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  G. Dom, B. Sabbe, W. Hulstijn and W. van den Brink  

studiesreview of behavioural decision-making and neuroimaging Substance use disorders and the orbitofrontal cortex: Systematic  

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BackgroundBackground Orbitofrontal cortexOrbitofrontal cortex

dysfunctionshave been frequentlydysfunctions have been frequently

documented inpeoplewith substance usedocumented inpeoplewith substance use

disorders.The exact role ofthis corticaldisorders.The exact role ofthis cortical

region, however, remains unspecified.region, however, remainsunspecified.

AimsAims To assess the functionalityoftheTo assess the functionalityofthe

orbitofrontal cortex inpeoplewithorbitofrontal cortex inpeoplewith

substance use disorders.substance use disorders.

MethodMethod Reports of studies usingReports of studies using

behavioural decision-making tasks and/orbehavioural decision-making tasks and/or

neuroimaging techniques to investigateneuroimaging techniques to investigate

orbitofrontalcortex functioningincasesoforbitofrontalcortex functioningincasesof

substancemisusewere reviewed.Studiessubstancemisusewerereviewed.Studies

focusingexclusivelyontobacco-smokingfocusing exclusivelyontobacco-smoking

andgamblingwere excluded.andgamblingwere excluded.

ResultsResults Fifty-two research articlesFifty-two research articles

were evaluated.Most studies showedwere evaluated.Most studies showed

significantdeficits in decision-making insignificantdeficits in decision-making in

peoplewith substance use disorders.Apeoplewith substance use disorders.A

consistent finding in theneuroimagingconsistent finding inthe neuroimaging

studieswashypoactivityofthestudieswashypoactivityofthe

orbitofrontal cortex afterdetoxification.orbitofrontal cortex afterdetoxification.

The associationbetweenhyperactivityofThe associationbetweenhyperactivityof

this region and craving orcue reactivitythis region and cravingor cue reactivity

wasnotconsistent across studies.wasnotconsistent across studies.

ConclusionsConclusions The orbitofrontal cortexThe orbitofrontal cortex

has animportant role in addictivehas animportant role in addictive

behaviours.Further studies are needed tobehaviours.Further studies are needed to

elucidate the underlyingneuronalelucidate the underlyingneuronal

substrates of cue reactivity, cravingandsubstrates of cue reactivity, cravingand

decision-making, and the implications fordecision-making, and the implications for

treatment andrelapse prevention.treatment andrelapse prevention.

Declaration of interestDeclaration of interest None.None.

Traditionally, research into addictive pro-Traditionally, research into addictive pro-

cesses and their treatment has focused oncesses and their treatment has focused on

the mesolimbic dopaminergic reward sys-the mesolimbic dopaminergic reward sys-

tem. Recently, however, interest in thetem. Recently, however, interest in the

potentially important role of the prefrontalpotentially important role of the prefrontal

cortex has increased; specifically, thecortex has increased; specifically, the

orbitofrontal cortex is frequently impli-orbitofrontal cortex is frequently impli-

cated. This region is critically involved incated. This region is critically involved in

inhibitory decision-making processes, espe-inhibitory decision-making processes, espe-

cially in reward-related behaviours. Itcially in reward-related behaviours. It

processes the reward value and/or affectiveprocesses the reward value and/or affective

valence of environmental stimuli, assessesvalence of environmental stimuli, assesses

the future consequences of the individual’sthe future consequences of the individual’s

own actions (response selection) and inhi-own actions (response selection) and inhi-

bits appropriate behaviours (responsebits appropriate behaviours (response

inhibition; Bechara & Damasio, 2002;inhibition; Bechara & Damasio, 2002;

Krawczyk, 2002; FanKrawczyk, 2002; Fan et alet al, 2003). Thus,, 2003). Thus,

the decision-making function of the orbito-the decision-making function of the orbito-

frontal cortex is suggested to be closelyfrontal cortex is suggested to be closely

related to the well-known addiction pro-related to the well-known addiction pro-

cesses of craving, salience, continued drugcesses of craving, salience, continued drug

use despite harmful consequences and re-use despite harmful consequences and re-

lapse (Goldstein & Volkow, 2002; Lubmanlapse (Goldstein & Volkow, 2002; Lubman

et alet al, 2004). We explore the evidence, 2004). We explore the evidence

supporting this hypothesis, integrating datasupporting this hypothesis, integrating data

from both behavioural decision-makingfrom both behavioural decision-making

and neuroimaging studies of participantsand neuroimaging studies of participants

with substance use disorders.with substance use disorders.

METHODMETHOD

We consulted the US National Library ofWe consulted the US National Library of

Medicine (Medline) to identify studies con-Medicine (Medline) to identify studies con-

ducted between January 1990 and Mayducted between January 1990 and May

2004. Only original research articles in-2004. Only original research articles in-

cluding study populations with substancecluding study populations with substance

use disorders were considered. Post-use disorders were considered. Post-

mortem studies and studies focusing onmortem studies and studies focusing on

tobacco-smoking or gambling only weretobacco-smoking or gambling only were

excluded.excluded.

The keywords used to search theThe keywords used to search the

database were SUBSTANCE ABUSEdatabase were SUBSTANCE ABUSE

oror DEPENDENCEDEPENDENCE oror DRUG ADDIC-DRUG ADDIC-

TION, CRAVINGTION, CRAVING oror DRUG CRAVING,DRUG CRAVING,

DECISION MAKING, NEUROIMAG-DECISION MAKING, NEUROIMAG-

INGING oror FUNCTIONAL IMAGING,FUNCTIONAL IMAGING,

ORBITOFRONTAL CORTEXORBITOFRONTAL CORTEX oror

VENTROMEDIAL PREFRONTAL COR-VENTROMEDIAL PREFRONTAL COR-

TEX, GAMBLING TASKTEX, GAMBLING TASK oror DECISION-DECISION-

MAKING TASK. Combinations of theseMAKING TASK. Combinations of these

search terms yielded 43 articles. Biblio-search terms yielded 43 articles. Biblio-

graphies were examined to identifygraphies were examined to identify

further citations. Imaging studies werefurther citations. Imaging studies were

included if they usedincluded if they used conservative statisti-conservative statisti-

cal thresholding methodscal thresholding methods (e.g. corrections(e.g. corrections

for multiple comparisons). Imaging studiesfor multiple comparisons). Imaging studies

in which the orbitofrontal cortex was notin which the orbitofrontal cortex was not

explicitly incorporated in the studyexplicitly incorporated in the study

design or in which the cue-presentationdesign or in which the cue-presentation

design might have been confounded bydesign might have been confounded by

habituation effects (e.g. repetitive, long-habituation effects (e.g. repetitive, long-

presentation stimuli) were excluded. Threepresentation stimuli) were excluded. Three

studies were excluded (Maasstudies were excluded (Maas et alet al, 1998;, 1998;

SchneiderSchneider et alet al, 2001; Wrase, 2001; Wrase et alet al, 2002)., 2002).

Ultimately 52 studies were included in thisUltimately 52 studies were included in this

review: 11 behavioural task studies andreview: 11 behavioural task studies and

41 neuroimaging studies.41 neuroimaging studies.

RESULTSRESULTS

Behavioural laboratory task studiesBehavioural laboratory task studies

The main results of the studies using behav-The main results of the studies using behav-

ioural decision-making tasks are shown inioural decision-making tasks are shown in

Table 1. One study used the Rogers Cam-Table 1. One study used the Rogers Cam-

bridge Gamble Task (RCGT; Rogersbridge Gamble Task (RCGT; Rogers et alet al,,

19991999aa) and ten studies used the Iowa Gam-) and ten studies used the Iowa Gam-

bling Task (IGT; Becharabling Task (IGT; Bechara et alet al, 1994). In, 1994). In

the RCGT, participants make a simplethe RCGT, participants make a simple

probabilistic judgement between twoprobabilistic judgement between two

mutually exclusive outcomes, and sub-mutually exclusive outcomes, and sub-

sequently place a bet based on their confi-sequently place a bet based on their confi-

dence in that decision. The involvement ofdence in that decision. The involvement of

the orbitofrontal cortex – and the anteriorthe orbitofrontal cortex – and the anterior

cingulate cortex – in performance on thecingulate cortex – in performance on the

Risk Task (an adaptation of the RCGTRisk Task (an adaptation of the RCGT

for use in functional imaging) was demon-for use in functional imaging) was demon-

strated in a positron emission tomographystrated in a positron emission tomography

(PET) study (Rogers(PET) study (Rogers et alet al, 1999, 1999bb). The only). The only

RCGT study demonstrated decision-makingRCGT study demonstrated decision-making

deficits in both individuals on ampheta-deficits in both individuals on ampheta-

mines and dependent on heroin, comparedmines and dependent on heroin, compared

with controls (Rogerswith controls (Rogers et alet al, 1999, 1999aa).).

The Iowa Gambling Task was devel-The Iowa Gambling Task was devel-

oped to assess decision-making in patientsoped to assess decision-making in patients

with ventromedial lesions. The task’s essen-with ventromedial lesions. The task’s essen-

tial feature is that it mimics real-lifetial feature is that it mimics real-life

situations in the way that it factors un-situations in the way that it factors un-

certainty, reward and punishment (Becharacertainty, reward and punishment (Bechara

et alet al, 1994, 2000) and emphasises the, 1994, 2000) and emphasises the

contribution of emotional processing tocontribution of emotional processing to

decision-making. To earn ‘pretend’ money,decision-making. To earn ‘pretend’ money,

participants need to learn the associationsparticipants need to learn the associations

between reward and punishment of fourbetween reward and punishment of four

card decks. In all ten IGT studies, par-card decks. In all ten IGT studies, par-

ticipants with substance use disordersticipants with substance use disorders

performed worse than the controls. Theperformed worse than the controls. The

2 0 92 0 9

BR I T I SH JOURNAL OF P SYCHIATRYBR IT I SH JOURNAL OF P SYCHIATRY ( 2 0 0 5 ) , 1 8 7, 2 0 9 ^ 2 2 0( 2 0 0 5 ) , 1 8 7, 2 0 9 ^ 2 2 0 R E V I E W A R T I C L ER E V I E W A R T I C L E

Substance use disorders and the orbitofrontalSubstance use disorders and the orbitofrontal

cortexcortex

Systematic review of behavioural decision-makingSystematic review of behavioural decision-making

and neuroimaging studiesand neuroimaging studies

G. DOM, B. SABBE, W. HULSTIJN and W. VAN DEN BRINKG. DOM, B. SABBE, W. HULSTIJN and W. VAN DEN BRINK

AUTHOR’S PROOFAUTHOR’S PROOF

DOM ET ALDOM ET AL

studies that also included patients withstudies that also included patients with

ventromedial lesions showed that, com-ventromedial lesions showed that, com-

pared with the control groups, a higher pro-pared with the control groups, a higher pro-

portion of the participants with substanceportion of the participants with substance

use disorders performed within the rangeuse disorders performed within the range

of the patients with lesions (Rogersof the patients with lesions (Rogers et alet al,,

19991999aa; Bechara & Damasio, 2002; Bechara; Bechara & Damasio, 2002; Bechara

et alet al, 2001, 2002). Taken together, the, 2001, 2002). Taken together, the

studies consistently demonstrate impairedstudies consistently demonstrate impaired

decision-making in patients with substancedecision-making in patients with substance

use disorders relative to controls.use disorders relative to controls.

Neuroimaging studiesNeuroimaging studies

Imaging studies during decision-makingImaging studies during decision-making

The studies using functional imaging duringThe studies using functional imaging during

decision-making are summarised in Tabledecision-making are summarised in Table

2. Fundamental to this review is the (only)2. Fundamental to this review is the (only)

PET study during IGT and a neutral controlPET study during IGT and a neutral control

task (Bollatask (Bolla et alet al, 2003). Performance on the, 2003). Performance on the

IGT within both a group of cocaine usersIGT within both a group of cocaine users

and a control group was positively corre-and a control group was positively corre-

lated with activation in the right mediallated with activation in the right medial

orbitofrontal cortex region. Between-grouporbitofrontal cortex region. Between-group

comparison showed greater metaboliccomparison showed greater metabolic

activity of this region during the IGT inactivity of this region during the IGT in

the cocaine user group. This may reflectthe cocaine user group. This may reflect

210210

AUTHOR’S PROOFAUTHOR’S PROOF

Table1Table1 Main results from studies using behavioural decision-making tasksMain results from studies using behavioural decision-making tasks

StudyStudy Substancemisuse sampleSubstancemisuse sample Control groupControl group AbstinenceAbstinence MethodMethod Decision-makingDecision-making

deficitsdeficits

PetryPetry et alet al (1998)(1998) Heroin (out-patients: 18 men,Heroin (out-patients: 18 men,

14 women)14 women)

33 men, 26 women33 men, 26 women BuprenorphineBuprenorphine

maintenancemaintenance

IGTIGT YesYes

RogersRogers et alet al (1999(1999aa)) Amphetamines (14 men, 4 women)Amphetamines (14 men, 4 women)

Opiates (13 men)Opiates (13 men)

16 men, 10 women16 men, 10 women 12h12h RCGTRCGT YesYes

GrantGrant et alet al (2000)(2000) Polydrugmisuse (27 men, 3 women)Polydrugmisuse (27 men, 3 women) 18 men, 4 women18 men, 4 women 36^38h36^38h IGTIGT YesYes

MazasMazas et alet al (2000)(2000) Early-onset alcoholism (15 men,Early-onset alcoholism (15 men,

12 women)12 women)

Control groupControl group

(14 men, 18 women)(14 men, 18 women)

ASP group (6 men,ASP group (6men,

2 women)2 women)

Sober at testingSober at testing IGTIGT YesYes

BecharaBechara et alet al (2001)(2001) Substance dependency (21men,Substance dependency (21men,

20 women)20 women)

20 men, 20 women20 men, 20 women 4415 days15 days IGTIGT YesYes

Petry (2001)Petry (2001) Substance use disorder (63 men)Substance use disorder (63 men) 21men21men 0 day0 day IGTIGT YesYes

Bechara & Damasio (2002)Bechara & Damasio (2002) Substance dependency (21men,Substance dependency (21men,

25 women)25 women)

21men, 28 women21men, 28 women 4415 days15 days IGT+SCRIGT+SCR YesYes

BecharaBechara et alet al (2002)(2002) VMPFC lesions (5 men, 5 women)VMPFC lesions (5 men, 5 women) Variant versionVariant version

IGT+SCRIGT+SCR

YesYes

Mintzer & Stitzer (2002)Mintzer & Stitzer (2002) Opioid-dependent MMT (7 men,Opioid-dependent MMT (7 men,

11women)11women)

10 men, 11women10 men, 11women 24h MMT24hMMT IGTIGT YesYes

ErnstErnst et alet al (2003)(2003) Same group as in GrantSame group as in Grant et alet al (2000)(2000) IGTIGT YesYes

Rotheram-FullerRotheram-Fuller et alet al

(2004)(2004)

MMT+tobacco smokers (9)MMT+tobacco smokers (9)

MMT non-smokers (9)MMT non-smokers (9)

Smokers (9)Smokers (9)

Non-smokers (10)Non-smokers (10)

MMTMMT IGTIGT YesYes

ASP, antisocial personality disorder; IGT, Iowa GamblingTask; MMT, methadonemaintenance therapy; RCGT, Rogers Cambridge GambleTask; SCR, skin conductance response;ASP, antisocial personality disorder; IGT, Iowa GamblingTask; MMT, methadonemaintenance therapy; RCGT, Rogers Cambridge GambleTask; SCR, skin conductance response;VMPFC, ventromedial prefrontal cortex.VMPFC, ventromedial prefrontal cortex.

Table 2Table 2 Functional imaging during decision-making tasksFunctional imaging during decision-making tasks

StudyStudy Main substance ofMain substance of

misuse (sample)misuse (sample)

TreatmentTreatment ControlControl

groupgroup

AbstinenceAbstinence MethodMethod OFCOFC

activationactivation

Other regions activatedOther regions activated

PaulusPaulus et alet al (2002)(2002) MethamphetamineMethamphetamine

(10 men)(10 men)11In-patientIn-patient 10 men10 men 22.4 days22.4 days TCPT,TCPT,

TCRT+fMRITCRT+fMRI

YesYes Sample group showed less task-relatedSample group showed less task-related

activity in theVMPFC and right OFCactivity in theVMPFC and right OFC

regionregion

BollaBolla et alet al (2003)(2003) Cocaine (10 men,Cocaine (10 men,

3 women)3 women)

10 men,10 men,

3 women3 women

25 days25 days PET (FDG)PET (FDG)

during IGTduring IGT

YesYes Larger activation in the right OFC and lessLarger activation in the right OFC and less

in the DLPFC in the cocaine groupin the DLPFC in the cocaine group

Performance on the IGT correlated withPerformance on the IGT correlated with

activation of right medial OFCactivation of rightmedial OFC

PaulusPaulus et alet al (2003)(2003) MethamphetamineMethamphetamine

(14 men)(14 men)

In-patientIn-patient 10 men,10 men,

4 women4 women

25 days25 days TCPT,TCPT,

TCRT+fMRITCRT+fMRI

YesYes Methamphetamine-dependent patientsMethamphetamine-dependent patients

showed less task-related activation in theshowed less task-related activation in the

OFC (BA10),DLPFC (BA 9), ACC (BA 32)OFC (BA10),DLPFC (BA 9), ACC (BA 32)

and parietal cortex (BA 7)and parietal cortex (BA 7)

ACC, anterior cingulate cortex; BA, Brodmann area; DLPFC, dorsolateral prefrontal cortex; FDG, fluorodeoxyglucose; fMRI, functional magnetic resonance imaging; IGT, IowaACC, anterior cingulate cortex; BA, Brodmann area; DLPFC, dorsolateral prefrontal cortex; FDG, fluorodeoxyglucose; fMRI, functionalmagnetic resonance imaging; IGT, IowaGamblingTask; OFC, orbitofrontal cortex; PET, positron emission tomography;TCPT, two-choice prediction task;TCRT, two-choice response task;VMPFC, ventromedial prefrontalGamblingTask; OFC, orbitofrontal cortex; PET, positron emission tomography;TCPT, two-choice prediction task;TCRT, two-choice response task;VMPFC, ventromedial prefrontalcortex.cortex.1. Methamphetamine dependency.1. Methamphetamine dependency.

SUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEXSUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEX

an effort to compensate for the intrinsicallyan effort to compensate for the intrinsically

weaker performance of the orbitofrontalweaker performance of the orbitofrontal

cortex in the cocaine group or an effort tocortex in the cocaine group or an effort to

compensate for weaker performance ofcompensate for weaker performance of

other regions involved in decision-making,other regions involved in decision-making,

such as the dorsolateral prefrontal cortex.such as the dorsolateral prefrontal cortex.

Although the cocaine user group’s perfor-Although the cocaine user group’s perfor-

mance on the IGT was inferior to that ofmance on the IGT was inferior to that of

the controls, the difference was not signifi-the controls, the difference was not signifi-

cant, possibly owing to the small samplecant, possibly owing to the small sample

size.size.

In a functional magnetic resonanceIn a functional magnetic resonance

imaging (fMRI) study, Paulusimaging (fMRI) study, Paulus et alet al (2002,(2002,

2003) used an experimental decision-2003) used an experimental decision-

making task, a two-choice prediction task,making task, a two-choice prediction task,

in which participation did not knowin which participation did not know aa

prioripriori which action was associated withwhich action was associated with

the best outcome, and a neutral control taskthe best outcome, and a neutral control task

(two-choice response task). Compared with(two-choice response task). Compared with

controls, participants dependent oncontrols, participants dependent on

methamphetamine showed less task-relatedmethamphetamine showed less task-related

activation in the orbitofrontal cortexactivation in the orbitofrontal cortex

(Brodmann areas (BA) 10 and 11), the(Brodmann areas (BA) 10 and 11), the

dorsolateral prefrontal cortex (BA 9) anddorsolateral prefrontal cortex (BA 9) and

the anterior cingulate cortex (BA 32) duringthe anterior cingulate cortex (BA 32) during

the prediction task relative to the responsethe prediction task relative to the response

task. This suggests a dysfunction of thetask. This suggests a dysfunction of the

orbitofrontal cortex, which is elicitedorbitofrontal cortex, which is elicited

primarily in choices associated withprimarily in choices associated with

uncertain outcomes.uncertain outcomes.

Imaging studies of cue reactivityImaging studies of cue reactivity

Twenty neuroimaging studies used a cueTwenty neuroimaging studies used a cue

exposure or drug priming paradigm toexposure or drug priming paradigm to

evoke cue reactivity. The findings, orderedevoke cue reactivity. The findings, ordered

by substance, are presented in Table 3.by substance, are presented in Table 3.

The results are conflicting. Thirteen studiesThe results are conflicting. Thirteen studies

demonstrated activation of the orbitofron-demonstrated activation of the orbitofron-

tal cortex in response to cue exposuretal cortex in response to cue exposure

(‘cue reactivity’), whereas six did not. How-(‘cue reactivity’), whereas six did not. How-

ever, several other areas were activated: theever, several other areas were activated: the

dorsolateral prefrontal cortex, amygdala,dorsolateral prefrontal cortex, amygdala,

insular cortices, anterior cingulate cortexinsular cortices, anterior cingulate cortex

and cerebellum. One study showed cueand cerebellum. One study showed cue

reactivity of the orbitofrontal cortex inreactivity of the orbitofrontal cortex in

male patients addicted to cocaine but notmale patients addicted to cocaine but not

in similarly addicted female patients (Kiltsin similarly addicted female patients (Kilts

et alet al, 2004). Seventeen studies included, 2004). Seventeen studies included

craving measures: two of these studies re-craving measures: two of these studies re-

ported no craving after exposure, whereasported no craving after exposure, whereas

six reported an association between thesix reported an association between the

intensity of drug craving or drug ‘high’intensity of drug craving or drug ‘high’

and orbitofrontal cortex activation. In theand orbitofrontal cortex activation. In the

remaining nine studies craving wasremaining nine studies craving was

associated with other regions.associated with other regions.

Priming dose effects (‘drug probing’)Priming dose effects (‘drug probing’). Six stu-. Six stu-

dies measured the effect of placebo and adies measured the effect of placebo and a

single dose of the drug of preference (or asingle dose of the drug of preference (or a

closely related drug; Stapletonclosely related drug; Stapleton et alet al, 1995;, 1995;

VolkowVolkow et alet al, 1996, 1999, 1996, 1999aa, 2003, 2003aa; Sell; Sell etet

alal, 2000; Adinoff, 2000; Adinoff et alet al, 2001). All but one, 2001). All but one

(Adinoff(Adinoff et alet al, 2003, 2003aa) demonstrated orbito-) demonstrated orbito-

frontal cortex activation in response tofrontal cortex activation in response to

drug administration. In addition, all butdrug administration. In addition, all but

two (Volkowtwo (Volkow et alet al, 1996, 2003, 1996, 2003aa) showed) showed

orbitofrontal cortex activation to be relatedorbitofrontal cortex activation to be related

to the subjective experience of craving.to the subjective experience of craving.

Cue exposure during early abstinenceCue exposure during early abstinence. Four-. Four-

teen studies used a cue exposure paradigmteen studies used a cue exposure paradigm

during early abstinence (1–28 days), withduring early abstinence (1–28 days), with

the exception of the study by Daglishthe exception of the study by Daglish et alet al

(2001) in which abstinence varied strongly.(2001) in which abstinence varied strongly.

Of the seven PET studies, four demon-Of the seven PET studies, four demon-

strated activation of the orbitofrontalstrated activation of the orbitofrontal

cortex in response to cue exposure (Grantcortex in response to cue exposure (Grant

et alet al, 1996; Wang, 1996; Wang et alet al, 1999; Daglish, 1999; Daglish etet

alal, 2001; Bonson, 2001; Bonson et alet al, 2002), whereas, 2002), whereas

two did not (Childresstwo did not (Childress et alet al, 1999; Kilts, 1999; Kilts etet

alal, 2001). One PET study demonstrated less, 2001). One PET study demonstrated less

activation of this region in female com-activation of this region in female com-

pared with male cocaine-addicted patientspared with male cocaine-addicted patients

(Kilts(Kilts et alet al, 2004). Remarkably, all studies, 2004). Remarkably, all studies

focusing on female patients with substancefocusing on female patients with substance

use disorders failed to demonstrate orbito-use disorders failed to demonstrate orbito-

frontal cortex activation in response tofrontal cortex activation in response to

cue exposure (Kiltscue exposure (Kilts et alet al, 2004; Tapert, 2004; Tapert etet

alal, 2004) or drug administration (Adinoff, 2004) or drug administration (Adinoff

et alet al, 2003, 2003aa). This suggests gender differ-). This suggests gender differ-

ences in the functionality of this regionences in the functionality of this region

and in the degree of its involvement inand in the degree of its involvement in

addictive processes.addictive processes.

Of the seven fMRI studies, threeOf the seven fMRI studies, three

demonstrated involvement of the orbito-demonstrated involvement of the orbito-

frontal cortex in cue reactivity (Garavanfrontal cortex in cue reactivity (Garavan

et alet al, 2000; Tapert, 2000; Tapert et alet al, 2003; Myrick, 2003; Myrick etet

alal, 2004). The between-study inconsisten-, 2004). The between-study inconsisten-

cies may be due to technical limitations.cies may be due to technical limitations.

In fMRI designs the investigation of theIn fMRI designs the investigation of the

orbitofrontal cortex can be complicated byorbitofrontal cortex can be complicated by

susceptibility to artefacts induced by thesusceptibility to artefacts induced by the

air–tissue interface (Londonair–tissue interface (London et alet al, 2000)., 2000).

Alternatively, differences in cue exposureAlternatively, differences in cue exposure

paradigms may influence results. Usingparadigms may influence results. Using

cocaine-related videotapes as cues, Wexlercocaine-related videotapes as cues, Wexler etet

alal (2001) found higher activity in the ante-(2001) found higher activity in the ante-

rior cingulate cortex of cocaine-dependentrior cingulate cortex of cocaine-dependent

patients, both before these patients experi-patients, both before these patients experi-

enced any craving and in the absence ofenced any craving and in the absence of

craving. Georgecraving. George et alet al (2001), using a sip(2001), using a sip

of alcohol and images of alcoholic bev-of alcohol and images of alcoholic bev-

erages, demonstrated thalamic involve-erages, demonstrated thalamic involve-

ment. In another study using videotapes,ment. In another study using videotapes,

cocaine craving was associated with thecocaine craving was associated with the

activation of 13 brain areas including theactivation of 13 brain areas including the

orbitofrontal and anterior cingulate cor-orbitofrontal and anterior cingulate cor-

tices (Garavantices (Garavan et alet al, 2000). In a PET study, 2000). In a PET study

using videotaped cues, Kiltsusing videotaped cues, Kilts et alet al (2001) de-(2001) de-

monstrated cue reactivity in the anteriormonstrated cue reactivity in the anterior

cingulate cortex, right inferior parietalcingulate cortex, right inferior parietal

cortex and caudate/lateral dorsal nucleus.cortex and caudate/lateral dorsal nucleus.

Although the activation of these multipleAlthough the activation of these multiple

brain areas may imply that craving relatesbrain areas may imply that craving relates

to several neuroanatomical circuits, oneto several neuroanatomical circuits, one

might – in line with Kiltsmight – in line with Kilts et alet al (2001) – ar-(2001) – ar-

gue that inductive cues such as videotapesgue that inductive cues such as videotapes

are too crude to allow a distinction betweenare too crude to allow a distinction between

activations due to conditioned drug cravingactivations due to conditioned drug craving

and activations associated with accom-and activations associated with accom-

panying features of psychophysiologicalpanying features of psychophysiological

arousal, anticipation,arousal, anticipation, memory retrieval,memory retrieval,

attention and behaviouralattention and behavioural planning.planning.

Finally, treatment status might influ-Finally, treatment status might influ-

ence results. In all but one of the cue expo-ence results. In all but one of the cue expo-

sure studies (Kiltssure studies (Kilts et alet al 2004) comparing2004) comparing

gender differences in patients treated forgender differences in patients treated for

cocaine addiction) in-patients systemati-cocaine addiction) in-patients systemati-

cally failed to demonstrate orbitofrontalcally failed to demonstrate orbitofrontal

cortex activation in response to cue expo-cortex activation in response to cue expo-

sure, whereas substance misusers respondedsure, whereas substance misusers responded

with activation. The only exception was thewith activation. The only exception was the

study by Georgestudy by George et alet al (2001); however, only(2001); however, only

‘mildly severe’ cases of alcoholism were in-‘mildly severe’ cases of alcoholism were in-

cluded, which might account for the lack ofcluded, which might account for the lack of

orbitofrontal cortex involvement in thisorbitofrontal cortex involvement in this

study.study.

In summary, these imaging studies evi-In summary, these imaging studies evi-

dence activation of multiple brain regionsdence activation of multiple brain regions

during cue exposure. The type of drug didduring cue exposure. The type of drug did

not differentially affect orbitofrontal cortexnot differentially affect orbitofrontal cortex

activity. Neither cue reactivity nor cravingactivity. Neither cue reactivity nor craving

was exclusively or reliably linked to activ-was exclusively or reliably linked to activ-

ation of this brain region. Other regionsation of this brain region. Other regions

most frequently associated with cue expo-most frequently associated with cue expo-

sure in patients with substance use dis-sure in patients with substance use dis-

orders are the anterior cingulate cortex,orders are the anterior cingulate cortex,

dorsolateral prefrontal cortex and amygdala.dorsolateral prefrontal cortex and amygdala.

‘Brain at rest’ imaging studies‘Brain at rest’ imaging studies

Of the 18 available studies testing the orbitoOf the 18 available studies testing the orbito--

frontal cortex in drug-dependent patientsfrontal cortex in drug-dependent patients

with the brain ‘at rest’, only 3 failed towith the brain ‘at rest’, only 3 failed to

demonstrate involvement of this region.demonstrate involvement of this region.

The studies can be divided into 13 meta-The studies can be divided into 13 meta-

bolic and 5 structural studies (Table 4).bolic and 5 structural studies (Table 4).

MetabolicstudiesMetabolicstudies. During early withdrawal. During early withdrawal

(less than 7 days of abstinence), the orbito-(less than 7 days of abstinence), the orbito-

frontal cortex metabolism in participantsfrontal cortex metabolism in participants

with substance use disorders was eitherwith substance use disorders was either

comparable with controls (Volkowcomparable with controls (Volkow et alet al,,

1998) or higher than in the control group1998) or higher than in the control group

(Volkow(Volkow et alet al, 1991; London, 1991; London et alet al, 2004)., 2004).

Studies during late withdrawal (Studies during late withdrawal (447 days)7 days)

or prolonged abstinence demonstrated sys-or prolonged abstinence demonstrated sys-

tematically low activity in the orbitofrontaltematically low activity in the orbitofrontal

211211

AUTHOR’S PROOFAUTHOR’S PROOF

DOM ET ALDOM ET AL

212212

AUTHOR’S PROOFAUTHOR’S PROOFTa

ble3

Table3

Neuroim

agingstudiesof

cuereactiv

ity

Neuroim

agingstudiesof

cuereactiv

ity

Stud

yStud

ySubstanceusegrou

pSubstanceusegrou

pCon

trolgrou

pCon

trolgrou

pAbstinence

Abstinence

Metho

dMetho

dBrainactivation

Brain

activation

Sample

Sample

Treatm

ent

Treatm

ent

OFC

OFC

activation

activation

Other

region

sactivated

Other

region

sactivated

OFC

activation

OFC

activation

relatedto

craving

relatedto

craving

Poly-sub

stance

misuse

Poly-sub

stance

misuse

Stapleton

Stapletonetal

etal

(1995)

(1995)

Poly-sub

stance

misuse

Poly-sub

stance

misuse

(20men;6

withASP

)(20men;6

withASP

)

Non

eNon

e10

men

10men

14days

14days

PET+

placebo(saline

PET+placebo(saline

i.v.)challenge

i.v.)challenge

Yes

Yes

Substancemisusegrou

pshow

edlower

absolute

Substancemisusegrou

pshow

edlower

absolute

metabolicratesinlateralo

ccipitalgyrusandhigher

metabolicratesinlateralo

ccipitalgyrusandhigher

norm

alised

metabolicratesin

tempo

raland

fron

tal

norm

alised

metabolicratesintempo

raland

fron

tal

areas,includ

ingtheOFC

areas,includ

ingtheOFC

No

No

Opiates

Opiates

Daglish

Daglishetal

etal

(200

1)(200

1)Opiatedepend

ency

Opiatedepend

ency

(11men,1

wom

an)

(11men,1

wom

an)

Out-patient

Out-patient

0010

days

to3

10days

to3

years

years

PET+

cueexpo

sure

PET+

cueexpo

sure

(neutralanddrug-

(neutralanddrug-

relatedautobio-

relatedautobio-

graphicalscripts)

graphicalscripts)

Yes

Yes

Activationof

OFC

correlated

withcravingmeasures

Activationof

OFC

correlated

withcravingmeasures

TheleftACC/m

edialprefron

talregionwas

activated

TheleftACC/m

edialprefron

talregionwas

activated

byop

iate-related

stim

uli,no

relation

shipwithcraving

byop

iate-related

stim

uli,no

relation

shipwithcraving

Yes

Yes

Sell

Selletal

etal

(200

0)(200

0)Opiateaddiction(10men)

Opiateaddiction(10men)

In-patient

In-patient

00MMT

MMT

PET+cueexpo

sure

PET+

cueexpo

sure

(video

)+heroin(20mg)

(video

)+heroin(20mg)

orplacebo

orplacebo

Yes

Yes

Craving

correlated

positivelywithincreasedrC

BFin

Craving

correlated

positivelywithincreasedrC

BFin

theinferior

PFCandOFC

theinferior

PFCandOFC

Yes

Yes

Alcoh

olAlcoh

ol

Geo

rge

Georgeetal

etal

(200

1)(200

1)Alcoh

oldepe

ndency

Alcoh

oldepend

ency

(8men,2

wom

en)

(8men,2

wom

en)

Non

eNon

e8men,2

8men,2

wom

enwom

en

24h

24h

fMRI+cueexpo

sure

(sip

fMRI+cueexpo

sure

(sip

ofalcoho

licbeverage+

ofalcoho

licbeverage+

pictures

ofalcoho

licpictures

ofalcoho

lic

and

andno

n-alcoho

licno

n-alcoho

lic

beverages)

beverages)

No

No

LeftDLP

FCandtheanterior

thalam

usLeftDLP

FCandtheanterior

thalam

us

Tapert

Tapert

etal

etal

(2003)

(2003)

Alcoh

olusedisorders

Alcoh

olusedisorders

(ado

lescents:9

boys,

(ado

lescents:9

boys,

6girls)

6girls)

Non

eNon

eAdo

lescents(9

Ado

lescents(9

boys,6

girls)

boys,6

girls)

72h

72h

fMRI+cueexpo

sure

fMRI+cueexpo

sure

(personalised

pictures

(personalised

pictures

ofalcoho

licandno

n-of

alcoho

licandno

n-

alcoho

licbeverages)

alcoho

licbeverages)

Yes

Yes

VentralACCandsubcallosal,prefrontal,orbital

VentralACCandsubcallosal,prefrontal,orbital

andlim

bicregion

smoreBO

LDrespon

sedu

ring

andlim

bicregion

smoreBO

LDrespon

sedu

ring

alcoho

l-related

cues

comparedwithcontrols.N

oalcoho

l-related

cues

comparedwithcontrols.N

o

cravingrepo

rted

afteralcoho

lpicture

task

cravingrepo

rted

afteralcoho

lpicture

task

No

No

Myrick

Myricketal

etal

(200

4)(200

4)Alcoh

olism

(8men,

Alcoh

olism

(8men,

2wom

en)

2wom

en)

Non

eNon

eSo

cial

Social

drinkers

(8drinkers

(8

men,2

wom

en)

men,2

wom

en)

24h

24h

fMRI+cueexpo

sure

(sip

fMRI+cueexpo

sure

(sip

ofalcoho

l+alcoho

l-of

alcoho

l+alcoho

l-

relatedandneutral

relatedandneutral

pictures)

pictures)

Yes

Yes

Craving

correlated

positivelywithbrain

Craving

correlated

positivelywithbrain

activity

intheOFC

,ACCandnu

cleus

activity

intheOFC

,ACCandnu

cleus

accumbens

region

accumbens

region

Yes

Yes

Tapert

Tapert

etal

etal

(200

4)(200

4)Alcoh

oldepe

ndency

Alcoh

oldepend

ency

(8wom

en)

(8wom

en)

Non

eNon

eSo

cialdrinkers

Socialdrinkers

(9wom

en)

(9wom

en)

48h

48h

fMRI+cueexpo

sure

fMRI+cueexpo

sure

(alcoh

olic-related

and

(alcoh

olic-related

and

neutralw

ords)

neutralw

ords)

No

No

After

cueexpo

sure,m

oreactivation

insubcallosal

After

cueexpo

sure,m

oreactivation

insubcallosal

cortex,A

CC,leftPF

Candbilateralinsulain

alcoho

l-cortex,A

CC,leftPF

Candbilateralinsulainalcoho

l-

ism

grou

pcomparedwithcontrols

ism

grou

pcomparedwithcontrols

No

No

((contin

uedoverleaf

continuedoverleaf

))

SUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEXSUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEX

213213

AUTHOR’S PROOFAUTHOR’S PROOFTa

ble3

Table3

((contin

ued

continued))

Stud

yStud

ySubstanceusegrou

pSubstanceusegrou

pCon

trolgrou

pCon

trolgrou

pAbstinence

Abstinence

Metho

dMetho

dBrain

activation

Brainactivation

Sample

Sample

Treatm

ent

Treatm

ent

OFC

OFC

activation

activation

Other

region

sOther

region

sOFC

activation

OFC

activation

relatedto

craving

relatedto

craving

Cannabis

Cannabis

Volko

wVo

lkow

etal

etal

(199

6)(199

6)Cannabisdepend

ency

Cannabisdepend

ency

(8men)

(8men)

Non

eNon

e8men

8men

0day

0day

PET+

THCchallenge

PET+

THCchallenge

Yes

Yes

Lower

baselin

ecerebellarmetabolism

inLo

wer

baselin

ecerebellarmetabolism

in

cann

abisusersthan

controls.C

erebellar

cann

abisusersthan

controls.C

ereb

ellar

metabolism

correlated

withsubjective

senseof

intox-

metabolism

correlated

withsubjective

senseof

intox-

icationdu

ring

THCintoxication

.Usergrou

pbu

tno

ticationdu

ring

THCintoxication

.Usergrou

pbu

tno

t

controlgroup

show

edsignificant

increasesinmeta-

controlgroup

show

edsignificant

increasesinmeta-

bolism

ofOFC

,prefron

taland

basalgangliadu

ring

bolism

ofOFC

,prefron

taland

basalgangliadu

ring

THCchallenge

THCchallenge

No

No

Cocaine

Cocaine

Grant

Grant

etal

etal

(199

6)(199

6)Cocaine

use(12men,

Cocaine

use(12men,

1wom

an)

1wom

an)

Non

eNon

e4men,1

wom

an4men,1

wom

an44

48h

48h

PET+cueexpo

sure

PET+

cueexpo

sure

(neutralanddrug-

(neutralanddrug-

related;

hand

lingdrug

related;

hand

lingdrug

paraph

ernalia,video

)paraph

ernalia,video

)

Yes

Yes

Intensityof

cravingcorrelated

withDLP

FC,amygdala

Intensityof

cravingcorrelated

withDLP

FC,amygdala

andcerebe

llum

activation

andcerebellum

activation

No

No

Childress

Childressetal

etal

(199

9)(199

9)Cocaine

depend

ency

Cocaine

depend

ency

(14men)

(14men)

Yes

Yes

6men

6men

13.5days

13.5days

PET+

cueexpo

sure

PET+

cueexpo

sure

(video

)(video

)

No

No

BaselinerC

BFwas

lower

intheACCregion

inthe

BaselinerC

BFwas

lower

intheACCregion

inthe

patientg

roup

;duringcueexpo

sure,p

atientshada

patientg

roup

;duringcueexpo

sure,p

atientsh

ada

higher

flowincrease

intheam

ygdalaandACC.

higher

flowincrease

intheam

ygdalaandACC.

Craving

was

associated

withrC

BFincreasesinlim

bic

Craving

was

associated

withrC

BFincreasesinlim

bic

(amygdalaandACC)and

decreasesinbasalganglia

(amygdalaandACC)and

decreasesinbasalganglia

No

No

Volko

wVo

lkow

etal

etal

(199

9(199

9aa))

Cocaine

use(20men)

Cocaine

use(20men)

In-patients

In-patients

0014

days

14days

PET+

placeboand

PET+

placeboand

methylphenidate

methylphenidate

challenge

challenge

Yes

Yes

Cocaine

usersshow

edmethylphenidate-

Cocaine

usersshow

edmethylphenidate-

indu

cedincreasesinthesupe

rior

cingulategyrusand

indu

cedincreasesin

thesuperior

cingulategyrusand

rightthalam

us.A

ctivationof

therightOFC

andright

rightthalam

us.A

ctivationof

therightOFC

andright

striatum

inpatientsrepo

rtingcraving

striatum

inpatientsrepo

rtingcraving

Yes

Yes

Wang

Wangetal

etal

(199

9)(199

9)Cocaine

use(5

wom

en,

Cocaine

use(5

wom

en,

8men)

8men)

Non

eNon

e00

7^9days

7^9days

PET+neutraltheme

PET+

neutraltheme

interview

interview

PET+

cocainethem

ePE

T+cocainethem

e

interview+hand

lingof

interview+hand

lingof

drug

paraph

ernalia

drug

paraph

ernalia

Yes

Yes

Absoluteandrelative

metabolism

was

higher

inOFC

,Absoluteandrelative

metabolism

was

higher

inOFC

,

leftinsularandcerebellarregion

sdu

ring

cocaine

leftinsularandcerebellarregion

sdu

ring

cocaine

them

ecomparedwithneutraltheme.Craving

them

ecomparedwithneutraltheme.Craving

correlated

withmetabolicvalues

inrightinsular

correlated

withmetabolicvalues

inrightinsular

region

region

No

No

Garavan

Garavan

etal

etal

(200

0)(200

0)Cocaine

use(crack-

Cocaine

use(crack-

smok

ing)

(14men,

smok

ing)

(14men,

3wom

en)

3wom

en)

Non

eNon

e9men,5

9men,5

wom

enwom

en

Not

specified

Not

specified

fMRI+cueexpo

sure

fMRI+cueexpo

sure

(nature^

sex^

cocaine

(nature^

sex^

cocaine

vide

o)+visuospatial

video)+visuospatial

working

mem

orytask

working

mem

orytask

Yes

Yes

13region

swereassociated

withcraving(e.g.O

FC,

13region

swereassociated

withcraving(e.g.O

FC,

DLP

FC,A

CC)

DLP

FC,A

CC)

Yes

Yes

((contin

uedoverleaf

continuedoverleaf

))

DOM ET ALDOM ET AL

214214

AUTHOR’S PROOFAUTHOR’S PROOFTa

ble3

Table3

((contin

ued

continued))

Stud

yStud

ySubstanceusegrou

pSubstanceusegrou

pCon

trolgrou

pCon

trolgrou

pAbstinence

Abstinence

Metho

dMetho

dBrainactivation

Brainactivation

Sample

Sample

Treatm

ent

Treatm

ent

OFC

OFC

activation

activation

Other

region

sOther

region

sOFC

activation

OFC

activation

relatedto

craving

relatedto

craving

Adino

ffAdino

ffetal

etal

(200

1)(200

1)Cocaine

depend

ency

Cocaine

depend

ency

(10men)

(10men)

In-patient

In-patient

10men

10men

14^28days

14^28days

SPEC

Tprocaine

and

SPEC

Tprocaine

and

placebo(saline)

placeb

o(saline)

challenge

challenge

Yes

Yes

Patientshadlower

rCBF

aftersalin

eandhigher

rCBF

Patientshadlower

rCBF

aftersalin

eandhigher

rCBF

afterprocaine

comparedwithcontrolsinOFC

region

afterprocaine

comparedwithcontrolsinOFC

region

No

No

Kilts

Kiltsetal

etal

(200

1)(200

1)Cocaine

(crack)

Cocaine

(crack)

depend

ency

(8men)

depend

ency

(8men)

In-patient

In-patient

007^17

days

7^17

days

PET+cueexpo

sure

PET+

cueexpo

sure

(imageryscript:n

eu-

(imageryscript:n

eu-

tral,druguseandanger

tral,druguseandanger

script)

script)

No

No

Craving

associated

withactiv

ationofam

ygdala,

Craving

associated

withactiv

ationofam

ygdala,sub

cal-

subcal-

losalgyrus,nucleus

accumbens,A

CC

losalgyrus,nucleus

accumbe

ns,A

CC

No

No

Wexler

Wexleretal

etal

(200

1)(200

1)Cocaine

depend

ency

Cocaine

depend

ency

(8men,3

wom

en)

(8men,3

wom

en)

In-patient

In-patient

13wom

en,

13wom

en,

8men

8men

14.9days

14.9days

fMRI+videotapes;

fMRI+videotapes;

happ

y,sad,andcocaine

happ

y,sad,andcocaine

video

video

No

No

Cocaine

videoelicited

activation

ofACCinbo

thCocaine

videoelicited

activation

ofACCinbo

th

patientsexperiencing

cravingandpatientsexperien

-patientsexperiencing

cravingandpatientsexperien-

cing

nocraving

cing

nocraving

No

No

Bon

son

Bon

sonetal

etal

(2002)

(2002)

Cocaine

use(9

men,

Cocaine

use(9

men,

2wom

en)

2wom

en)

Non

eNon

e00

2days

2days

PET+cueexpo

sure

PET+

cueexpo

sure

(script,vide

oandhand

-(script,videoandhand

-

lingofparaph

ernalia)

lingofparaph

ernalia)

Yes

Yes

Positive

correlationwithcravingwas

observed

inPo

sitive

correlationwithcravingwas

observed

in

rightDLP

FC(BA9),leftlateralOFC

(BA12/47),left

rightDLP

FC(BA9),leftlateralOFC

(BA12/47),left

insula(BA13)and

leftam

ygdala/rhinalcortex

insula(BA13)and

leftam

ygdala/rhinalcortex

Yes

Yes

Adino

ffAdino

ffetal

etal

(2003

(2003aa

))Cocaine

depend

ency

Cocaine

depend

ency

(10wom

en)

(10wom

en)

In-patient

In-patient

10wom

en10

wom

en9^

28days

9^28

days

SPEC

T+cocaineand

SPEC

T+cocaineand

placebo(saline)

placeb

o(saline)

challenge

challenge

Samestud

ydesign

asSamestud

ydesign

as

Adino

ffAdino

ffetal

etal

(200

1)(200

1)

No

No

Blunted

limbicrC

BFrespon

seafterprocaine.

Blunted

limbicrC

BFrespon

seafterprocaine.

IncreasedrC

BFrespon

seinbilateralinsular

and

IncreasedrC

BFrespon

seinbilateralinsular

and

leftsuperior

fron

talregions

afterprocaine

leftsuperior

fron

talregions

afterprocaine

Volko

wVo

lkow

etal

etal

(2003

(2003aa

))Activecocaineuse(25)

Activecocaineuse(25)

Non

eNon

e00

Current

Current

users

users

PET(FDG)

PET(FDG)

Yes

Yes

Methylphenidate

increasedwho

le-brainmetabolism

Methylphenidate

increasedwho

le-brainmetabolism

inbo

thexpe

cted

andno

texp

ectedcond

itions.

inbo

thexpe

cted

andno

texp

ectedcond

itions.

Largestincreaseincerebe

llum,o

ccipitalcortex

and

Largestincreaseincerebellum,o

ccipitalcortex

and

thalam

usthalam

us

Craving

was

associated

withthalam

usactivation

Craving

was

associated

withthalam

usactivation

Greater

increase

forun

expe

cted

methylphenidate

Greater

increase

forun

expe

cted

methylphenidate

than

expe

cted

methylphenidate

inleftlateralO

FCthan

expe

cted

methylphenidate

inleftlateralO

FC

No

No

Kilts

Kiltsetal

etal

(200

4)(200

4)Cocaine

depend

ency

Cocaine

depend

ency

(8wom

en)

(8wom

en)

Out-patient

Out-patient

Cocaine

depen-

Cocaine

depe

n-

dency(8

men)

dency(8

men)

1^14

days

1^14

days

PET+

cueexpo

sure

PET+

cueexpo

sure

(imageryscript:

(imageryscript:

neutral,drug

useand

neutral,drug

useand

angerscript)

angerscript)

No

No

(wom

en)

(wom

en)

Supe

rior

tempo

ralgyrus,d

orsalanteriorandpo

ster-

Superior

tempo

ralgyrus,d

orsalanteriorandpo

ster-

iorcingulatecortex,n

ucleus

accumbens

andcentral

iorcingulatecortex,nucleus

accumbens

andcentral

sulcus

wereactivatedinfemalepatients

sulcus

wereactivatedinfemalepatients

Com

paredwithmen,lessactivation

inam

ygdala,

Com

paredwithmen,lessactivation

inam

ygdala,

insula,O

FC,ventralcingulatecortex;greater

activ-

insula,O

FC,ventralcingulatecortex;greater

activ-

ationincentralsulcusandwidelydistribu

tedcortical

ationincentralsulcusandwidelydistribu

tedcortical

areas

areas

ACC,anteriorcingulatecortex;A

SP,antisocialp

ersonalitydisorder;B

A,B

rodm

annarea;B

OLD

,blood

oxygen

leveldependent;D

LPFC

,dorsolateralprefron

talcor

tex;

FDG,fluorod

eoxyglucose;

fMRI,functio

nalm

agne

ticresonanceim

aging;

ACC,anteriorcingulatecortex

;ASP,antisocialp

ersonalitydisorder;B

A,B

rodm

annarea;B

OLD

,blood

oxygen

leveldependent;D

LPFC

,dorsolateralprefron

talcortex;

FDG,fluorod

eoxyglucose;

fMRI,functio

nalm

agne

ticresonanceim

aging;

MMT,methado

nemaintenance

therapy;OFC

,orbitofrontalcortex;P

ET,p

ositron

emissio

ntomography;PF

C,prefron

talcortex;

SPEC

T,sin

gleproton

emissio

ncompu

tedtomography;TH

C,tetrahydrocannabino

l.MMT,methado

nemaintenance

therapy;OFC

,orbitofrontalcortex;P

ET,p

ositron

emissio

ntomography;PF

C,prefron

talcortex;

SPEC

T,sin

gleproton

emissio

ncompu

tedtomography;THC,tetrahydrocannabino

l.

SUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEXSUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEX

215215

AUTHOR’S PROOFAUTHOR’S PROOFTa

ble4

Table4

Mainresultsof

‘brain

atrest’imagingstudies

Mainresultsof

‘brain

atrest’imagingstudies

Stud

yStud

ySubstanceusegrou

pSubstanceusegrou

pCon

trolgrou

pCon

trolgrou

pAbstinence

Abstinence

Metho

dMetho

dOFC

abno

rmality

OFC

abno

rmality

Involvem

entof

otherregion

sInvolvem

entof

otherregion

s

Sample

Sample

Treatm

ent

Treatm

ent

Alcoh

olAlcoh

ol

Volkow

Volko

wetal

etal

(1993)

(1993)

Alcoh

olism,earlyon

set

Alcoh

olism,earlyon

set

(10men)

(10men)

In-patient

In-patient

12men

12men

16days

16days

PET+

placebo(i.v.salin

e:PE

T+placeb

o(i.v.salin

e:

baselin

ePE

T+lorazepam

baselin

ePE

T+lorazepam

(i.v.30

(i.v.30

mmg/kg)

g/kg

)

Yes

Yes

Lorazepam

decreasesregion

albrainmetabolism.T

heLo

razepam

decreasesregion

albrainmetabolism.T

he

alcoho

lism

grou

pshow

edablun

tedrespon

seon

loraze-

alcoho

lism

grou

pshow

edablun

tedrespon

seon

loraze-

pam

administrationin

OFC

,thalamus

andbasalganglia

pam

administrationinOFC

,thalamus

andbasalganglia

Volkow

Volko

wetal

etal

(1997)

(1997)

Alcoh

olism,earlyon

set,

Alcoh

olism,earlyon

set,

FH+(10men)

FH+(10men)

In-patient

In-patient

16men

16men

Firsttrialat2^3

Firsttrialat2^3

weeks’abstinence

weeks’abstinence

Second

trialat6^

8Second

trialat6^

8

weeks’abstinence

weeks’abstinence

PET,

samedesign

asin

PET,

samedesign

asin

Volko

wVolko

wetal

etal

(1993)

(1993)

Yes

Yes

Baselineregion

albrainmetabolism

alcoho

lics

Baselineregion

albrainmetabolism

alcoho

lics55

controls

controls

during

firsttrial(earlywithd

rawal).Second

trial(late

during

firsttrial(earlywithd

rawal).Second

trial(late

withd

rawal)b

rainmetabolism

alcoho

lics

withd

rawal)b

rainmetabolism

alcoho

lics55

controlsin

controlsin

cingulategyrusandOFC

.Trend

towards

blun

tedlora-

cingulategyrusandOFC

.Trend

towards

blun

tedlora-

zepam

respon

seintheOFC

inalcoho

lism

grou

pdu

ring

zepam

respon

seintheOFC

inalcoho

lism

grou

pdu

ring

second

trial

second

trial

Dao-C

astellana

Dao-C

astellana

etal

etal

(199

8)(199

8)

Alcoh

olism

(11men,

Alcoh

olism

(11men,

6wom

en)

6wom

en)

In-patient

In-patient

6men,

6men,

3wom

en3wom

en

1weekto

1mon

th1weekto

1mon

thMRI+PE

TMRI+PE

TYe

sYe

sHypom

etabolism

predom

inantlyinthemediofron

tal

Hypom

etabolism

predom

inantlyin

themediofron

tal

cortex

cortex

Catafau

Catafau

etal

etal

(199

9)(199

9)Alcoh

oldepend

ency,type2,

Alcoh

oldepend

ency,type2,

Cloninger

(16men)

Cloninger

(16men)

In-patient

In-patient

8men,

8men,

5wom

en5wom

en

FirstSPEC

T:10

days

FirstSPEC

T:10

days

Second

SPEC

T:12

Second

SPEC

T:12

days

days

SPEC

TSPEC

T

SPEC

T+naltrexo

neSPEC

T+naltrexo

ne

Yes

Yes

Baselineperfusionpatterns

show

edfron

talrCBF

im-

Baselineperfusionpatterns

show

edfron

talrCBF

im-

pairmentinalcoho

lism

grou

pinleftOFC

andprefrontal

pairmentinalcoho

lism

grou

pinleftOFC

andprefrontal

cortex.A

singlenaltrexo

nedo

seindu

ceddecreasesin

cortex.A

singlenaltrexo

nedo

seindu

ceddecreasesin

basalgangliaandleftmesialtem

poralrCBF

basalgangliaandleftmesialtem

poralrCBF

Fein

Fein

etal

etal

(2002)

(2002)

Alcoh

oldepend

ency

Alcoh

oldepend

ency

(24men)

(24men)

Non

eNon

eLightd

rink

ing,

Lightd

rink

ing,

17men

17men

Soberat

MRI

Soberat

MRI

MRI

MRI

No

No

Reduced

glob

algrey-m

attervolumein

PFC,largest

Reduced

glob

algrey-m

attervolumeinPF

C,largest

differencepo

steriorPF

CandDLP

FCdiffe

rencepo

steriorPF

CandDLP

FC

Goldstein

Goldstein

etal

etal

(2002

(2002aa

))Earlyon

setalcoho

lism

Earlyon

setalcoho

lism

(17men),cocaineaddiction

(17men),cocaineaddiction

(17men)

(17men)

In-patient

In-patient

17men

17men

Sober/cleanat

urine

Sober/cleanat

urine

testbe

fore

scanning

testbe

fore

scanning

PET(FDG)

PET(FDG)

Stroop

interference

task

Stroop

interference

task

Yes

Yes

HigherOFC

activation

was

associated

withpo

orer

HigherOFC

activation

was

associated

withpo

orer

performance

incontrolgroup

andbe

tter

performance

performance

incontrolgroup

andbe

tter

performance

ontheStroop

task

insubstancemisusegrou

pon

theStroop

task

insubstancemisusegrou

p

Laakso

Laakso

etal

etal

(2002)

(2002)

ASP+type

2alcoho

lism

ASP+type

2alcoho

lism

(24men)

(24men)

In-patient

In-patient

33men

33men

Severalm

onths

Severalm

onths

MRI,ROIanalysis

MRI,ROIanalysis

Yes

Yes

Alcoh

olism

grou

phadsm

allervolumeinleftDLP

FC,

Alcoh

olism

grou

phadsm

allervolumeinleftDLP

FC,

OFC

andMFC

OFC

andMFC

Cocaine

Cocaine

Volkow

Volko

wetal

etal

(1991)

(1991)

Cocaine

use+

otherdrug

Cocaine

use+

otherdrug

use(15men)

use(15men)

Out-patient

Out-patient

17men

17men

12hto

1week(

12hto

1week(nn¼10)

10)

2^4weeks

(2^

4weeks

(nn¼5)5)

PET

PET

Yes

Yes

Patientsstud

iedwithin1weekof

cocainewithd

rawal

Patientsstud

iedwithin1weekof

cocainewithd

rawal

(but

notthosewith2^

4weeks

ofwithd

rawal)h

adhigh-

(but

nottho

sewith2^

4weeks

ofwithd

rawal)h

adhigh-

erlevelsof

glob

albrainmetabolism

andhigher

metabo-

erlevelsof

glob

albrainmetabolism

andhigher

metabo-

lism

intheOFC

andbasalgangliathan

controls

lism

intheOFC

andbasalgangliathan

controls

Correlation

foun

dbe

tweennu

mberof

days

ofabsti-

Correlation

foun

dbe

tweennu

mbe

rof

days

ofabsti-

nenceandmetabolism

intheOFC

andbasalganglia

nenceandmetabolism

intheOFC

andbasalganglia

Correlation

foun

dbe

tweencravingandmetabolic

Correlation

foun

dbe

tweencravingandmetabolic

activity

inPF

CandOFC

activity

inPF

CandOFC

((contin

uedoverleaf

continuedoverleaf

))

DOM ET ALDOM ET AL

216216

AUTHOR’S PROOFAUTHOR’S PROOFTa

ble4

Table4

((contin

ued

continued))

Stud

yStud

ySubstanceusegrou

pSubstanceusegrou

pCon

trolgrou

pCon

trolgrou

pAbstinence

Abstinence

Metho

dMetho

dOFC

abno

rmality

OFC

abno

rmality

Involvem

entof

otherregion

sInvolvem

entof

otherregion

s

Sample

Sample

Treatm

ent

Treatm

ent

Volkow

Volko

wetal

etal

(199

8)(199

8)Activecocaineuse

Activecocaineuse

(9men,4

wom

en)

(9men,4

wom

en)

Non

eNon

e6men,8

6men,8

wom

enwom

en

5days

5days

PET+

placebo(i.v.salin

e)PE

T+placebo(i.v.salin

e)

PET+

lorazepam

(i.v.

PET+

lorazepam

(i.v.

3030mmg

/kg)

g/kg

)

No

No

Lorazepam

decreasedglob

alandregion

albrainglucose

Lorazepam

decreasedglob

alandregion

albrainglucose

metabolism,m

oreinthecocainegrou

pthan

inthe

metabolism,m

oreinthecocainegrou

pthan

inthe

controls.D

ifferencesgreatestinstriatum

,thalamus

and

controls.D

ifferencesgreatestinstriatum

,thalamus

and

parietalcortex.A

tbaselinewho

le-brainmetabolism

inparietalcortex.A

tbaselinewho

le-brainmetabolism

in

cocainegrou

pcocainegrou

p44controls(spe

cificallytempo

ralcortex,

controls(spe

cificallytempo

ralcortex,

thalam

usandstriatum

)thalam

usandstriatum

)

Franklin

Franklin

etal

etal

(2002)

(2002)

Cocaine

depe

ndency

Cocaine

depend

ency

(13men)

(13men)

Yes

Yes

16men

16men

5days

5days

VBM

VBM

Yes

Yes

Decreased

grey-m

atterdensityinOFC

(+insular,

Decreased

grey-m

atterdensityinOFC

(+insular,

tempo

raland

anterior

cingulatecortices)

tempo

raland

anterior

cingulatecortices)

Lim

Lim

etal

etal

(2002)

(2002)

Cocaine

depe

ndency

Cocaine

depend

ency

(12men)

(12men)

Yes

Yes

10men,3

10men,3

wom

enwom

en

556mon

ths

6mon

ths

DTI

DTI

Yes

Yes

Disrupted

white-m

atterintegrityof

inferior

fron

tal

Disrupted

white-m

atterintegrityof

inferior

fron

tal

brainregion

s,includ

ingOFC

region

brainregion

s,includ

ingOFC

region

Adino

ffAdino

ffetal

etal

(2003

(2003bb

))Cocaine

depe

ndency

Cocaine

depend

ency

(12men,1

wom

an)

(12men,1

wom

an)

7men,8

7men,8

wom

enwom

en

21^55days

21^55days

SPEC

T+IGT

SPEC

T+IGT

Yes

Yes

Lower

leftDLP

FCandrightOFC

restingrC

BFLo

wer

leftDLP

FCandrightOFC

restingrC

BF

Matochik

Matochiketal

etal

(2003)

(2003)

Cocaine

use(11men,

Cocaine

use(11men,

3wom

en)

3wom

en)

Non

eNon

e7men,4

7men,4

wom

enwom

en

20days

(in-patient

20days

(in-patient

mon

itoring)

mon

itoring)

MRI(VBM)

MRI(VBM

)

VOIanalyses

VOIanalyses

Yes

Yes

Lower

grey-m

atterdensityinmedialand

lateralaspects

Lower

grey-m

atterdensityinmedialand

lateralaspects

ofOFC

(+cingulategyrus,lateralP

FC)

ofOFC

(+cingulategyrus,lateralPFC

)

Methamph

etam

ine

Methamph

etam

ine

Volkow

Volko

wetal

etal

(200

1)(200

1)Methamph

etam

inedepen-

Methamph

etam

inedepe

n-

dency(6

men,9

wom

en)

dency(6

men,9

wom

en)

Out-patient

Out-patient

14men,6

14men,6

wom

enwom

en

2weeks

to35

2weeks

to35

mon

ths

mon

ths

PET([

PET([

1111C]racloprideand

C]racloprideand

FDG)

FDG)

Yes

Yes

Methamph

etam

inegrou

phadlower

levelofD

Methamph

etam

inegrou

phadlower

levelofD

22receptor

receptor

availabilitythan

controlgroup

(16%

incaud

ateand10%

availabilitythan

controlgroup

(16%

incaud

ateand10%

inpu

tamen);D

inpu

tamen);D

22receptor

availabilitywas

associated

receptor

availabilitywas

associated

withmetabolicrate

intheOFC

inbo

thgrou

pswithmetabolicrate

intheOFC

inbo

thgrou

ps

Goldstein

Goldstein

etal

etal

(2002

(2002bb

))Methamph

etam

inedepen-

Methamph

etam

inedepe

n-

dency(3

men,11wom

en)

dency(3

men,11wom

en)

Drug

Drug

rehabilitation

rehabilitation

centre

centre

17men,5

17men,5

wom

enwom

en

442weeks

2weeks

PET(FDG)

PET(FDG)

MPQ

harm

avoidance

MPQ

harm

avoidance

scale

scale

Yes

Yes

HigherMPQ

scores

wereassociated

withhigher

HigherMPQ

scores

wereassociated

withhigher

relative

OFC

metabolism

inmethamph

etam

inegrou

prelative

OFC

metabolism

inmethamph

etam

inegrou

p

Chang

Chang

etal

etal

(2002)

(2002)

Methamph

etam

inedepen-

Methamph

etam

inedepe

n-

dency(10men,10wom

en)

dency(10men,10wom

en)

Out-patient

Out-patient

10men,10

10men,10

wom

enwom

en

8mon

ths

8mon

ths

MRI+pe

rfusionMRI

MRI+perfusionMRI

No

No

Decreased

relative

rCBF

basalgangliaandrightp

arietal

Decreased

relative

rCBF

basalgangliaandrightp

arietal

brainregion

,increased

relative

rCBF

tempo

roparietal

brainregion

,increased

relative

rCBF

tempo

roparietal

andoccipitalregions

andoccipitalregions

Sekine

Sekine

etal

etal

(2003)

(2003)

Methamph

etam

ineuse

Methamph

etam

ineuse

(11men)

(11men)

??9men

9men

5,6mon

ths

5,6mon

ths

PET([

PET([

1111C]W

IN35,428

)C]W

IN35,428

)Ye

sYe

sDop

aminetransporterdensitylower

inmetaham

phe-

Dop

aminetransporterdensitylower

inmetaham

phe-

taminegrou

pin

OFC

,DLP

FCandam

ygdala.R

eduction

taminegrou

pinOFC

,DLP

FCandam

ygdala.R

eduction

inOFC

andDLP

FCcorrelated

negativelywithscoreof

inOFC

andDLP

FCcorrelated

negativelywithscoreof

psychiatricsymptom

sanddu

ration

ofmethamph

eta-

psychiatricsymptom

sanddu

ration

ofmethamph

eta-

mineuse

mineuse

Lond

onLo

ndon

etal

etal

(200

4)(200

4)Methamph

etam

inedepen-

Methamph

etam

inedepe

n-

dency(11men,6

wom

en)

dency(11men,6

wom

en)

In-patient

In-patient

10men,8

10men,8

wom

enwom

en

4^7days

4^7days

PET(FDG)

PET(FDG)

Yes

Yes

Methamph

etam

inegrou

phadhigher

relative

rCGM

inMethamph

etam

inegrou

phadhigher

relative

rCGM

in

lateralO

FC,low

erinACCandinsula.Inthisgrou

ptrait

lateralO

FC,low

erinACCandinsula.Inthisgrou

ptrait

anxietycovaried

negativelywithOFC

activity

anxietycovaried

negativelywithOFC

activity

ACC,anteriorcingulatecortex;A

SP,antisocialp

ersonalitydisorder;D

LPFC

,dorsolateralprefron

talcortex;

DTI,diffu

siontensor

imaging;FD

G,fluorod

eoxyglucose;FH

+,p

ositivefamily

history;fM

RI,functio

nalm

agne

ticresonanceim

aging;

ACC,anteriorcingulatecortex;A

SP,antisocialp

ersonalitydisorder;D

LPFC

,dorsolateralprefron

talcortex;

DTI,diffu

siontensor

imaging;FD

G,fluorod

eoxyglucose;FH

+,p

ositivefamily

history;fM

RI,functio

nalm

agne

ticresonanceim

aging;

IGT,IowaGam

blingTask;

MFC

,medialfrontalcortex;M

PQ,Tellegen’sMultid

imensio

nalPersonalityQue

stionn

aire;M

RI,magne

ticresonanceim

aging;

OFC

,orbitofrontalcortex;P

ET,p

ositron

emissio

ntomography;PF

C,prefron

talcortex;

IGT,IowaGam

blingTask;

MFC

,medialfrontalcortex;M

PQ,Tellegen’sMultid

imensio

nalPersonalityQue

stionn

aire;M

RI,magne

ticresonanceim

aging;

OFC

,orbitofrontalcortex;P

ET,p

ositron

emissio

ntomography;PF

C,prefron

talcortex;

rCBF,regionalcerebralblood

flow;rCGM,regionalcerebralglucose

metabolism;R

OI,region

ofinterest;SPE

CT,sin

gleph

oton

emissio

ncompu

tedtomography;VBM

,voxel-based

morph

ometry;V

OI,volumeof

interest.

rCBF,regionalcerebralblood

flow;rCGM,regionalcerebralglucose

metabolism;R

OI,region

ofinterest;SPE

CT,sin

gleph

oton

emissio

ncompu

tedtomography;VBM

,voxel-based

morph

ometry;V

OI,volumeof

interest.

SUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEXSUBSTANCE MISUSE AND THE ORBITOFRONTAL CORTEX

cortex region (Dao-Castellanacortex region (Dao-Castellana et alet al, 1998;, 1998;

CatafauCatafau et alet al, 1999; Volkow, 1999; Volkow et alet al, 2001;, 2001;

AdinoffAdinoff et alet al, 2003, 2003bb; Sekine; Sekine et alet al, 2003;, 2003;

LondonLondon et alet al, 2004). Although the studies, 2004). Although the studies

using a lorazepam challenge do not strictlyusing a lorazepam challenge do not strictly

qualify as ‘brain at rest’, they all demon-qualify as ‘brain at rest’, they all demon-

strate hypofunctionality of this brain regionstrate hypofunctionality of this brain region

after withdrawal (Volkowafter withdrawal (Volkow et alet al, 1993,, 1993,

1997, 1998). One study administering the1997, 1998). One study administering the

Iowa Gambling Task after PET recordingIowa Gambling Task after PET recording

(Adinoff(Adinoff et alet al, 2003, 2003bb) showed performance) showed performance

on this task to be positively correlated withon this task to be positively correlated with

dorsolateral prefrontal cortex and anteriordorsolateral prefrontal cortex and anterior

cingulate cortex metabolism at rest. Allcingulate cortex metabolism at rest. All

studies of substance use disorder thatstudies of substance use disorder that

included measures of psychiatric symptomsincluded measures of psychiatric symptoms

or psychological traits indicated involve-or psychological traits indicated involve-

ment of the orbitofrontal cortex in anxietyment of the orbitofrontal cortex in anxiety

and disordered mood (Goldsteinand disordered mood (Goldstein et alet al,,

20022002aa,,bb; Sekine; Sekine et alet al, 2003; London, 2003; London et alet al,,

2004).2004).

Only one study, using perfusion mag-Only one study, using perfusion mag-

netic resonance imaging, failed to demon-netic resonance imaging, failed to demon-

strate any difference in the orbitofrontalstrate any difference in the orbitofrontal

cortex in long-abstinent people withcortex in long-abstinent people with

methamphetamine dependency relative tomethamphetamine dependency relative to

a normal control group (Changa normal control group (Chang et alet al,,

2002). This may reflect brain recovery.2002). This may reflect brain recovery.

Recently, WangRecently, Wang et alet al (2004) demonstrated(2004) demonstrated

partial recovery of brain function after long-partial recovery of brain function after long-

lasting abstinence in methamphetamine-lasting abstinence in methamphetamine-

dependent patients.dependent patients.

Structural studiesStructural studies. Three studies revealed. Three studies revealed

smaller volumes (Laaksosmaller volumes (Laakso et alet al, 2002) and, 2002) and

decreased grey-matter density in the orbito-decreased grey-matter density in the orbito-

frontal cortex (Franklinfrontal cortex (Franklin et alet al, 2002; Mato-, 2002; Mato-

chickchick et alet al, 2003). Another study showed, 2003). Another study showed

disruption in white-matter integrity, pre-disruption in white-matter integrity, pre-

dominantly in the inferior frontal braindominantly in the inferior frontal brain

regions, indicative of disrupted connectivityregions, indicative of disrupted connectivity

in the orbitofrontal cortex region (Limin the orbitofrontal cortex region (Lim etet

alal, 2002). One study (Fein, 2002). One study (Fein et alet al, 2002) did, 2002) did

not report orbitofrontal cortex abnormal-not report orbitofrontal cortex abnormal-

ities but did demonstrate reduced globalities but did demonstrate reduced global

prefrontal grey-matter volume in treatment-prefrontal grey-matter volume in treatment-

naıve heavy drinkers without severenaıve heavy drinkers without severe

behavioural consequences of their alcoholbehavioural consequences of their alcohol

use.use.

Taken together, the structural andTaken together, the structural and

metabolic studies demonstrate involvementmetabolic studies demonstrate involvement

of the orbitofrontal cortex in people withof the orbitofrontal cortex in people with

addictions. The main findings concerningaddictions. The main findings concerning

this region are its hyperactivation duringthis region are its hyperactivation during

early withdrawal, hypoactivation afterearly withdrawal, hypoactivation after

withdrawal or during prolonged absti-withdrawal or during prolonged absti-

nence, and its involvement in mood andnence, and its involvement in mood and

anxiety changes in patients with substanceanxiety changes in patients with substance

use disorders.use disorders.

DISCUSSIONDISCUSSION

Fifty-two studies were evaluated. Behav-Fifty-two studies were evaluated. Behav-

ioural decision-making tasks consistentlyioural decision-making tasks consistently

demonstrate impairments in decision-demonstrate impairments in decision-

making in patients with substance use dis-making in patients with substance use dis-

orders compared with controls. In contrast,orders compared with controls. In contrast,

the relationship between orbitofrontalthe relationship between orbitofrontal

cortex activity, cue reactivity and cravingcortex activity, cue reactivity and craving

is not consistent across the studies re-is not consistent across the studies re-

viewed. Studies during acute withdrawalviewed. Studies during acute withdrawal

reveal hyperactivation of the orbitofrontalreveal hyperactivation of the orbitofrontal

cortex, whereas studies during abstinencecortex, whereas studies during abstinence

demonstrate hypoactivation of this regiondemonstrate hypoactivation of this region

and structural abnormalities in individualsand structural abnormalities in individuals

with substance use disorders.with substance use disorders.

Decision-making and theDecision-making and theorbitofrontal cortexorbitofrontal cortex

The results obtained with the behaviouralThe results obtained with the behavioural

decision-making tasks warrant furtherdecision-making tasks warrant further

elucidation. First, it remains uncertainelucidation. First, it remains uncertain

whether the different tasks all measurewhether the different tasks all measure

the same cognitive entity. An overlap inthe same cognitive entity. An overlap in

thethe decision-making functions tapped bydecision-making functions tapped by

the IGTthe IGT and the RCGT has been demon-and the RCGT has been demon-

strated (Monterossostrated (Monterosso et alet al, 2001). However,, 2001). However,

no data are available comparing the two-no data are available comparing the two-

choice prediction task (Pauluschoice prediction task (Paulus et alet al, 2002,, 2002,

2003) with the IGT and the RCGT. Second,2003) with the IGT and the RCGT. Second,

studies analysing the relationship betweenstudies analysing the relationship between

behavioural decision-making tasks and thebehavioural decision-making tasks and the

orbitofrontal cortex as their anatomicalorbitofrontal cortex as their anatomical

correlate are limited and conflicting. Thecorrelate are limited and conflicting. The

sole neuroimaging study during IGT perfor-sole neuroimaging study during IGT perfor-

mance showed a task-related increase inmance showed a task-related increase in

orbitofrontal cortex metabolism in theorbitofrontal cortex metabolism in the

cocaine users group (Bollacocaine users group (Bolla et alet al, 2003). In, 2003). In

contrast, studies using the two-choicecontrast, studies using the two-choice

prediction task found decreases inprediction task found decreases in

task-task-related activity in the right orbito-related activity in the right orbito-

frontal cortex and the anterior cingulatefrontal cortex and the anterior cingulate

cortex of methamphetamine-dependentcortex of methamphetamine-dependent

participants (Paulusparticipants (Paulus et alet al, 2002, 2003). This, 2002, 2003). This

inconsistency may reflect intrinsic differ-inconsistency may reflect intrinsic differ-

ences between these decision-making tasks.ences between these decision-making tasks.

Anatomically, both the orbitofrontal andAnatomically, both the orbitofrontal and

the anterior cingulate cortex are involvedthe anterior cingulate cortex are involved

in all three decision-making tasks. As toin all three decision-making tasks. As to

the IGT, which is a complex task dependingthe IGT, which is a complex task depending

on a variety of cognitive processes, otheron a variety of cognitive processes, other

regions seem to contribute as well (i.e. theregions seem to contribute as well (i.e. the

dorsolateral prefrontal cortex, amygdaladorsolateral prefrontal cortex, amygdala

and insular regions; Clarkand insular regions; Clark et alet al, 2003)., 2003).

Taken together, as discussed byTaken together, as discussed by

LubmanLubman et alet al (2004), the orbitofrontal(2004), the orbitofrontal

and anterior cingulate cortices are criticallyand anterior cingulate cortices are critically

involved in inhibitory decision-making pro-involved in inhibitory decision-making pro-

cesses, especially involving reward-relatedcesses, especially involving reward-related

behaviours (Elliottbehaviours (Elliott et alet al, 2000; Kiehl, 2000; Kiehl et alet al,,

2000; Fan2000; Fan et alet al, 2003; Rogers, 2003; Rogers et alet al,,

2004). Specifically, these regions process2004). Specifically, these regions process

the reward value and/or affective valencethe reward value and/or affective valence

of environmental stimuli, assess the futureof environmental stimuli, assess the future

consequences of the individual’s ownconsequences of the individual’s own

actions (response selection) and inhibit in-actions (response selection) and inhibit in-

appropriate behaviours (response inhibi-appropriate behaviours (response inhibi-

tion; Elliotttion; Elliott et alet al, 2000; Kiehl, 2000; Kiehl et alet al, 2000;, 2000;

Bechara & Damasio, 2002; Krawczyk,Bechara & Damasio, 2002; Krawczyk,

2002; Fan2002; Fan et alet al, 2003). Dysfunctions within, 2003). Dysfunctions within

these regions have recently been proposedthese regions have recently been proposed

as a key neural mechanism underlyingas a key neural mechanism underlying

addiction (Jentsch & Taylor, 1999; Gold-addiction (Jentsch & Taylor, 1999; Gold-

stein & Volkow, 2002; Volkowstein & Volkow, 2002; Volkow et alet al,,

20032003bb; Lubman; Lubman et alet al, 2004)., 2004).

The orbitofrontal cortex, cueThe orbitofrontal cortex, cuereactivity and cravingreactivity and craving

Findings concerning the relationship be-Findings concerning the relationship be-

tween the orbitofrontal cortex, cue reactiv-tween the orbitofrontal cortex, cue reactiv-

ity and craving are inconsistent across theity and craving are inconsistent across the

studies. Of 20 studies, 13 demonstratedstudies. Of 20 studies, 13 demonstrated

cue exposure to be associated with hyperac-cue exposure to be associated with hyperac-

tivity of the orbitofrontal cortex. One studytivity of the orbitofrontal cortex. One study

demonstrated cue-induced hyperactivity indemonstrated cue-induced hyperactivity in

male patients with cocaine addiction butmale patients with cocaine addiction but

not in female patients. In addition, othernot in female patients. In addition, other

brain regions are involved as well: thebrain regions are involved as well: the

amygdala, dorsolateral prefrontal cortexamygdala, dorsolateral prefrontal cortex

and anterior cingulate cortex were the mostand anterior cingulate cortex were the most

commonly reported loci of activation.commonly reported loci of activation.

The inconsistencies between the variousThe inconsistencies between the various

studies may originate from differences instudies may originate from differences in

study design, drug use status, treatmentstudy design, drug use status, treatment

status or gender. First, different cue expo-status or gender. First, different cue expo-

sure paradigms have been used. As yet,sure paradigms have been used. As yet,

not enough is known about the effects eli-not enough is known about the effects eli-

cited by the different types of non-chemicalcited by the different types of non-chemical

cues (videotapes, drug paraphernalia, scriptcues (videotapes, drug paraphernalia, script

reading) and chemical cues (single dosereading) and chemical cues (single dose

administration, ethanol odour). Possibly,administration, ethanol odour). Possibly,

different cues affect different brain circuits.different cues affect different brain circuits.

Second, drug use status seems important.Second, drug use status seems important.

Withdrawal is consistently linked withWithdrawal is consistently linked with

orbitofrontal cortex activation. In addition,orbitofrontal cortex activation. In addition,

single drug-dose administration (drug prob-single drug-dose administration (drug prob-

ing) systematically evokes hyperactivity ofing) systematically evokes hyperactivity of

this region; this is of high clinical relevance,this region; this is of high clinical relevance,

since it is known that during abstinence thesince it is known that during abstinence the

use of a limited amount of the drug ofuse of a limited amount of the drug of

choice is a powerful trigger of craving andchoice is a powerful trigger of craving and

reinstatement of drug-taking habits in peo-reinstatement of drug-taking habits in peo-

ple with addictions. Third, treatment statusple with addictions. Third, treatment status

may relate to cue reactivity. Wilsonmay relate to cue reactivity. Wilson et alet al

(2004) proposed the treatment-seeking(2004) proposed the treatment-seeking

state of the participants as a variablestate of the participants as a variable

explaining the disparity in brain-regionexplaining the disparity in brain-region

activation in response to cue exposure.activation in response to cue exposure.

217217

AUTHOR’S PROOFAUTHOR’S PROOF

DOM ET ALDOM ET AL

Non-treatment-seeking people with addic-Non-treatment-seeking people with addic-

tions could anticipate more actual drugtions could anticipate more actual drug

use shortly after testing than those whouse shortly after testing than those who

were treatment-seeking. The studies onwere treatment-seeking. The studies on

cue exposure in the current review lendcue exposure in the current review lend

some support to this hypothesis. Finally,some support to this hypothesis. Finally,

gender differences might mediate differ-gender differences might mediate differ-

ences in orbitofrontal cortex cue reactivity.ences in orbitofrontal cortex cue reactivity.

In the three studies of women with sub-In the three studies of women with sub-

stance use disorders, cue exposure elicitedstance use disorders, cue exposure elicited

no activity in this brain region; this suggestsno activity in this brain region; this suggests

that processing of reward/salience maythat processing of reward/salience may

involve different neural circuits in meninvolve different neural circuits in men

and women. Noteworthy in this respect isand women. Noteworthy in this respect is

that, increasingly, research is revealingthat, increasingly, research is revealing

gender differences in IGT performance,gender differences in IGT performance,

with men performing better than womenwith men performing better than women

(Reavis & Overman, 2001; Bolla(Reavis & Overman, 2001; Bolla et alet al,,

2004; Overman, 2004).2004; Overman, 2004).

The relationship between orbitofrontalThe relationship between orbitofrontal

cortex activity and experiences of cravingcortex activity and experiences of craving

remains unclear. Craving is a complex pro-remains unclear. Craving is a complex pro-

cess that may involve several interactingcess that may involve several interacting

brain regions (for a review, see Franken,brain regions (for a review, see Franken,

2003). Craving is associated with the2003). Craving is associated with the

learned response that links the drug andlearned response that links the drug and

its environment to an intensely pleasurableits environment to an intensely pleasurable

experience. Anatomically, the consolida-experience. Anatomically, the consolida-

tion of this memory (trait craving) is likelytion of this memory (trait craving) is likely

to involve the amygdala, hippocampusto involve the amygdala, hippocampus

and the nucleus accumbens shell. Theand the nucleus accumbens shell. The

actual conscious experience of craving asactual conscious experience of craving as

a result of cue reactivity has been postu-a result of cue reactivity has been postu-

lated to be linked to the orbitofrontal cortexlated to be linked to the orbitofrontal cortex

and possibly the anterior cingulate cortexand possibly the anterior cingulate cortex

(Goldstein & Volkow, 2002). However, in(Goldstein & Volkow, 2002). However, in

our review the data did not conclusivelyour review the data did not conclusively

support this hypothesis. In only 6 of the 17support this hypothesis. In only 6 of the 17

studies (35%) was craving associated withstudies (35%) was craving associated with

orbitofrontal cortex activation. In 9 otherorbitofrontal cortex activation. In 9 other

studies other brain regions were implicated.studies other brain regions were implicated.

Further research is warranted to differentiateFurther research is warranted to differentiate

the roles of the orbitofrontal and anteriorthe roles of the orbitofrontal and anterior

cingulate cortices and other regions involvedcingulate cortices and other regions involved

in cue reactivity and craving.in cue reactivity and craving.

Orbitofrontal cortex activityOrbitofrontal cortex activityafter withdrawalafter withdrawal

The structural and metabolic neuroimagingThe structural and metabolic neuroimaging

studies after drug withdrawal consistentlystudies after drug withdrawal consistently

demonstrated a decrease in orbitofrontaldemonstrated a decrease in orbitofrontal

cortical volume, metabolism and function-cortical volume, metabolism and function-

ality. These findings are in line with otherality. These findings are in line with other

reports revealing reductions in dopaminereports revealing reductions in dopamine

DD22 receptor density in people with sub-receptor density in people with sub-

stance use disorders (Volkowstance use disorders (Volkow et alet al, 1999, 1999bb,,

2001). Among other regions, the areas2001). Among other regions, the areas

affected are the dopaminergic projectionsaffected are the dopaminergic projections

from the striatum (nucleus accumbens) tofrom the striatum (nucleus accumbens) to

the cingulate gyrus, prefrontal cortex andthe cingulate gyrus, prefrontal cortex and

the orbitofrontal cortex. This deficit maythe orbitofrontal cortex. This deficit may

play an important part in addictiveplay an important part in addictive

processes, conceptualised as a process ofprocesses, conceptualised as a process of

hedonic homoeostatic dysregulation (Koobhedonic homoeostatic dysregulation (Koob

& Le Moal, 1997). Clinical correlates of a& Le Moal, 1997). Clinical correlates of a

hedonic dysregulation are the dysthymichedonic dysregulation are the dysthymic

or depressive episodes that are frequentlyor depressive episodes that are frequently

observed after detoxification. These moodobserved after detoxification. These mood

changes can be persistent and difficult tochanges can be persistent and difficult to

treat. Such an anhedonic state can be atreat. Such an anhedonic state can be a

serious hazard in maintaining abstinenceserious hazard in maintaining abstinence

and may induce a relapse. The studies byand may induce a relapse. The studies by

LondonLondon et alet al (2004), Sekine(2004), Sekine et alet al (2003),(2003),

and Goldsteinand Goldstein et alet al (2002(2002bb) suggest involve-) suggest involve-

ment of the orbitofrontal cortex in moodment of the orbitofrontal cortex in mood

and anxiety disorders in methamphetamineand anxiety disorders in methamphetamine

addiction.addiction.

General remarksGeneral remarks

In addition to their drug of preference,In addition to their drug of preference,

many participants in the studies wemany participants in the studies we

reviewed used (and misused) multiple otherreviewed used (and misused) multiple other

substances. Although poly-substancesubstances. Although poly-substance

misuse is of particular clinical interest,misuse is of particular clinical interest,

becoming a common pattern of drug mis-becoming a common pattern of drug mis-

use, it complicates the interpretation ofuse, it complicates the interpretation of

the results. Furthermore, although most ofthe results. Furthermore, although most of

the participants with substance use dis-the participants with substance use dis-

orders were nicotine-dependent, nicotineorders were nicotine-dependent, nicotine

status was never taken into account in thestatus was never taken into account in the

various studies. This might also have biasedvarious studies. This might also have biased

the results reported, since nicotine use itselfthe results reported, since nicotine use itself

has been linked to changes in orbitofrontalhas been linked to changes in orbitofrontal

and anterior cingulate cortical metabolismand anterior cingulate cortical metabolism

(Brody(Brody et alet al, 2002). Future studies should, 2002). Future studies should

take into account this potential confound-take into account this potential confound-

ing factor, either by excluding smokers oring factor, either by excluding smokers or

by statistical adjustment for smoking status.by statistical adjustment for smoking status.

Finally, the findings in the studies underFinally, the findings in the studies under

review do not allow a distinction to bereview do not allow a distinction to be

made between cause and consequence.made between cause and consequence.

Functional and structural deficits inFunctional and structural deficits in

decision-making cognition and orbitofron-decision-making cognition and orbitofron-

tal cortex integrity can be either a conse-tal cortex integrity can be either a conse-

quence of or a pre-existent vulnerability toquence of or a pre-existent vulnerability to

addictive behaviour. For some drugs of mis-addictive behaviour. For some drugs of mis-

use such as methamphetamine, evidence ofuse such as methamphetamine, evidence of

their (sometimes long-lasting) neurotoxictheir (sometimes long-lasting) neurotoxic

effects is growing (Wangeffects is growing (Wang et alet al, 2004). How-, 2004). How-

ever, the findings reported on in this reviewever, the findings reported on in this review

seem to be relatively independent of theseem to be relatively independent of the

type of substance misused. The observedtype of substance misused. The observed

abnormalities are probably not substance-abnormalities are probably not substance-

specific but rather constitute a commonspecific but rather constitute a common

deficit in addicted states and/or a commondeficit in addicted states and/or a common

predisposing vulnerability (Blumpredisposing vulnerability (Blum et alet al,,

2000). In this context, it might be of inter-2000). In this context, it might be of inter-

est to mention the evidence demonstratingest to mention the evidence demonstrating

involvement of the orbitofrontal cortex ininvolvement of the orbitofrontal cortex in

non-chemical addictions such as gamblingnon-chemical addictions such as gambling

(Cavedini(Cavedini et alet al, 2002; Potenza, 2002; Potenza et alet al, 2003;, 2003;

GoudriaanGoudriaan et alet al, 2004)., 2004).

Collectively, both the behavioural andCollectively, both the behavioural and

neuroimaging studies included in thisneuroimaging studies included in this

review point to an important role of thereview point to an important role of the

orbitofrontal cortex in addictive processes.orbitofrontal cortex in addictive processes.

They lend further support for the modelThey lend further support for the model

developed by Volkowdeveloped by Volkow et alet al (2003(2003bb, 2004),, 2004),

who propose a network of four brainwho propose a network of four brain

circuits involved in addiction (memory,circuits involved in addiction (memory,

drive, reward and control). In this model,drive, reward and control). In this model,

exposure to the drug or to drug-related cuesexposure to the drug or to drug-related cues

activates the memory of the expectedactivates the memory of the expected

reward, resulting in hyperactivation of thereward, resulting in hyperactivation of the

reward and motivational circuits whilereward and motivational circuits while

decreasing the activity in the cognitive con-decreasing the activity in the cognitive con-

trol system. The deficits highlighted in ourtrol system. The deficits highlighted in our

review are indicative of an important rolereview are indicative of an important role

for the orbitofrontal cortex in a brainfor the orbitofrontal cortex in a brain

circuit mediating goal-directed behaviour,circuit mediating goal-directed behaviour,

leading to compulsive drug-seeking andleading to compulsive drug-seeking and

relapse. In doing so, the orbitofrontal cor-relapse. In doing so, the orbitofrontal cor-

tex contributes to the perpetuation of thetex contributes to the perpetuation of the

addiction.addiction.

ACKNOWLEDGEMENTACKNOWLEDGEMENT

The authors thank Eric Achten, MD, PhD, of theThe authors thank Eric Achten, MD, PhD, of theWorkgroup fMRI Ghent, University of Ghent,Workgroup fMRI Ghent, University of Ghent,Belgium, for his assistance in analysing the neuro-Belgium, for his assistance in analysing the neuro-imaging studies.imaging studies.

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2 2 02 2 0

AUTHOR’S PROOFAUTHOR’S PROOF

CLINICAL IMPLICATIONSCLINICAL IMPLICATIONS

&& Pharmacological and behavioural treatment should allow for the powerful effectPharmacological and behavioural treatment should allow for the powerful effectdrug probing has on hyperactivation of the orbitofrontal cortex and the associateddrug probing has on hyperactivation of the orbitofrontal cortex and the associatedrisk of craving and reinstatement of drug use.risk of craving and reinstatement of drug use.

&& Future research should focus on the aetiological, diagnostic and therapeuticFuture research should focus on the aetiological, diagnostic and therapeuticaspects of mood disorders and anhedonic states following withdrawal related toaspects ofmood disorders and anhedonic states following withdrawal related tochronic hypofunctionality of this brain region.chronic hypofunctionality of this brain region.

&& Extensive documentation of treatment status is warranted in future imagingExtensive documentation of treatment status is warranted in future imagingstudies on cue reactivity and craving.studies on cue reactivity and craving.

LIMITATIONSLIMITATIONS

&& The Iowa GamblingTask is not specific for orbitofrontal cortex functionality.The Iowa GamblingTask is not specific for orbitofrontal cortex functionality.Studies usingmore specific behavioural tasks should be used in research intoStudies usingmore specific behavioural tasks should be used in research intosubstancemisuse.substancemisuse.

&& Our review exclusively highlights the role of the orbitofrontal cortex in decision-Our review exclusively highlights the role of the orbitofrontal cortex in decision-making.Other behavioural aspects characteristic of addictive processes (e.g. impulsemaking.Other behavioural aspects characteristic of addictive processes (e.g. impulsecontrol) related to this region have not been considered.control) related to this region have not been considered.

&& Studies specifically focusing on gambling and tobacco-smoking were excluded.Studies specifically focusing on gambling and tobacco-smoking were excluded.Future reviews should take these populations into account.Future reviews should take these populations into account.

G.DOM,MD, Psychiatric Centre Brothers Alexians,Boechout,Belgium;B. SABBE,MD, PhD,CollaborativeG.DOM,MD, Psychiatric Centre Brothers Alexians,Boechout,Belgium;B. SABBE,MD, PhD,CollaborativeAntwerp Psychiatric Research Institute (CAPRI),University of Antwerp,Belgium;W.HULSTIJN,PhD,NijmegenAntwerp Psychiatric Research Institute (CAPRI),University of Antwerp,Belgium;W.HULSTIJN, PhD,NijmegenInstitute for Cognition and Information,Nijmegen,The Netherlands, and CAPRI,University of Antwerp,Institute for Cognition and Information,Nijmegen,The Netherlands, and CAPRI,University of Antwerp,Belgium;W.VANDENBRINK,MD, PhD,Department of Psychiatry, Academic Medical Centre,University ofBelgium;W.VANDENBRINK,MD, PhD,Department of Psychiatry, Academic Medical Centre,University ofAmsterdam, and Amsterdam Institute for Addiction Research (AIAR), Amsterdam,The NetherlandsAmsterdam, and Amsterdam Institute for Addiction Research (AIAR), Amsterdam,The Netherlands

Correspondence:Dr G.Dom,Psychiatric Centre Brothers Alexians, Provinciesteenweg 408, 2530Correspondence:Dr G.Dom,Psychiatric Centre Brothers Alexians, Provinciesteenweg 408, 2530Boechout,Belgium.Tel: +32 3455 7531; e-mail: geert.domBoechout,Belgium.Tel: +32 3455 7531; e-mail: geert.dom@@fracarita.orgfracarita.org

(First received 13 September 2004, final revision 24 January 2005, accepted 28 January 2005)(First received 13 September 2004, final revision 24 January 2005, accepted 28 January 2005)

A role for psychedelicsA role for psychedelicsin psychiatryin psychiatry??

I read with interest the editorial ‘CanI read with interest the editorial ‘Can

psychedelics have a role in psychiatry oncepsychedelics have a role in psychiatry once

again?’ (Sessa, 2005). Aside from over-again?’ (Sessa, 2005). Aside from over-

coming current legislative barriers, atten-coming current legislative barriers, atten-

tion needs to be given to education abouttion needs to be given to education about

known research into this field, a functionknown research into this field, a function

which this editorial usefully starts to fulfil.which this editorial usefully starts to fulfil.

The concern remains that the image ofThe concern remains that the image of

psychedelics was not shaped by the alreadypsychedelics was not shaped by the already

existing extensive professional literature,existing extensive professional literature,

but by the mass media sensationalisingbut by the mass media sensationalising

the accidents of unsupervised self-the accidents of unsupervised self-

experimentation (Grof, 2001). It couldexperimentation (Grof, 2001). It could

therefore be surmised that decisivetherefore be surmised that decisive

influences will be a variety of political,influences will be a variety of political,

legal, economic and mass–psychologicallegal, economic and mass–psychological

factors, rather than the results of currentfactors, rather than the results of current

and ongoing scientific research. Interestand ongoing scientific research. Interest

from the psychiatric community will befrom the psychiatric community will be

paramount if this research information isparamount if this research information is

to be critically reviewed with a view to clin-to be critically reviewed with a view to clin-

ical application.ical application.

The difference between psychedelicsThe difference between psychedelics

(entheogens) and other psychotropic drugs(entheogens) and other psychotropic drugs

is that entheogens work as ‘non-specificis that entheogens work as ‘non-specific

amplifiers of the psyche’, inducing anamplifiers of the psyche’, inducing an

altered or non-ordinary state of conscious-altered or non-ordinary state of conscious-

ness (Grof, 2000). The content and natureness (Grof, 2000). The content and nature

of the experiences are not thought to beof the experiences are not thought to be

artificial products of their pharmacologicalartificial products of their pharmacological

interaction with the brain (‘toxic psy-interaction with the brain (‘toxic psy-

choses’) but authentic expressions of thechoses’) but authentic expressions of the

psyche revealing its functioning on levelspsyche revealing its functioning on levels

not ordinarily available for observationnot ordinarily available for observation

and study. In order to conceptualise this,and study. In order to conceptualise this,

a vastly extended cartography of the psychea vastly extended cartography of the psyche

(Grof, 2000), one which challenges our(Grof, 2000), one which challenges our

biomedical psychiatric model, is required.biomedical psychiatric model, is required.

Within psychiatry, entheogenic sub-Within psychiatry, entheogenic sub-

stances (one of several methods of inducingstances (one of several methods of inducing

a non-ordinary state of consciousness)a non-ordinary state of consciousness)

could contribute to a powerful form of ex-could contribute to a powerful form of ex-

periential psychotherapy; an importantperiential psychotherapy; an important

addition to a psychiatric armamentarium,addition to a psychiatric armamentarium,

working with domains of the psycheworking with domains of the psyche

traditionally ignored in our ethnocentrictraditionally ignored in our ethnocentric

Western model (SchlitzWestern model (Schlitz et alet al, 2005)., 2005).

Potential credence for this field dependsPotential credence for this field depends

upon whether we view all non-ordinaryupon whether we view all non-ordinary

states of consciousness as pathological orstates of consciousness as pathological or

whether in some cases, some ‘psychotic’whether in some cases, some ‘psychotic’

experiences can be seen to have potentialexperiences can be seen to have potential

value as well as being potentially damaging.value as well as being potentially damaging.

There is ongoing interest among mentalThere is ongoing interest among mental

health professionals in the concept ofhealth professionals in the concept of

spiritual emergence as well as the thera-spiritual emergence as well as the thera-

peutic power of altered states of con-peutic power of altered states of con-

sciousness, the subject of a recent 1 daysciousness, the subject of a recent 1 day

meeting held jointly with the Royalmeeting held jointly with the Royal

College of Psychiatrists and the RoyalCollege of Psychiatrists and the Royal

Society of Medicine (http://www.rcpsych.Society of Medicine (http://www.rcpsych.

ac.uk/college/sig/spirit/index.asp). I wouldac.uk/college/sig/spirit/index.asp). I would

certainly value a continuing debatecertainly value a continuing debate

exploring this area.exploring this area.

Grof, S. (2000)Grof, S. (2000) Psychology of the Future: Lessons fromPsychology of the Future: Lessons fromModern Consciousness ResearchModern Consciousness Research. Albany,NY: State. Albany,NY: StateUniversity of NewYork Press.University of NewYork Press.

Grof, S. (2001)Grof, S. (2001) LSD PsychotherapyLSD Psychotherapy. Sarasota, FL:. Sarasota, FL:Multidisciplinary Association for Psychedelic Studies.Multidisciplinary Association for Psychedelic Studies.

Schlitz, M., Amorok,T. & Micozzi, M. (2005)Schlitz, M., Amorok,T. & Micozzi, M. (2005)Consciousness and Healing: Integral Approaches toConsciousness and Healing: Integral Approaches toMind^Body MedicineMind^Body Medicine. St Louis,MO: Churchill. St Louis,MO: ChurchillLivingstone/Elsevier.Livingstone/Elsevier.

Sessa, B. (2005)Sessa, B. (2005) Can psychedelics have a role inCan psychedelics have a role inpsychiatry once again?psychiatry once again? British Journal of PsychiatryBritish Journal of Psychiatry,, 186186,,457^458.457^458.

N.CrowleyN.Crowley Amersham General Hospital,Amersham General Hospital,Buckinghamshire Mental Health NHS Trust,UK.Buckinghamshire Mental Health NHS Trust,UK.E-mail: nicola.crowleyE-mail: nicola.crowley@@bmh.nhs.ukbmh.nhs.uk

The editorial by Dr Sessa is both timely andThe editorial by Dr Sessa is both timely and

encouraging. The almost complete denial,encouraging. The almost complete denial,

not only by the media but also by thenot only by the media but also by the

psychiatric establishment, that lysergicpsychiatric establishment, that lysergic

acid diethylamide (LSD) and relatedacid diethylamide (LSD) and related

psychedelics had an important place in thepsychedelics had an important place in the

therapy of a wide range of psychoneurotictherapy of a wide range of psychoneurotic

disorders is astonishing. This clearly has adisorders is astonishing. This clearly has a

psychodynamic explanation.psychodynamic explanation.

The interest shown during the 1950sThe interest shown during the 1950s

and 1960s by the psychiatric establishmentand 1960s by the psychiatric establishment

in the use of the psycholytic agents is evenin the use of the psycholytic agents is even

greater than Dr Sessa indicates. Thegreater than Dr Sessa indicates. The

meeting of the ‘American Psychologicalmeeting of the ‘American Psychological

Association’ at which the therapeutic useAssociation’ at which the therapeutic use

of LSD was discussed was actually held atof LSD was discussed was actually held at

the Annual Meeting of the prestigiousthe Annual Meeting of the prestigious

American Psychiatric Association, inAmerican Psychiatric Association, in

1955, rather than 1951 (Cholden, 1956).1955, rather than 1951 (Cholden, 1956).

Subsequently, the role of psychedelics inSubsequently, the role of psychedelics in

therapy was the subject of a number oftherapy was the subject of a number of

national and international conferences.national and international conferences.

Perhaps the most significant of these wasPerhaps the most significant of these was

held in London in February 1961, whenheld in London in February 1961, when

the Royal Medico-Psychological Associa-the Royal Medico-Psychological Associa-

tion, the forerunner of the Royal Collegetion, the forerunner of the Royal College

of Psychiatrists, devoted the whole of its 3of Psychiatrists, devoted the whole of its 3

day quarterly meeting to the subjectday quarterly meeting to the subject

(Crocket(Crocket et alet al, 1963)., 1963).

Dr Sessa touches briefly on the questionDr Sessa touches briefly on the question

of the possible resumption of psycholyticof the possible resumption of psycholytic

therapy. There have been a number oftherapy. There have been a number of

recent suggestions that this could oncerecent suggestions that this could once

more become a possibility. Psychiatristsmore become a possibility. Psychiatrists

tempted to enter this field (assuming thattempted to enter this field (assuming that

the appropriate drugs – LSD, 3,4-methyl-the appropriate drugs – LSD, 3,4-methyl-

enedioxymethamphetamine (MDMA),enedioxymethamphetamine (MDMA),

psilocybin – are made legally available topsilocybin – are made legally available to

doctors) should bear in mind that thedoctors) should bear in mind that the

success of psycholytic therapy dependedsuccess of psycholytic therapy depended

on careful training, not only of the thera-on careful training, not only of the thera-

pist, but also of the nurses and otherspist, but also of the nurses and others

who formed the therapeutic team. Thatwho formed the therapeutic team. That

expertise at one time reached a high level,expertise at one time reached a high level,

and all that has been lost. My hope is thatand all that has been lost. My hope is that

research and practice will continue, andresearch and practice will continue, and

that it will be supported by the College.that it will be supported by the College.

Cholden, L. (ed.) (1956)Cholden, L. (ed.) (1956) Proceedings of the Round TableProceedings of the Round Tableon Lysergic Acid Diethylamide and Mescaline inon Lysergic Acid Diethylamide and Mescaline inExperimental PsychiatryExperimental Psychiatry.NewYork: Grune & Stratton..NewYork: Grune & Stratton.

Crocket, R., Sandison, R. A. & Walk, A. (eds) (1963)Crocket, R., Sandison, R. A. & Walk, A. (eds) (1963)Hallucinogenic Drugs and theirTherapeutic UseHallucinogenic Drugs and theirTherapeutic Use..Proceedings of the Quarterly Meeting of the RoyalProceedings of the Quarterly Meeting of the RoyalMedico-Psychological Association in London 1961.Medico-Psychological Association in London 1961.London: H.K. Lewis.London: H.K. Lewis.

Sessa, B. (2005)Sessa, B. (2005) Can psychedelics have a role inCan psychedelics have a role inpsychiatry once again?psychiatry once again? British Journal of PsychiatryBritish Journal of Psychiatry,, 186186,,457^458.457^458.

R. SandisonR. Sandison 28 The Southend, Ledbury,28 The Southend, Ledbury,Herefordshire HR8 2EY,UKHerefordshire HR8 2EY,UK

Dr Sessa is to be congratulated on hisDr Sessa is to be congratulated on his

welcome review of research into psyche-welcome review of research into psyche-

delic drugs. We are reminded of the hopedelic drugs. We are reminded of the hope

that these drugs ‘could be for psychiatrythat these drugs ‘could be for psychiatry

what the microscope is for biology or thewhat the microscope is for biology or the

telescope is to astronomy: an essential tooltelescope is to astronomy: an essential tool

to explore the parts of the internal worldto explore the parts of the internal world

that are usually inaccessible’.that are usually inaccessible’.

4 8 34 8 3

BR I T I SH JOURNAL OF P SYCHIATRYBR IT I SH JOURNAL OF P SYCHIATRY ( 2 0 0 5 ) , 1 8 7, 4 8 3 ^ 4 9 0( 2 0 0 5 ) , 1 8 7, 4 8 3 ^ 4 9 0

CorrespondenceCorrespondence

EDITED BY KIRIAKOS XENITIDIS and COLIN CAMPBELLEDITED BY KIRIAKOS XENITIDIS and COLIN CAMPBELL

ContentsContents && Arole for psychedelics in psychiatry?Arole for psychedelics inpsychiatry? && Kraepelinian dichotomyKraepelinian dichotomy &&

CBT for refractory symptomsin schizophreniaCBT for refractory symptomsin schizophrenia && Olanzapine co-therapyin bipolarOlanzapine co-therapyin bipolar

disorderdisorder && ECT in depressionECT in depression && Hospital admissionrates and diagnosisHospital admissionrates and diagnosis && ObesityObesity

and schizophreniaand schizophrenia && Zerotolerance of violenceZero tolerance of violence

CORRESPONDENCECORRESPONDENCE

Grof (1975, 1990) has been the mostGrof (1975, 1990) has been the most

prominent explorer of these inaccessibleprominent explorer of these inaccessible

regions for over 40 years and once researchregions for over 40 years and once research

into lysergic acid diethylamide (LSD)into lysergic acid diethylamide (LSD)

became impossible, developed a techniquebecame impossible, developed a technique

for inducing non-ordinary states of con-for inducing non-ordinary states of con-

sciousness called ‘holotropic breathwork’.sciousness called ‘holotropic breathwork’.

This offers many of the features of theThis offers many of the features of the

psychedelic state without the need to takepsychedelic state without the need to take

a drug. Using insights from the use ofa drug. Using insights from the use of

LSD and holotropic breathwork in thou-LSD and holotropic breathwork in thou-

sands of people, Grof (1975) proposed ansands of people, Grof (1975) proposed an

extended model of the psyche withextended model of the psyche with

psychodynamic, perinatal and trans-psychodynamic, perinatal and trans-

personal layers. These are provocativepersonal layers. These are provocative

models of mind which challenge existingmodels of mind which challenge existing

Western paradigms of consciousness andWestern paradigms of consciousness and

which probably reinforce mainstreamwhich probably reinforce mainstream

suspicion of any insights purporting to arisesuspicion of any insights purporting to arise

from the psychedelic experience. However,from the psychedelic experience. However,

they do represent a serious attempt tothey do represent a serious attempt to

explore, describe and understand theexplore, describe and understand the

complex features of the non-ordinary statecomplex features of the non-ordinary state

of consciousness and its theoreticalof consciousness and its theoretical

implications.implications.

Holotropic breathwork is marketedHolotropic breathwork is marketed

more as a means of personal explorationmore as a means of personal exploration

than psychotherapy, but careful prepara-than psychotherapy, but careful prepara-

tion, the context, a highly supportivetion, the context, a highly supportive

setting and integration after the non-setting and integration after the non-

ordinary state of consciousness are deemedordinary state of consciousness are deemed

crucial if the experience is to have valuecrucial if the experience is to have value

(Grof, 1990). This approach is in contrast(Grof, 1990). This approach is in contrast

to the views of Strassman (http://www.to the views of Strassman (http://www.

tripzine.com/interviews.asp?idtripzine.com/interviews.asp?id¼strassman)strassman)

who researched the use of N,N-dimethyl-who researched the use of N,N-dimethyl-

tryptamine (DMT) in 65 volunteers be-tryptamine (DMT) in 65 volunteers be-

tween 1990 and 1995 in a hospitaltween 1990 and 1995 in a hospital

setting with little attention to thesetting with little attention to the

surroundings. Strassman (2000) concludedsurroundings. Strassman (2000) concluded

that DMT probably did not have athat DMT probably did not have a

beneficial effect in itself, that its use wasbeneficial effect in itself, that its use was

high risk and that psychiatrists generallyhigh risk and that psychiatrists generally

did not have the experience, sensitivity ordid not have the experience, sensitivity or

training to support, contain, direct ortraining to support, contain, direct or

interpret the more unusual experiencesinterpret the more unusual experiences

that arise. Thus, although the drug is easilythat arise. Thus, although the drug is easily

taken, the context and setting is a littletaken, the context and setting is a little

more complicated and is at least asmore complicated and is at least as

important.important.

My point is that psychedelic drugs areMy point is that psychedelic drugs are

just one of a number of methods for thejust one of a number of methods for the

induction of a non-ordinary state of con-induction of a non-ordinary state of con-

sciousness. Non-drug methods for thesciousness. Non-drug methods for the

induction, exploration of and therapeuticinduction, exploration of and therapeutic

uses for non-ordinary states of conscious-uses for non-ordinary states of conscious-

ness may prove to be more productive forness may prove to be more productive for

psychiatrists interested in this area, givenpsychiatrists interested in this area, given

the controversy that the use of psychedelicthe controversy that the use of psychedelic

drugs will always arouse.drugs will always arouse.

Grof, S. (1975)Grof, S. (1975) Realms of the Human Unconscious:Realms of the Human Unconscious:Observations from LSD ResearchObservations from LSD Research.NewYork:Viking Press..NewYork:Viking Press.

Grof, S. (1990)Grof, S. (1990) The Holotropic MindThe Holotropic Mind.NewYork:Harper.NewYork:HarperCollins.Collins.

Sessa, B. (2005)Sessa, B. (2005) Can psychedelics have a role inCan psychedelics have a role inpsychiatry once again?psychiatry once again? British Journal of PsychiatryBritish Journal of Psychiatry,, 186186,,457^458.457^458.

Strassman, R. (2000)Strassman, R. (2000) DMT: the Spirit Molecule: aDMT: the Spirit Molecule: aDoctor’s Revolutionary Research into the Biology of Near-Doctor’s Revolutionary Research into the Biology of Near-Death and Mystical ExperiencesDeath and Mystical Experiences. Rochester,VT: Park.Rochester,VT: ParkStreet Press.Street Press.

T. ReadT. Read Department of Psychiatry,Royal LondonDepartment of Psychiatry,Royal LondonHospital,Whitechapel, London E11BB,UK.Hospital,Whitechapel, London E11BB,UK.E-mail:Tim.ReadE-mail:Tim.Read@@elcmht.nhs.ukelcmht.nhs.uk

In his stimulating editorial, Dr Sessa gives aIn his stimulating editorial, Dr Sessa gives a

history of the enthusiasm for psychedelichistory of the enthusiasm for psychedelic

psychotherapy that enjoyed a brief flower-psychotherapy that enjoyed a brief flower-

ing following Hoffman’s discovery ofing following Hoffman’s discovery of

lysergic acid diethylamide (LSD) in 1943.lysergic acid diethylamide (LSD) in 1943.

Dr Sessa argues that the time may now haveDr Sessa argues that the time may now have

come for a reappraisal of the role of suchcome for a reappraisal of the role of such

substances in psychiatry. Having myselfsubstances in psychiatry. Having myself

recently had cause to look at this literaturerecently had cause to look at this literature

(Edwards, 2005), I find myself somewhat(Edwards, 2005), I find myself somewhat

less keen on a reinstatement of this practice.less keen on a reinstatement of this practice.

Within the historical frame one couldWithin the historical frame one could

argue that the proper subject for the caseargue that the proper subject for the case

study is the conduct and attitude of the pro-study is the conduct and attitude of the pro-

fessionals who were the enthusiasts of thatfessionals who were the enthusiasts of that

time. The tone of the contemporary publi-time. The tone of the contemporary publi-

cations was in general remarkable for acations was in general remarkable for a

willingness to get ahead of the researchwillingness to get ahead of the research

evidence, and rush to positive and at timesevidence, and rush to positive and at times

even messianic conclusions. Here are someeven messianic conclusions. Here are some

examples of writings within that genre:examples of writings within that genre:

‘These agents have a part to play in our‘These agents have a part to play in our

survival as a species . . .’ (Osmond, 1957);survival as a species . . .’ (Osmond, 1957);

‘The wonder of LSD is that it can bring‘The wonder of LSD is that it can bring

within the capabilities of ordinary peoplewithin the capabilities of ordinary people

the experience of universal love’ (Davidson,the experience of universal love’ (Davidson,

1961); ‘I feel that those on the moving edge1961); ‘I feel that those on the moving edge

of new culture will eventually use theseof new culture will eventually use these

tools in a way that will utterly transformtools in a way that will utterly transform

the nature of human consciousness’the nature of human consciousness’

(Einhorn, 1971).(Einhorn, 1971).

What one sees in those kinds of state-What one sees in those kinds of state-

ments is the dubious ambition of therapistsments is the dubious ambition of therapists

to gain possession of chemical magic andto gain possession of chemical magic and

exert power over their drugged patients –exert power over their drugged patients –

the therapist as shaman rather than asthe therapist as shaman rather than as

evidence-based practitioner. But that I’mevidence-based practitioner. But that I’m

sure is not Dr Sessa’s intention.sure is not Dr Sessa’s intention.

Davidson, R. S. (1961)Davidson, R. S. (1961) Introduction: a psychologistIntroduction: a psychologistexplains. Inexplains. In Exploring Inner Space: Personal ExperiencesExploring Inner Space: Personal ExperiencesUnder LSDUnder LSD (ed. J.Dunlap), pp. 3^10. London:Victor(ed. J. Dunlap), pp. 3^10. London:VictorGollancz.Gollancz.

Edwards,G. (2005)Edwards,G. (2005) Matters of SubstanceMatters of Substance. London:. London:Penguin.Penguin.

Einhorn, I. (1971)Einhorn, I. (1971) From Data Collection to PatternFrom Data Collection to PatternRecognition. Annual Report of the Smithsonian InstituteRecognition. Annual Report of the Smithsonian Institute,,pp. 537^548.Washington,DC: Smithsonian Institute.pp. 537^548.Washington,DC: Smithsonian Institute.

Osmond,H. (1957)Osmond,H. (1957) A review of the clinical effects ofA review of the clinical effects ofpsychomimetic agents.psychomimetic agents. Annals of the New York AcademyAnnals of the New York Academyof Sciencesof Sciences,, 6666, 418^434., 418^434.

Sessa, B. (2005)Sessa, B. (2005) Can psychedelics have a role inCan psychedelics have a role inpsychiatry once again?psychiatry once again? British Journal of PsychiatryBritish Journal of Psychiatry,, 186186,,457^458.457^458.

G. EdwardsG. Edwards National Addiction Centre,National Addiction Centre,4 Windsor Walk, PO 48, London SE5 8AF,UK4 Windsor Walk, PO 48, London SE5 8AF,UK

Author’s reply:Author’s reply: I am most grateful for theI am most grateful for the

correspondence regarding my article oncorrespondence regarding my article on

psychedelics. Dr Read is right to point outpsychedelics. Dr Read is right to point out

the various techniques for inducing a non-the various techniques for inducing a non-

ordinary state of consciousness. As well asordinary state of consciousness. As well as

the breathwork developed by Grof (1990),the breathwork developed by Grof (1990),

humankind has historically used medita-humankind has historically used medita-

tion, exercise, fasting, chanting, dancingtion, exercise, fasting, chanting, dancing

and even sex to induce transformingand even sex to induce transforming

internal changes. What all these statesinternal changes. What all these states

have in common is the final goal ofhave in common is the final goal of

increased awareness and a loosening ofincreased awareness and a loosening of

the ego – facilitating personal explorationthe ego – facilitating personal exploration

and being useful therapeutically to aidand being useful therapeutically to aid

psychotherapy. As well as non-drug-psychotherapy. As well as non-drug-

iinduced non-ordinary states of conscious-nduced non-ordinary states of conscious-

ness, psychedelics may have an importantness, psychedelics may have an important

role to play – both in psychotherapy androle to play – both in psychotherapy and

in the scientific study of consciousness.in the scientific study of consciousness.

I agree with Dr Edward’s commentsI agree with Dr Edward’s comments

about statements made by some overenthu-about statements made by some overenthu-

siastic individuals of the psychedelic move-siastic individuals of the psychedelic move-

ment. Many clinicians of the 1960s (not toment. Many clinicians of the 1960s (not to

mention writers, artists and pop stars) sawmention writers, artists and pop stars) saw

LSD as a magic wand, a common panaceaLSD as a magic wand, a common panacea

to assure ‘better living through chemistry’.to assure ‘better living through chemistry’.

It was this attitude that killed genuineIt was this attitude that killed genuine

scientific study and kept the therapeuticscientific study and kept the therapeutic

potential of psychedelics shelved for sopotential of psychedelics shelved for so

long.long.

Psychedelics cannot save the world, butPsychedelics cannot save the world, but

they may have a role to play as adjunctsthey may have a role to play as adjuncts

to the psychotherapeutic treatment ofto the psychotherapeutic treatment of

neuroses. We must at least study andneuroses. We must at least study and

research their potential with modern ran-research their potential with modern ran-

domised controlled trials. For the hundredsdomised controlled trials. For the hundreds

of clinicians and thousands of patients ofof clinicians and thousands of patients of

the 1950s and 1960s that witnessed the safethe 1950s and 1960s that witnessed the safe

and effective usage of psychedelics, theseand effective usage of psychedelics, these

substances did appear to be useful (Masterssubstances did appear to be useful (Masters

& Houston, 1973). But as a profession we& Houston, 1973). But as a profession we

need to distance ourselves from theneed to distance ourselves from the

Timothy Leary-esque, messianic approachTimothy Leary-esque, messianic approach

to psychedelics, if we are to allow a dis-to psychedelics, if we are to allow a dis-

passionate and scientific study of theirpassionate and scientific study of their

potential.potential.

4 8 44 8 4

CORRESPONDENCECORRESPONDENCE

I was pleased to read Dr Crowley’sI was pleased to read Dr Crowley’s

in-depth understanding of the complexityin-depth understanding of the complexity

and value of the altered state ofand value of the altered state of

consciousness. Thankfully, there are clini-consciousness. Thankfully, there are clini-

cians such as Dr Crowley with the con-cians such as Dr Crowley with the con-

fidence not to dismiss the non-ordinaryfidence not to dismiss the non-ordinary

state of consciousness as mere ‘acute confu-state of consciousness as mere ‘acute confu-

sion’, but to believe that psychedelics, andsion’, but to believe that psychedelics, and

non-drug non-ordinary states of conscious-non-drug non-ordinary states of conscious-

ness, can inform and enlighten us with newness, can inform and enlighten us with new

approaches to understanding the mechan-approaches to understanding the mechan-

isms (and associated pathologies) of theisms (and associated pathologies) of the

brain. Since the earliest human societiesbrain. Since the earliest human societies

we have sought knowledge and healingwe have sought knowledge and healing

from these states – perhaps now this tech-from these states – perhaps now this tech-

nique can be utilised in a scientific andnique can be utilised in a scientific and

evidence-based approach to relieve the bur-evidence-based approach to relieve the bur-

den of anxiety disorders for today’s patients.den of anxiety disorders for today’s patients.

I am most grateful to Dr Sandison forI am most grateful to Dr Sandison for

his kind and supportive words – and thankhis kind and supportive words – and thank

him for the correction regarding the date ofhim for the correction regarding the date of

the American Psychiatric Association con-the American Psychiatric Association con-

ference in 1955. I share his astonishmentference in 1955. I share his astonishment

at the medical profession’s inability orat the medical profession’s inability or

unwillingness to embrace the therapeuticunwillingness to embrace the therapeutic

potential of psychedelic substances. Thispotential of psychedelic substances. This

shortcoming is augmented by the fact thatshortcoming is augmented by the fact that

the hiatus in research over the past 40 yearsthe hiatus in research over the past 40 years

appears to have been for socio-politicalappears to have been for socio-political

rather than scientific reasons – and it israther than scientific reasons – and it is

those pioneering psychiatrists like Drthose pioneering psychiatrists like Dr

Sandison who are right to feel disheartened.Sandison who are right to feel disheartened.

I am enthusiastic, however, at theI am enthusiastic, however, at the

current re-emergence of interest in thiscurrent re-emergence of interest in this

field. There are increasing numbers offield. There are increasing numbers of

randomised controlled trials of psychedelicsrandomised controlled trials of psychedelics

(largely from the USA) and these may yield(largely from the USA) and these may yield

results that guide future therapeuticresults that guide future therapeutic

applications (http://www.maps.org; http://applications (http://www.maps.org; http://

www.heffter.org). There is also increasingwww.heffter.org). There is also increasing

interest in using psychedelics in conscious-interest in using psychedelics in conscious-

ness research in the UK (http://www.ness research in the UK (http://www.

beckleyfoundation.org).beckleyfoundation.org).

I do hope that my article, and a forth-I do hope that my article, and a forth-

coming meeting to be held at the Collegecoming meeting to be held at the College

(contact me at drbensessa(contact me at drbensessa@@hotmail.comhotmail.com

for further details), can help raise aware-for further details), can help raise aware-

ness of this subject. I also agree with Drness of this subject. I also agree with Dr

Sandison in his plea for continued supportSandison in his plea for continued support

from the College to bring this subject tofrom the College to bring this subject to

the attention of doctors in the UK.the attention of doctors in the UK.

Grof, S. (1990)Grof, S. (1990) The Holotropic MindThe Holotropic Mind.NewYork:Harper.NewYork:HarperCollins.Collins.

Masters, R. E. L. & Houston, J. (1973)Masters, R. E. L. & Houston, J. (1973) The Varieties ofThe Varieties ofPsychedelic ExperiencePsychedelic Experience (2nd edn). London:Turnstone(2nd edn). London:TurnstoneBooks.Books.

B. SessaB. Sessa The Park Hospital,Old Road,The Park Hospital,Old Road,Headington,Oxford OX3 7LQ,UK. E-mail:Headington,Oxford OX3 7LQ,UK. E-mail:drbensessadrbensessa@@hotmail.comhotmail.com

Kraepelinian dichotomyKraepelinian dichotomy

Craddock & Owen (2005) attribute theCraddock & Owen (2005) attribute the

proposed demise of the Kraepelinianproposed demise of the Kraepelinian

dichotomy to advances in genetic epidemio-dichotomy to advances in genetic epidemio-

logy, and rightly emphasise the need tology, and rightly emphasise the need to

integrate data across multiple domains inintegrate data across multiple domains in

large numbers of people. However, it maylarge numbers of people. However, it may

also be important to use a population-basedalso be important to use a population-based

approach. This involves extra effort butapproach. This involves extra effort but

avoids being misled by convenience samplesavoids being misled by convenience samples

which may not be representative of thewhich may not be representative of the

population. This is illustrated by Fig. 1 inpopulation. This is illustrated by Fig. 1 in

the editorial of Craddock & Owen whichthe editorial of Craddock & Owen which

suggests that prototypical schizophreniasuggests that prototypical schizophrenia

and prototypical bipolar disorder are rela-and prototypical bipolar disorder are rela-

tively rare in clinical populations. Work intively rare in clinical populations. Work in

population-based samples suggests thatpopulation-based samples suggests that

there is an early, insidious-onset psychosisthere is an early, insidious-onset psychosis

with a poor outcome affecting predomi-with a poor outcome affecting predomi-

nantly men – a ‘neurodevelopmental’ formnantly men – a ‘neurodevelopmental’ form

of schizophrenia which is very close toof schizophrenia which is very close to

dementia praecox (Castledementia praecox (Castle et alet al, 1998). This, 1998). This

prototypical form of schizophrenia togetherprototypical form of schizophrenia together

with protoypical bipolar disorder accountswith protoypical bipolar disorder accounts

for 50% of people with psychosis in afor 50% of people with psychosis in a

treated prevalence sample, demonstratingtreated prevalence sample, demonstrating

the utility of Kraepelin’s division. In ourthe utility of Kraepelin’s division. In our

experience affective and non-affectiveexperience affective and non-affective

psychoses can be accounted for by thesepsychoses can be accounted for by these

prototypical forms and a further two latentprototypical forms and a further two latent

classes which appear to be valid (Murrayclasses which appear to be valid (Murray

et alet al, 2005). Whether such empirically, 2005). Whether such empirically

derived classes might provide better pheno-derived classes might provide better pheno-

types for genetic studies is as yettypes for genetic studies is as yet

undetermined.undetermined.

Until biological markers are identifiedUntil biological markers are identified

there is perhaps only one way to improvethere is perhaps only one way to improve

our classification. Large-scale, empirical,our classification. Large-scale, empirical,

population-based studies of psychiatricpopulation-based studies of psychiatric

symptoms, demography, course, treatmentsymptoms, demography, course, treatment

response and outcomes are suggested toresponse and outcomes are suggested to

reclassify these disorders from first princi-reclassify these disorders from first princi-

ples and provide an atheoretical frameworkples and provide an atheoretical framework

which may capture underlying patho-which may capture underlying patho-

physiological substrates. Such studiesphysiological substrates. Such studies

should, as described by Craddock & Owen,should, as described by Craddock & Owen,

integrate both dimensional and categoricalintegrate both dimensional and categorical

approaches but also require a develop-approaches but also require a develop-

mental perspective across the life span.mental perspective across the life span.

The debate about the Kraepelinian dichot-The debate about the Kraepelinian dichot-

omy illustrates the lack of evidence-basedomy illustrates the lack of evidence-based

diagnostic classification in psychiatry as adiagnostic classification in psychiatry as a

discipline. It would be fitting if psychiatricdiscipline. It would be fitting if psychiatric

genetics, which has been severely impededgenetics, which has been severely impeded

by the lack of a robust nosology, focusedby the lack of a robust nosology, focused

the collective will of practitioners tothe collective will of practitioners to

establish the evidence base required for aestablish the evidence base required for a

psychiatric classification which at lastpsychiatric classification which at last

reflects nature.reflects nature.

Castle, D. J.,Wessely, S., van Os, J.,Castle, D. J.,Wessely, S., van Os, J., et alet al (1998)(1998)Subtypes of schizophrenia. InSubtypes of schizophrenia. In Psychosis in the Inner City:Psychosis in the Inner City:The Camberwell First Episode StudyThe Camberwell First Episode Study, pp. 37^49.Hove:, pp. 37^49.Hove:Psychology Press.Psychology Press.

Craddock,N. & Owen, M. J. (2005)Craddock, N. & Owen, M. J. (2005) The beginning ofThe beginning ofthe end of the Kraepelinian dichotomy.the end of the Kraepelinian dichotomy. British Journal ofBritish Journal ofPsychiatryPsychiatry,, 186186, 364^366., 364^366.

Murray,V., McKee, I., Miller, P. M.,Murray,V., McKee, I., Miller, P. M., et alet al (2005)(2005)Dimensions and classes of psychosis in a populationDimensions and classes of psychosis in a populationcohort: a four class, four dimension model ofcohort: a four class, four dimension model ofschizophrenia and affective psychoses.schizophrenia and affective psychoses. PsychologicalPsychologicalMedicineMedicine,, 3535, 499^510., 499^510.

V.MurrayV.Murray Scottish Centre for Autism,RoyalScottish Centre for Autism,RoyalHospital for Sick Children,Glasgow G3 8SJ,UK.Hospital for Sick Children,Glasgow G3 8SJ,UK.E-mail:Val.MurrayE-mail:Val.Murray@@yorkhill.scot.nhs.ukyorkhill.scot.nhs.uk

Authors’ reply:Authors’ reply: We are in full agreementWe are in full agreement

with Dr Murray regarding the utility ofwith Dr Murray regarding the utility of

large-scale, population-based studies. Theselarge-scale, population-based studies. These

are highly desirable and will, we hope, beare highly desirable and will, we hope, be

facilitated by the recent establishment offacilitated by the recent establishment of

the Mental Health Research Networkthe Mental Health Research Network

(http://www.mhrn.info) under the auspices(http://www.mhrn.info) under the auspices

of the UK Clinical Research Collaborationof the UK Clinical Research Collaboration

(http://www.ukcrc.org). We also agree that(http://www.ukcrc.org). We also agree that

longitudinal variables such as course, out-longitudinal variables such as course, out-

come and treatment response might become and treatment response might be

key to classification, as Kraepelin supposed.key to classification, as Kraepelin supposed.

However, although we have not under-However, although we have not under-

taken relevant population studies ourselves,taken relevant population studies ourselves,

we are not convinced that Kraepelinianwe are not convinced that Kraepelinian

dichotomous categories are any more usefuldichotomous categories are any more useful

in population-based samples than in clinicalin population-based samples than in clinical

samples. We find the studies of Van Os andsamples. We find the studies of Van Os and

colleagues (e.g. Krabbendamcolleagues (e.g. Krabbendam et alet al, 2004), 2004)

persuasive that dimensional measures arepersuasive that dimensional measures are

useful in describing psychosis-relateduseful in describing psychosis-related

morbidity in the general population and,morbidity in the general population and,

contrary to the proposition of Dr Murray,contrary to the proposition of Dr Murray,

we would expect dimensions to bewe would expect dimensions to be moremore

useful than categories in populationsuseful than categories in populations

unselected for severe illness.unselected for severe illness.

Finally, we would like to restate andFinally, we would like to restate and

further emphasise our optimism about thefurther emphasise our optimism about the

likely rate of progress in identifying bio-likely rate of progress in identifying bio-

logical markers that can validate psychi-logical markers that can validate psychi-

atric diagnoses. Markers (in the form ofatric diagnoses. Markers (in the form of

genetic polymorphisms) have already beengenetic polymorphisms) have already been

identified that challenge current nosology.identified that challenge current nosology.

For example, using the Bipolar AffectiveFor example, using the Bipolar Affective

Disorder Dimension Scale (which ratesDisorder Dimension Scale (which rates

affective and psychotic dimensions;affective and psychotic dimensions;

CraddockCraddock et alet al, 2004) in a study of over, 2004) in a study of over

600 cases each of schizophrenia and bipolar600 cases each of schizophrenia and bipolar

disorder, we have demonstrated that a riskdisorder, we have demonstrated that a risk

variant within thevariant within the Neuregulin 1Neuregulin 1 gene,gene,

which has been associated with risk ofwhich has been associated with risk of

schizophrenia in several samples (reviewedschizophrenia in several samples (reviewed

in Craddockin Craddock et alet al, 2005), may confer, 2005), may confer

4 8 54 8 5

CORRESPONDENCECORRESPONDENCE

specific risk for a form of psychotic illnessspecific risk for a form of psychotic illness

characterised by features of both maniacharacterised by features of both mania

and mood-incongruent psychosis (Greenand mood-incongruent psychosis (Green

et alet al, 2005). Other findings of a similar, 2005). Other findings of a similar

nature are currently emerging from ournature are currently emerging from our

own studies and those of other groups,own studies and those of other groups,

and we anticipate that we are entering aand we anticipate that we are entering a

period during which psychiatric researchperiod during which psychiatric research

and practice will be placed on much firmerand practice will be placed on much firmer

nosological foundations than has beennosological foundations than has been

possible in the past.possible in the past.

Declaration of interestDeclaration of interest

N.C. and M.J.O. are consultants to Glaxo-N.C. and M.J.O. are consultants to Glaxo-

SmithKline and have received grant fundingSmithKline and have received grant funding

and honoraria from GlaxoSmithKline,and honoraria from GlaxoSmithKline,

AstraZeneca and Lilly.AstraZeneca and Lilly.

Craddock,N., Jones, I., Kirov,G.,Craddock,N., Jones, I., Kirov,G., et alet al (2004)(2004) TheTheBipolar Affective Disorder Dimension ScaleBipolar Affective Disorder Dimension Scale(BADDS) ^ a dimensional scale for rating lifetime(BADDS) ^ a dimensional scale for rating lifetimepsychopathology in bipolar spectrum disorder.psychopathology in bipolar spectrum disorder. BMCBMCPsychiatryPsychiatry,, 44, 19., 19.

Craddock,N.,O’Donovan, M. C. & Owen, M. J.Craddock,N.,O’Donovan, M. C. & Owen, M. J.(2005)(2005) The genetics of schizophrenia and bipolarThe genetics of schizophrenia and bipolardisorder: dissecting psychosis.disorder: dissecting psychosis. Journal of MedicalJournal of MedicalGeneticsGenetics,, 4242, 288^299., 288^299.

Green, F. K., Raybould, R., Macgregor, S.,Green, F. K., Raybould, R., Macgregor, S., et alet al(2005)(2005) Operation of the schizophrenia susceptibilityOperation of the schizophrenia susceptibilitygene, neuregulin 1, across traditional diagnosticgene, neuregulin 1, across traditional diagnosticboundaries to increase risk for bipolar disorder.boundaries to increase risk for bipolar disorder. ArchivesArchivesof General Psychiatryof General Psychiatry,, 6262, 642^648., 642^648.

Krabbendam, L., Myin-Germeys, I., De Graaf, R.,Krabbendam, L., Myin-Germeys, I., De Graaf, R.,et alet al (2004)(2004) Dimensions of depression, mania andDimensions of depression, mania andpsychosis in the general population.psychosis in the general population. PsychologicalPsychologicalMedicineMedicine,, 3434, 1177^1186., 1177^1186.

N.Craddock, M. J.OwenN.Craddock, M. J.Owen Department ofDepartment ofPsychological Medicine,Henry Wellcome Building,Psychological Medicine,Henry Wellcome Building,School of Medicine,Cardiff University,Heath Park,School of Medicine,Cardiff University,Heath Park,Cardiff CF14 4XN,UK.Cardiff CF14 4XN,UK.E-mail: craddocknE-mail: craddockn@@Cardiff.ac.ukCardiff.ac.uk

CBT for refractory symptomsCBT for refractory symptomsin schizophreniain schizophrenia

ValmaggiaValmaggia et alet al (2005) report an interesting(2005) report an interesting

randomised controlled trial evaluatingrandomised controlled trial evaluating

cognitive–behavioural therapy (CBT) forcognitive–behavioural therapy (CBT) for

refractory psychotic symptoms of schizo-refractory psychotic symptoms of schizo-

phrenia resistant to atypical antipsychoticphrenia resistant to atypical antipsychotic

medication. They conclude that patientsmedication. They conclude that patients

should not be excluded from psychologicalshould not be excluded from psychological

help on the grounds that they are too ill tohelp on the grounds that they are too ill to

benefit from therapy, and CBT forbenefit from therapy, and CBT for

psychotic symptoms should be available inpsychotic symptoms should be available in

in-patient facilities.in-patient facilities.

We feel the conclusions drawn by theWe feel the conclusions drawn by the

authors do not truly reflect their results.authors do not truly reflect their results.

ValmaggiaValmaggia et alet al report that their primaryreport that their primary

hypothesis was that CBT would be morehypothesis was that CBT would be more

effective than supportive counselling ineffective than supportive counselling in

reducing auditory hallucinations and delu-reducing auditory hallucinations and delu-

sional beliefs. They used the Positive andsional beliefs. They used the Positive and

Negative Syndrome Scale (PANSS) and Psy-Negative Syndrome Scale (PANSS) and Psy-

chotic Symptoms Rating Scale (PSYRATS)chotic Symptoms Rating Scale (PSYRATS)

to measure outcomes. The post-treatmentto measure outcomes. The post-treatment

score on the PANSS positive sub-scale ofscore on the PANSS positive sub-scale of

those receiving CBT was not significantlythose receiving CBT was not significantly

different from that of the control group.different from that of the control group.

On the PSYRATS no significant effect wasOn the PSYRATS no significant effect was

found on the delusions. Benefits of CBTfound on the delusions. Benefits of CBT

were found on the auditory hallucinationswere found on the auditory hallucinations

scale for physical characteristics and cogni-scale for physical characteristics and cogni-

tive interpretation but not for emotionaltive interpretation but not for emotional

characteristics. However, the benefits no-characteristics. However, the benefits no-

ticed were not sustained at follow-up. Itticed were not sustained at follow-up. It

would have been helpful if the authorswould have been helpful if the authors

had used anhad used an a prioria priori definition of what con-definition of what con-

stitutes a clinically meaningful improve-stitutes a clinically meaningful improve-

ment and provided the actual figures forment and provided the actual figures for

the dichotomous outcome.the dichotomous outcome.

Also, if we look at the numbers neededAlso, if we look at the numbers needed

to treat (NNT) calculations, the authorsto treat (NNT) calculations, the authors

have accurately reported the lack of statisti-have accurately reported the lack of statisti-

cal significance (PANSS positive symptomcal significance (PANSS positive symptom

scale, NNTscale, NNT¼8, 95% CI 3–8, 95% CI 3–1; PSYRATS; PSYRATS

factor 2, NNTfactor 2, NNT¼6, 95% CI 2–6, 95% CI 2–1; delusion; delusion

scale factor 1, NNTscale factor 1, NNT¼4, 95% CI 2–4, 95% CI 2–1;;

factor 2, NNTfactor 2, NNT¼12, 95% CI 3–12, 95% CI 3–1). The). The

only finding with reasonable confidenceonly finding with reasonable confidence

intervals seems to be cognitive interpreta-intervals seems to be cognitive interpreta-

tion on the auditory hallucination scale oftion on the auditory hallucination scale of

the PSYRATS (NNTthe PSYRATS (NNT¼3, 95% CI 2–13).3, 95% CI 2–13).

The authors also draw our attention toThe authors also draw our attention to

the fact that clozapine is effective in 32%the fact that clozapine is effective in 32%

of cases in producing a clinical improve-of cases in producing a clinical improve-

ment (NNTment (NNT¼5, 95% CI 4–7; Wahlbeck5, 95% CI 4–7; Wahlbeck etet

alal, 1999). They seem to suggest that the, 1999). They seem to suggest that the

figures from the current study reveal thefigures from the current study reveal the

effects of CBT to be similar to clozapine.effects of CBT to be similar to clozapine.

However, it should be noted that this figureHowever, it should be noted that this figure

reported by Wahlbeckreported by Wahlbeck et alet al is for globalis for global

improvement, whereas Valmaggiaimprovement, whereas Valmaggia et alet al dodo

not give any figures for global improvementnot give any figures for global improvement

and hence in our opinion these results areand hence in our opinion these results are

not comparable. To conclude from thesenot comparable. To conclude from these

results that CBT could induce a changeresults that CBT could induce a change

in psychotic symptoms seems to bein psychotic symptoms seems to be

overestimating the beneficial effects.overestimating the beneficial effects.

Patients with schizophrenia who arePatients with schizophrenia who are

resistant to clozapine form one of the mostresistant to clozapine form one of the most

difficult-to-treat groups. Jonesdifficult-to-treat groups. Jones et alet al (2004)(2004)

concluded that trial-based data supportingconcluded that trial-based data supporting

the wide use of CBT for people with schizo-the wide use of CBT for people with schizo-

phrenia or other psychotic illnesses are farphrenia or other psychotic illnesses are far

from conclusive. The randomised con-from conclusive. The randomised con-

trolled study of Valmaggiatrolled study of Valmaggia et alet al evaluatingevaluating

interventions in this population is welcome.interventions in this population is welcome.

Jones,C., Cormac, I., Silveira da Mota Neto, J. I.,Jones,C.,Cormac, I., Silveira da Mota Neto, J. I.,et alet al (2004)(2004) Cognitive behaviour therapy forCognitive behaviour therapy for

schizophrenia.schizophrenia. Cochrane Database of Systematic ReviewsCochrane Database of Systematic Reviews,,issue 4.Oxford: Update Software.issue 4.Oxford: Update Software.

Valmaggia, L. R.,Van der Gaag, M.,Tarrier, N.,Valmaggia, L. R.,Van der Gaag, M.,Tarrier, N., et alet al(2005)(2005) Cognitive^behavioural therapy for refractoryCognitive^behavioural therapy for refractorypsychotic symptoms of schizophrenia resistant topsychotic symptoms of schizophrenia resistant toatypical antipsychotic medication:Randomisedatypical antipsychotic medication: Randomisedcontrolled trial.controlled trial. British Journal of PsychiatryBritish Journal of Psychiatry,, 186186,,324^330.324^330.

Wahlbeck, K., Cheine, M. & Essali, M. A. (1999)Wahlbeck, K., Cheine, M. & Essali, M. A. (1999)Clozapine versus typical neuroleptic medication forClozapine versus typical neuroleptic medication forschizophrenia.schizophrenia. Cochrane Database of Systematic ReviewsCochrane Database of Systematic Reviews,,issue 4.Oxford: Update Software.issue 4.Oxford: Update Software.

M. Jayaram, P.HosalliM. Jayaram, P.Hosalli St Mary’s House,St Mary’s House,St Mary’s Road, Leeds LS7 3JX,UK.St Mary’s Road, Leeds LS7 3JX,UK.E-mail: Mahesh.JayaramE-mail: Mahesh.Jayaram@@leedsmh.nhs.ukleedsmh.nhs.uk

Olanzapine co-therapy in bipolarOlanzapine co-therapy in bipolardisorderdisorder

BakerBaker et alet al (2004) report an interesting(2004) report an interesting postpost

hochoc analysis from a randomised double-analysis from a randomised double-

blind, placebo-controlled study evaluatingblind, placebo-controlled study evaluating

the efficacy of olanzapine co-therapy inthe efficacy of olanzapine co-therapy in

patients with bipolar disorder who hadpatients with bipolar disorder who had

adequate responses to valproate or lithiumadequate responses to valproate or lithium

monotherapy (Tohenmonotherapy (Tohen et alet al, 2002). The, 2002). The

authors describe a secondary analysisauthors describe a secondary analysis

assessing response among dysphoric andassessing response among dysphoric and

non-dysphoric patients with bipolar Inon-dysphoric patients with bipolar I

disorder.disorder.

The authors conclude that olanzapineThe authors conclude that olanzapine

in combination with either lithium orin combination with either lithium or

valproate was effective in improving thevalproate was effective in improving the

severity of depressive symptoms coexistingseverity of depressive symptoms coexisting

with acute mania. This conclusion is basedwith acute mania. This conclusion is based

on statistically significant differences inon statistically significant differences in

mean changes in Hamilton Rating Scalemean changes in Hamilton Rating Scale

for Depression (HRSD) score. However,for Depression (HRSD) score. However,

the authors have not reported the standardthe authors have not reported the standard

deviations for these mean changes. Hence itdeviations for these mean changes. Hence it

is difficult to ascertain whether the data areis difficult to ascertain whether the data are

skewed. It is possible that a few patientsskewed. It is possible that a few patients

showing large changes on the HRSD couldshowing large changes on the HRSD could

have skewed the data. It was also puzzlinghave skewed the data. It was also puzzling

that the authors reported that the differencethat the authors reported that the difference

in the HRSD score between combinationin the HRSD score between combination

and monotherapy groups was larger forand monotherapy groups was larger for

dysphoric patients. One would expectdysphoric patients. One would expect

participants in the non-dysphoric group toparticipants in the non-dysphoric group to

have much lower baseline scores so thathave much lower baseline scores so that

there would be less chance of a significantthere would be less chance of a significant

reduction. (The mean HRSD baseline scorereduction. (The mean HRSD baseline score

in the non-dysphoric group was 10.42in the non-dysphoric group was 10.42

(s.d.(s.d.¼5.27) and in the dysphoric group5.27) and in the dysphoric group

25.18 (s.d.25.18 (s.d.¼4.62).)4.62).)

We are also of the view that reportingWe are also of the view that reporting

study outcomes in terms of mean changesstudy outcomes in terms of mean changes

on a rating scale does not provide meaning-on a rating scale does not provide meaning-

ful information for clinicians. Reportingful information for clinicians. Reporting

results using dichotomous outcomeresults using dichotomous outcome

4 8 64 8 6

CORRESPONDENCECORRESPONDENCE

measures such as ‘improved’ and ‘notmeasures such as ‘improved’ and ‘not

improved’ with a meaningful cut-off pointimproved’ with a meaningful cut-off point

defineddefined a prioria priori would be helpful.would be helpful.

Clinicians would be more interested inClinicians would be more interested in

outcome measures such as complete remis-outcome measures such as complete remis-

sion of symptoms, return to premorbidsion of symptoms, return to premorbid

levels of functioning, etc. To address thelevels of functioning, etc. To address the

question of whether olanzapine is helpfulquestion of whether olanzapine is helpful

for patients with dysphoric mania it wouldfor patients with dysphoric mania it would

be helpful to know how many in the olan-be helpful to know how many in the olan-

zapine co-therapy group achieved completezapine co-therapy group achieved complete

remission and whether there was any statis-remission and whether there was any statis-

tical difference between groups. It wouldtical difference between groups. It would

have been interesting if Bakerhave been interesting if Baker et alet al had alsohad also

provided dichotomous outcomes based onprovided dichotomous outcomes based on

the Clinical Global Impression scale forthe Clinical Global Impression scale for

bipolar disorder (CGI–BP; Spearingbipolar disorder (CGI–BP; Spearing et alet al,,

1997), as this was administered during the1997), as this was administered during the

course of the trial and data should becourse of the trial and data should be

readily available.readily available.

It is not uncommon to come acrossIt is not uncommon to come across

reporting of various outcome measuresreporting of various outcome measures

and multiple analysis of a randomisedand multiple analysis of a randomised

controlled trial. However, whether thiscontrolled trial. However, whether this

adds to clinical knowledge is questionable.adds to clinical knowledge is questionable.

We agree with BakerWe agree with Baker et alet al that it is import-that it is import-

ant to explore the pharmacological optionsant to explore the pharmacological options

for dysphoric mania as the availablefor dysphoric mania as the available

options are limited. However, we needoptions are limited. However, we need

more pragmatic outcome measures thatmore pragmatic outcome measures that

are easily understood by clinicians andare easily understood by clinicians and

can be applied in routine practice rathercan be applied in routine practice rather

than being lost in multiple analysis.than being lost in multiple analysis.

Systematic reviews such as that on the useSystematic reviews such as that on the use

of olanzapine for mania also highlight theof olanzapine for mania also highlight the

lack of pragmatic outcome measures inlack of pragmatic outcome measures in

the reporting of randomised controlledthe reporting of randomised controlled

studies (Rendellstudies (Rendell et alet al, 2003). We hope, 2003). We hope

future reports of such studies will use out-future reports of such studies will use out-

come measures that are more applicablecome measures that are more applicable

to the real world.to the real world.

Baker, R.W., Brown, E., Akiskal,H. S.,Baker, R.W., Brown, E., Akiskal,H. S., et alet al (2004)(2004)Efficacy of olanzapine combined with valproate orEfficacy of olanzapine combined with valproate orlithium in the treatment of dysphoric mania.lithium in the treatment of dysphoric mania. BritishBritishJournal of PsychiatryJournal of Psychiatry,, 185185, 472^478., 472^478.

Rendell, J. M., Gijsman,H. J., Keck, P.,Rendell, J. M.,Gijsman,H. J., Keck, P., et alet al (2003)(2003)Olanzapine alone or in combination for acute mania.Olanzapine alone or in combination for acute mania.Cochrane Database of Systematic ReviewsCochrane Database of Systematic Reviews, issue1.Oxford:, issue1.Oxford:Update Software.Update Software.

Spearing, M. K., Post, R. M., Leverich, G. S.,Spearing, M. K., Post, R. M., Leverich, G. S., et alet al(1997)(1997) Modification of the Clinical Global ImpressionModification of the Clinical Global Impression(CGI) scale for use in bipolar illness: CGI^BP.(CGI) scale for use in bipolar illness: CGI^BP. PsychiatryPsychiatryResearchResearch,, 7373, 159^171., 159^171.

Tohen, M.,Chengappa, K.N., Suppes,T.,Tohen, M.,Chengappa, K.N., Suppes,T., et alet al (2002)(2002)Efficacy of olanzapine in combination with valproate orEfficacy of olanzapine in combination with valproate orlithium in the treatment of mania in patients partiallylithium in the treatment of mania in patients partiallynonresponsive to valproate or lithiummonotherapy.nonresponsive to valproate or lithiummonotherapy.Archives of General PsychiatryArchives of General Psychiatry,, 5959, 62^69., 62^69.

P.Hosalli, M. JayaramP.Hosalli, M. Jayaram Leeds Mental HealthLeeds Mental HealthTrust, Leeds,UK. E-mail: Prakash.HosalliTrust, Leeds,UK. E-mail: Prakash.Hosalli@@leedsmh.leedsmh.nhs.uknhs.uk

ECT in depressionECT in depression

Schulze-RauschenbachSchulze-Rauschenbach et alet al (2005) found(2005) found

in their comparison of unilateral electro-in their comparison of unilateral electro-

convulsive therapy (ECT) and repetitiveconvulsive therapy (ECT) and repetitive

transcranial magnetic stimulation (rTMS)transcranial magnetic stimulation (rTMS)

that these two procedures have similarthat these two procedures have similar

efficacy in the treatment of majorefficacy in the treatment of major

depression. However, the rate of treatmentdepression. However, the rate of treatment

response for ECT in their study was 46%,response for ECT in their study was 46%,

well below the figures found in otherwell below the figures found in other

studies (Medical Research Council, 1965).studies (Medical Research Council, 1965).

The authors state that the response rateThe authors state that the response rate

for ECT might have been higher if a higherfor ECT might have been higher if a higher

dosage had been used, but that this woulddosage had been used, but that this would

have increased the risk of side-effects. Thishave increased the risk of side-effects. This

argument is misleading, just as comparingargument is misleading, just as comparing

a sub-therapeutic dose of amitriptylinea sub-therapeutic dose of amitriptyline

and placebo would be. The authors shouldand placebo would be. The authors should

have compared the incidence of side-effectshave compared the incidence of side-effects

between treatments, but at therapeutic doses.between treatments, but at therapeutic doses.

This comparison would probably have con-This comparison would probably have con-

firmed the prevalent belief that ECT is morefirmed the prevalent belief that ECT is more

effective than rTMS in the treatment ofeffective than rTMS in the treatment of

major depression (Aarremajor depression (Aarre et alet al, 2003)., 2003).

Aarre,T. F., Dahl, A. A., Johansen, J. B.,Aarre,T. F., Dahl, A. A., Johansen, J. B., et alet al (2003)(2003)Efficacy of repetitive transcranial magnetic stimulation inEfficacy of repetitive transcranial magnetic stimulation indepression: a review of the evidence.depression: a review of the evidence. Nordic Journal ofNordic Journal ofPsychiatryPsychiatry,, 5757, 227^232., 227^232.

Medical Research Council (1965)Medical Research Council (1965) Chemical trial of theChemical trial of thetreatment of depressive illness.treatment of depressive illness. BMJBMJ,, ii, 881^886., 881^886.

Schulze-Rauschenbach, S. C., Harms,U.,Schulze-Rauschenbach, S. C.,Harms,U.,Schlaepfer,T.E.,Schlaepfer,T.E., et alet al (2005)(2005)DistinctiveneurocognitiveDistinctiveneurocognitiveeffects of repetitive transcranial magnetic stimulationeffects of repetitive transcranial magnetic stimulationand electroconvulsive therapy in major depression.and electroconvulsive therapy in major depression.British Journal of PsychiatryBritish Journal of Psychiatry,, 186186, 410^416., 410^416.

R. EubaR. Euba Memorial Hospital, Shooters Hill,LondonMemorial Hospital, Shooters Hill, LondonSE18 3RZ,UK. E-mail: Rafael.EubaSE18 3RZ,UK. E-mail: Rafael.Euba@@oxleas.nhs.ukoxleas.nhs.uk

Schulze-RauschenbachSchulze-Rauschenbach et alet al (2005) com-(2005) com-

pared repetitive transcranial magneticpared repetitive transcranial magnetic

stimulation (rTMS) and unilateral electro-stimulation (rTMS) and unilateral electro-

convulsive therapy (ECT) and reported aconvulsive therapy (ECT) and reported a

similar treatment response rate. The rTMSsimilar treatment response rate. The rTMS

methodology produced an impressivemethodology produced an impressive

improvement with no cognitive side-effects.improvement with no cognitive side-effects.

However, the reported similar treat-However, the reported similar treat-

ment effect with ECT could be misleading,ment effect with ECT could be misleading,

as it is partly due to the rather low successas it is partly due to the rather low success

rate of ECT in this study. The Hamiltonrate of ECT in this study. The Hamilton

Rating Scale for Depression (HRSD) scoreRating Scale for Depression (HRSD) score

in the ECT group was reduced by a modestin the ECT group was reduced by a modest

35%. For comparison, the non-psychotic35%. For comparison, the non-psychotic

patients in the largest recent ECT studypatients in the largest recent ECT study

(the CORE study; Petrides(the CORE study; Petrides et alet al, 2001), 2001)

achieved a 74.5% reduction on theachieved a 74.5% reduction on the

HRSD–24 (24-item version).HRSD–24 (24-item version).

We started an audit of ECT at ourWe started an audit of ECT at our

regional psychiatric hospital 1 year ago.regional psychiatric hospital 1 year ago.

So far 23 consecutive patients withSo far 23 consecutive patients with

treatment-resistant depression, who hadtreatment-resistant depression, who had

an HRSD–17 (17-item version) score ofan HRSD–17 (17-item version) score of

15 or above (the cut-off used by Schulze-15 or above (the cut-off used by Schulze-

RauschenbachRauschenbach et alet al), have completed at), have completed at

least six ECT sessions. We observed aleast six ECT sessions. We observed a

55% improvement on the HRSD–17: from55% improvement on the HRSD–17: from

24.6 to 11.0 points. The decrease on the24.6 to 11.0 points. The decrease on the

self-rated Beck Depression Inventory wasself-rated Beck Depression Inventory was

20.1 points (an improvement of 49.9%).20.1 points (an improvement of 49.9%).

This compares with a decrease of only 7.6This compares with a decrease of only 7.6

points (24%) in the ECT group ofpoints (24%) in the ECT group of

Schulze-RauschenbachSchulze-Rauschenbach et alet al. Even more. Even more

importantly, the remission rate in theirimportantly, the remission rate in their

study was very low. Using the remissionstudy was very low. Using the remission

criterion ofcriterion of 447 points on the HRSD–177 points on the HRSD–17

(Thase, 2003), only one of their 13 ECT(Thase, 2003), only one of their 13 ECT

patients (8%) achieved remission (as shownpatients (8%) achieved remission (as shown

in Fig. 1). This contrasts with a rate ofin Fig. 1). This contrasts with a rate of

43.5% (10 out of 23 patients) in our study43.5% (10 out of 23 patients) in our study

and 74.7% (189 out of 253 patients) in theand 74.7% (189 out of 253 patients) in the

CORE study. Four of our patients scored 0CORE study. Four of our patients scored 0

or 1 point at the end of treatment.or 1 point at the end of treatment.

There could be at least two reasons forThere could be at least two reasons for

the low response rate in the ECT group ofthe low response rate in the ECT group of

Schulze-RauschenbachSchulze-Rauschenbach et alet al. First, uni-. First, uni-

lateral ECT is less effective than bilaterallateral ECT is less effective than bilateral

ECT, and when used at a simulation inten-ECT, and when used at a simulation inten-

sity of 100–150% above seizure threshold,sity of 100–150% above seizure threshold,

it has produced only a 30% response rateit has produced only a 30% response rate

(Sackeim(Sackeim et alet al, 2000). Only four patients, 2000). Only four patients

in our series and none in the CORE studyin our series and none in the CORE study

had unilateral ECT. Second, patients withhad unilateral ECT. Second, patients with

psychotic depression respond better topsychotic depression respond better to

ECT (PetridesECT (Petrides et alet al, 2001). None of the pa-, 2001). None of the pa-

tients of Schulze-Rauschenbachtients of Schulze-Rauschenbach et alet al hadhad

psychotic symptoms, but 13 (56.5%) inpsychotic symptoms, but 13 (56.5%) in

our group and 77 (30.4%) in the COREour group and 77 (30.4%) in the CORE

study did. This cannot explain all thestudy did. This cannot explain all the

difference, as the non-psychotic patientsdifference, as the non-psychotic patients

in our group still showed an improvementin our group still showed an improvement

of 48% on both HRSD–17 and Beckof 48% on both HRSD–17 and Beck

Depression Inventory scores.Depression Inventory scores.

Properly administered bilateral ECTProperly administered bilateral ECT

still remains by far the most effectivestill remains by far the most effective

treatment for severe depression.treatment for severe depression.

Petrides, G., Fink, M.,Husain, M. M.,Petrides, G., Fink, M.,Husain, M. M., et alet al (2001)(2001)ECTremission rates in psychotic versus nonpsychoticECTremission rates in psychotic versus nonpsychoticdepressed patients: a report from CORE.depressed patients: a report from CORE. Journal of ECTJournal of ECT,,1717, 244^253., 244^253.

Sackeim,H. A., Prudic, J., Devanand, D. P.,Sackeim,H. A., Prudic, J., Devanand, D. P., et alet al(2000)(2000) A prospective, randomised, double-blindA prospective, randomised, double-blindcomparison of bilateral and right unilateralcomparison of bilateral and right unilateralelectroconvulsive therapy at different stimuluselectroconvulsive therapy at different stimulusintensities.intensities. Archives of General PsychiatryArchives of General Psychiatry,, 5757, 425^434., 425^434.

Schulze-Rauschenbach, S. C.,Harms,U.,Schulze-Rauschenbach, S. C.,Harms,U.,Schlaepfer,T. E.,Schlaepfer,T. E., et alet al (2005)(2005) DistinctiveDistinctiveneurocognitive effects of repetitive transcranialneurocognitive effects of repetitive transcranialmagnetic stimulation and electroconvulsive therapy inmagnetic stimulation and electroconvulsive therapy inmajor depression.major depression. British Journal of PsychiatryBritish Journal of Psychiatry,, 186186,,410^416.410^416.

4 8 74 8 7

CORRESPONDENCECORRESPONDENCE

Thase, M. E. (2003)Thase, M. E. (2003) Evaluating antidepressantEvaluating antidepressanttherapies: remission as the optimal outcome.therapies: remission as the optimal outcome. Journal ofJournal ofClinical PsychiatryClinical Psychiatry,, 6464 (suppl. 13),18^25.(suppl.13), 18^25.

G. KirovG. Kirov Department of Psychological Medicine,Department of Psychological Medicine,College of Medicine,Cardiff University,Heath Park,College of Medicine,Cardiff University,Heath Park,Cardiff CF14 4XN,UK. E-mail: kirovCardiff CF14 4XN,UK. E-mail: kirov@@Cardiff.ac.ukCardiff.ac.ukN.KhalidN. Khalid Whitchurch Hospital,Cardiff and ValeWhitchurch Hospital,Cardiff and ValeNHS Trust,Cardiff,UKNHS Trust,Cardiff,UKJ.Tredget, A. KennedyJ.Tredget, A. Kennedy Department ofDepartment ofPsychological Medicine,Cardiff University,UKPsychological Medicine,Cardiff University,UKM. AtkinsM. Atkins Whitchurch Hospital,Cardiff and ValeWhitchurch Hospital,Cardiff and ValeNHS Trust,Cardiff,UKNHS Trust,Cardiff,UK

Authors’ reply:Authors’ reply: We welcome the letters ofWe welcome the letters of

Dr KirovDr Kirov et alet al and of Dr Euba who addressand of Dr Euba who address

the important issue of clinical efficacy ofthe important issue of clinical efficacy of

electroconvulsive therapy (ECT), whichelectroconvulsive therapy (ECT), which

may be greater when bilateral ECT is usedmay be greater when bilateral ECT is used

instead of unilateral ECT. We have littleinstead of unilateral ECT. We have little

doubt that this is true, but bilateral ECTdoubt that this is true, but bilateral ECT

is associated with more unwanted effectsis associated with more unwanted effects

on cognition than unilateral ECT (Nationalon cognition than unilateral ECT (National

Institute for Clinical Excellence, 2003).Institute for Clinical Excellence, 2003).

This is the main reason why unilateralThis is the main reason why unilateral

ECT is still frequently applied, certainly atECT is still frequently applied, certainly at

the beginning of a course of treatment.the beginning of a course of treatment.

Some patients experience severe and persis-Some patients experience severe and persis-

tent memory deficits after ECT (see Dona-tent memory deficits after ECT (see Dona-

hue, 2000). In their systematic review,hue, 2000). In their systematic review,

RoseRose et alet al (2003) found that about one-(2003) found that about one-

third of patients reported significant mem-third of patients reported significant mem-

ory loss after ECT. One can question theory loss after ECT. One can question the

validity of this worrisome figure on meth-validity of this worrisome figure on meth-

odological grounds, as the studies reviewedodological grounds, as the studies reviewed

by Roseby Rose et alet al used questionnaires instead ofused questionnaires instead of

neuropsychological assessments. Neverthe-neuropsychological assessments. Neverthe-

less, cognitive alterations can be very dis-less, cognitive alterations can be very dis-

turbing for the patient, and there remainsturbing for the patient, and there remains

a need to examine this controversial issuea need to examine this controversial issue

further.further.

In assessing the somewhat lower clini-In assessing the somewhat lower clini-

cal response obtained in our study com-cal response obtained in our study com-

pared with others, it should be borne inpared with others, it should be borne in

mind that all our patients were treatmentmind that all our patients were treatment

refractory (i.e. they had unsuccessful treat-refractory (i.e. they had unsuccessful treat-

ment response to at least two differentment response to at least two different

types of antidepressants, each given in atypes of antidepressants, each given in a

sufficient dosage range for at least 4 weeks).sufficient dosage range for at least 4 weeks).

Patients with resistance to antidepressantPatients with resistance to antidepressant

treatment are known to have reduced ratestreatment are known to have reduced rates

of response (Sackheimof response (Sackheim et alet al, 2000). For, 2000). For

example, less than 30% of those withexample, less than 30% of those with

depression who had failed to respond todepression who had failed to respond to

one adequate medication trial finallyone adequate medication trial finally

responded to low-dose or moderate-doseresponded to low-dose or moderate-dose

right unilateral ECT, in contrast to aboutright unilateral ECT, in contrast to about

50% who had not received such an50% who had not received such an

adequate antidepressant trial (Sackheimadequate antidepressant trial (Sackheim etet

alal, 2000). Thus, the therapeutic effect of, 2000). Thus, the therapeutic effect of

ECT in our study was well within theECT in our study was well within the

expected range both for the group ofexpected range both for the group of

patients studied and the type of ECTpatients studied and the type of ECT

applied. It should also be noted that partici-applied. It should also be noted that partici-

pants in the CORE study (Petridespants in the CORE study (Petrides et alet al,,

2001) cited by Dr Kirov and colleagues2001) cited by Dr Kirov and colleagues

were about 10 years older on average thanwere about 10 years older on average than

patients in our study, and that ECTpatients in our study, and that ECT

response rates in the CORE study wereresponse rates in the CORE study were

higher for older patients.higher for older patients.

We have stated quite explicitly that ourWe have stated quite explicitly that our

study was not designed to compare thestudy was not designed to compare the

absolute or relative effectiveness of repeti-absolute or relative effectiveness of repeti-

tive transcranial magnetic stimulationtive transcranial magnetic stimulation

(rTMS) or ECT. As outlined in our paper,(rTMS) or ECT. As outlined in our paper,

some preliminary randomised trials suggestsome preliminary randomised trials suggest

that rTMS might be as effective even asthat rTMS might be as effective even as

bilateral ECT in non-bilateral ECT in non-psychotic patientspsychotic patients

but, although the meta-but, although the meta-analytic evidenceanalytic evidence

for the clinical efficacy of ECT is strong,for the clinical efficacy of ECT is strong,

the evidence for strong efficacy of rTMSthe evidence for strong efficacy of rTMS

in depression is less conclusive.in depression is less conclusive.

Our primary intention was to highlightOur primary intention was to highlight

the continuing need to delineate the cogni-the continuing need to delineate the cogni-

tive side-effects of ECT in comparison withtive side-effects of ECT in comparison with

other treatments. Weighing benefits andother treatments. Weighing benefits and

side-effects of a specific form of ECT treat-side-effects of a specific form of ECT treat-

ment for a specific patient may have to takement for a specific patient may have to take

into account age, prior response to treat-into account age, prior response to treat-

ments, sensitivity to memory side-effectsments, sensitivity to memory side-effects

and other factors. Physicians and patientsand other factors. Physicians and patients

need better evidence about such side-need better evidence about such side-

effects, preferably from randomisedeffects, preferably from randomised

controlled trials, but also from audits suchcontrolled trials, but also from audits such

as that reported by Kirovas that reported by Kirov et alet al, to make, to make

informed decisions on the use of ECT,informed decisions on the use of ECT,

particularly as other forms of treatmentparticularly as other forms of treatment

become available.become available.

Donahue, A. B. (2000)Donahue, A. B. (2000) Electroconvulsive therapy andElectroconvulsive therapy andmemory loss: a personal journey.memory loss: a personal journey. Journal of ECTJournal of ECT,, 1616,,133^143.133^143.

National Institute for Clinical Excellence (2003)National Institute for Clinical Excellence (2003)Guidance on the Use of ElectroconvulsiveTherapyGuidance on the Use of ElectroconvulsiveTherapy..London:NICE (http://www.nice.org.uk/pdf/London:NICE (http://www.nice.org.uk/pdf/59ectfullguidance.pdf ).59ectfullguidance.pdf ).

Petrides, G., Fink M.,Hussain, M. M.,Petrides, G., Fink M.,Hussain, M. M., et alet al (2001)(2001)ECTremission roles in psychotic versus nonpsychoticECTremission roles in psychotic versus nonpsychoticdepressed patients: a report from CORE.depressed patients: a report from CORE. Journal of ECTJournal of ECT,,1717, 244^253., 244^253.

Rose, D., Fleishmann, P.,Wykes,T.,Rose, D., Fleishmann, P.,Wykes,T., et alet al (2003)(2003)Patients’ perspectives on electroconvulsive therapy:Patients’ perspectives on electroconvulsive therapy:systematic review.systematic review. BMJBMJ,, 326326, 1363., 1363.

Sackeim,H. A., Prudic, J., Devanand, D. P.,Sackeim,H. A., Prudic, J., Devanand, D. P., et alet al(2000)(2000) A prospective, randomised, double-blindA prospective, randomised, double-blindcomparison of bilateral and right unilateralcomparison of bilateral and right unilateralelectroconvulsive therapy at different stimuluselectroconvulsive therapy at different stimulusintensities.intensities. Archives of General PsychiatryArchives of General Psychiatry,, 5757, 425^434., 425^434.

M.Wagner, S. Schulze-Rauschenbach,M.Wagner, S. Schulze-Rauschenbach,T. SchlaepferT. Schlaepfer Department of Psychiatry,Department of Psychiatry,University of Bonn, Sigmund-Freud Strasse 25,University of Bonn, Sigmund-Freud Strasse 25,D 53105 Bonn,GermanyD 53105 Bonn,Germany

Hospital admission ratesHospital admission ratesand diagnosisand diagnosis

We read with interest the article byWe read with interest the article by

ThompsonThompson et alet al (2004) on changing(2004) on changing

patterns of hospital admission for adultpatterns of hospital admission for adult

psychiatric illness. Although they ack-psychiatric illness. Although they ack-

nowledged the limitations of routinelynowledged the limitations of routinely

collected admissions data, the authorscollected admissions data, the authors

reported a lower than anticipated propor-reported a lower than anticipated propor-

tion of all admissions in the schizophreniation of all admissions in the schizophrenia

and related psychoses categories andand related psychoses categories and

greater than anticipated proportions forgreater than anticipated proportions for

depression and anxiety and substance mis-depression and anxiety and substance mis-

use. A further analysis of admissions foruse. A further analysis of admissions for

substance misuse suggested that this didsubstance misuse suggested that this did

not include a large number of patients withnot include a large number of patients with

dual diagnosis and that psychotic disorderdual diagnosis and that psychotic disorder

secondary to alcohol or drug misusesecondary to alcohol or drug misuse

accounted for around 10% of admissionsaccounted for around 10% of admissions

for substance misuse.for substance misuse.

On a variety of indices, Manchester hasOn a variety of indices, Manchester has

the highest level of need for mental healththe highest level of need for mental health

services in England (Gloverservices in England (Glover et alet al, 1999)., 1999).

Using a similar methodology, we haveUsing a similar methodology, we have

analysed the 2003/4 admissions data foranalysed the 2003/4 admissions data for

Manchester and found marked differencesManchester and found marked differences

from the patterns reported by Thompsonfrom the patterns reported by Thompson

et alet al: 42% of admissions in Manchester: 42% of admissions in Manchester

were for schizophrenia and relatedwere for schizophrenia and related

psychoses (national average 26%), withpsychoses (national average 26%), with

only 18% for depression or anxietyonly 18% for depression or anxiety

(national average 29.6%) and 6.5% for(national average 29.6%) and 6.5% for

substance misuse (national average 19.1%).substance misuse (national average 19.1%).

Further examination of the admissions forFurther examination of the admissions for

substance misuse in Manchester showedsubstance misuse in Manchester showed

that 57% were for psychoses secondary tothat 57% were for psychoses secondary to

alcohol or drug misuse.alcohol or drug misuse.

Our own earlier analyses of admissionsOur own earlier analyses of admissions

in the north west of England (Harrisonin the north west of England (Harrison etet

alal, 1995) also found marked variation, 1995) also found marked variation

according to diagnostic group andaccording to diagnostic group and

suggested that health districts with highersuggested that health districts with higher

levels of deprivation admitted a higher pro-levels of deprivation admitted a higher pro-

portion of patients with psychotic diag-portion of patients with psychotic diag-

noses and fewer patients with anxiety andnoses and fewer patients with anxiety and

depression. Similarly, the King’s Funddepression. Similarly, the King’s Fund

report into London’s mental health (King’sreport into London’s mental health (King’s

Fund, 1997) argued that a high proportionFund, 1997) argued that a high proportion

of admissions for schizophrenia reflectedof admissions for schizophrenia reflected

increased need for services. This couldincreased need for services. This could

explain some of the regional variation inexplain some of the regional variation in

admissions according to diagnostic groupadmissions according to diagnostic group

reported by Thompsonreported by Thompson et alet al and our ownand our own

recent findings. Admissions for substancerecent findings. Admissions for substance

misuse may also be influenced by depriva-misuse may also be influenced by depriva-

tion and availability of in-patient beds,tion and availability of in-patient beds,

with some areas only admitting patientswith some areas only admitting patients

with secondary psychoses rather than drugwith secondary psychoses rather than drug

or alcohol dependence.or alcohol dependence.

4 8 84 8 8

CORRESPONDENCECORRESPONDENCE

The continued variation in the use of in-The continued variation in the use of in-

patient facilities across England requirespatient facilities across England requires

further attention, particularly as it suggestsfurther attention, particularly as it suggests

that current means of resource allocationthat current means of resource allocation

do not adequately address the markeddo not adequately address the marked

impact of deprivation on need for mentalimpact of deprivation on need for mental

health services.health services.

Glover,G. R., Leese, M. & McCrone, P. (1999)Glover,G. R., Leese, M. & McCrone, P. (1999) MoreMoresevere mental illness is more concentrated in deprivedsevere mental illness is more concentrated in deprivedareas.areas. British Journal of PsychiatryBritish Journal of Psychiatry,, 175175, 544^548., 544^548.

Harrison, J., Barrow, S. & Creed, F. (1995)Harrison, J., Barrow, S. & Creed, F. (1995) SocialSocialdeprivation and psychiatric admission rates amongdeprivation and psychiatric admission rates amongdifferent diagnostic groups.different diagnostic groups. British Journal of PsychiatryBritish Journal of Psychiatry,,167167, 456^462., 456^462.

King’s Fund (1997)King’s Fund (1997) edited by Sonia Johnson.edited by Sonia Johnson. London’sLondon’sMental Health.The Report of the King’s Fund LondonMental Health.The Report of the King’s Fund LondonCommissionCommission. London:King’s Fund.. London:King’s Fund.

Thompson, A., Shaw, M.,Harrison,G.,Thompson, A., Shaw, M.,Harrison,G., et alet al (2004)(2004)Problems of hospital admission for adult psychiatricProblems of hospital admission for adult psychiatricillness in England: analysis of Hospital Episode Statisticsillness in England: analysis of Hospital Episode Statisticsdata.data. British Journal of PsychiatryBritish Journal of Psychiatry,, 185185, 334^341., 334^341.

J. A.HarrisonJ. A.Harrison Manchester Mental Health andManchester Mental Health andSocial CareTrust,Chorlton House, 70 ManchesterSocial CareTrust,Chorlton House, 70 ManchesterRoad,Manchester M21 9UN,UK.Road,Manchester M21 9UN,UK.E-mail: Judith.HarrisonE-mail: Judith.Harrison@@mhsc.manchester.nhs.ukmhsc.manchester.nhs.uk

F. CreedF. Creed University of Manchester,UK.University of Manchester,UK.

Obesity and schizophreniaObesity and schizophrenia

After reading less than half of ‘MetabolicAfter reading less than half of ‘Metabolic

syndrome and schizophrenia’ (Thakore,syndrome and schizophrenia’ (Thakore,

2005) I checked the Declaration of interest2005) I checked the Declaration of interest

and found the expected link to the pharma-and found the expected link to the pharma-

ceutical industry. On rereading the wholeceutical industry. On rereading the whole

paper carefully I could not pinpoint a singlepaper carefully I could not pinpoint a single

statement that seemed wrong. However,statement that seemed wrong. However,

the uneasy general impression remainedthe uneasy general impression remained

that the author attempted to suggest thatthat the author attempted to suggest that

the metabolic syndrome was rather a resultthe metabolic syndrome was rather a result

of schizophrenia itself and/or the associatedof schizophrenia itself and/or the associated

stress than the antipsychotic drugs. There-stress than the antipsychotic drugs. There-

fore, I would like to draw attention to thefore, I would like to draw attention to the

high probability that patients with schizo-high probability that patients with schizo-

phrenia were rarely overweight before thephrenia were rarely overweight before the

advent of neuroleptics. First, Kretschmeradvent of neuroleptics. First, Kretschmer

(1961) found that 50.3% of 5233 people(1961) found that 50.3% of 5233 people

with schizophrenia had a leptosome (orwith schizophrenia had a leptosome (or

asthenischasthenisch) body build, for which he mea-) body build, for which he mea-

sured an average waist/hip ratio of 0.67sured an average waist/hip ratio of 0.67

(74.1/84.7 cm) in men and 0.82 (67.7/(74.1/84.7 cm) in men and 0.82 (67.7/

82.2 cm) in women. Only 13.7% of 523382.2 cm) in women. Only 13.7% of 5233

people with schizophrenia werepeople with schizophrenia were pyknischpyknisch,,

characterised by a strong development ofcharacterised by a strong development of

circumference of the holes for the intestinescircumference of the holes for the intestines

((starke Umfangsentwicklung der Eingewei-starke Umfangsentwicklung der Eingewei-

dehohlendehohlen) and an average waist/hip ratio of) and an average waist/hip ratio of

0.97 (88.8/92.0 cm) in men and 0.84 (78.7/0.97 (88.8/92.0 cm) in men and 0.84 (78.7/

94.2 cm) in women. The rest of the94.2 cm) in women. The rest of the

schizophrenia sample was classified asschizophrenia sample was classified as

athletic, dysphasic orathletic, dysphasic or uncharakteristischuncharakteristisch

(not typical of any of the aforementioned).(not typical of any of the aforementioned).

Among the 1361 people with manic–Among the 1361 people with manic–

depressive illness, 64.6% weredepressive illness, 64.6% were pyknischpyknisch

and only 19.2% leptosome. The leptosomeand only 19.2% leptosome. The leptosome

body build, which does not seem to indicatebody build, which does not seem to indicate

a risk of developing the metabolic syn-a risk of developing the metabolic syn-

drome, was thought of as typical fordrome, was thought of as typical for

schizophrenia.schizophrenia.

Second, I asked a student to classify theSecond, I asked a student to classify the

patients with schizophrenia on old photo-patients with schizophrenia on old photo-

graphs in Bleuler’s textbook (1969) asgraphs in Bleuler’s textbook (1969) as

probably underweight, normal weight orprobably underweight, normal weight or

overweight, without letting her know theoverweight, without letting her know the

reason. She quite rightly protested that shereason. She quite rightly protested that she

could not carry out the task with anycould not carry out the task with any

certainty. However, as she appears rathercertainty. However, as she appears rather

underweight herself and as most peopleunderweight herself and as most people

tend to use themselves as a yardstick, it istend to use themselves as a yardstick, it is

unlikely that she underestimated the num-unlikely that she underestimated the num-

ber of overweight patients with schizo-ber of overweight patients with schizo-

phrenia. She classified 25% (5 out of 20)phrenia. She classified 25% (5 out of 20)

as overweight, 60% (12 out of 20) asas overweight, 60% (12 out of 20) as

normal weight and 15% (3 out of 20) asnormal weight and 15% (3 out of 20) as

underweight. Thus, in spite of Thakore’sunderweight. Thus, in spite of Thakore’s

paper, I still think that neuroleptic drugspaper, I still think that neuroleptic drugs

contribute considerably to the developmentcontribute considerably to the development

of obesity and its consequences.of obesity and its consequences.

Declaration of interestDeclaration of interest

None.None.

Bleuler, M. (1969)Bleuler, M. (1969) Lehrbuch der PsychiatrieLehrbuch der Psychiatrie. Berlin:. Berlin:Springer.Springer.

Kretschmer, E. (1961)Kretschmer, E. (1961) Korperbau und CharakterKo« rperbau und Charakter (23rd/(23rd/24th edn).Berlin: Springer.24th edn).Berlin: Springer.

Thakore, J.H. (2005)Thakore, J.H. (2005) Metabolic syndrome andMetabolic syndrome andschizophrenia.schizophrenia. British Journal of PsychiatryBritish Journal of Psychiatry,, 186186, 455^456., 455^456.

C.ThielsC.Thiels Department of Social Sciences,Department of Social Sciences,University of Applied Sciences,D33615 Bielefeld,University of Applied Sciences,D33615 Bielefeld,Germany. E-mail: cornelia.thielsGermany. E-mail: cornelia.thiels@@fh-bielefeld.defh-bielefeld.de

Author’s reply:Author’s reply: In response to ProfessorIn response to Professor

Thiels letter, intra-abdominal fat (IAF) isThiels letter, intra-abdominal fat (IAF) is

critical in determining the overall risk ofcritical in determining the overall risk of

physical morbidity and one does not needphysical morbidity and one does not need

to be overweight, or indeed obese in theto be overweight, or indeed obese in the

conventional sense, to have an excess ofconventional sense, to have an excess of

IAF (Thakore, 2005). For example, patientsIAF (Thakore, 2005). For example, patients

with melancholic depression, who by defi-with melancholic depression, who by defi-

nition have usually lost weight, have twicenition have usually lost weight, have twice

as much visceral fat as matched controls,as much visceral fat as matched controls,

and have higher mortality rates than theand have higher mortality rates than the

general population (Thakoregeneral population (Thakore et alet al, 1997)., 1997).

Hence, the patients with schizophreniaHence, the patients with schizophrenia

described by Kretschmer may have beendescribed by Kretschmer may have been

underweight or of normal weight but stillunderweight or of normal weight but still

have carried excessive amounts of IAF,have carried excessive amounts of IAF,

which would have increased their risk ofwhich would have increased their risk of

developing a host of physical problems.developing a host of physical problems.

The waist/hip ratio is an indirectThe waist/hip ratio is an indirect

anthropometric measure of IAF whoseanthropometric measure of IAF whose

value is greatly influenced by exactly wherevalue is greatly influenced by exactly where

the tape measure is placed. Using a directthe tape measure is placed. Using a direct

measure of IAF, computed tomographicmeasure of IAF, computed tomographic

scanning, we have shown in two separatescanning, we have shown in two separate

studies that first-episode drug naıve non-studies that first-episode drug naıve non-

obese patients with schizophrenia have overobese patients with schizophrenia have over

three times as much IAF as matchedthree times as much IAF as matched

controls (Thakorecontrols (Thakore et alet al, 2002; Ryan, 2002; Ryan et alet al,,

2004). The amounts of IAF in both of these2004). The amounts of IAF in both of these

samples were far in excess of what onesamples were far in excess of what one

would see in simple obesity, but were simi-would see in simple obesity, but were simi-

lar to what one might observe in patientslar to what one might observe in patients

with Cushing’s syndrome. There is littlewith Cushing’s syndrome. There is little

doubt that most of the widely useddoubt that most of the widely used

neuroleptics (old and new) cause weightneuroleptics (old and new) cause weight

gain. Yet, using computed tomographicgain. Yet, using computed tomographic

scanning, an acknowledged gold standard,scanning, an acknowledged gold standard,

we have shown that there is no significantwe have shown that there is no significant

increase in IAF with two commonly usedincrease in IAF with two commonly used

atypical antipsychotics (Ryanatypical antipsychotics (Ryan et alet al, 2004)., 2004).

Therefore, we should be asking questionsTherefore, we should be asking questions

such as what has a greater physical impactsuch as what has a greater physical impact

on patients with schizophrenia – the illness,on patients with schizophrenia – the illness,

with all of its associated stress and poorwith all of its associated stress and poor

lifestyle choices, or the medications usedlifestyle choices, or the medications used

to control symptomatology?to control symptomatology?

Declaration of interestDeclaration of interest

J.H.T. has in the past received unrestrictedJ.H.T. has in the past received unrestricted

educational grants from Bristol-Myerseducational grants from Bristol-Myers

Squibb, Eli Lilly and Pfizer but is currentlySquibb, Eli Lilly and Pfizer but is currently

receiving no funding from pharmaceuticalreceiving no funding from pharmaceutical

companies.companies.

Ryan,M.C.M., Flanagan, S.,Kinsella,U.,Ryan,M.C.M., Flanagan, S., Kinsella,U., et alet al (2004)(2004)Atypical antipsychotics and visceral fat distribution inAtypical antipsychotics and visceral fat distribution infirst episode, drug-na|ve patients with schizophrenia.first episode, drug-na|«ve patients with schizophrenia.Life SciencesLife Sciences,, 7474, 1999^2008., 1999^2008.

Thakore, J.H. (2005)Thakore, J.H. (2005) Metabolic syndrome andMetabolic syndrome andschizophrenia.schizophrenia. British Journal of PsychiatryBritish Journal of Psychiatry,, 186186, 455^456., 455^456.

Thakore, J.H., Richards, P. J., Reznek, R.H.,Thakore, J.H., Richards, P. J., Reznek, R.H., et alet al(1997)(1997) Increased intraabdominal fat deposition inIncreased intraabdominal fat deposition inpatients with major depressive illness as measured bypatients with major depressive illness as measured bycomputed tomography.computed tomography. Biological PsychiatryBiological Psychiatry,, 4141,,1140^1142.1140^1142.

Thakore, J.H., Mann, J. N.,Vlahoos, J.,Thakore, J.H., Mann, J. N.,Vlahoos, J., et alet al (2002)(2002)Increased visceral fat distribution in drug-na|ve andIncreased visceral fat distribution in drug-na|«ve anddrug-free patients with schizophrenia.drug-free patients with schizophrenia. InternationalInternationalJournal of Obesity Related Metabolic DisordersJournal of Obesity Related Metabolic Disorders,, 2626,,137^141.137^141.

J.H.ThakoreJ.H.Thakore Neuroscience Centre, St Vincent’sNeuroscience Centre, St Vincent’sHospital,Richmond Road, Fairview,Dublin 3, Ireland.Hospital,Richmond Road, Fairview,Dublin 3, Ireland.E-mail: jthakoreE-mail: jthakore@@rcsi.iercsi.ie

4 8 94 8 9

CORRESPONDENCECORRESPONDENCE

Zero tolerance of violenceZero tolerance of violence

BehrBehr et alet al (2005) rightly draw attention(2005) rightly draw attention

to the advantages of those with variousto the advantages of those with various

forms of mental disturbance, in someforms of mental disturbance, in some

circumstances, being held to be accountablecircumstances, being held to be accountable

for their actions (see also Smith &for their actions (see also Smith &

Donovan, 1990; Prins, 2002, 2005:Donovan, 1990; Prins, 2002, 2005:

chapter 2).chapter 2). However, their comments con-However, their comments con-

cerning the degree to which alcohol andcerning the degree to which alcohol and

other drugs may totally erode criminal re-other drugs may totally erode criminal re-

sponsibility need slight qualification. It issponsibility need slight qualification. It is

of course true that, in general terms, the in-of course true that, in general terms, the in-

gestion of alcohol and other drugs not onlygestion of alcohol and other drugs not only

does not excuse culpability, but may in factdoes not excuse culpability, but may in fact

exacerbate it. There are, however, instancesexacerbate it. There are, however, instances

where specific intent has to be proved (aswhere specific intent has to be proved (as

for example in homicide), where the inges-for example in homicide), where the inges-

tion of such substances may negate full re-tion of such substances may negate full re-

sponsibility (Homicide Act 1957, Sectionsponsibility (Homicide Act 1957, Section

2). In addition, the unknowing ingestion2). In addition, the unknowing ingestion

of alcohol, for example ‘spiking’ someone’sof alcohol, for example ‘spiking’ someone’s

non-alcoholic beverage with alcohol, maynon-alcoholic beverage with alcohol, may

be held to exclude responsibility. Thebe held to exclude responsibility. The

law on this whole topic is somewhatlaw on this whole topic is somewhat

complicated, and has, from time to time,complicated, and has, from time to time,

led to some equivocal decisions in theled to some equivocal decisions in the

higher courts.higher courts.

Behr,G.M., Ruddock, J. P., Benn, P.,Behr,G.M., Ruddock, J. P., Benn, P., et alet al (2005)(2005) ZeroZerotolerance of violence by users of mental health services:tolerance of violence by users of mental health services:the need for an ethical framework.the need for an ethical framework. British Journal ofBritish Journal ofPsychiatryPsychiatry,, 187187, 7^8., 7^8.

Prins,H. (2002)Prins,H. (2002) Cui bono? Withholding treatmentCui bono? Withholding treatmentfrom violent and abusive patients in NHS trusts: ‘Wefrom violent and abusive patients in NHS trusts: ‘Wedon’t have to take this’.don’t have to take this’. Journal of Forensic PsychiatryJournal of Forensic Psychiatry,, 1313,,391^406.391^406.

Prins,H. (2005)Prins,H. (2005) Offenders, Deviants or Patients?Offenders, Deviants or Patients? (3rd(3rdedn).NewYork: Brunner^Routledge.edn).NewYork: Brunner^Routledge.

Smith, J. & Donovan, M. (1990)Smith, J. & Donovan, M. (1990) The prosecution ofThe prosecution ofpsychiatric in-patients.psychiatric in-patients. Journal of Forensic PsychiatryJournal of Forensic Psychiatry,, 11,,379^383.379^383.

H. PrinsH. Prins 1Home Close Road,Houghton on the1Home Close Road,Houghton on theHill, Leicester LE7 9GT,UKHill, Leicester LE7 9GT,UK

One hundred years agoOne hundred years ago

The First Belgian CongressThe First Belgian Congressof Neurology and Psychiatryof Neurology and PsychiatryOONN Sept. 28th and 29th there was held atSept. 28th and 29th there was held at

Liege, in connexion with the InternationalLiege, in connexion with the International

Exhibition which is now in progress in theExhibition which is now in progress in the

city, the first Belgian Congress of Neuro-city, the first Belgian Congress of Neuro-

logy and Psychiatry. The opening meetinglogy and Psychiatry. The opening meeting

took place in the buildings of the university,took place in the buildings of the university,

where M. de Latour, Director-General ofwhere M. de Latour, Director-General of

the Ministry of Justice, received delegatesthe Ministry of Justice, received delegates

from France, Germany, Holland, Switzer-from France, Germany, Holland, Switzer-

land, Turkey, and Roumania. Dr. Glorieuxland, Turkey, and Roumania. Dr. Glorieux

began the formal business of the Congressbegan the formal business of the Congress

by delivering an address dealing with theby delivering an address dealing with the

occurrence of neurasthenia among theoccurrence of neurasthenia among the

working classes. This disease was, heworking classes. This disease was, he

remarked, popularly supposed to beremarked, popularly supposed to be

confined almost entirely to persons forconfined almost entirely to persons for

whom the struggle for existence was awhom the struggle for existence was a

mental rather than a physical one, thoughmental rather than a physical one, though

probably the unrestrained pursuit ofprobably the unrestrained pursuit of

pleasure was also in some degree respon-pleasure was also in some degree respon-

sible for its development. Statistics, how-sible for its development. Statistics, how-

ever, showed that in both Germany andever, showed that in both Germany and

Belgium the incidence of neurasthenia uponBelgium the incidence of neurasthenia upon

artisans was very marked, while in Scandi-artisans was very marked, while in Scandi-

navia insurance companies have been sonavia insurance companies have been so

severely taxed by the extension of theseverely taxed by the extension of the

malady that they have found it advisablemalady that they have found it advisable

to construct special sanatoriums. Dr.to construct special sanatoriums. Dr.

Glorieux referred to the view that neur-Glorieux referred to the view that neur-

asthenia may be due to the toxic effects ofasthenia may be due to the toxic effects of

influenza but he himself attributed theinfluenza but he himself attributed the

disease to the insanitary environment indisease to the insanitary environment in

which work is often carried on and hewhich work is often carried on and he

looked to the more general introductionlooked to the more general introduction

of machinery and the consequent regulationof machinery and the consequent regulation

of the conditions of labour for improve-of the conditions of labour for improve-

ment in this regard. In the afternoon Mdlle.ment in this regard. In the afternoon Mdlle.

Joteyko, chief of the Psycho-PhysiologicalJoteyko, chief of the Psycho-Physiological

Laboratory of the University of Brussels,Laboratory of the University of Brussels,

contributed a paper on the Sense of Paincontributed a paper on the Sense of Pain

and Dr. Lannois of Lyons one upon Epi-and Dr. Lannois of Lyons one upon Epi-

leptiform Spasm of the Foot, while Dr.leptiform Spasm of the Foot, while Dr.

Heilporn of Antwerp described a case ofHeilporn of Antwerp described a case of

Acromegaly. The morning of the secondAcromegaly. The morning of the second

day was devoted to a visit to the asylumday was devoted to a visit to the asylum

of St. Agatha and to the discussion of Dr.of St. Agatha and to the discussion of Dr.

Cuylit’s paper entitled ‘Work in the Thera-Cuylit’s paper entitled ‘Work in the Thera-

peutics of Mental Maladies.’ A visit waspeutics of Mental Maladies.’ A visit was

also paid to thealso paid to the maison de santemaison de sante at Glainat Glain

and after lunch the scientific section of theand after lunch the scientific section of the

exhibition was inspected.exhibition was inspected.

REFERENCEREFERENCE

LancetLancet, 7 October 1905, 1049., 7 October 1905, 1049.

Researched by Henry Rollin, Emeritus ConsultantResearched by Henry Rollin, Emeritus ConsultantPsychiatrist,Horton Hospital, Epsom, SurreyPsychiatrist,Horton Hospital, Epsom, Surrey

CorrigendumCorrigendum

Substance use disorders and the orbitofron-Substance use disorders and the orbitofron-

tal cortex. Systematic review of behaviouraltal cortex. Systematic review of behavioural

decision-making and neuroimaging studies.decision-making and neuroimaging studies.

BJPBJP,, 187187, 209–220. The fourth sentence of, 209–220. The fourth sentence of

the first paragraph (p. 209) should read: Itthe first paragraph (p. 209) should read: It

processes the reward value and/or affectiveprocesses the reward value and/or affective

valence of environmental stimuli, assessesvalence of environmental stimuli, assesses

the future consequences of the individual’sthe future consequences of the individual’s

own actions (response selection) and inhi-own actions (response selection) and inhi-

bits inappropriate behaviours (responsebits inappropriate behaviours (response

inhibition; Bechara & Damasio, 2002;inhibition; Bechara & Damasio, 2002;

Krawczyk, 2002; FanKrawczyk, 2002; Fan et alet al, 2003)., 2003).

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