Neurobiology of Early Psychosis Bjp

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CHRISTOS PANTELIS

MATCHERI S. KESHAVAN, GREGOR BERGER, ROBERT B. ZIPURSKY, STEPHEN J. WOOD andNeurobiology of early psychosis

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BackgroundBackground Neurobiological studiesNeurobiological studies

ofthe earlycourse of psychoses, such asofthe earlycourse of psychoses, such as

schizophrenia, allow investigation of schizophrenia, allowinvestigation of

pathophysiology withoutthe confounds of pathophysiology withoutthe confounds of

illness chronicityand treatment.illness chronicityand treatment.

AimsAims To review the recent literature onTo review the recent literature onthe biologyof the earlycourse of the biologyof the earlycourse of

psychoses.psychoses.

MethodMethod We carried out a criticalWe carried out a critical

appraisal ofthe recent findings intheappraisal oftherecent findingsin the

neurobiology of early psychoses, usingneurobiology of early psychoses, using

structural, functional and neurochemicalstructural, functional and neurochemical

imaging techniques.imaging techniques.

ResultsResults Brain structuralalterations areBrain structural alterations are

present earlyin theillness and may pre-present earlyin theillness and may pre-

date symptom onset.Some changes,date symptom onset.Some changes,

notably those infrontal and temporalnotably those infrontal and temporal

lobes, can progress during the earlylobes, can progress during the early

phases ofthe illness.Functionalandphases ofthe illness.Functional and

neurochemicalbrain abnormalitiescanneurochemicalbrain abnormalities can

also be seen in the premorbid andthealso be seen inthe premorbid andthe

early phases oftheillness. Some, althoughearly phases oftheillness. Some, although

not all, changes can be trait-likewhereasnot all, changes can be trait-like whereas

some others might progress during thesome others might progress during the

early years.early years.

ConclusionsConclusions A better understandingA better understandingof suchchanges, especially during theof suchchanges, especiallyduring the

criticalperiods ofthe prodrome, aroundcritical periods ofthe prodrome, around

thetransitionto the psychotic phase andthetransitionto the psychotic phase and

during the earlyphases ofthe illnessisduring the earlyphases oftheillnessis

crucial forcontinued researchintocrucial forcontinued researchinto

preventive intervention strategies.preventive intervention strategies.

Declaration of interestDeclaration of interest None.None.

Despite over a century of research, theDespite over a century of research, the

pathophysiology of schizophrenia and re-pathophysiology of schizophrenia and re-

lated psychotic disorders remains unclear.lated psychotic disorders remains unclear.

Early observations of the neurobiology of Early observations of the neurobiology of

schizophrenia and related psychoses largelyschizophrenia and related psychoses largely

relied either on post-mortem studies of relied either on post-mortem studies of

mostly older patients with chronic schizo-mostly older patients with chronic schizo-

phrenia or on neuroimaging studies of phrenia or on neuroimaging studies of patients with established schizophrenia,patients with established schizophrenia,

many of whom were treated with medica-many of whom were treated with medica-

tions. These findings, therefore, are limitedtions. These findings, therefore, are limited

by the potential confounds of the effects of by the potential confounds of the effects of

ageing, illness chronicity and medication.ageing, illness chronicity and medication.

Studies of individuals in the earlyStudies of individuals in the early

phases of schizophrenia avoid such con-phases of schizophrenia avoid such con-

founds and allow us to elucidate the effectsfounds and allow us to elucidate the effects

of primary illness processes (Keshavan &of primary illness processes (Keshavan &

Schooler, 1992). First, these studies allowSchooler, 1992). First, these studies allow

prospective longitudinal evaluation of theprospective longitudinal evaluation of the

course and predictive value of the neuro-course and predictive value of the neuro-

biological changes. Most neurobiologicalbiological changes. Most neurobiologicalstudies in early psychosis do not considerstudies in early psychosis do not consider

the heterogeneity of the initial presentation,the heterogeneity of the initial presentation,

and this may explain some of the contradic-and this may explain some of the contradic-

tory findings. Early psychosis represents atory findings. Early psychosis represents a

broad range of possible diagnostic andbroad range of possible diagnostic and

prognostic categories that include, but areprognostic categories that include, but are

not limited to, the more traditionallynot limited to, the more traditionally

studied schizophrenia and schizoaffectivestudied schizophrenia and schizoaffective

disorder. Only about half of patients withdisorder. Only about half of patients with

early psychosis (Hardingearly psychosis (Harding et al et al , 1987;, 1987;

Moller & Von Zerssen, 1995) will developMoller & Von Zerssen, 1995) will develop

a chronic form of schizophrenia with poora chronic form of schizophrenia with poor

levels of functioning and major impairmentlevels of functioning and major impairmentin cognition. Second, not everyone who hasin cognition. Second, not everyone who has

features of the prodromal phases of thefeatures of the prodromal phases of the

illness goes on to develop the psychotic ill-illness goes on to develop the psychotic ill-

ness. Studies of the prodromal and earlyness. Studies of the prodromal and early

course of psychotic disorders provide ancourse of psychotic disorders provide an

opportunity to elucidate the neuro-opportunity to elucidate the neuro-

biological mechanisms responsible forbiological mechanisms responsible for

the transition from the prodrome tothe transition from the prodrome to

schizophrenia or other psychotic disorders.schizophrenia or other psychotic disorders.

The importance of studying the neuro-The importance of studying the neuro-

biology of early psychosis stems from thebiology of early psychosis stems from the

recent emphasis on early identificationrecent emphasis on early identification

and preventive intervention in disordersand preventive intervention in disorderssuch as schizophrenia (Wyatt, 1991;such as schizophrenia (Wyatt, 1991;

LiebermanLieberman et al et al , 2001). The onset of psy-, 2001). The onset of psy-

chotic symptoms in schizophrenia is oftenchotic symptoms in schizophrenia is often

preceded by a premorbid phase, charac-preceded by a premorbid phase, charac-

terised by subtle neuromotor and cognitiveterised by subtle neuromotor and cognitive

impairments that may date back to birth.impairments that may date back to birth.

The prodromal phase is associated withThe prodromal phase is associated with

cognitive impairment, affective symptoms,cognitive impairment, affective symptoms,social withdrawal, and/or sub-thresholdsocial withdrawal, and/or sub-threshold

(attenuated) positive symptoms. Recent(attenuated) positive symptoms. Recent

studies suggest that more than a third of studies suggest that more than a third of

patients presenting with prodromalpatients presenting with prodromal

symptoms, if untreated, ‘convert’ to schizo-symptoms, if untreated, ‘convert’ to schizo-

phrenia or a related psychotic disorderphrenia or a related psychotic disorder

(McGorry(McGorry et al et al , 2002; Yung, 2002; Yung et al et al , 2003)., 2003).

The duration of the psychotic symptomsThe duration of the psychotic symptoms

prior to treatment typically averages aboutprior to treatment typically averages about

a year, and the average prodromal durationa year, and the average prodromal duration

is about 3 years across studies (McGlashan,is about 3 years across studies (McGlashan,

1996). If untreated, the early phases1996). If untreated, the early phases

of schizophrenia result in a progressiveof schizophrenia result in a progressiveaccrual of morbidity; the longer the periodaccrual of morbidity; the longer the period

of untreated illness, the worse appears toof untreated illness, the worse appears to

be the outcome (Liebermanbe the outcome (Lieberman et al et al , 2001;, 2001;

McGorryMcGorry et al et al , 2001; Keshavan, 2001; Keshavan et al et al ,,

20032003aa). Studies of patients at ‘ultra-high). Studies of patients at ‘ultra-high

risk’ of psychosis and in the early phaserisk’ of psychosis and in the early phase

schizophrenia and related disorders areschizophrenia and related disorders are

critical for our prevention and earlycritical for our prevention and early

intervention efforts, since the deteriorativeintervention efforts, since the deteriorative

processes of this illness may set in duringprocesses of this illness may set in during

this critical time window (McGlashan,this critical time window (McGlashan,

1996).1996).

Neurobiological investigations in earlyNeurobiological investigations in earlypsychosis have greatly benefited frompsychosis have greatly benefited from

recent conceptual models that haverecent conceptual models that have

suggested a number of testable hypotheses.suggested a number of testable hypotheses.

The traditional (or ‘early’) neurodevelop-The traditional (or ‘early’) neurodevelop-

mental model posits abnormalities in foetalmental model posits abnormalities in foetal

brain development as mediating the failurebrain development as mediating the failure

of brain functions in early adulthood. Anof brain functions in early adulthood. An

array of data, such as an increased rate of array of data, such as an increased rate of

obstetric complications, minor physicalobstetric complications, minor physical

abnormalities, neurological soft signs andabnormalities, neurological soft signs and

subtle behavioural abnormalities in chil-subtle behavioural abnormalities in chil-

dren who later developed schizophrenia,dren who later developed schizophrenia,

support this model for schizophrenia insupport this model for schizophrenia inparticular, but most likely also for a rangeparticular, but most likely also for a range

of other neuropsychiatric disorders. How-of other neuropsychiatric disorders. How-

ever, their prevalence in the non-affectedever, their prevalence in the non-affected

population is substantial and their positivepopulation is substantial and their positive

predictive value for the development of predictive value for the development of

schizophrenia is limited (Murray & Lewis,schizophrenia is limited (Murray & Lewis,

1987; Weinberger, 1987). The illness onset,1987; Weinberger, 1987). The illness onset,

typically in adolescence and early adult-typically in adolescence and early adult-

hood, is suggestive of brain maturationalhood, is suggestive of brain maturational

abnormality around or prior to the onsetabnormality around or prior to the onset

of psychosis. Excessive synaptic/dendriticof psychosis. Excessive synaptic/dendritic

pruning around the peri-onset phase of pruning around the peri-onset phase of

illness (Feinberg, 1982, 1990; Keshavanillness (Feinberg, 1982, 1990; Keshavanet al et al , 1994) has been postulated as one, 1994) has been postulated as one

s 8s 8

B R I T I S H J O U R N A L O F P S Y C H I A T RYB R I T I S H J O U R N A L O F P S Y C H I A T RY ( 2 0 0 5 ) , 1 8 7 ( s u p p l . 4 8 ) , s 8 ^ s 1 8( 2 0 0 5 ) , 1 8 7 ( s u p p l . 4 8 ) , s 8 ^ s 1 8

Neurobiology of early psychosis*Neurobiology of early psychosis*

MATCHERI S. KESHAVAN, GREGOR BERGER, ROBERT B. ZIPURSKY,MATCHERI S. KESHAVAN, GREGOR BERGER, ROBERT B. ZIPURSKY,

STEPHEN J. WOOD and CHRISTOS PANTELISSTEPHEN J. WOOD and CHRISTOS PANTELIS

*Paper presented attheThird International Early*Paper presented attheThird International Early

Psychosis Conference,Copenhagen,Denmark,Psychosis Conference,Copenhagen,Denmark,

September 2002.September 2002.



N E U R O B I O LO G Y O F E A R L Y P S Y C H O S I SN E U R O B I OL O G Y O F E A R L Y P S Y C H O S I S

potential pathological mechanism under-potential pathological mechanism under-

pinning the onset of psychosis in adoles-pinning the onset of psychosis in adoles-

cence or early adulthood, but thecence or early adulthood, but the

understanding of the underlying neuro-understanding of the underlying neuro-

biology of this phase of illness is stillbiology of this phase of illness is still

limited. The idea that active biologicallimited. The idea that active biological

changes could occur during the prodromalchanges could occur during the prodromalphase or the often lengthy period of phase or the often lengthy period of

untreated psychosis has led to the neuro-untreated psychosis has led to the neuro-

degenerative models (Garver, 1987;degenerative models (Garver, 1987;

McGorry & McConville, 2000; LiebermanMcGorry & McConville, 2000; Lieberman

et al et al , 2001). Unifying models have also, 2001). Unifying models have also

been proposed and include two (Bayerbeen proposed and include two (Bayer et et

al al , 1999) and three hit models (Keshavan, 1999) and three hit models (Keshavan

& Hogarty, 1999; Velakoulis& Hogarty, 1999; Velakoulis et al et al , 2000;, 2000;

PantelisPantelis et al et al , 2003, 2003cc) of schizophrenia;) of schizophrenia;

environmental factors, such as illicit drugenvironmental factors, such as illicit drug

use and psychosocial stress, also may beuse and psychosocial stress, also may be

the potential secondary triggers accomp-the potential secondary triggers accomp-

anying the onset and course of schizo-anying the onset and course of schizo-phrenia (Allin & Murray, 2002; Buhlerphrenia (Allin & Murray, 2002; Buhler et et

al al , 2002). Neurobiological studies of early, 2002). Neurobiological studies of early

psychoses have the potential to examinepsychoses have the potential to examine

predictions generated by these seeminglypredictions generated by these seemingly

contrasting models.contrasting models.

METHODMETHOD

We summarise the structural, functionalWe summarise the structural, functional

and neurochemical brain changes in theand neurochemical brain changes in the

early phase of psychotic disorders and theirearly phase of psychotic disorders and their

implications for future research and newimplications for future research and new

innovative treatment approaches. A fullinnovative treatment approaches. A fullreview of the extensive literature in thisreview of the extensive literature in this

area is beyond the scope of this paper; thearea is beyond the scope of this paper; the

main themes are summarised here, and themain themes are summarised here, and the

reader is also referred to larger worksreader is also referred to larger works

(Copolov(Copolov et al et al , 2000; Keshavan, 2000; Keshavan et al et al ,,

2000; Lieberman2000; Lieberman et al et al , 2001; Callicott,, 2001; Callicott,

2003; Pantelis2003; Pantelis et al et al , 2003, 2003cc).).

RESULTSRESULTS

Structural neuroimaging studiesStructural neuroimaging studies

Over the past quarter century, computedOver the past quarter century, computed

tomography (CT) (Johnstonetomography (CT) (Johnstone et al et al , 1976;, 1976;WeinbergerWeinberger et al et al , 1979; Pfefferbaum, 1979; Pfefferbaum et al et al ,,

1988) and magnetic resonance imaging1988) and magnetic resonance imaging

(MRI) studies (Lawrie & Abukmeil, 1998;(MRI) studies (Lawrie & Abukmeil, 1998;

ShentonShenton et al et al , 2001) have aimed to charac-, 2001) have aimed to charac-

terise significant abnormalities in brainterise significant abnormalities in brain

structure in patients with schizophrenia andstructure in patients with schizophrenia and

to reinforce the view that schizophreniato reinforce the view that schizophrenia

was indeed a disease of the central nervouswas indeed a disease of the central nervous

system. The observed differences in brainsystem. The observed differences in brain

structure include larger ventricularstructure include larger ventricular

volumes,volumes, smaller cerebral grey mattersmaller cerebral grey matter

volumes and smaller hippocampal volumes.volumes and smaller hippocampal volumes.

The key question of more recent interestThe key question of more recent interesthas been whether these findings reflect ahas been whether these findings reflect a

static or an active pathological processstatic or an active pathological process

(Weinberger & McClure, 2002), a distinc-(Weinberger & McClure, 2002), a distinc-

tion critical to developing a conceptualtion critical to developing a conceptual

model to explain the development of model to explain the development of

schizophrenia.schizophrenia.

Earlier cross-sectional CT and MRIEarlier cross-sectional CT and MRI

studies failed to find a relationship betweenstudies failed to find a relationship betweenillness duration and brain findings inillness duration and brain findings in

chronically ill subjects (Zipurskychronically ill subjects (Zipursky et al et al ,,

1988; Marsh1988; Marsh et al et al , 1994). In a more recent, 1994). In a more recent

study Hulshoff Polstudy Hulshoff Pol et al et al (2002) used MRI to(2002) used MRI to

study whole brain grey matter volumes overstudy whole brain grey matter volumes over

the adult age range in 159 patients withthe adult age range in 159 patients with

schizophrenia and 158 healthy comparisonschizophrenia and 158 healthy comparison

subjects. They found a significant group-subjects. They found a significant group-

by-age interaction with grey matterby-age interaction with grey matter

volumes declining at a more rapid rate involumes declining at a more rapid rate in

patients with schizophrenia. In anotherpatients with schizophrenia. In another

study of patients with established schizo-study of patients with established schizo-

phrenia that examined brain grey matterphrenia that examined brain grey matterusing a voxel-based analysis method,using a voxel-based analysis method,

VelakoulisVelakoulis et al et al (2000) found that duration(2000) found that duration

of illness was associated with a reduction inof illness was associated with a reduction in

grey matter volume in the right medialgrey matter volume in the right medial

temporal lobe and medial cerebellum, andtemporal lobe and medial cerebellum, and

the anterior cingulate bilaterally. With thisthe anterior cingulate bilaterally. With this

study design, however, it is not possible tostudy design, however, it is not possible to

know whether this effect can be explainedknow whether this effect can be explained

by sampling bias (i.e. the older the patients,by sampling bias (i.e. the older the patients,

the more likely they are to be drawn fromthe more likely they are to be drawn from

poor outcome chronically ill samples) orpoor outcome chronically ill samples) or

whether this reflects progressive changeswhether this reflects progressive changes

that one might actually see within individ-that one might actually see within individ-uals over time.uals over time.

It could be the case that being psychoticIt could be the case that being psychotic

is in some way toxic to the brain and thatis in some way toxic to the brain and that

by controlling the psychosis with anti-by controlling the psychosis with anti-

psychotic medication, the progression of psychotic medication, the progression of

brain abnormalities might be limited. Anbrain abnormalities might be limited. An

MRI study in never-treated chronic schizo-MRI study in never-treated chronic schizo-

phrenia patients (ill for over 10 years) inphrenia patients (ill for over 10 years) in

South India (McCreadieSouth India (McCreadie et al et al , 2002) found, 2002) found

no association between illness duration andno association between illness duration and

ventricular volume. Hoventricular volume. Ho et al et al (2003) studied(2003) studied

156 patients with a first episode of schizo-156 patients with a first episode of schizo-

phrenia and also failed to detect any signif-phrenia and also failed to detect any signif-icant correlations between duration of icant correlations between duration of

untreated psychosis and brain volumetricuntreated psychosis and brain volumetric

measures. Alternatively, the progression of measures. Alternatively, the progression of

brain changes might be self-limiting, withbrain changes might be self-limiting, with

maximal differences achieved in the firstmaximal differences achieved in the first

years of the illness. Pursuing this possibilityyears of the illness. Pursuing this possibility

requires studying patients early in therequires studying patients early in the

course of their illness and carrying outcourse of their illness and carrying out

follow-up scans.follow-up scans.

Studies of first-episode schizophreniaStudies of first-episode schizophrenia

(Lim(Lim et al et al , 1996; Zipursky, 1996; Zipursky et al et al , 1998), 1998)

suggest that patients with first-episodesuggest that patients with first-episode

psychosis differ from healthy comparisonpsychosis differ from healthy comparisonindividuals on structural brain measures,individuals on structural brain measures,

but less so than observed in samples of but less so than observed in samples of

chronically ill patients with schizophrenia.chronically ill patients with schizophrenia.

At first glance, this might seem to supportAt first glance, this might seem to support

the view that progression of these abnorm-the view that progression of these abnorm-

alities is taking place over the course of thealities is taking place over the course of the

illness. As suggested above, an equally ten-illness. As suggested above, an equally ten-

able possibility is that a selection effect mayable possibility is that a selection effect maybe taking place by which subjects withbe taking place by which subjects with

more pronounced brain differences earlymore pronounced brain differences early

in their illness might be more likely toin their illness might be more likely to

find themselves in a poor outcomefind themselves in a poor outcome

chronically ill group (Zipurskychronically ill group (Zipursky et al et al ,,

1998). Longitudinal studies are required1998). Longitudinal studies are required

in order to distinguish between these twoin order to distinguish between these two

hypotheses.hypotheses.

Longitudinal follow-up studies of Longitudinal follow-up studies of

patients with first-episode psychosis havepatients with first-episode psychosis have

yielded conflicting results. Gur and collea-yielded conflicting results. Gur and collea-

gues described changes in MRI measuresgues described changes in MRI measures

in 20 patients with first-episode schizo-in 20 patients with first-episode schizo-phrenia, 20 previously treated patientsphrenia, 20 previously treated patients

and 17 controls studied twice over periodsand 17 controls studied twice over periods

ranging from 12 to 68 monthsranging from 12 to 68 months (Gur(Gur et et

al al , 1998); patients with first-, 1998); patients with first-episodeepisode

psychosis had more pronounced left frontalpsychosis had more pronounced left frontal

lobe volume reductions than previouslylobe volume reductions than previously

treated patients and greater bilateral tissuetreated patients and greater bilateral tissue

reductions in the temporal lobes. However,reductions in the temporal lobes. However,

greater reductions in frontal and temporalgreater reductions in frontal and temporal

volumes were highly correlated withvolumes were highly correlated with

greater medication doses in the patientsgreater medication doses in the patients

with first-episode psychosis but not inwith first-episode psychosis but not in

previously treated patients. Woodpreviously treated patients. Wood et al et al (2001) in their longitudinal MRI study of (2001) in their longitudinal MRI study of

30 patients with first-episode psychosis,30 patients with first-episode psychosis,

12 patients with established schizophrenia12 patients with established schizophrenia

and 26 control subjects identified signifi-and 26 control subjects identified signifi-

cant reductions in whole brain volume thatcant reductions in whole brain volume that

were most apparent in the early phase of were most apparent in the early phase of

the illness and showed a greater loss withthe illness and showed a greater loss with

greater inter-scan interval over a 4-yeargreater inter-scan interval over a 4-year

period. In a recent more detailed analysisperiod. In a recent more detailed analysis

of this cohort, this loss of brain volumeof this cohort, this loss of brain volume

was explained by grey matter loss in dorsalwas explained by grey matter loss in dorsal

prefrontal and parietal cortical regions (Sunprefrontal and parietal cortical regions (Sun

et al et al , 2003). Cahn, 2003). Cahn et al et al (2002) have(2002) havedescribed decreases in total grey matterdescribed decreases in total grey matter

volume and increases in lateral ventriclevolume and increases in lateral ventricle

volume in 34 patients with first-episodevolume in 34 patients with first-episode

schizophrenia compared with 36 healthyschizophrenia compared with 36 healthy

comparison subjects scanned over a 1-yearcomparison subjects scanned over a 1-year

interval. The decrease in global grey matterinterval. The decrease in global grey matter

volume was, however, significantly corre-volume was, however, significantly corre-

lated with higher cumulative doses of anti-lated with higher cumulative doses of anti-

psychotic medication. That the associationpsychotic medication. That the association

between medication dose and duration hasbetween medication dose and duration has

not been evident in studies of more chroni-not been evident in studies of more chroni-

cally ill patients suggests that there may becally ill patients suggests that there may be

a ceiling effect such that once the differ-a ceiling effect such that once the differ-ences are apparent early in treatment, littleences are apparent early in treatment, little

s 9s 9



K E S H A VA N E T A LK E S H A VA N E T A L

further progression takes place (Liebermanfurther progression takes place (Lieberman

et al et al , 2003)., 2003).

Medications may explain some, but notMedications may explain some, but not

all, of the structural brain abnormalitiesall, of the structural brain abnormalities

reported in schizophrenia. Differences inreported in schizophrenia. Differences in

ventricular volume have been reported inventricular volume have been reported in

studies prior to the introduction of anti-studies prior to the introduction of anti-psychotic medications in never-treatedpsychotic medications in never-treated

patients (McCreadiepatients (McCreadie et al et al , 2002) and in, 2002) and in

unaffected (and untreated) family membersunaffected (and untreated) family members

(Cannon(Cannon et al et al , 1998; Sharma, 1998; Sharma et al et al , 1998)., 1998).

Smaller intracranial volumes have beenSmaller intracranial volumes have been

reported in both affected and unaffectedreported in both affected and unaffected

monozygotic twins who are discordantmonozygotic twins who are discordant

for schizophrenia, suggesting that geneticfor schizophrenia, suggesting that genetic

risk may contribute to the expressionrisk may contribute to the expression

of the brain abnormalities reported inof the brain abnormalities reported in

schizophrenia (Baareschizophrenia (Baare et al et al , 2001)., 2001).

That brain findings are present at theThat brain findings are present at the

time of the first episode does not establishtime of the first episode does not establishthat they have been present or stable sincethat they have been present or stable since

birth. Just as schizophrenia may evolvebirth. Just as schizophrenia may evolve

through a prodromal stage in many individ-through a prodromal stage in many individ-

uals, it is possible that the brain changes areuals, it is possible that the brain changes are

also evolving during this time and drivingalso evolving during this time and driving

the clinical deterioration characteristic of the clinical deterioration characteristic of

the prodromal period. The recent interestthe prodromal period. The recent interest

in identifying individuals at ultra-high riskin identifying individuals at ultra-high risk

for developing psychosis (Phillipsfor developing psychosis (Phillips et al et al ,,

2002) allows imaging of patients prior to2002) allows imaging of patients prior to

and after emergence of the illness and there-and after emergence of the illness and there-

by study of the neurobiology of transitionby study of the neurobiology of transition

to psychosis. Individuals at genetic risk forto psychosis. Individuals at genetic risk fordeveloping schizophrenia had smallerdeveloping schizophrenia had smaller

volumes of the left amygdala–hippocampalvolumes of the left amygdala–hippocampal

complex and thalamic nuclei than controlscomplex and thalamic nuclei than controls

(Lawrie(Lawrie et al et al , 2001; Keshavan, 2001; Keshavan et al et al ,,

20022002aa). In the Edinburgh High Risk Study,). In the Edinburgh High Risk Study,

over a 2-year follow-up period, at-riskover a 2-year follow-up period, at-risk

participants as a group did not showparticipants as a group did not show

greater regional brain volume changes thangreater regional brain volume changes than

healthy controls, although at-risk partici-healthy controls, although at-risk partici-

pants with psychotic symptoms showedpants with psychotic symptoms showed

greater changes over the follow-up periodgreater changes over the follow-up period

than those without psychotic symptomsthan those without psychotic symptoms

(Miller(Miller et al et al , 2002). Pantelis, 2002). Pantelis et al et al (2003(2003aa))carried out a longitudinal study of individ-carried out a longitudinal study of individ-

uals treated in the PACE clinic inuals treated in the PACE clinic in

Melbourne, a specialist service for peopleMelbourne, a specialist service for people

at ultra-high risk for psychosis (for defini-at ultra-high risk for psychosis (for defini-

tion of criteria see Yungtion of criteria see Yung et al et al , 1996), which, 1996), which

involved baseline and 12-month follow-upinvolved baseline and 12-month follow-up

scans. Of the 75 participants who had ascans. Of the 75 participants who had a

baseline scan, 23 developed psychosis andbaseline scan, 23 developed psychosis and

52 did not. At their initial scan, those52 did not. At their initial scan, those

who later became psychotic had less greywho later became psychotic had less grey

matter in the right medial temporal, lateralmatter in the right medial temporal, lateral

temporal and inferior frontal cortex and intemporal and inferior frontal cortex and in

the cingulate cortex bilaterally. Ten indi-the cingulate cortex bilaterally. Ten indi-viduals who were rescanned had developedviduals who were rescanned had developed

psychosis in the follow-up period and 11psychosis in the follow-up period and 11

had not. Grey matter volume reductionshad not. Grey matter volume reductions

were more pronounced in those whowere more pronounced in those who

became psychotic, suggesting that an activebecame psychotic, suggesting that an active

disease process may be taking place in thedisease process may be taking place in the

brain. Some of the patients received anti-brain. Some of the patients received anti-

psychotic medication in the intervalpsychotic medication in the intervalbetween scans, so treatment cannot bebetween scans, so treatment cannot be

ruled out as an explanation for the differen-ruled out as an explanation for the differen-

tial changes found in those who becametial changes found in those who became

psychotic. The absence of an age-matchedpsychotic. The absence of an age-matched

healthy comparison group further limitshealthy comparison group further limits

the interpretation of this study. Newthe interpretation of this study. New

techniques, such as diffusion tensortechniques, such as diffusion tensor

imaging, may provide important opportu-imaging, may provide important opportu-

nities to study brain development longi-nities to study brain development longi-

tudinally in individuals in the early stagestudinally in individuals in the early stages

of schizophrenia (Begreof schizophrenia (Begre et al et al , 2003)., 2003).

Cognition, electrophysiologyCognition, electrophysiology

and functional neuroimagingand functional neuroimaging

studiesstudies

In general, cognitive studies of early psy-In general, cognitive studies of early psy-

chosis have mirrored the findings in chronicchosis have mirrored the findings in chronic

schizophrenia, with a similar pattern of im-schizophrenia, with a similar pattern of im-

pairments in executive function, attentionpairments in executive function, attention

and memory being identified (Heinrichs &and memory being identified (Heinrichs &

Zakzanis, 1998). However, the magnitudeZakzanis, 1998). However, the magnitude

of the impairments found in some of theseof the impairments found in some of these

studies indicates a smaller magnitude of studies indicates a smaller magnitude of

deficits, although this may depend on thedeficits, although this may depend on the

particular domain being examined. Thisparticular domain being examined. Thishas been shown both when tests are orga-has been shown both when tests are orga-

nised into sub-batteries by domain (e.g.nised into sub-batteries by domain (e.g.

Hoff Hoff et al et al , 1992; Bilder, 1992; Bilder et al et al , 2000) and, 2000) and

when individual tests are examinedwhen individual tests are examined

(Mohamed(Mohamed et al et al , 1999). There has, how-, 1999). There has, how-

ever, been debate about whether theever, been debate about whether the

impairment is generalised or whether thereimpairment is generalised or whether there

is evidence of a difference between cogni-is evidence of a difference between cogni-

tive domains (despite the similarity intive domains (despite the similarity in

results). Some studies (e.g. Mohamedresults). Some studies (e.g. Mohamed et et

al al , 1999) suggest that although small differ-, 1999) suggest that although small differ-

ences can be found between differentences can be found between different

domains, the effect size of the differencesdomains, the effect size of the differencesbetween domains is overshadowed by thebetween domains is overshadowed by the

much larger effect size of the differencemuch larger effect size of the difference

between the patients and the controls (inbetween the patients and the controls (in

the Mohamedthe Mohamed et al et al study the largest effectstudy the largest effect

size for differences between domains wassize for differences between domains was

770.52, but for the difference between0.52, but for the difference between

patients and controls 25 out of 30 testspatients and controls 25 out of 30 tests

had a Cohen’shad a Cohen’s d d of greater than 0.75).of greater than 0.75).

Although this may be partly attributed toAlthough this may be partly attributed to

poor matching of tests assessing differentpoor matching of tests assessing different

domains, it also suggests that the differencedomains, it also suggests that the difference

between domains might not be clinicallybetween domains might not be clinically

meaningful. Other authors have suggestedmeaningful. Other authors have suggestedthat although a generalised deficit isthat although a generalised deficit is

present, there is a differential impairment.present, there is a differential impairment.

This is most often found to be in the areaThis is most often found to be in the area

of memory and learning (e.g. Saykinof memory and learning (e.g. Saykin et al et al ,,

1994; Hutton1994; Hutton et al et al , 1998) although the, 1998) although the

domains of attention and/or executive skillsdomains of attention and/or executive skills

are also the lower scores in the profile (e.g.are also the lower scores in the profile (e.g.

AlbusAlbus et al et al , 1996). Saykin, 1996). Saykin et al et al (1994) and(1994) andBilderBilder et al et al (2000) utilised standardised(2000) utilised standardised

residualised scores as a means to overcomeresidualised scores as a means to overcome

the problems associated with poorlythe problems associated with poorly

matched tasks. They both found that verbalmatched tasks. They both found that verbal

memory and learning scores were lowermemory and learning scores were lower

than predicted on the basis of other scores,than predicted on the basis of other scores,

providing support for a differential impair-providing support for a differential impair-

ment. In contrast, in the study by Weickertment. In contrast, in the study by Weickert

et al et al (2000), in which groups of patients(2000), in which groups of patients

were defined according to the extent of awere defined according to the extent of a

generalised intellectual impairment, consis-generalised intellectual impairment, consis-

tent deficits on the Wisconsin Card Sortingtent deficits on the Wisconsin Card Sorting

Test (WCST) were found, providing furtherTest (WCST) were found, providing furtherevidence for differential impairment inevidence for differential impairment in

executive function.executive function.

Such data, supporting a differentialSuch data, supporting a differential

rather than generalised impairment, arerather than generalised impairment, are

also consistent with the findings from brainalso consistent with the findings from brain

structural (described above) and functionalstructural (described above) and functional

imaging studies implicating regions of theimaging studies implicating regions of the

prefrontal cortex and their connectionsprefrontal cortex and their connections

with other areas, particularly subcorticalwith other areas, particularly subcortical

and limbic regions (Liddleand limbic regions (Liddle et al et al , 2000;, 2000;

PantelisPantelis et al et al , 2002). The most consistent, 2002). The most consistent

finding in schizophrenia has been of hypo-finding in schizophrenia has been of hypo-

frontality, which is most apparent whenfrontality, which is most apparent whenpatients are tested while undertakingpatients are tested while undertaking

neuropsychological tasks relevant to theneuropsychological tasks relevant to the

prefrontal cortex (Velakoulis & Pantelis,prefrontal cortex (Velakoulis & Pantelis,

1996; Davidson & Heinrichs, 2003),1996; Davidson & Heinrichs, 2003),

although this notion has been challengedalthough this notion has been challenged

(Manoach(Manoach et al et al , 1999; Callicott, 1999; Callicott et al et al ,,

2000). In their meta-analysis of 155 struc-2000). In their meta-analysis of 155 struc-

tural (MRI) and functional (positrontural (MRI) and functional (positron

emission tomography and single photonemission tomography and single photon

emission tomography) imaging studies of emission tomography) imaging studies of

frontal and temporal lobe regions,frontal and temporal lobe regions,

Davidson & Heinrichs (2003) found thatDavidson & Heinrichs (2003) found that

hypofrontality during cognitive activationhypofrontality during cognitive activationshowed the strongest effect and distin-showed the strongest effect and distin-

guished approximately half of schizo-guished approximately half of schizo-

phrenia patients from healthy controlsphrenia patients from healthy controls

(Cohen’s(Cohen’s d d ¼770.81; for resting studies,0.81; for resting studies,

d d ¼770.65), whereas temporal lobe function0.65), whereas temporal lobe function

did not discriminate the groups. In contrast,did not discriminate the groups. In contrast,

for structural imaging, the largest effectfor structural imaging, the largest effect

sizes were found for left superior temporalsizes were found for left superior temporal

gyrus and left and right hippocampalgyrus and left and right hippocampal

volumes (volumes (d d ¼770.55,0.55, 770.55,0.55, 770.58,0.58,

respectively). A preliminary meta-analysisrespectively). A preliminary meta-analysis

of 14 functional MRI studies found thatof 14 functional MRI studies found that

resting scans, regardless of cognitiveresting scans, regardless of cognitivetask use, differed between patients withtask use, differed between patients with

s1 0s1 0




schizophrenia and control individuals,schizophrenia and control individuals,

whereas patients displayed less robustwhereas patients displayed less robust

activation to cognitive challenge (Kinder-activation to cognitive challenge (Kinder-

mannmann et al et al , 1997). Although such meta-, 1997). Although such meta-

analyses are informative, available studiesanalyses are informative, available studies

have not been able to address some keyhave not been able to address some key

questions, including: (a) other brain regionsquestions, including: (a) other brain regionsin which abnorin which abnormal function has been iden-mal function has been iden-

tified (e.g. Cartertified (e.g. Carter et al et al , 1997; Haznedar, 1997; Haznedar et et

al al , 1997; Yucel, 1997; Yucel et al et al , 2002); (b) the inter-, 2002); (b) the inter-

action between different regions that isaction between different regions that is

currently relevant to the notion of disturbedcurrently relevant to the notion of disturbed

connectivity (e.g. Fletcherconnectivity (e.g. Fletcher et al et al , 1999); and, 1999); and

(c) the relationship between structural and(c) the relationship between structural and

functional imaging measures (e.g. Wein-functional imaging measures (e.g. Wein-

bergerberger et al et al , 1992; Bertolino, 1992; Bertolino et al et al , 2000;, 2000;

BilderBilder et al et al , 2000;, 2000; CallicottCallicott et al et al , 2000)., 2000).

Further, meta-Further, meta-analyses have not addressedanalyses have not addressed

the importance of controlling for behav-the importance of controlling for behav-

ioural performance on tasks used duringioural performance on tasks used duringactivation studies. For example, in theactivation studies. For example, in the

studies by Manoachstudies by Manoach et al et al (1999) and by(1999) and by

CallicottCallicott et al et al (2000) patients showing only(2000) patients showing only

a slight impairment in performance ona slight impairment in performance on

graded tasks of executive function hadgraded tasks of executive function had

greater rather than less activation in dorsalgreater rather than less activation in dorsal

prefrontal cortex.prefrontal cortex.

The current functional imaging litera-The current functional imaging litera-

ture is also limited in addressing issues suchture is also limited in addressing issues such

as illness stage and medication-relatedas illness stage and medication-related

effects, as there are relatively few studieseffects, as there are relatively few studies

in the earliest stages of psychosis, especiallyin the earliest stages of psychosis, especially

in neuroleptic-naıve or unmedicatedin neuroleptic-naı ¨ve or unmedicatedpatients and even fewer in high-risk popu-patients and even fewer in high-risk popu-

lations. In the resting study of 70 unmedi-lations. In the resting study of 70 unmedi-

cated patients with schizophrenia, whocated patients with schizophrenia, who

had at least 4 weeks off medication, Siegelhad at least 4 weeks off medication, Siegel

and colleagues (Millerand colleagues (Miller et al et al , 2002), found, 2002), found

reduced activity in medial rather than dor-reduced activity in medial rather than dor-

sal prefrontal cortex and in associated re-sal prefrontal cortex and in associated re-

gions of striatum and thalamus. Similarly,gions of striatum and thalamus. Similarly,

StevensStevens et al et al (1998) found that inferior(1998) found that inferior

and ventral regions were hypofunctioning.and ventral regions were hypofunctioning.

However, such studies do not take accountHowever, such studies do not take account

of the long-term effects of medication andof the long-term effects of medication and

illness duration. In conillness duration. In contrast, Barchtrast, Barch et al et al (2001), in their well-(2001), in their well-designed functionaldesigned functional

MRI study examined neuroleptic-naıve firstMRI study examined neuroleptic-naı ¨ve first

episode patients with schizophrenia using aepisode patients with schizophrenia using a

context-dependent working memory taskcontext-dependent working memory task

and found that dorsolateral prefrontal cor-and found that dorsolateral prefrontal cor-

tex, rather than other prefrontal regions,tex, rather than other prefrontal regions,

was specifically implicated from the outsetwas specifically implicated from the outset

of illness. These results are consistent withof illness. These results are consistent with

the findings of impaired working memorythe findings of impaired working memory

deficits in first-episode psychosis (Huttondeficits in first-episode psychosis (Hutton

et al et al , 1998; Proffitt, 1998; Proffitt et al et al , 2000; Wood, 2000; Wood et et

al al , 2002). Two other studies in neuro-, 2002). Two other studies in neuro-

leptic-naıve patients confirmed hypo-leptic-naı ¨ve patients confirmed hypo-frontality at illness onset (Parelladafrontality at illness onset (Parellada et al et al ,,

1998; Riehemann1998; Riehemann et al et al , 2001). The only, 2001). The only

available functional imaging study in aavailable functional imaging study in a

high-risk prepsychotic sample is consistenthigh-risk prepsychotic sample is consistent

with the findings at illness onset (Keshavanwith the findings at illness onset (Keshavan

et al et al , 2002, 2002bb), which is also consistent with), which is also consistent with

deficits in working memory in a similardeficits in working memory in a similar

population (Woodpopulation (Wood et al et al , 2003)., 2003).In parallel with the debate aboutIn parallel with the debate about

whether brain structural abnormalities arewhether brain structural abnormalities are

static or progressive, various studies havestatic or progressive, various studies have

assessed the stability of cognitive deficitsassessed the stability of cognitive deficits

over time and a few recent studies haveover time and a few recent studies have

examined change in brain function longi-examined change in brain function longi-

tudinally. While the comparison of firsttudinally. While the comparison of first

episode with chronic patients suggests someepisode with chronic patients suggests some

decline in function, longitudinal studiesdecline in function, longitudinal studies

have found little change over the yearshave found little change over the years

following the first episode (Censitsfollowing the first episode (Censits et al et al ,,

1997; Gold1997; Gold et al et al , 1999; Hoff , 1999; Hoff et al et al , 1999)., 1999).

In addition, a meta-analytical study of In addition, a meta-analytical study of memory (Alemanmemory (Aleman et al et al , 1999) found little, 1999) found little

difference in effect size between studiesdifference in effect size between studies

with chronic compared with first-episodewith chronic compared with first-episode

populations. Relationships have been iden-populations. Relationships have been iden-

tified between change in clinical symptomstified between change in clinical symptoms

and change in neuropsychological scores.and change in neuropsychological scores.

For example, some studies (CensitsFor example, some studies (Censits et al et al ,,

1997; Gold1997; Gold et al et al , 1999; Brewer, 1999; Brewer et al et al ,,

2001; Schuepbach2001; Schuepbach et al et al , 2002) have found, 2002) have found

that change in negative symptoms is asso-that change in negative symptoms is asso-

ciated with change in neuropsychologicalciated with change in neuropsychological

scores, whereas another (Hoff scores, whereas another (Hoff et al et al , 1999), 1999)

found a similar relationship with changefound a similar relationship with changein positive symptoms. These studies needin positive symptoms. These studies need

to be interpreted with caution, particularlyto be interpreted with caution, particularly

as few have distinguished between primaryas few have distinguished between primary

and secondary negative symptoms (Kirk-and secondary negative symptoms (Kirk-

patrickpatrick et al et al , 2001). Overall, the longi-, 2001). Overall, the longi-

tudinal and some cross-sectional studiestudinal and some cross-sectional studies

(e.g. meta-analyses that compare the effect(e.g. meta-analyses that compare the effect

size associated with first-episode andsize associated with first-episode and

chronic schizophrenia) support the viewchronic schizophrenia) support the view

that fairly extensive cognitive deficits arethat fairly extensive cognitive deficits are

present by the first episode of psychosispresent by the first episode of psychosis

and that they are likely to be a stable,and that they are likely to be a stable,

ongoing, trait-like feature of the person’songoing, trait-like feature of the person’sillness. This impairment appears to beillness. This impairment appears to be

relatively unaffected by the person’s levelrelatively unaffected by the person’s level

of clinical symptoms.of clinical symptoms.

In this context, it is worth noting theIn this context, it is worth noting the

unreliability of the term ‘first episode’ andunreliability of the term ‘first episode’ and

the potential implications this has for defin-the potential implications this has for defin-

ing the onset of the cognitive deficits in psy-ing the onset of the cognitive deficits in psy-

chosis. The term ‘first episode’ has beenchosis. The term ‘first episode’ has been

used to cover a relatively long period of used to cover a relatively long period of

time. For example, in the Bildertime. For example, in the Bilder et al et al

(2000) study, 21% of participants were(2000) study, 21% of participants were

tested more than a year after the onset of tested more than a year after the onset of

treatment, while the mean illness durationtreatment, while the mean illness durationin the Saykinin the Saykin et al et al (1994) study was 2 years.(1994) study was 2 years.

This is further confused by the fact that theThis is further confused by the fact that the

term ‘illness duration’ could be used toterm ‘illness duration’ could be used to

cover the duration of untreated psychosiscover the duration of untreated psychosis

before contact with the psychiatric service.before contact with the psychiatric service.

Caution in accurately defining the term firstCaution in accurately defining the term first

episode is needed to ensure that activeepisode is needed to ensure that active

changes are occurring in the earliest phasechanges are occurring in the earliest phaseof illness. For example, in a recent studyof illness. For example, in a recent study

of the cognitive abilities of patients withof the cognitive abilities of patients with

first-episode psychosis who were within 6first-episode psychosis who were within 6

months of psychosis onset, in comparisonmonths of psychosis onset, in comparison

with a group of patients with chronicwith a group of patients with chronic

schizophrenia and normal control partici-schizophrenia and normal control partici-

pants (Woodpants (Wood et al et al , 2002), the patients with, 2002), the patients with

first-episode psychosis had no impairmentfirst-episode psychosis had no impairment

on a visual associative memory task,on a visual associative memory task,

whereas patients with chronic schizo-whereas patients with chronic schizo-

phrenia were significantly impaired. Inphrenia were significantly impaired. In

contrast, the impairments of both patientcontrast, the impairments of both patient

groups on a spatial working memory taskgroups on a spatial working memory taskwere very similar. This suggests that therewere very similar. This suggests that there

may be some differential impairment inmay be some differential impairment in

cognitive function over the illness course,cognitive function over the illness course,

with some present at or prior to the onsetwith some present at or prior to the onset

of the disorder, whereas others arise withof the disorder, whereas others arise with

prolonged psychosis. Clearly, longitudinalprolonged psychosis. Clearly, longitudinal

studies are needed from the earliest phasestudies are needed from the earliest phase

of psychotic disorders to elucidate whetherof psychotic disorders to elucidate whether

deficits develop as the illness progresses.deficits develop as the illness progresses.

The limited available longitudinal func-The limited available longitudinal func-

tional imaging studies have focused on thetional imaging studies have focused on the

effects of medication, and have demon-effects of medication, and have demon-

strated differences between typical andstrated differences between typical andatypical antipsychotics (Honeyatypical antipsychotics (Honey et al et al , 1999;, 1999;

LiddleLiddle et al et al , 2000; Miller, 2000; Miller et al et al , 2001),, 2001),

suggesting some consistency with thesuggesting some consistency with the

neuropsychological studies that have identi-neuropsychological studies that have identi-

fied improvement in neuropsychologicalfied improvement in neuropsychological

function with atypical neurolepticsfunction with atypical neuroleptics

(Meltzer & McGurk, 1999; Bilder(Meltzer & McGurk, 1999; Bilder et al et al ,,

2002).2002).

Another approach that is helpful in ad-Another approach that is helpful in ad-

dressing the issue of whether neuropsycho-dressing the issue of whether neuropsycho-

logical and functional impairments arelogical and functional impairments are

stable trait features of schizophrenia andstable trait features of schizophrenia and

psychosis is to examine neuropsychologicalpsychosis is to examine neuropsychologicaland brain activity in prepsychotic, high-and brain activity in prepsychotic, high-

risk, individuals. Neuropsychological inves-risk, individuals. Neuropsychological inves-

tigations have been performed as part of tigations have been performed as part of

investigations, including the long-terminvestigations, including the long-term

high-risk studies that followed children intohigh-risk studies that followed children into

adulthood, such as the New York, Stonyadulthood, such as the New York, Stony

Brook, Copenhagen and Israeli High-RiskBrook, Copenhagen and Israeli High-Risk

Studies, whereas more recent strategies, ex-Studies, whereas more recent strategies, ex-

emplified by the Edinburgh High Risk, andemplified by the Edinburgh High Risk, and

Melbourne Ultra High-Risk Studies, haveMelbourne Ultra High-Risk Studies, have

used alternative approaches in order toused alternative approaches in order to

increase the yield and reduce the period of increase the yield and reduce the period of

follow-up required. Various groups havefollow-up required. Various groups haveadopted the ultra-high risk strategy andadopted the ultra-high risk strategy and

s11s11




results on neuropsychological functioningresults on neuropsychological functioning

from these studies are beginning to emergefrom these studies are beginning to emerge

(Cornblatt, 2002; Hambrecht(Cornblatt, 2002; Hambrecht et al et al , 2002;, 2002;

BrewerBrewer et al et al , 2003; Wood, 2003; Wood et al et al , 2003)., 2003).

The early high-risk studies are summarisedThe early high-risk studies are summarised

elsewhere in special issues of elsewhere in special issues of SchizophreniaSchizophrenia

BulletinBulletin in 1985 (vol. 11, issue 1) and 1987in 1985 (vol. 11, issue 1) and 1987(vol. 13, issue 3). Briefly, with respect to(vol. 13, issue 3). Briefly, with respect to

neuropsychology these earlier studiesneuropsychology these earlier studies

focused on attention, with more limitedfocused on attention, with more limited

information available with respect to otherinformation available with respect to other

cognitive domains (Weintraub, 1987;cognitive domains (Weintraub, 1987;

MirskyMirsky et al et al , 1995; Wolf & Cornblatt,, 1995; Wolf & Cornblatt,

1996). The New York High-Risk Study1996). The New York High-Risk Study

has been most informative in this respect,has been most informative in this respect,

with the demonstration that childhood defi-with the demonstration that childhood defi-

cits in attention, motor skills and short-cits in attention, motor skills and short-

term memory, measured at 7–12 yearsterm memory, measured at 7–12 years

of age, identified 58%, 75% and 83%of age, identified 58%, 75% and 83%

(respectively) of those who later developed(respectively) of those who later developeda schizophrenia-related psychosisa schizophrenia-related psychosis

(Erlenmeyer-(Erlenmeyer-KimlingKimling et al et al , 2000). How-, 2000). How-

ever, other groups have only partly repli-ever, other groups have only partly repli-

cated these findings. The Edinburgh Highcated these findings. The Edinburgh High

Risk Study found that verbal memory andRisk Study found that verbal memory and

executive function did distinguish betweenexecutive function did distinguish between

young relatives with andyoung relatives with and without psychoticwithout psychotic

symptoms during follow-up; other cogni-symptoms during follow-up; other cogni-

tive measures showed few clear differencestive measures showed few clear differences

(Cosway(Cosway et al et al , 2002). This lack of replica-, 2002). This lack of replica-

tion may depend on the domains assessedtion may depend on the domains assessed

and the timing of the assessment (Andersen,and the timing of the assessment (Andersen,

2003; Pantelis2003; Pantelis et al et al , 2003, 2003cc; Wood; Wood et al et al ,,20032003).).

The more recent studies have compre-The more recent studies have compre-

hensively assessed neuropsychologicalhensively assessed neuropsychological

function, although not all data have beenfunction, although not all data have been

published as yet. In the studies by thepublished as yet. In the studies by the

Edinburgh group, slightly lower levels of Edinburgh group, slightly lower levels of

global cognitive function were identifiedglobal cognitive function were identified

in a high-risk cohort than in a groupin a high-risk cohort than in a group

of matched controls (Byrneof matched controls (Byrne et al et al , 1999)., 1999).

When this difference was controlledWhen this difference was controlled

for, the high-risk group was significantlyfor, the high-risk group was significantly

impaired only on a global memory testimpaired only on a global memory test

and on a sentence completion test thatand on a sentence completion test thatimplicates executive functions. However,implicates executive functions. However,

none of the participants in that study hadnone of the participants in that study had

become acutely psychotic at the time of become acutely psychotic at the time of

publication, which highlights one of thepublication, which highlights one of the

problems of research in high-risk popula-problems of research in high-risk popula-

tions, namely, that it will remain uncleartions, namely, that it will remain unclear

to what extent neuropsychologicalto what extent neuropsychological

deficits identified premorbidly are predic-deficits identified premorbidly are predic-

tive of the later onset of schizophrenia untiltive of the later onset of schizophrenia until

there has been an adequate follow-upthere has been an adequate follow-up

period to determine who will developperiod to determine who will develop

psychosis, such as in the New York High-psychosis, such as in the New York High-

Risk Study discussed above. AnotherRisk Study discussed above. Anotherapproach has been to identify cases fromapproach has been to identify cases from

long-term population-based follow-uplong-term population-based follow-up

studies, as in the Dunedin Multidisciplinarystudies, as in the Dunedin Multidisciplinary

Health and Development Study (PoultonHealth and Development Study (Poulton et et

al al , 2000), which identified reduced intelli-, 2000), which identified reduced intelli-

gence and receptive language skills ingence and receptive language skills in

children between the ages of 3 and 9 yearschildren between the ages of 3 and 9 years

who later fulfilled criteria for schizo-who later fulfilled criteria for schizo-phreniform disorder (Cannonphreniform disorder (Cannon et al et al , 2002)., 2002).

Although difficult to set up and under-Although difficult to set up and under-

take, such an approach is particularly infor-take, such an approach is particularly infor-

mative as it does not focus only on themative as it does not focus only on the

offspring of patients with schizophrenia.offspring of patients with schizophrenia.

Although these studies provide evidenceAlthough these studies provide evidence

that early neuropsychological deficits maythat early neuropsychological deficits may

be markers of impending illness later in life,be markers of impending illness later in life,

the question of specificity of these findingsthe question of specificity of these findings

to schizophrenia remains unclear.to schizophrenia remains unclear.

In order to address the long follow-upIn order to address the long follow-up

period required and the low number of period required and the low number of

individuals developing psychosis in theindividuals developing psychosis in thehigh-risk and population-based studieshigh-risk and population-based studies

described, the Melbourne group havedescribed, the Melbourne group have

utilised an ultra-high-risk strategy toutilised an ultra-high-risk strategy to

identify young people at imminent risk of identify young people at imminent risk of

developing a psychotic illness. Using thisdeveloping a psychotic illness. Using this

approach about 40% of individuals makeapproach about 40% of individuals make

the transition to psychosis within 12the transition to psychosis within 12

months of presentation (Yungmonths of presentation (Yung et al et al ,,

1998). Initial findings (including neuro-1998). Initial findings (including neuro-

imaging findings described earlier) at base-imaging findings described earlier) at base-

line, prior to illness transition, haveline, prior to illness transition, have

identified deficits in spatial workingidentified deficits in spatial working

memory ability in those who subsequentlymemory ability in those who subsequentlydeveloped psychosis (Wooddeveloped psychosis (Wood et al et al , 2003),, 2003),

which were similar to those observed inwhich were similar to those observed in

patients with schizophreniform psychosispatients with schizophreniform psychosis

and established schizophrenia (Woodand established schizophrenia (Wood et et

al al , 2002). Deficits in olfactory function, 2002). Deficits in olfactory function

are also found specifically in those develop-are also found specifically in those develop-

ing schizophrenia (Brewering schizophrenia (Brewer et al et al , 2003). In, 2003). In

contrast, preliminary findings indicate thatcontrast, preliminary findings indicate that

some other aspects of memory are notsome other aspects of memory are not

impaired (Pantelisimpaired (Pantelis et al et al , 2003, 2003bb). These). These

data, taken together with findings indata, taken together with findings in

patients with first-episode and chronicpatients with first-episode and chronic

psychosis using the same tasks, providepsychosis using the same tasks, providefurther evidence that particular domainsfurther evidence that particular domains

of function are differentially impaired, andof function are differentially impaired, and

raise the possibility that other domainsraise the possibility that other domains

may only become apparent as the illnessmay only become apparent as the illness

develops a more chronic course.develops a more chronic course.

A complementary approach to examin-A complementary approach to examin-

ing brain function uses event-related braining brain function uses event-related brain

potentials (ERPs), which can track changespotentials (ERPs), which can track changes

in brain functioning over a short period of in brain functioning over a short period of

time, thereby providing dynamic infor-time, thereby providing dynamic infor-

mation about the progression of brainmation about the progression of brain

activity during cognitive tasks. Although aactivity during cognitive tasks. Although a

number of ERP components have beennumber of ERP components have beenstudied in schizophrenia, most work instudied in schizophrenia, most work in

early psychosis has focused on mismatchearly psychosis has focused on mismatch

negativity and P300 (for review seenegativity and P300 (for review see

SalisburySalisbury et al et al , 2003). The mismatch, 2003). The mismatch

negativity is a negative auditorynegativity is a negative auditory ERP,ERP,

occurring 150–250 ms after presentationoccurring 150–250ms after presentation

of ‘deviant’ stimuli, which are elicited byof ‘deviant’ stimuli, which are elicited by

interspersing infrequent sounds (differinginterspersing infrequent sounds (differingin pitch, duration, intensity or spatial loca-in pitch, duration, intensity or spatial loca-

tion) in a sequence of repetitive sounds. Thetion) in a sequence of repetitive sounds. The

mismatch negativity is evoked automati-mismatch negativity is evoked automati-

cally, is preconscious, is thought to havecally, is preconscious, is thought to have

generators in auditory cortices but may alsogenerators in auditory cortices but may also

have a prefrontal generator (Salisburyhave a prefrontal generator (Salisbury et al et al ,,

2003), and may reflect activity of 2003), and may reflect activity of N N --

methyl-methyl-DD-aspartate (NMDA) receptors-aspartate (NMDA) receptors

(Umbricht(Umbricht et al et al , 2000, 2003). Mismatch, 2000, 2003). Mismatch

negativity is reduced in patients with estab-negativity is reduced in patients with estab-

lished schizophrenia (Cattslished schizophrenia (Catts et al et al , 1995;, 1995;

Javitt Javitt et al et al , 2000, 2000bb), has been shown to be), has been shown to be

specific to schizophrenia (Cattsspecific to schizophrenia (Catts et al et al ,,1995; Umbricht1995; Umbricht et al et al , 2003), and these, 2003), and these

deficits (considered to reflect transientdeficits (considered to reflect transient

memory traces) have been related tomemory traces) have been related to

impaired performance on an attentionalimpaired performance on an attentional

task (Javitttask (Javitt et al et al , 2000, 2000bb). In contrast,). In contrast,

patients with first-episode psychosis earlypatients with first-episode psychosis early

in their course of illness are unimpairedin their course of illness are unimpaired

(Salisbury(Salisbury et al et al , 2002), whereas patients, 2002), whereas patients

within the first 3 years of illness show awithin the first 3 years of illness show a

mild deficit (Javittmild deficit (Javitt et al et al , 2000, 2000aa). Prelimi-). Prelimi-

nary longitudinal findings of a small samplenary longitudinal findings of a small sample

of patients over the first 2 years of illnessof patients over the first 2 years of illness

have been presented by Salisburyhave been presented by Salisbury et al et al (2001), and these authors consider that(2001), and these authors consider that

the mismatch negativity may index progres-the mismatch negativity may index progres-

sive neurodegeneration in schizophrenia,sive neurodegeneration in schizophrenia,

involving superior temporal gyrusinvolving superior temporal gyrus

(Salisbury(Salisbury et al et al , 2003), which may be, 2003), which may be

mediated by NMDA (Olneymediated by NMDA (Olney et al et al , 1999)., 1999).

However, a genetic contribution has alsoHowever, a genetic contribution has also

been suggested by recent evidence thatbeen suggested by recent evidence that

patients with schizophrenia and their first-patients with schizophrenia and their first-

degree relatives show deficits in mismatchdegree relatives show deficits in mismatch

negativity (Michienegativity (Michie et al et al , 2002), but Jessen, 2002), but Jessen

et al et al (2001) found that relatives were im-(2001) found that relatives were im-

paired but patients did not differ frompaired but patients did not differ fromcontrols. Further, in a study of children atcontrols. Further, in a study of children at

high risk for schizophrenia, mismatch nega-high risk for schizophrenia, mismatch nega-

tivity showed some reduction (Schreibertivity showed some reduction (Schreiber et et

al al , 1992). These findings indicate that, 1992). These findings indicate that

further studies from the earliest phase of further studies from the earliest phase of

psychosis, in prepsychotic individuals, andpsychosis, in prepsychotic individuals, and

studies of unaffected family members arestudies of unaffected family members are

required to assess the evolution and charac-required to assess the evolution and charac-

teristics of this marker of pre-attentive pro-teristics of this marker of pre-attentive pro-

cessing. If mismatch negativity does providecessing. If mismatch negativity does provide

an index of progressive changes in schizo-an index of progressive changes in schizo-

phrenia, and if they are found to be relatedphrenia, and if they are found to be related

to the structural imaging findings describedto the structural imaging findings describedabove, this index may provide informationabove, this index may provide information

s1 2s1 2




about the mechanisms underlying suchabout the mechanisms underlying such

changes.changes.

In contrast to the mismatch negativityIn contrast to the mismatch negativity

which is pre-attentive, the P300 occurs towhich is pre-attentive, the P300 occurs to

a stimulus that is actively detected and pro-a stimulus that is actively detected and pro-

cessed and is elicited by the ‘oddball’cessed and is elicited by the ‘oddball’

paradigm (for review see Salisburyparadigm (for review see Salisbury et al et al ,,2003). Because subjects actively attend to2003). Because subjects actively attend to

detect the rare occurrence of an infrequentdetect the rare occurrence of an infrequent

target, deficits of or disruption to selectivetarget, deficits of or disruption to selective

attention processes will disrupt the P300.attention processes will disrupt the P300.

Typically, patients with chronic schizo-Typically, patients with chronic schizo-

phrenia show a robust reduction in P300phrenia show a robust reduction in P300

amplitude, which is trait-like (Jeon &amplitude, which is trait-like (Jeon &

Polich, 2001; SalisburyPolich, 2001; Salisbury et al et al , 2003), and, 2003), and

these deficits are considered to reflectthese deficits are considered to reflect

impairments in sustained attention andimpairments in sustained attention and

higher level cognitive abilities, includinghigher level cognitive abilities, including

working memory (Kimbleworking memory (Kimble et al et al , 2000)., 2000).

Symptom remission and atypical neuro-Symptom remission and atypical neuro-leptics have been associated with someleptics have been associated with some

increase in P300 (Fordincrease in P300 (Ford et al et al , 1994;, 1994;

UmbrichtUmbricht et al et al , 1998), although the impair-, 1998), although the impair-

ment does not normalise (Salisburyment does not normalise (Salisbury et al et al ,,

2003). Further, Mathalon2003). Further, Mathalon et al et al (2000) have(2000) have

shown that while auditory and visual P300sshown that while auditory and visual P300s

track symptom changes over time, onlytrack symptom changes over time, only

auditory P300s remained abnormal whenauditory P300s remained abnormal when

patients were least symptomatic, suggestingpatients were least symptomatic, suggesting

that the latter was a trait marker. Examin-that the latter was a trait marker. Examin-

ation of neuroleptic-naıve patients withation of neuroleptic-naı ¨ve patients with

first-episode psychosis indicates that thefirst-episode psychosis indicates that the

P300 abnormality is present prior to medi-P300 abnormality is present prior to medi-cation (Radwancation (Radwan et al et al , 1991; Hirayasu, 1991; Hirayasu et al et al ,,

1998). The early studies of individuals at1998). The early studies of individuals at

genetic high risk for developing schizo-genetic high risk for developing schizo-

phrenia are reviewed elsewhere (Friedmanphrenia are reviewed elsewhere (Friedman

& Squires-Wheeler, 1994). These studies& Squires-Wheeler, 1994). These studies

have found that P300 latencies are pro-have found that P300 latencies are pro-

longed in these individuals (Schreiberlonged in these individuals (Schreiber et et

al al , 1992; Friedman & Squires-Wheeler,, 1992; Friedman & Squires-Wheeler,

1994), although there are no reports com-1994), although there are no reports com-

paring those who subsequently developedparing those who subsequently developed

psychosis with those who did not. Thesepsychosis with those who did not. These

studies are also consistent with P300studies are also consistent with P300

abnormalities identified in unaffectedabnormalities identified in unaffectedrelatives of patients with schizophreniarelatives of patients with schizophrenia

(Blackwood(Blackwood et al et al , 1991; Frangou, 1991; Frangou et al et al ,,

1997; Turetsky1997; Turetsky et al et al , 2000), which have, 2000), which have

also been related to neuropsychologicalalso been related to neuropsychological

deficits observed in patients and theirdeficits observed in patients and their

relatives (Roxboroughrelatives (Roxborough et al et al , 1993)., 1993).

In the meta-analysis by Jeon & PolichIn the meta-analysis by Jeon & Polich

(2001), smaller P300 amplitude was con-(2001), smaller P300 amplitude was con-

firmed in patients with schizophrenia com-firmed in patients with schizophrenia com-

pared with control subjects and differed inpared with control subjects and differed in

its effect size topography across the midlineits effect size topography across the midline

and temporal electrode sites. These findingsand temporal electrode sites. These findings

are consistent with evidence that the P300are consistent with evidence that the P300is reduced over the midline and that thereis reduced over the midline and that there

is a left temporal abnormality, which hasis a left temporal abnormality, which has

been associated with reduced volume of been associated with reduced volume of

the left posterior superior temporal gyrusthe left posterior superior temporal gyrus

(McCarley(McCarley et al et al , 1993). Further, in patients, 1993). Further, in patients

with first-episode schizophrenia a smallerwith first-episode schizophrenia a smaller

left temporal P300 was also associated withleft temporal P300 was also associated with

left posterior superior temporal gyrus andleft posterior superior temporal gyrus andplanum temporale volumes, whereasplanum temporale volumes, whereas

patients with affective psychosis did notpatients with affective psychosis did not

show these impairments or associationsshow these impairments or associations

(McCarley(McCarley et al et al , 2002). Left superior tem-, 2002). Left superior tem-

poral gyrus volumes have been associatedporal gyrus volumes have been associated

with formal thought disorder (Shentonwith formal thought disorder (Shenton et et

al al , 2001). This left temporal abnormality, 2001). This left temporal abnormality

has been described in patients who ceasedhas been described in patients who ceased

medication (Fauxmedication (Faux et al et al , 1993). A left-, 1993). A left-

lateralised P300 deficit has also beenlateralised P300 deficit has also been

described in schizotypal personalitydescribed in schizotypal personality

disorder (Niznikiewiczdisorder (Niznikiewicz et al et al , 2000)., 2000).

These studies of ERPs and their neuro-These studies of ERPs and their neuro-biological correlates need to be examinedbiological correlates need to be examined

in the recent high-risk or ultra-high-riskin the recent high-risk or ultra-high-risk

studies, and may provide trait/state indices,studies, and may provide trait/state indices,

whereas longitudinal studies may providewhereas longitudinal studies may provide

insights about disease progression.insights about disease progression.

In vivoIn vivo neurochemistryneurochemistry

Magnetic resonance spectroscopy (MRS)Magnetic resonance spectroscopy (MRS)

provides us with a non-invasive tool to in-provides us with a non-invasive tool to in-

vestigate metabolites in the living humanvestigate metabolites in the living human

brain. This technique overcomes one majorbrain. This technique overcomes one major

limitation of post-mortem analysis: thelimitation of post-mortem analysis: theinvestigation of investigation of in vivoin vivo brain metabolitesbrain metabolites

during the peri-onset and early phases of during the peri-onset and early phases of

the illness and the investigation of medi-the illness and the investigation of medi-

cation effects on these metabolites. Muchcation effects on these metabolites. Much

MRS work has focused on investigatingMRS work has focused on investigating

phosphorus-containing (phosphorus-containing (3131P MRS) andP MRS) and

proton-containing metabolites (proton-containing metabolites (11H MRS)H MRS)

(for reviews see Keshavan(for reviews see Keshavan et al et al , 2000;, 2000;

StanleyStanley et al et al , 2000)., 2000).3131P-MRS investigations in drug-naıveP-MRS investigations in drug-naı ¨ve

patients with first-episode psychosis suggestpatients with first-episode psychosis suggest

increased membrane breakdown at theincreased membrane breakdown at the

onset of psychosis (Pettegrewonset of psychosis (Pettegrew et al et al , 1991;, 1991;StanleyStanley et al et al , 1995; Fukuzako, 1995; Fukuzako et al et al , 1999), 1999)

and in most studies there appears to beand in most studies there appears to be

reduced membrane generation in earlyreduced membrane generation in early

and chronic schizophrenia. Cell membraneand chronic schizophrenia. Cell membrane

changes occur prominently during cell gen-changes occur prominently during cell gen-

eration and synaptogenesis, but also witheration and synaptogenesis, but also with

degenerative processes, such as apoptoticdegenerative processes, such as apoptotic

elimination of dendrites and axons (prun-elimination of dendrites and axons (prun-

ing) and cell death. Cell membrane altera-ing) and cell death. Cell membrane altera-

tions of patients with schizophrenia aretions of patients with schizophrenia are

also well documented in peripheral andalso well documented in peripheral and

post-mortem brain tissue at different stagespost-mortem brain tissue at different stages

of the disorder (for review see Bergerof the disorder (for review see Berger et al et al ,,2002). Such findings may reflect either a2002). Such findings may reflect either a

reduction in glia-, synapto- and neuro-reduction in glia-, synapto- and neuro-

genesis associated with chronic schizo-genesis associated with chronic schizo-

phrenia and/or accelerated programmedphrenia and/or accelerated programmed

cell loss (apoptosis) and/or dendritic andcell loss (apoptosis) and/or dendritic and

axonal pruning at the onset of the disorder.axonal pruning at the onset of the disorder.

Studies of adolescent offspring at increasedStudies of adolescent offspring at increased

genetic risk for schizophrenia showgenetic risk for schizophrenia showmembrane alterations similar to thosemembrane alterations similar to those

observed in patients with early schizo-observed in patients with early schizo-

phrenia (Klemmphrenia (Klemm et al et al , 2001; Keshavan, 2001; Keshavan et et

al al , 2003, 2003bb); these changes are more pro-); these changes are more pro-

nounced in the at-risk adolescents whonounced in the at-risk adolescents who

have already begun to manifest psycho-have already begun to manifest psycho-

pathology (Keshavanpathology (Keshavan et al et al , 2003, 2003bb). Inter-). Inter-

estingly, patients with manic psychosisestingly, patients with manic psychosis

appear to have an increase in membraneappear to have an increase in membrane

precursors (Katoprecursors (Kato et al et al , 1993), which may, 1993), which may

reflect a compensatory increase in cellreflect a compensatory increase in cell

generation and/or synaptogenesis duringgeneration and/or synaptogenesis during

manic exacerbation of psychotic disorders.manic exacerbation of psychotic disorders.Investigations using high-fieldInvestigations using high-field 3131P MRSP MRS

(e.g. at 4 T) in early psychosis are just(e.g. at 4 T) in early psychosis are just

emerging (Thebergeemerging (Theberge et al et al , 2002)., 2002).

Proton MRS provides us with a tool forProton MRS provides us with a tool for

measuringmeasuring in vivoin vivo brain metabolites,brain metabolites,

includingincluding N N -acetylaspartate (NAA), crea--acetylaspartate (NAA), crea-

tine, choline, myo-inositol, glutamine, glu-tine, choline, myo-inositol, glutamine, glu-

tamate, glutathione andtamate, glutathione and gg-amino butyric-amino butyric

acid (GABA).acid (GABA). N N -acetylaspartate is mainly-acetylaspartate is mainly

synthesised in neurons and is therefore re-synthesised in neurons and is therefore re-

garded as a putative marker for neuronalgarded as a putative marker for neuronal

loss or dysfunction (Urenjakloss or dysfunction (Urenjak et al et al , 1993;, 1993;

Rudkin & Arnold, 1999). However, NAARudkin & Arnold, 1999). However, NAAlevels also depend on the capacity of gliallevels also depend on the capacity of glial

cells which are involved in the uptake andcells which are involved in the uptake and

degradation of this metabolite (Passanidegradation of this metabolite (Passani et et

al al , 1998; Baslow, 2000; Bhakoo, 1998; Baslow, 2000; Bhakoo et al et al ,,

2001).2001). N N -acetylaspartate is also a major-acetylaspartate is also a major

acetyl-donor for the elongation of long-acetyl-donor for the elongation of long-

chain fatty acids and is important forchain fatty acids and is important for

generation of membrane phospholipids,generation of membrane phospholipids,

the basic molecules of all cell membranes.the basic molecules of all cell membranes.

Furthermore, NAA is important for mito-Furthermore, NAA is important for mito-

chondrial metabolism and excitatorychondrial metabolism and excitatory

neurotransmission (Tsai & Coyle, 1995;neurotransmission (Tsai & Coyle, 1995;

LimLim et al et al , 1996)., 1996).Reductions in NAA peaks were foundReductions in NAA peaks were found

in most studies of patients with chronicin most studies of patients with chronic

schizophrenia encompassing several differ-schizophrenia encompassing several differ-

ent brain regions (hippocampus, thalamusent brain regions (hippocampus, thalamus

and frontal cortex), were variably presentand frontal cortex), were variably present

in first-degree relatives, and were asso-in first-degree relatives, and were asso-

ciated with cortical atrophy and negativeciated with cortical atrophy and negative

symptoms (for discussion and referencessymptoms (for discussion and references

see Keshavansee Keshavan et al et al , 2000; Vance, 2000; Vance et al et al ,,

2000).2000). N N -acetylaspartate reductions in the-acetylaspartate reductions in the

prefrontal cortex have been found to beprefrontal cortex have been found to be

associated with reduced physiologicalassociated with reduced physiological

capacity for working memory as well ascapacity for working memory as well aswith exaggerated responses of dopaminewith exaggerated responses of dopamine

s1 3s1 3




neurons to amphetamine, a surrogate bio-neurons to amphetamine, a surrogate bio-

logical measure of positive symptomslogical measure of positive symptoms

(Weinberger(Weinberger et al et al , 2001). However, proton, 2001). However, proton

MRS studies in drug-naıve patients withMRS studies in drug-naı ¨ve patients with

first-first-episode psychosis have been lessepisode psychosis have been less

conclusive (Keshavanconclusive (Keshavan et al et al , 2000), and, 2000), and

the data suggest that neuronal integrity inthe data suggest that neuronal integrity inearly phases of illness may still be intactearly phases of illness may still be intact

and neuronal circuits only functionallyand neuronal circuits only functionally

impaired (Barthaimpaired (Bartha et al et al , 1997, 1999)., 1997, 1999). N N --

acetylaspartate reductions have been foundacetylaspartate reductions have been found

to be correlated with increased illnessto be correlated with increased illness

duration (Endeduration (Ende et al et al , 2000) supporting the, 2000) supporting the

possibility of a progressive impairment of possibility of a progressive impairment of

neuronal integrity as the illneuronal integrity as the illness unfolds.ness unfolds.

N N -acetylaspartate changes may also repre--acetylaspartate changes may also repre-

sent dynamic measures of neuropathologicalsent dynamic measures of neuropathological

change as a function of illness and/or changechange as a function of illness and/or change

(Bertolino(Bertolino et al et al , 2001). Future longitudinal, 2001). Future longitudinal

MRS studies before and after transition toMRS studies before and after transition topsychosis may contribute to a better under-psychosis may contribute to a better under-

standing of the relevance of NAA findingsstanding of the relevance of NAA findings

in the early phase of schizophrenia andin the early phase of schizophrenia and

related disorders.related disorders.

DISCUSSIONDISCUSSION

Structural imaging studies point to in-Structural imaging studies point to in-

creases in cerebrospinal fluid volumes andcreases in cerebrospinal fluid volumes and

widespread grey matter reductions in vary-widespread grey matter reductions in vary-

ing degrees across samples of patients withing degrees across samples of patients with

schizophrenia. These differences are moreschizophrenia. These differences are moreprominent in patients with chronic psycho-prominent in patients with chronic psycho-

sis as compared with patients with first-sis as compared with patients with first-

episode psychosis and are also present, to aepisode psychosis and are also present, to a

smaller degree, in unaffected relatives,smaller degree, in unaffected relatives,

unaffected co-twins and individuals atunaffected co-twins and individuals at

ultra-high risk for developing schizophreniaultra-high risk for developing schizophrenia

and related disorders. These differencesand related disorders. These differences

appear to deviate to some degree fromappear to deviate to some degree from

normal with time but it is unclear whethernormal with time but it is unclear whether

this is a direct effect of some antipsychoticthis is a direct effect of some antipsychotic

medications or due to the illness processmedications or due to the illness process

itself. Consistent with structural findings,itself. Consistent with structural findings,

11H MRS studies suggest that impairmentsH MRS studies suggest that impairmentsin neuronal integrity are more prominentin neuronal integrity are more prominent

in chronic as compared with first-episodein chronic as compared with first-episode

patients, and can also be found to somepatients, and can also be found to some

degree in unaffected first-degree relatives.degree in unaffected first-degree relatives.3131P MRS studies suggest alterations inP MRS studies suggest alterations in

membrane phospholipid metabolism earlymembrane phospholipid metabolism early

in the course of the illness; these changesin the course of the illness; these changes

are correlated with cognitive impairmentsare correlated with cognitive impairments

and negative symptoms, although theirand negative symptoms, although their

possible disease-related progress remainspossible disease-related progress remains

to be documented by longitudinal data.to be documented by longitudinal data.

Studies of cognitive and electro-Studies of cognitive and electro-

physiological processes in schizophreniaphysiological processes in schizophreniahave suggested general as well as selectivehave suggested general as well as selective

neuropsychological impairments, withneuropsychological impairments, with

some deficits being present early in a trait-some deficits being present early in a trait-

like manner and some others showing pro-like manner and some others showing pro-

gression. Functional imaging studies havegression. Functional imaging studies have

allowed characterisation of the functionalallowed characterisation of the functional

neuroanatomical circuitry involved earlyneuroanatomical circuitry involved early

in the illness; again, the course of in the illness; again, the course of these func-these func-tional changes and the illness versus treat-tional changes and the illness versus treat-

ment effects over time remain unclear.ment effects over time remain unclear.

Overall, the pathophysiological significanceOverall, the pathophysiological significance

of the neurobiological observations inof the neurobiological observations in

early psychoses remains vague, althoughearly psychoses remains vague, although

tantalising clues are beginning to appear.tantalising clues are beginning to appear.

Several lines of future research are of Several lines of future research are of

promise in this burgeoning field. First,promise in this burgeoning field. First,

advances in neuroimaging technology nowadvances in neuroimaging technology now

allow us to examine the neurobiology of allow us to examine the neurobiology of

psychosis in finer detail. High-field magnetspsychosis in finer detail. High-field magnets

((**3 T or higher) allow better spatial3 T or higher) allow better spatial

resolution for structural imaging studies;resolution for structural imaging studies;better neurochemical resolution for MRSbetter neurochemical resolution for MRS

may help investigation of key metabolites,may help investigation of key metabolites,

such as glutamate and GABA. Multimodalsuch as glutamate and GABA. Multimodal

imaging studies combining functional MRIimaging studies combining functional MRI

and ERP techniques will increase temporaland ERP techniques will increase temporal

resolution and allow close examination of resolution and allow close examination of

disordered cognitive processes. Second,disordered cognitive processes. Second,

observations that the early course of schizo-observations that the early course of schizo-

phrenia is associated with progressivephrenia is associated with progressive

changes in brain structure and functionchanges in brain structure and function

highlight the importance of longitudinalhighlight the importance of longitudinal

studies of individuals at ultra-high risk forstudies of individuals at ultra-high risk for

developing psychosis who are not receivingdeveloping psychosis who are not receivingantipsychotic medication to track theantipsychotic medication to track the

underlying biology of transition to theunderlying biology of transition to the

psychotic illnesses, as well as studies of psychotic illnesses, as well as studies of

patients with first-episode psychosis topatients with first-episode psychosis to

determine the biology of disease progres-determine the biology of disease progres-

sion following illness onset. Recognisingsion following illness onset. Recognising

these biological processes can eventuallythese biological processes can eventually

help to develop phase-specific treatmentshelp to develop phase-specific treatments

that may be able to protect the vulnerablethat may be able to protect the vulnerable

individual from the emergence and/orindividual from the emergence and/or

progression of the illness. Third, theprogression of the illness. Third, the

observations of similar, albeit less severe,observations of similar, albeit less severe,

neurobiological changes in relatives of neurobiological changes in relatives of patients with schizophrenia and other psy-patients with schizophrenia and other psy-

chotic disorders suggest that these studieschotic disorders suggest that these studies

may help us to better define the endopheno-may help us to better define the endopheno-

type of these illnesses, and eventually elu-type of these illnesses, and eventually elu-

cidate the susceptibility genes for illnesscidate the susceptibility genes for illness

onset, treatment response or outcome.onset, treatment response or outcome.

Finally, neurobiological research in earlyFinally, neurobiological research in early

psychosis, to be successful, requires servicepsychosis, to be successful, requires service

structures that can access adequatestructures that can access adequate

numbers of early psychosis patients. Thenumbers of early psychosis patients. The

recent emergence of specialised early recog-recent emergence of specialised early recog-

nition and intervention services for earlynition and intervention services for early

psychotic disorderspsychotic disorders throughout the worldthroughout the world(Edwards & McGorry,(Edwards & McGorry, 2002) will make2002) will make

neurobiological research in early psychosesneurobiological research in early psychoses

both timely and feasible.both timely and feasible.

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s1 6s1 6

CLINICIAL IMPLICATIONSCLINICIAL IMPLICATIONS

&& It is important to understand the neurobiological changes during the premorbidIt is important to understand the neurobiological changes during the premorbid

phase of psychoses to identify persons at increasedrisk and for prevention efforts.phase of psychoses to identify persons at increasedrisk and for prevention efforts.

&& Clarification of the biology of transition to psychosis in prodromal patients isClarification of the biology of transition to psychosis in prodromal patients iscritical for our efforts to identify early and potentially prevent the emergence of critical for our efforts to identify early and potentially prevent the emergence of

psychotic illness.psychotic illness.

&& A better knowledge of the biological changes during the early phases can help toA better knowledge of the biological changes during the early phases can help to

develop strategies for minimising long-term morbidity and disability.develop strategies for minimising long-term morbidity and disability.

LIMITATIONSLIMITATIONS

&& Although several neurobiological changes have been consistently found in earlyAlthough several neurobiological changes have been consistently found in early

schizophrenia, none is specific to be of diagnostic value at this time.schizophrenia, none is specific to be of diagnostic value at this time.

&& The implications of the neurobiological alterations for treatment are still unclear.The implications of the neurobiological alterations for treatment are still unclear.

&& Neurobiological researchin the early phases of schizophrenia is oftenhamperedbyNeurobiological researchin theearly phases of schizophrenia is oftenhamperedby the lack of specialised health service settings that can adequately access adequate thelackof specialised health service settings that can adequately access adequate

numbers of such people.numbers of such people.

MATCHERI S.KESHAVAN, MD, Depar tment of Psychiatry and B ehavioral Neurosciences,Wayne StateMATCHERI S. KESHAVAN, MD, Depar tment of Psychiatry and Behavioral Neurosciences,Wayne State

University, Detroit, Michigan,USA; GREGOR BERGER, MD, ORYGEN Research Centre, Department of University, Detroit, Michigan,USA; GREGOR BERGER, MD, ORYGEN Research Centre,Department of

Psychiatry, The University of Melbourne, Parkville, Australia; ROBERT B. ZIPURSKY, MD, Centre for AddictionPsychiatry, The University of Melbourne, Parkville, Australia; ROBERT B. ZIPURSKY, MD, Centre for Addiction

and Mental Health, Department of Psychiatry, University of Toronto,Canada; STEPHEN J.WOOD, PhD,and Mental Health,Department of Psychiatry, University of Toronto,Canada; STEPHEN J.WOOD, PhD,

CHRISTOS PANTELIS, FRANZCP, Melbourne Neuropsychiatry Centre, Depar tment of Psychiatry, TheCHRISTOS PANTELIS,FRANZCP, Melbourne Neuropsychiatry Centre, Depar tment of Psychiatry, The

University of Melbourne, Parkville, AustraliaUniversity of Melbourne, Parkville, Australia

Correspondence: Dr Matcheri S. Keshavan,Department of Psychiatry and Behavioral Neurosciences,WayneCorrespondence: Dr Matcheri S.Keshavan, Department of Psychiatry and Behavioral Neurosciences,Wayne

State University, UCH 9B, 4201 St Antoine Boulevard, Detroit, Michigan,USA. Tel: +1 313 993 6732;State University, UCH 9B, 4201 St Antoine B oulevard,Detroit, Michigan,USA. Tel: +1 313 9 93 6732;

fax: +1 313 57 7 590 0; e -mail: mkeshavafax: +1 313 57 7 590 0; e -mail: mkeshava@@med.wayne.edumed.wayne.edu




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