba et al. 1987; Cullberg and Nyback 1992;Jaskiw et al. 1994; Goldman et al. 1996) found no signifi-cant correlation between VBR and outcome.

In the first of these 8 studies (Weinberger et al. 1979),73 RDC-diagnosed patients were scanned using a slicethickness of 8 mm. Schizophrenia was diagnosed in 65patients, whereas 4 patients suffered from a schizo-affec-tive disorder, 3 from an affective disorder, and 1 frommental retardation. Cumulative duration of hospitalizationwas used as the outcome measure. Although this study didnot establish a relationship with outcome, another study(Weinberger et al. 1980) that included partially the samepatient sample found that poor response on neurolepticdrug therapy was related to ventricular enlargement. Thesecond of these eight CT studies (Boronow et al. 1985)obtained images from 10 mm slices from 30 patients.According to RDC, 23 were diagnosed with schizophreniaand 7 with a schizoaffective disorder. Patient outcomewas defined as the cumulative duration of hospitalization.In another such study (Kanba et al. 1987), 37 DSM-IIIschizophrenia patients were scanned. Slices at 10 mmintervals were obtained to visualize the ventricles. Theoutcome measure used was the cumulative duration ofhospitalization. A fourth study (Gattaz et al. 1988) wasdesigned to relate CT measures with response to drugtherapy in 30 RDC schizophrenia patients. We wereunable to find information on the thickness of slices pro-duced by the scans. Although patients with abnormal CTparameters showed a poor response to drug therapy, norelation with outcome, as measured by cumulative dura-tion of hospitalization, was found. The study by Cullbergand NybMck (1992) involved 33 DSM-II1-R schizophre-nia patients. Scans with 10 mm cuts were taken and out-come was measured by cumulative duration of hospital-ization. In the Jaskiw et al. study (1994), the QLS wasused to evaluate outcome in seven patients with schizo-phrenia, diagnosed according to the DSM-III—R criteria.CT scans with 8 mm slices were taken. Patients were fol-lowed up for 7 years to determine whether ventricularenlargement is progressive after onset of schizophrenia.The last-of the CT studies that-did not find a significantcorrelation between outcome and VBR and did not createsubgroups of patients (Goldman et al. 1996) included 59DSM-III-R schizophrenia subjects. Ventricular size wasmeasured using scans with 10 mm slices. Patients' func-tioning was evaluated with the Strauss-Carpenter outcomescale.

One of the 8 CT studies that did not use subgroups ofpatients found a significant correlation between VBR andoutcome. Klausner et al. (1992) obtained scans with 10mm cuts in 88 DSM-III-R schizophrenia patients.

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Outcome was measured using the GAS and number ofhospitalizations.

Discussion

This article reviews studies that investigated brain mor-phology and outcome in patients with schizophrenia. Thedata suggest that a relationship may exist between theextent of ventricular enlargement and outcome in schizo-phrenia patients. Because these studies used a variety ofmethods, they do not allow definitive conclusions. Wereviewed all studies that examined outcome and brainpathology, even if that was not the main focus of a partic-ular study. Indeed, limiting the review to studies thatfocused primarily on outcome and brain pathology wouldhave produced a more consistent result (i.e., six of eightstudies that investigated primarily outcome did find a rela-tionship between brain structure and outcome).

Whether reduced volumes for specific brain regionsare associated with poor outcome is unclear. It could bespeculated that regional brain differences are more likelyto be related to specific outcome measures, whereas aspe-cific measures of brain pathology such as ventricularenlargement are more likely to be related to global out-come measures. This may explain the fact that a relation-ship with outcome is found mainly with ventricularmeasures.

Increased ventricular volume indicated poor outcomeboth in studies where outcome was measured by variousscales as well as in studies that used a single item as anoutcome measure. All the outcome scales used have anacceptable interrater reliability and provide a more detailedevaluation of outcome compared with measurements basedon single items. Also, single-item outcome measurementsmay more often be affected by variables not associatedwith schizophrenia, such as fluctuations in hospital admin-istrative needs or sociocultural changes. Indeed, the sevenstudies that used hospitalization as the outcome measurefound no relationship with brain structure.

Ventricular enlargement is a global measure of brainpathology that implies a reduction in brain tissue volume.Whether this reduction is caused by an arrest in the devel-opment of specific brain regions or by active tissue loss isunclear. Several brain regions may be involved in thepathological process responsible for this volume reduc-tion, such as the frontal and temporal lobes, hippocam-pus/amygdala, superior temporal gyrus, and basal ganglia.In one study a relationship between decreased anteriorbrain volume and poor outcome was found (Harvey et al.1993).

It may be fruitful to study frontal lobe structure inrelation to outcome in light of recent evidence from struc-

tural and functional imaging studies suggesting that thefrontal lobes are related to one of the core symptoms inschizophrenia, that is, the negative symptoms (Williamsonet al. 1991; Raine et al. 1992; Wolkin et al. 1992;Buchanan et al. 1993; Shioiri et al. 1994). A study byBaare" et al. (1996) showed that diminished volume of asubregion of the frontal lobes, the orbitofrontal lobe, wasrelated to increased negative symptomatology. In turn,outcome in patients with schizophrenia may be related tothe degree of negative symptomatology (Deister andMarneros 1994; Fenton and McGlashan 1994; Mayerhoffet al. 1994). Because negative symptomatology may belinked to structural and functional abnormalities in thefrontal lobe as well as to poor outcome, a relationshipbetween poor outcome and frontal lobe dysfunction mayexist.

In contrast, positive symptoms appear to be associ-ated with abnormalities in regions of the brain other thanthe frontal lobes. Results from MRI studies indicate thatpositive symptomatology may be related to volume loss inthe upper part of the temporal lobes, the superior temporalgyrus (Shenton et al. 1992; Rossi et al. 1994; Menon et al.1995; Petty et al. 1995). This is consistent with the devel-opment of positive symptoms in some cases of temporallobe epilepsy and their appearance following damage ofthe temporal lobe area (Flor Henry 1969). The finding thatpositive symptoms may not be related to outcome couldbe explained by the fact that the positive symptoms aremore responsive to treatment with typical neurolepticmedication (Kane et al. 1988). Thus, positive symptomsmay have only a minor effect on outcome as compared tonegative symptoms.

Apart from considerations about the methods used tomeasure specific brain regions, the procedure used tomeasure outcome is important. Outcome, as it is assessedat various points during the course of illness, may be vari-able (Carpenter and Kirkpatrick 1988; Marengo 1994).Data from long-term followup studies indicate that, in thefirst 10 to 15 years of disease, outcome may be unstable(Harding 1988; McGlashan 1988; Breier et al. 1991) andthat most of the decline in functioning occurs during thisperiod. Therefore, studies examining a possible relation-ship between outcome and brain structure should be con-ducted in patients where outcome has stabilized (i.e., aftermore than 15 years of illness).

Significantly, to date no CT or MRI studies linkingoutcome to brain structure have been performed usingpatient samples with a duration of illness longer than 15years. Some information on this subject can be obtainedfrom other studies. In an echoencephalographic study, partof a large followup study (Huber et al. 1979), schizophre-nia patients with an average duration of illness of morethan 22 years were examined. Poor outcome patients had

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larger transverse diameters of the third ventricle inechoencephalograms than patients with a better outcome.The long-term followup studies suggest that outcome inpatients with schizophrenia may vary with length of ill-ness. Whether structural brain abnormalities in schizo-phrenia change during the course of illness is unclear,although a recently published study (DeLisi 1997) sug-gests that the brain abnormalities seen in schizophreniamay be progressive. This implies that differences in theduration of patients' illness may influence the results ofstudies. Studies surveying chronically ill patients mighthave selected subjects with more structural changes inbrain size and with different outcomes than those studiesthat selected patients with a recent onset of disease (e.g.,first-episode studies).

In conclusion, ventricular enlargement in patientswith schizophrenia may be related to poor outcome.However, because ventricular enlargement only globallyreflects structural brain abnormalities, specific brainregions such as the frontal lobes need to be investigated inrelation to outcome, particularly when defined after atleast 15 years of illness.

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The Authors

Wouter G. Staal, M.D., is a Research Fellow inPsychiatry, Hilleke E. Hulshoff Pol, Ph.D., is AssistantProfessor of Psychiatry, and Rene S. Kahn, M.D., Ph.D.,is Professor of Psychiatry and Chairman of theDepartment of Psychiatry, University Hospital Utrecht,Utrecht, The Netherlands.

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Outcome of Schizophrenia in Relation to Brain Abnormalities

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