El Mito de La Esquizofrenia Como Enfermedad Cerebral Progresiva

7/27/2019 El Mito de La Esquizofrenia Como Enfermedad Cerebral Progresiva

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Schizophrenia Bulletin

doi:10.1093/schbul/sbs135

The Author 2012. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.

org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original workis properly cited.

The Myth o Schizophrenia as a Progressive Brain Disease

Robert B. Zipursky*,1, Thomas J. Reilly2, Robin M. Murray2

1Department o Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada; 2Department oPsychosis Studies, Institute o Psychiatry, Kings College, De Crespigny Park, London, UK

*To whom correspondence should be addressed; St Josephs Healthcare Hamilton, 100 West 5th Street, Hamilton, Ontario L8N3K7,Canada; tel: 905-522-1155 x 36250, ax: 905-381-5633, e-mail: [email protected]

Schizophrenia has historically been considered to be a dete-riorating disease, a view reinorced by recent MRI ndingso progressive brain tissue loss over the early years o illness.On the other hand, the notion that recovery rom schizo-

phrenia is possible is increasingly embraced by consumerand amily groups. This review critically examines the evi-dence rom longitudinal studies o (1) clinical outcomes, (2)MRI brain volumes, and (3) cognitive unctioning. First,the evidence shows that although approximately 25% opeople with schizophrenia have a poor long-term outcome,ew o these show the incremental loss o unction that is

characteristic o neurodegenerative illnesses. Second, MRIstudies demonstrate subtle developmental abnormalities atrst onset o psychosis and then urther decreases in braintissue volumes; however, these latter decreases are expli-cable by the eects o antipsychotic medication, substance

abuse, and other secondary actors. Third, while patientsdo show cognitive decits compared with controls, cognitive

unctioning does not appear to deteriorate over time. Themajority o people with schizophrenia have the potential toachieve long-term remission and unctional recovery. Theact that some experience deterioration in unctioning overtime may refect poor access, or adherence, to treatment,the eects o concurrent conditions, and social and nan-cial impoverishment. Mental health proessionals need to

join with patients and their amilies in understanding thatschizophrenia is not a malignant disease that inevitablydeteriorates over time but rather one rom which most peo-

ple can achieve a substantial degree o recovery.

Key words: MRI/cognition/outcome/prognosis/remission/recovery

Introduction

Schizophrenia is a leading cause o disability worldwide.1Kraepelin originally characterized the illness as having acourse that led almost inevitably to severe cognitive and

behavioral decline,2 and many clinicians and neuroscientistsstill consider it to be a progressive brain disease that leadsto chronicity and social incapacity.3,4 This view has beenreinorced by recent neuroimaging studies that have shownsupposedly progressive changes in brain structure.5,6A progressive neuropathological process would provide astraightorward paradigm to understand the relationshipbetween pathophysiology and a poor illness outcome.

This idea o schizophrenia as a progressive disease othe brain has also been an important part o the ratio-nale or developing early intervention services. Indeed,the notion that psychosis itsel may be toxic to thebrain7 provided a major impetus or programs designedto minimize the duration o untreated psychosis (DUP)in order to prevent urther brain tissue loss.8 However,the widespread development over the past 2 decades o

specialized clinical programs to treat young people expe-riencing a rst episode o psychosis (FEP) has also pro-vided new opportunities to evaluate the outcome o theillness together with the course o structural brain dier-ences and cognitive decits. In this article, we will reviewthe evidence concerning these 3 aspects o the illness inorder to evaluate whether it is consistent with the view oschizophrenia as a progressive brain disease.

Defnitions

In order to characterize the outcome rom schizophrenia,it is necessary to dene the patient samples and measureso outcome ound in dierent studies. Longitudinalstudies that have ollowed patients ater their FEP varyin their inclusion criteria. Some studies o rst episodeschizophrenia (FES) have included patients meeting criteriaor schizophrenia or schizoaective disorder,9,10 while othershave included those meeting criteria or schizophreniormdisorder.11 In this review, studies using these more narrowdenitions will be reerred to as studies o FES. Thosestudies that have included other psychotic disorders such as

Schizophrenia Bulletin Advance Access published November 20, 2012
mailto:[email protected]:[email protected]


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R. B. Zipursky et al.

delusional disorder, brie psychotic disorder, and psychosisnot otherwise specied, but excluded patients whosepsychosis is due to a primary aective disorder, will bereerred to as studies o FEP. Studies o FES and FEP alsovary in the age range o subjects, the duration o time thatthe person has been ill prior to involvement in the study,and the duration o treatment prior to entering the study. In

discussing the outcome rom a FES or FEP, we have takenan inclusive approach because many studies do not providespecic details about age and duration criteria utilized.

Denitions or remission also vary considerably.12,13Remission criteria have typically required that positivesymptoms be reduced to a mild level o severity, while cri-teria vary or the severity o negative symptoms and dura-tion required to meet the threshold or remission.9 The termremission will be used here to reer to patients whosepositive symptoms have diminished to levels consideredto be mild or lower in the presence o negative symptomsthat are no greater than moderate in severity. The terms

unctional recovery and recovery are also used in thisreview. Functional recovery reers to the achievement oan adequate level o social and vocational unctioning thatinvolves appropriate role unctioning, capacity or indepen-dent living, and social interactions at a regular requency.10A range o denitions o the term recovery have beenused in the schizophrenia literature and vary considerablybetween researchers, clinicians, and consumers.12,14 The termrecovery is used in this article to reer to levels o socialand vocational unctioning that are within the normal rangetogether with a remission o psychiatric symptoms.10,12

Outcome o Schizophrenia

Longitudinal ollow-up studies o patients diagnosed ashaving schizophrenia have consistently ound that about40% achieve social or unctional recovery.1517 While thisnding in itsel casts doubt on whether schizophrenia isinherently progressive, there is no question that schizophre-nia can be a very disabling illness that causes many o thoseaected to suer a substantial decline in their unctioningand in their ability to realize their ull potential. Two ques-tions arise concerning this disability. First, does it resultrom stable decits that are established early in the illnessor rom a progressive decline in unctioning over the course

o the illness? Second, does any unctional decline refectthe impact o underlying biological disease mechanismsor rather the cumulative impact o adverse social actorsand their interaction with the patient? To address thesequestions, it is instructive to begin by considering whetherpatients who experience a FES or FEP can achieve periodso remission and recovery over the course o their illness.

Remission

With appropriate care, including the skillul prescriptiono antipsychotic medication, the early years ollowing a

FEP are not typically periods o decline but rather osubstantial ongoing improvement in symptom sever-ity and unctioning.1719 Lieberman et al reported that83% o patients with a FES experience a remission inpsychotic symptoms within the rst year o treatment.9This is comparable to estimates o rates o remission o70%74% or patients with a FEP.18,20,21 These high rates

o remission may in part refect the eects o the asser-tive treatment received in research-intensive servicesand specialized FEP services, as well as the samplingapproaches used. However, the evidence to date suggeststhat those patients who achieve remission ater their rstepisode are, on average, able to maintain similar rates oremission over the longer term as well; ie, the proportionrelapsing is matched by others remitting.11 Thus, Girgiset al described the outcome o 160 Chinese patientswith a FES who were randomized to clozapine or chlor-promazine or 2 years and then ollowed naturalisticallyor 7 years.11 Between years 2 and 9, the percentage o

patients rated as being in remission remained stable at78% irrespective o their initial assignment to clozapineor chlorpromazine.

It is true that those who have had a FES run a high risko relapse. Robinson et al reported that 82% o patientswho achieved a remission rom their FES experienced arelapse within 5 years, with comparable percentages orelapsed patients going on to have a second and thirdrelapse.22 Those who discontinue medications in the earlyyears are at especially high risk with reports o the per-centage relapsing within 1 year as high as 78%23 comparedwith rates o 0%12% or those who remain on antipsy-

chotic medications.

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Thus, while remitted patients whodiscontinue maintenance treatment have high relapserates, those who are adherent have an equally high likeli-hood o remaining in remission. Adherence rates may beenhanced by eorts to better inorm patients o the riskand consequences o relapse and by optimizing pharma-cologic management to minimize bothersome side eects.

Functional Recovery

Unortunately, one cannot assume that patients whoare in remission will have an adequate quality o lie.Rates o unctional recovery are lower than rates o

remission.10,1517,28 In a systematic review o outcomesollowing a FEP, Menezes et al16 ound that approximately40% o patients achieved unctional recovery whetherthe ollow-up period was less than, or greater than,2 years. The percentage o patients considered to have apoor outcome was also estimated to remain stable atapproximately 25%.16 These estimates are in keeping withthe results o Lambert et al15 who carried out a 3-yearollow-up study o 369 patients with a FES and oundthat the percentage considered to be in a unctionalremission (dened as the ulllment o occupationalstatus, independent living, and social relationships)


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Myth o Progression

remained stable at approximately 40% at 1-year and3-year ollow-up points. Similarly, Henry et al29 oundthat 30.5% o 428 patients assessed a median o 7.4 yearsater their FEP met criteria or social-vocational recovery.

As with remission, however, the proportion recovereddoes not appear to either increase or decrease with time.Bertelsen et al ound that only 17% o patients with a

rst episode o illness within the schizophrenia spectrumwere considered recovered ater 2 years, comparable tothe rate o 18% ound at 5 years.19 Thus, while rates orecovery may vary across samples and with dierent cri-teria or recovery, they appear to remain stable withina given sample at least or the rst 25 years o illness.The multicentre International Study o Schizophreniasupported by the World Health Organization ound thatthe percentage time spent psychotic in the rst 2 years oollow-up ater a FES was the best predictor o symptomand disability scores at 15-year ollow-up.30 Thus patientswho do not experience remission and are doing poorly

in the rst 2 years o illness are likely to be part o the25% o patients reported to have a poor outcome over thelonger term. In summary, rates o symptomatic and unc-tional remission and rates o poor outcome appear to berelatively stable even over extended periods o ollow-up.This pattern o stability would not occur in an illness thatis by nature progressive.

There is little reason to believe that clinical deteriora-tion that is oten observed in patients with schizophreniais an inevitability. Rather it may be a refection not onlyo nonadherence and resulting relapses but also o theconsequences o other critical determinants o health

such as poverty, homelessness, unemployment, and lacko social support, as well as other comorbidities, that alltoo oten complicate the course o schizophrenia.31

Why Do Clinicians Have Such a Pessimistic View?

The view that most people with schizophrenia becomemarkedly disabled continues to be held by many clini-cians. In their seminal article, The Clinicians Illusion,Cohen and Cohen32 cited schizophrenia as an exampleo an illness or which the Clinicians Illusion is particu-larly relevant. The Clinicians Illusion is, the attributiono the characteristics and course o those patients who

are currently ill to the entire population contracting theillness. This illusion occurs because clinicians typicallycare or those patients currently suering rom the illness(ie, a prevalence sample), rather than o all those whohave ever contracted the illness (ie, an incidence sample).Patients who are remitted or well stabilized are less likelyto be seen in specialized psychiatric services, and i theyare seen at all, it is more likely to be by their amily doc-tor. Cohen and Cohen demonstrated that the likelihoodthat a patient will appear in such specialized clinics (ie, ina prevalence sample) is proportional to the duration otheir illness. As a result, prevalence samples are greatly

biased toward those who have been ill or many years,while those who have had brie periods o illness areunderrepresented.

Cohen and Cohen also pointed out another impor-tant biasing artiact known as Berksons Fallacy:those who have other disabilities that are not caus-ally connected to the condition being investigated are

more likely to enter the ormal treatment system. Asa result, patients may have clusters o problems thatadversely contribute to their outcome but are not con-sequent upon the condition being treated. It is commonin specialized schizophrenia clinics to see patients withconcurrent problems o low intellectual unctioning anddevelopmental disabilities, as well as with mood, anxietypersonality, and substance use disorders. The high preva-lence o these problems in a specialized clinic does notargue or these diculties being a direct consequence oschizophrenia. Rather, individuals with these problems inaddition to having schizophrenia are more likely to nd

themselves sin such specialized clinics. Each o these con-ditions can be very disabling on their own, and when theyoccur together with schizophrenia, the net impact will bemore severe disability. However, it may not be the natu-ral course o schizophrenia, the principal actor respon-sible or the poor outcome. Thus, the act that clinicalresearchers who write about schizophrenia mainly seepatients who are prooundly disabled is more likely torefect reerral and sampling biases than the progressivenature o schizophrenia per se.

The Search or Progressive Brain Changes

Researchers have sought to identiy structural brainchanges in schizophrenia since the time o Kraepelin.2Postmortem33 and pneumoencephalographic studies34,35provided support or the presence o atrophic brainchanges in some patients with chronic schizophrenia.However, the opportunity to systematically investigatebrain structure emerged in the 1970s and 1980s.Computed tomography (CT) revealed that patientswith schizophrenia on average had larger intracranialcerebrospinal fuid (CSF) volumes, including larger lateralventricles36,37 and cortical sulci.38,39 Subsequent MRIstudies demonstrated widespread decits in gray matter

volumes40,41

and white matter volumes.42

The magnitudeo these group dierences was observed to be greateror more chronically ill patients.43 From the outset, bothCT and MRI studies sought to demonstrate associationsbetween illness duration and the magnitude o CSF andgray matter volumes, but with little success.40,44

MRI studies conrmed signicant brain volume reduc-tions in patients with chronic schizophrenia and also dem-onstrated their presence in patients presenting with theirFES or FEP.45,46 However, the magnitude o the eectsobserved or CSF increases and gray matter decreasesin the early phase o the illness has been ound to be


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modest relative to those observed in more chronically illpatients.4547 The possibility that this dierence might beconsistent with a progressive neuropathological processhas been enticing. Alternative hypotheses, that this dier-ence refects a sampling bias or the eects o medicationsand other actors secondary to the illness, have receivedless attention to date. I patients who have more strik-

ing dierences in CSF and gray matter volumes at thetime o their rst episode are more likely to have a pooroutcome,4853 then such patients will have an increasedlikelihood o being represented in samples recruited romservices or chronically ill patients.54 Patients with a pooroutcome may also be more likely to have neurodevelop-mental problems and/or substance abuse that may inde-pendently be associated both with similar structural brainchanges and with worse outcome. Whether the dierencesin the magnitude o structural brain changes observed inrst episode compared with more chronically ill patientsare due to progressive changes or sampling eects is best

addressed through longitudinal studies.

Longitudinal Studies and the Eects o AntipsychoticMedication

Longitudinal MRI studies have now shown that braintissue volumes decrease and CSF volumes increase overtime to a greater degree in patients with schizophreniathan control subjects.47,55,56 However, there is now com-pelling evidence that antipsychotic medications have animportant role in contributing to these progressivechanges.57,58 Lieberman et al59 ollowed patients treatedwith either olanzapine or haloperidol or a FEP or

2 years; patients treated with haloperidol but not olan-zapine had worsening decits in gray matter volumes thatwere already apparent ater 12 weeks o treatment. It wasunclear whether the relative volume reductions seen inthe haloperidol-treated group refected a disease processthat was ameliorated by olanzapine but not haloperidol,a drug eect caused by haloperidol but not olanzapine,an increase in relative tissue volume related to the weightgain and metabolic eects associated with olanzapine, ora statistical artiact caused by sample attrition.60

Ho et al61 have now demonstrated an association betweenantipsychotic treatment and brain volume reductions in

patients ascertained with a FES who were scanned longi-tudinally over an average o 7.2 years. Antipsychotics wereassociated with decreases in gray- and white matter volumeswith higher doses resulting in greater decreases.61

That antipsychotic medications can result in reductionsin brain tissue volumes has been put beyond doubt byanimal studies.62,63 Both haloperidol and olanzapine ledto decreases in gray matter and white matter in macaquemonkeys treated chronically or 1727 months.62 Like thebrain changes described in schizophrenia, these decitswere diusely distributed across the rontal, parietal,temporal, occipital, and cerebellar areas. Similar ndings

have been demonstrated using postmortem samples andex vivo MRI using chronic doses o haloperidol andolanzapine in chronically treated rats.63 Animal modelsprovide the opportunity to better characterize the eectso antipsychotics on brain tissue and to determine theextent to which they may be progressive or reversible.Indeed, Vernon et al64 have shown that MRI scans nor-

malize in rats ollowing withdrawal o the antipsychotic.Results rom a longitudinal study o patients with a FESin Sao Paulo, Brazil, suggests that dierences observed atthe time o the rst episode (ater the initiation o anti-psychotics) may also be reversible to some degree withmedication discontinuation.65

Eects o Substance Use

Recent studies have reported that cannabis6668 and ciga-rette smoking69 are associated with MRI ndings odiminished brain tissue volumes in psychotic and nonpsy-chotic populations. Rates o cannabis use and smoking

are much higher in patients who develop schizophreniaand may contribute to the presence o brain volume di-erences at the time o the FEP.70 Rais et al67 ound thatcannabis-using patients who were ollowed or 5 yearsater a FES had greater losses in gray matter volumes andincreases in lateral ventricle volumes than patients whowere not abusing cannabis. Alcohol is also known to leadto reduction in brain tissue volumes7173 and to compoundthe dierences observed in patients with schizophrenia.71That cannabis, alcohol, and smoking may all contribute tothe magnitude o gray matter decits observed in patientswith schizophrenia is supported by recent ndings by

Stone et al74 who ound that at low to moderate levels, allwere associated with lower gray matter volumes in indi-viduals at high risk o psychosis and in healthy controls.

Eects o Liestyle

Many patients with schizophrenia have a sedentaryliestyle that may also contribute to the decits in braintissue volumes observed. Colcombe et al75 ound thataerobic exercise increased gray matter and white mattervolumes in elderly community volunteers who hadbeen sedentary. This is consistent with animal studies,which have demonstrated that exercise can increasenew capillary ormation, dendritic growth, and newcell production in the hippocampus.76,77 Pajonk et al78carried out a randomized controlled trial o the eects oexercise and showed that increased physical activity leadsto increases in hippocampal volumes in both patientswith schizophrenia and healthy controls.

Stress and the Hypothalamic-Pituitary-Adrenal Axis

The elevated glucocorticoid levels associated with chronicstress that patients with schizophrenia maniest may alsocontribute to the smaller brain tissue volumes observed.


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Eects o stress and glucocorticoids on hippocampaland ventricular volumes have been demonstrated in ani-mal models and in humans with Cushings syndrome,79and these are known to be at least partially reversible. 80,81In patients with a FEP, cortisol levels have been oundto be raised and to correlate inversely with hippocampalvolumes.82

Duration o Untreated Psychosis

I psychosis were in some way toxic to the brain, as Wyattsuggested,7 then one would predict that there would bean association between the DUP and the magnitude ostructural brain dierences, particularly i the baselineMRI scans were obtained prior to treatment with anti-psychotic medication. DUP has been ound to be corre-lated with brain tissue volumes in some studies8,8386 butnot in others.44,45,87 Moreover, the direction o causalitythat underlies any association remains to be established

because greater decits in brain tissue volumes in thosewith greater DUP could refect a more insidious onseto psychosis in those patients with greater longstandingdecits in brain tissue volumes.84 Certainly, there has beenno evidence to support the idea that longer DUP initiatesa process o progressive and continuing brain change.

Cognitive Studies

There is now an extensive literature characterizing thecognitive decits o patients with schizophrenia. The de-icits reported typically all between 1 and 2 standard devi-ations below the mean o healthy controls.88,89 Cognitive

decits in patients with schizophrenia are associated withinability to unction in the community90 and, as a result,have been the ocus o specic clinical interventions.91Measures o cognitive unctioning have been shown tocorrelate with measures o brain structure in patientswith schizophrenia and healthy controls.9295 I progres-sive brain tissue loss occurs over the course o schizophre-nia, one might predict that this would be accompanied byprogressive deterioration in cognitive unctioning. Thelatter does not appear to be the case.96,97

The Time Course o Cognitive Defcits

When cognitive decits are rst present and whetherthere is some stage o the illness during which they prog-ress have been areas o intensive study.98,99 Cognitive de-icits have been clearly demonstrated at the time o theFEP.89,98,100 Cognition has been demonstrated to remainstable or improve96,101103 rather than deteriorate ollowinga FEP. The improvement reported in some studies mayrefect practice eects rather than real improvement.104Nevertheless, there is a consensus that this improvementplateaus ollowing a FEP or FES, ater which cognitiondoes not worsen over time beyond what can be expectedwith normal aging.97,99,102 Whether elderly patients with

schizophrenia may experience a phase o cognitive declinethat is o greater slope than that observed in otherwisehealthy people105,106 remains a possibility that requiresurther investigation.

Cognitive decits are present in a proportion o chil-dren who later develop schizophrenia.107110 Meta-analyseshave ound that children who later develop schizophrenia

are 0.40.5 standard deviations below the populationaverage on intelligence quotient (IQ).111,112 This is consid-erably smaller than the decits described in patients at thetime o their FES, and it raises the question o whetherthere is an active period prior to the rst episode in whichurther decline occurs. Longitudinal data rom a largeUS birth cohort have provided evidence that cognitivedecits are present when assessed at age 7 in children whohave gone on to develop schizophrenia as adults, but weresubstantially larger on some measures when reassessed atage 35.98 Using a ollow-back design with patients pre-senting with a FES, Bilder et al113 ound that individu-

als who had a FES had decits in school perormancethat were apparent in the rst grade and increased sub-stantially in magnitude when retested in the 12th grade.While these studies provide support or a relative declinein cognitive perormance in individuals who subsequentlydevelop schizophrenia compared with controls, it was notinitially clear rom these studies whether the increasinggap in cognitive perormance refects an absolute declinein those who go on to develop schizophrenia.

The Dunedin Multidisciplinary Health and DevelopmentStudy provided the opportunity to investigate thetrajectory o childhood cognitive unctioning in individuals

subsequently diagnosed with schizophrenia.

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Cognitivetesting was administered at age 7, 9, 11, and 13 years; resultsdid not show any absolute decline in cognition but insteadshowed 2 interrelated problems, an early static decit andthen a developmental lag. Children destined to developschizophrenia entered primary school struggling withverbal reasoning and then ell urther behind their peers inattention and working memory as they got older. While itcannot be ruled out that the group dierences may have beendue to other comorbid disorders in the group o childrenwho went on to develop schizophrenia as adults, the resultsdo not suggest that this group experienced any absolutedeterioration in cognitive unctioning. This is consistent

with the ndings o Russell et al who demonstrated thatindividuals who had attended a child psychiatric clinic anaverage o 6 years beore their FES had decits in IQ whenrst seen but showed no additional decit when ollowed upnearly 2 decades later.115

In accord with the above, individuals considered to beat clinical high risk or psychosis have been demonstratedto have signicant cognitive decits with those who even-tually develop psychosis having greater decits than thosewho do not.116 However, studies by Keee et al117 andBecker et al118 were not able to demonstrate any urtherdeterioration in cognition in those at-risk subjects who


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subsequently transitioned to psychosis. The potential orsuch studies to identiy signicant deterioration in cog-nition has been limited by their small sample sizes andtheir identication o at-risk subjects late in the prodro-mal phase.

ConclusionsThe notion that schizophrenia is by nature a progressivedeteriorating illness was central to the concept o dementiapraecox as originally outlined by Kraepelin.2 When struc-tural brain abnormalities and cognitive decits were dem-onstrated in the late 1970s these were taken as conrmingthat the illness was indeed a dementia o the young.36

It is true that people with schizophrenia as a groupshow modest decreases in certain brain tissue volumesat the time o the FEP but much research suggests thatthese, at least in part, refect neurodevelopmental abnor-malities.119 In addition, MRI studies in the last decade

have suggested a progressive component that can bedetected ater illness onset.120 However, the pathologicalnature o these changes remains unclear.121 There is nodirect evidence or a toxic eect o psychosis on braintissue, and emerging evidence rom human and animalstudies suggests that these changes are in part consequentupon antipsychotic medication.57,58 Furthermore, there isevidence that cannabis, alcohol, smoking, stress-relatedhypercortisolemia, and low physical activity also contrib-ute to the changes in cortical and ventricular volumesobserved over the course o schizophrenia. Together withthe eects o antipsychotic medications, these actors

appear to account or the majority o the so-called pro-gressive brain changes. Their importance lies in the actthat at least some may be reversible.

The ndings rom neuropsychology consistently con-tradict the idea o schizophrenia as a progressive demen-tia. Cognitive decits are present at a young age in somechildren who later develop schizophrenia together withslower cognitive development in a range o domains,which results in urther divergence in cognitive ability bythe time psychosis develops. However, there is no evidencethat lasting cognitive decline occurs during the transitionto psychosis or ollowing its onset.

Thus, the idea that schizophrenia is a progressive brain

disease is not supported by the weight o longitudinalneuroimaging and cognitive studies, and it is not consis-tent with what is now known about the clinical course oschizophrenia. It is important or optimum clinical carethat the idea that underlying schizophrenia there existsan intrinsically malignant process be reconsidered. It hascontributed to an undue pessimism among mental healthproessionals and their consequent alienation rom su-erers and their representatives, who increasingly advo-cate or the recovery model.14,122

Furthermore, etiological and clinical research suggeststhat schizophrenia is not a discrete illness with a single

cause or course, rather it appears to be a syndrome withmultiple interacting causes, both genetic and environ-mental, and a heterogeneous outcome.123 Thus we canbetter conceive individuals diagnosed with schizophreniaas having a vulnerability to psychotic reactions to a rangeo biological124 and social risk actors.125 The greater thecumulative load o risk actors beore onset, and also

incurred subsequently, the more likely the individual isto have a poor outcome. Some individuals, especiallythose with developmental impairment, start their jour-ney through illness with considerable impairment o theirability to cope with urther stressors and show deteriora-tion in their social unctioning; others may start with lessvulnerability but are exposed to repeated social adversi-ties that prevent their recovery.

Rejecting the concept o schizophrenia as a progressivebrain disease does not negate the serious and disablingproblems that many patients with schizophreniaexperience. No doubt, many patients experience a

decline in many spheres o unctioning. Further researchis certainly required to determine whether there is anactive period o developmental or degenerative changesthat take place prior to the syndrome being expressedand diagnosed. However, it is important or patients,amily members, clinicians, and the public more broadlyto recognize that the deterioration that many patientsexperience over the long-term is not an inevitable part othe illness course. Sadly, many people with schizophreniado not have access to the skilled mental health servicesand social supports that are needed or them to achieverecovery and a good quality o lie. It is crucial to appreciate

that the terrible social sequelae o schizophrenia such ashomelessness, poverty, unemployment, hospitalization,and imprisonment are not the inevitable outcomes o aprogressive brain disease but highlight the challenges weace in providing the needed services and supports, and inengaging ill people in models o care which they are likelyto accept and appreciate.

Funding

This work was supported by the Morgan Firestone Chairin Psychiatry at McMaster University.

Acknowledgments

The authors have declared that there are no conficts ointerest in relation to the subject o this study.

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