the two syndrome crow no sb.pdf

VOL. 11, NO. 3, 1985 The Two-SyndromeConcept: Originsand Current Status

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by Timothy J. Crow Abstract

The two-syndrome concept postulatestwo "dimensions of pathology"underlying schizophrenia—areversible (and potentiallyneuroleptic-responsive) componentand a sometimes progressive andrelatively irreversible componentassociated with the deficit state andpoor long-term outcome. Negativesymptoms (narrowly defined) appearto be more closely associated withthe latter component (the type IIsyndrome), as also are cognitiveimpairments, abnormal involuntarymovements, and behavioraldeterioration. This syndrome isassumed to be more closely relatedthan the type I syndrome of positivesymptoms to the structural brainchanges inferred from pneumoen-cephalograms, computed tomographyscans, and recent post-mortemstudies. However, since bothsyndromes often occur in the samepatient—sometimes at the same pointin time—they presumably have thesame etiology.

Whether the celebrated razor is that"entities are not to be multipliedwithout necessity" or, as BertrandRussell (1946) suggests William ofOccam actually wrote, that "It isvain to do with more what can bedone with fewer," the principle issurely profound. Explanatoryconcepts must be simple and as fewas can be.

Since Kraepelin (1919), thesimplest view of schizophrenia is thatit is a single disease with a singlepathology. With respect to etiology(when the relatively rare schizo-phrenia-like psychoses ofamphetamine intoxication andtemporal lobe epilepsy are excluded),there is as yet little reason to doubthe was right. Dr. Sommers, in hercontribution to this issue, misquotesme as suggesting the two symptom

classes characterize etiologicallydistinct schizophrenic subtypes. I donot believe I can be misunderstood ashaving said this. Indeed, I believe asimpler view (i.e., that manic-depressive psychosis and schizo-phrenia have the same basic etiology;Crow 1984) is still tenable. It mayturn out not to be so, and schizo-phrenia may eventually be shown tohave many etiologies, as Bleuler(1950) implied, but until one etiologyis established and this etiology isshown to be absent in some cases,Occam's razor should be applied.

For the same reasons, the viewthat more than one "dimension ofpathology" underlies the manifes-tations of schizophrenia (Crow 1980;Crow et al. 1982) requires a defense.The concept that two pathologicalprocesses are present and that thesecan be related to particular constel-lations of symptoms arose from threestudies conducted in the Division ofPsychiatry at Northwick Parkbetween its inception in 1974 and1978:

1. The first computed tomographic(CT) study in schizophrenia(Johnstone et al. 1976, 1978b)demonstrated that cerebralventricular area in a group of chronicinstitutionalized patients was signif-icantly greater than that in a groupof age- and premorbid occupation-matched controls. Ventricularenlargement could not be explainedby previous physical treatments, andwithin the schizophrenic group wascorrelated (significantly) withcognitive impairment and (nonsignif-icantly) with the presence of negativesymptoms.

2. A study of the therapeuticeffects of the two isomers of the

Reprint requests should be sent toDr. T.J. Crow at Division of Psychiatry,Clinical Research Centre, Northwick ParkHospital, Watford Road, Harrow,Middlesex, HA1 3UJ, United Kingdom.

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472 SCHIZOPHRENIA BULLETIN

thioxanthene flupenthixol (Johnstoneet al. 1°78<J) tested the dopamineblockade hypothesis of the antipsy-chotic effect (B-flupenthixol beingmore than 1,000 times less potentthan the a-isomer as a dopamineantagonist). In recently admittedpatients with acute episodes ofschizophrenia, the a-isomer wassignificantly more active than the B-isomer, which itself was no moreeffective than placebo. In thesepatients negative symptoms (flat-tening of affect and poverty ofspeech) were relatively infrequentand seldom severe, but when presentshowed little tendency to improve onplacebo and no differential responseto dopamine receptor blockade.

3. In a post-mortem study (Owenet al. 1978), dopamine turnover(assessed by homovanillic acid ordihydroxyphenylacetic acid concen-trations) was not increased butnumbers of D2 dopamine receptors(assessed as JH-spiperone binding)were increased. Although thequestion of whether this change isrelated to the disease process ratherthan to neuroleptic drugs is not yetresolved (see, for example, Mackayet al. 1982; Crow et al. 1984), inlater work (Crow et al. 1981b) thenumber of D2 receptors in post-mortem brain was found significantlyrelated to positive, but not negative,symptoms assessed in life.

Together these observationspresented a crisis of interpretation. Ifschizophrenia was a unitary diseaseprocess, was this to be seen as aprimarily neurochemical disturbance(as suggested by the dopaminehypothesis and the responsiveness ofat least some schizophrenicsymptoms to neuroleptic drugs)? Oras a destructive process leading tostructural brain changes andintellectual impairment as the resultsof the CT scan study and someearlier pneumoencephalographic

studies (e.g., Huber 1957; Haug1962; Asano 1967) might lead one tosuspect? The dopamine hypothesishad its attractions (in my view, it isthe only neurochemical theory that isstill viable), but it could not explainthe intellectual impairments or whysome patients do badly in spite ofneuroleptic medication. Nor couldthe less popular view that schizo-phrenia is a low-grade early onsetform of dementia explain the notinfrequent, apparently completerecoveries after individual episodes ofillness, the effectiveness ofneuroleptic medication, or the abilityof amphetamine-like compounds toprovoke delusions and hallucinationsclosely resembling those seen in idio-pathic schizophrenia.

For these reasons, when reviewingthe neurochemistry of schizophrenia,I outlined the difficulties for theunitary viewpoint and suggested therecent findings could only beaccommodated if one assumed thatmore than one "dimension ofpathology" was present (Crow 1980).Specifically, I suggested there was aneurochemical component (perhapsrelated to dopaminergic transmission)responsive to neuroleptic medication,and a structural component relatedto poor long-term outcome and tothe intellectual impairment thatundoubtedly sometimes occurs. Withthe results of the flupenthixol isomerstrial (Johnstone et al. 1978a) in mind,I suggested the drug-responsivecomponent could be related topositive symptoms. On the basis ofthe CT scan study (Johnstone et al.1976, 1978b) and other data showinga relationship between negativesymptoms and intellectualimpairment (Owens and Johnstone1980), I proposed that the negativesymptoms, which in the flupenthixolisomers study had appeared resistantto neuroleptic medication, were moreclosely related to poor long-term

outcome, and that this component(i.e., negative symptoms andintellectual impairment) wasassociated with structural changes inthe brain. Thus, the paradox that thesymptoms of the disease sometimesremit and more often respond toneuroleptic drugs, but at the sametime the disease not infrequently hasa poor long-term outcomeunresponsive to drugs, could beresolved on the basis that there arepotentially reversible (perhapsdopamine-related) and irreversiblecomponents. (See table 1.)

An important aspect of thishypothesis is that it attempts torelate the two postulatedpathological processes to clinicalmanifestations. I see now (and thediverse contributions to this issueamply demonstrate the point) thatthe definition of positive andnegative symptoms is crucial towhether one regards this aspect ofthe concept as having content. Inbrief, it is essential that one adopt anarrow definition of negativesymptoms. In the Northwick Parkstudies, we had two advantages: (1)Before it was published, DavidGoldberg drew my attention to theschizophrenia rating scale(Krawiecka, Goldberg, and Vaughan1977), which he and the late MariaKrawiecka had devised. It is simpleto use, has explicit operational rules,and focuses on eight key areas:delusions, hallucinations, thoughtdisorder (incoherence of speech),flattening or incongruity of affect,poverty of speech, retard-ation, depression, and anxiety. Weused this scale in all our early workand indeed still find it useful andpractical. (2) Eve Johnstone earlyconcluded that flattening and incon-gruity of affect could and should berated separately. When this is done,there are nine items in the scale. Ofthese, three (depression, anxiety, and



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VOL. 11, NO. 3, 1985 473

Table 1. Two syndromes in schizophrenia1

Type I Type II

Characteristic symptoms

Type of Illness inwhich most commonlyseen

Response to neuroleptlcs

Outcome

IntellectualImpairment

Postulatedpathological

Hallucinations, delusions,thought disorder(positive symptoms)

Acute schizophrenia

Good

Reversible

Absent

Increased dopaminereceptors

process

Affective flattening,poverty of speech,loss of drive(negative symptoms)

Chronic schizophrenia,the "defect" state

Poor

Irreversible?

Sometimes present

Cell loss andstructural changes inthe brain

1 Reprinted, with permission, from Crow (1980).

retardation) are nonspecific; two(delusions and hallucinations) areclearly positive symptoms; two more(thought disorder and incongruity ofaffect) may be so considered,although the decision is less obvious;and two (flattening of affect andpoverty of speech) are clearlynegative.

Origins of the Positive andNegative SymptomTerminology

Berrios (1985) has traced thehistorical origins of the positive-negative symptom terminology in theneurological literature. He attributesits introduction to Reynolds (1858),and he is surely right to assert thatthe implications that HughlingsJackson attributed to the distinction(viz. that positive symptoms aresecondary "release" phenomena,which result from the destruction oftissue, which leads directly to thenegative symptoms) are inappro-

priate to the psychiatric literature.Hughlings Jackson is an esteemedauthority but irrelevant to recentdiscussions of schizophrenia. A looseadherence to his views has been thesource of confusion, particularlyinsofar as some have been tempted toequate Bleuler's "fundamental"symptoms, from which he thoughtthe "accessory" symptoms werederived, with negative symptoms.

Berrios attributes the introductionto the psychiatric literature of theconcept of positive and negativesymptoms as independent phenomenato de Clerambault (1942). Andreasen(this volume) refers to Fish's (1962)book on schizophrenia as one ofits recent sources, but I have beenunable to identify a point in thatbook (except in relation to thoughtdisorder, p. 25) where Fish discussesthe issue in a way which gives anyindication that he regarded it assignificant. On the other hand, theterminology has been used quitewidely in the United Kingdom—forexample, by J.L.T. Birley, J.K. Wing,

and their collaborators (see, forexample, Wing and Brown 1970, pp.18-19; Wing 1978). Wing (1978)contrasts "florid or positive orproductive" symptoms seen particu-larly in acute episodes with thenegative components of the clinical"poverty syndrome," which heidentifies as "emotional apathy,slowness of thought and movement,underactivity, lack of drive, povertyof speech and social withdrawal"(pp. 4-5). He considers that there arethree basic groupings—the positivesyndrome of acute schizophrenia, thenegative (or clinical poverty)syndrome of chronic schizophrenia,and combinations of the two. This isroughly the concept we adopted atNorthwick Park, although by the useof the Krawiecka scale we havedefined negative symptoms morenarrowly, and would regard certainof the symptoms that Wing lists(e.g., underactivity and socialwithdrawal) as less specific and insome circumstances secondary topositive symptoms. Wing also



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considers the tripartite scheme (i.e.,positive symptoms, negativesymptoms, and both together) anoversimplification and, for example,draws attention to the frequency ofthought disorder as a component ofthe chronic syndrome.

Another line of thought regardingpositive and negative symptoms andtheir interrelationships was followedby Strauss, Carpenter, and Bartko(1974). These authors quoteKraepelin in support of the singleprocess concept:

We are justified in regarding themajority at least of the clinicalpictures which are broughttogether here as an expression of asingle morbid process, thoughoutwardly they often diverge veryfar from one another [Kraepelin1919, p. 3]

and contrast this concept with thetitle of Bleuler's book DementiaPraecox, or The Group of Schizo-phrenias. Strauss, Carpenter, andBartko (1974) trace their use of thepositive-negative terminology back toHughlings Jackson, but they do notadopt his inference of a causalsequence between them. They includeas positive symptoms "disorders ofcontent of thought and perception,certain types of form of thought(e.g., distracribility), and certainbehaviors (e.g., catatonic motordisorders)," (p. 65) and as negativesymptoms "blunting of affect,apathy, and certain kinds of formalthought disorder, such as blocking"(p. 65). This last inclusion issomewhat surprising, as also is theseauthors' insistence that "disorders ofrelating" constitute a third dimensionthat has to be considered quiteseparate from both positive andnegative symptom components(p. 65).

Strauss, Carpenter, and Bartko(1974) conclude regarding their threegroups of symptoms that:

1. Positive symptoms candevelop or resolve over a relativelyshort period of time. Sometimesthey can be traced directly toorganic causes. In other instances,they appear to originate in certainkinds of family communicationpatterns. The several causes ofthose symptoms that have beenidentified and their minimalprognostic importance suggeststhat they are a nonspecificresponse to a variety of conditionsand not necessarily part of alongstanding process.

2. Negative symptoms, on theother hand, tend to be associatedwith chronicity. It is not clear,however, whether negativesymptoms and the process theyreflect are the source of thechronicity, the result of it, or acombination of both relationships.

3. Disorders of personalrelationships have their ownantecedents and have importantprognostic implications for futurefunctioning in this area and foroutcome of positive and negativesymptoms as well. In this waydisorders of social relationshipsappear to represent a process withimportant implications for all ofthe schizophrenic manifestations,[pp. 68-69]

The key concepts here, includingthe positive-negative dichotomy, aresimilar to those used by Wing andcolleagues in the MRC SocialPsychiatry Unit and those which wehave adopted at Northwick Park.Specifically, the concept that positiveand negative syndromes representdifferent components of the processand that the negative component isless variable and more closelyassociated with poor long-termoutcome than the positive componentis common ground. On the otherhand, the necessity to postulate athird component of "disorderedpersonal relationships" and, byimplication, to suggest that this, likethe positive and negative syndromes,has its own underlying diseaseprocess is not clearly established.Nor does it appear that the

psychological connections thatStrauss, Carpenter, and Bartko favorare necessary to the concept.

Thus, the case for two (but notdearly for three) processes was wellargued by two separate groups onthe basis of the differing time coursesof two clusters of symptoms. Bothgroups recognized that somesymptoms (e.g., thought disorder)did not fit easily into one or othercategory.

Strauss, Carpenter, and Bartko(1974) draw attention to an earlierusage of the positive-negativesymptom concept in schizophrenia.Snezhnevsky (1968) wrote that

Symptoms that contribute to thedifferent schizophrenic syndromesmay be pathologically productive,or so-called positive. Alternativelythey may be negative symptoms,expressive of "flaws," defects anddisintegration. Both types combineas a unit, exhibiting organic inter-dependence and constituting theelements of a syndromestructure . . . . However, althoughthey form a unit, the positive andnegative disturbances are notequivalent to each other. In simpleschizophrenia as well as in remis-sions after acute attacks, negativer p t o m s may sometimes emerge

ie without coincident positiveones. I.F. Ovchinnikov [in 1966]has pointed out that the positiveand negative symptoms aredisposed as if on two levels. Thepositive is the higher level and ischaracterised by marked vari-ability . . . . The lower or negativelevel by contrast is invariable. . . . The invariability of the

negative disturbances is veryclearly demonstrated duringcontemporary therapy withmodern psycnotropic drugs. As aresult of therapy, the positivedisturbances undergo some degreeof change and become morerudimentary. In some cases theymay disappear altogether, andmodem therapy may create abarrier to the emergence of certainfeatures, for instance, of catatonia.The negative disturbances,however, are refractory to therapy \



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and do not change. They may,nevertheless, become usually to acertain extent compensated, [pp.432-433]

These quotations make it clear thatthe adjectives "positive" and"negative" had been adopted inrelation to the symptoms of schizo-phrenia earlier in the Russian than inthe Western literature. The conceptof the relationship between thegroups of symptoms outlined bySnezhnevsky is closely similar to thatwhich has been later adoptedelsewhere—e.g., at Northwick Park.Since Carpenter, Snezhnevsky,Strauss, and Wing all contributed tothe World Health OrganizationInternational Pilot Study of Schizo-phrenia, one may suppose that thisproject played a role in disseminatingthe concept.

The concept of the two syndromes(Crow 1980; Crow et al. 1982a) owesmuch to this background but addspredictions concerning the nature ofthe underlying processes, and anexplanation of why one group ofsymptoms is more fixed than theother (that it is related to structuralbrain changes). There was alsogreater emphasis on intellectualimpairment (arising from studies ofCrow and Mitchell 1975, Crow andStevens 1978, and Owens andJohnstone 1980) as a possiblecorrelate of "organic" deficit than isapparent in the earlier concepts.1

The definition of positive andnegative symptoms is clearly crucialto these concepts. My suggestion asto the strategy we should follow isthat having arrived at the concept

1 It should be noted that in a followupstudy of patients in the community(Johnstone et al. 1981), by contrast withthe earlier inpatient study, cognitiveimpairment assessed on the Withers andHinton Battery correlated with bothpositive and negative symptoms.

that there are two (or at least two)syndromes, and that these havedifferent clinical and biological corre-lates, we should not assume thatevery symptom need be categorizedas positive or negative. Rather, weshould adopt a narrow definition andlook for those symptoms thatcorrelate well with the defect state(or clinical poverty syndrome) on theone hand or with the florid syndromeof the acute episode on the other.Poverty of speech and flattening ofaffect seem good candidates for theformer, and delusions and halluci-nations for the latter syndrome.

Definition of NegativeSymptoms

The concept that the definition ofnegative symptoms should be narrowis in direct contrast to the strategyadopted by some contributors to thisvolume, especially Andreasen andSommers. Thus, Andreasen includesas negative symptoms, in addition toaffective flattening and poverty ofspeech, "avolition and apathy,anhedonia and asociality, and atten-tional impairment." Of theseadditional symptoms, some (e.g.,apathy and asociality) are complexand might well be thought sometimesto occur as a secondary consequenceof positive symptoms, anhedonia (ifit can be distinguished from affectiveflattening) might well be thoughtrelated to depression, and attentionalimpairment (as Cornblatt andcolleagues have shown) may be moreclosely related to positive thannegative symptoms. Sommersincludes "emotional" as well as social"withdrawal" (an issue that has beendealt with by Angrist, Rotrosen, andGershon 1978b; see below) and statesthat the terms positive and negative"imply nothing regarding eitherpathophysiology or the necessary

relationship between positive andnegative symptoms" (pp. 364-365),both of which issues are seen asremaining open to empirical investi-gation. She then goes on to assertthat the terms "residual symptoms"or "defect/deficit state" should not beequated with negative symptoms.This sounds an admirable counsel ofscientific purity until one considersthe problems in arriving at anindependent definition of whatconstitutes a "true" negativesymptom. As Sommers recognizes,an appeal to clinical authority isunsatisfactory. So also is the simpleconcept of loss of normal function.For example, if the net is thrown aswide as Andreasen and Sommerssometimes seem to favor, it willinclude such features as job loss andmarital failure. This is far tooinclusive to be interesting.

These issues are also relevant toother contributions. Thus, SolomonGoldberg, in his defense of theconcept that negative symptomsrespond to neuroleptic drugs,includes as negative symptoms(which he apparently has no qualmsin equating with Bleulerian funda-mental symptoms) indifference to theenvironment, apathy, hebephrenicsymptoms, inappropriate affect, poorsocial participation, poor self-careand "confusion." Carpenter,Heinrichs, and Alphs are surelycorrect to insist on their distinctionbetween primary and secondarynegative symptoms. According tothis view, several of the abovesymptoms, and particularly poorsocial participation and self-care, canbe seen as potentially secondary topositive symptoms.2

2 "Loss of drive", included in theoriginal two-syndrome concept (table 1)but not rated on the Krawiecka scale maywell belong to this category.



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We were well aware of thisproblem when we reported thefindings of our trial of the isomers offlupenthixol. The first reference is tothe important analysis of the findingsof the National Institute of MentalHealth trial to which Goldbergrightly draws attention (Goldberg,Klerman, and Cole 1965). In thediscussion section of our article(Johnstone et al. 1978a) is thefollowing paragraph:

Improvement in individualsymptoms was largely confined to"positive"symptoms [figure 2 ofJohnstone et al. 1978a]. Both non-specific and "negative" schizo-phrenic symptoms showed littletendency to improve and no differ-ential response to drug therapy.Thus the scope of the antipsychoticeffect may be more limited thanwas suggested by an analysis ofthe 1964 National Institute ofMental Health trial (Goldberg etal. 1965), in which the benefit ofneuroleptic drugs appeared to beas great on some negative featuresof the disease (e.g. socialwithdrawal, lack of self-care) as onthe positive symptoms. Negativesymptoms (identified in a clinicalinterview rather than on behaviourratings as in the earlier study) areuncommon in acute schizophreniabut are prominent in the "defectstate" in which neuroleptics maybe less effective (Letemendia andHarris, 1967).

This view is compatible with thoseof Carpenter, Wagman, andHeinrichs (submitted for publication,1984) and Angrist, Rotrosen, andGershon (1980a), who adopt anarrow definition of negativesymptoms to identify the nondrug-responsive component. Affectiveflattening and poverty of speech(defined in an interview that allowsone to exclude symptoms with whichthese might be confused) appear tobe the two symptoms that fall mostconsistently in this category.

A most notable departure in theopposite direction is the statistical

reanalysis by Gibbons et al. (thisissue) of the clinical data thatSolomon Goldberg and colleaguesoriginally collected. As Goldberg hasnoted, these ratings have alreadyyielded the conclusion that allsymptoms of schizophrenia, asassessed by these scales, areresponsive to neuroleptic medication.According to Gibbons' statisticalretreatment, three syndromes of"negative symptoms" are present.One of these loads highly on "fixedfacial expression" but also on"apathy toward treatments" and"apathy toward environment," andanother loads on "fixed facialexpression" as well as "poverty ofspeech" but also loads on "thoughtblocking" (surely a positive symptomwhen properly assessed) and "slowmovement" (from which the authorsderive their factor label of"retardation"). The most surprisingconclusion reached by Gibbons andcolleagues concerns their "Bleulerianfactor 3," which includes "incoherentspeech, irrelevant speech, wanderingspeech, and inappropriate affect." Itis difficult to envisage how thesespeech abnormalities are distin-guished from each other, but moredifficult still to understand how allthese symptoms can be classified asnegative. Certainly our own findings,and indeed those of the trial fromwhich the data of Gibbons et al.were taken, suggest that thesesymptoms are neuroleptic-responsive.To describe these symptoms asnegative appears to be stretching theconcept much too far. Only byequating the concept of negativesymptoms with Bleuler's fundamentalsymptoms (some of which arenotoriously difficult to define),presumably on the basis of aJacksonian logic that negativesymptoms are bound to be morefundamental than other types ofsymptoms, can this be understood.

Gibbons et al. appear to have beenled up the garden path by HughlingsJackson and dropped in the pond byEugen Bleuler.

In all these studies, much dependson how symptoms are defined andhow carefully they are rated. Onp. 368 of Sommers' contributionoccurs a statement which aroused mycuriosity. Discussing the need fordefined norms, Sommers writes that"In the absence of such standards,raters must rely on their ownexperience and clinical intuition (asituation which suggests that ratersshould typically be among the most,rather than the least, trained andskillful members of the researchteam)." Does this mean, oneis bound to ask, that the ratingsin some American studies are notmade by the principal workersthemselves? Are ratings sometimescarried out by workers who are notco-authors7 If this is the case,perhaps editors should insist that itbe made more explicit. It couldaccount for apparent discrepanciesbetween the quality of findings andthe interpretations which are placedupon them. In the North wick Parkstudies, the raters have been themost, and not the least, clinicallyexperienced of the co-authors.

Many of the problems reduce tothe question of what should beconsidered a negative symptom. Asthe contributions to this issue of theSchizophrenia Bulletin indicate,opinions vary widely. Contrary tothe views favored by Andreasen andSommers, I suggest that no a prioridefinition of what constitutes anegative symptom will be generallyacceptable. What is rated inAndreasen's schedule of negativesymptoms seems to me to include asubstantial part of the entire range ofthe diverse consequences of thedisease. Sommers also is in search ofa Platonic ideal of what constitutes a



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VOL. 11, NO. 3, 1985 477

"true" negative symptom, but Isuspect it is unattainable. Rather, Isuggest we should adopt a pragmaticstance and ask what definition ofnegative symptoms gives us an inter-esting way forward. Already wehave the suggestion, explicit in thetwo-syndrome concept but presentearlier in the working hypotheses ofWing, Strauss, and their colleagues,that among the manifestations of thedisease labeled as negative are somethat are better correlated than themore obvious positive symptomswith chronicity and poor long-termoutcome. Symptoms included in thiscategory are clearly flattening ofaffect and poverty of speech. Aworthwhile question is whether thereare other symptoms that can bereliably assessed which are as goodor better. One can also ask how

these particular symptoms are bestassessed either in a research interviewor in clinical practice.

The two-syndrome concept alsoincludes the proposition that thosesymptoms which correlate withchronicity are less responsive thanpositive symptoms to neurolepticdrugs. The way forward for those,like Goldberg, who maintain thesingle dimension view of pathology,is to demonstrate that negativesymptoms, even when defined strictlyas above, are just as responsive toneuroleptics as positive symptoms.Indeed the original NIMH trial couldbe further analyzed along these linesbecause it appears that among theratings made available to Gibbons etal. were assessments of fixed facialexpression and poverty of speech.These items were not separately

Figure 1. Interrelationships between negative symptoms andother characteristics

Poorbehavioral

performance

Positivesymptoms

Negativesymptoms

Cognitiveimpairment

Neurologicalsigns

Significant relationships between various parameters In a population of 500 Inpatlents withchronic schizophrenia (from Owens and Johnstone 1980). Negative symptoms are signif-icantly related to Intellectual Impairment and behavioral disturbance, and each of thesefeatures Is related to the presence of neurological signs, Including abnormal Involuntarymovements. This constellation thus corresponds to the type II syndrome. In this populationnone of these features are related to the presence of positive symptoms (the type Isyndrome),a: p < .02; b: p < .01; c: p < .001.

analyzed in the article to whichGoldberg refers. How were theyactually rated? Were the drug-placebo differences with respect tothese symptoms as great as forpositive symptoms and "secondary"negative symptoms such as lack ofself-care and social withdrawal?

Does the Two-SyndromeConcept Hold Up?

A number of recent investigations arerelevant and address issues otherthan those already considered:

1. Are positive and negativesymptom components independentvariables? The most extensive studyof this issue is the survey of 500patients with a Feighner diagnosis ofprobable schizophrenia in ShenleyHospital (our area mental hospital inNorthwest London) reported by mycolleagues, Owens and Johnstone(1980). These workers assessedmental state with the Krawieckascales and also obtained ratings ofbehavioral impairment (from nursingstaff), and of neurological andcognitive status.

From a correlational analysis themain findings (figure 1) were signif-icant interrelationships amongnegative symptoms, intellectualimpairment, poor behavior, and thepresence of neurological signs. Thesesymptoms were unrelated to physicaltreatments, and to the presence ofpositive symptoms.

Thus, in this population of chronicinstitutionalized patients, positiveand negative symptom components(defined on the Krawiecka scale) arerelatively independent variables. Thisis essentially in agreement with thefindings of Cornblatt et al. (thisvolume) and Lewine, Fogg, andMeltzer (1983) but in disagreementwith the proposal of Andreasen thatpositive and negative symptoms betreated as a single continuum.



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Assuming that it is true that theseare indeed independent dimensions, itis worth considering some limitationson the situations in which this mightbe established. Thus, for instance, itcan clearly only be demonstrated in apopulation restricted to patients withschizophrenia—if other patients areincluded, the two groups ofsymptoms (because they arepresumably at least more frequent in,although not specific to, patientswith schizophrenia) will tend tocorrelate together. Secondly, becausesome negative symptoms (e.g.,poverty of speech in its extreme formof mutism) make positive symptomsdifficult to elicit, a spurious negativerelationship between positive andnegative symptoms, such as thatpostulated by Andreasen, may berecorded (Johnstone, in press).

2. Do negative symptoms identifythe nondopaminergic component?Beside the trial of the isomers offlupenthixol Gohnstone et al. 1978a),the study most relevant to this issueis that of Angrist, Rotrosen, andGershon (1980a, 1980b). Theseworkers found that symptom exacer-bation by amphetamine predictedpotential response to neurolepticdrugs (Angrist, Rotrosen, andGershon 1980b) in conformity withthe dopamine hypothesis. In areanalysis of individual BriefPsychiatric Rating Scale (BPRS)symptom scores, they found thatpositive symptoms were exacerbatedby amphetamine and improved byneuroleptics, while negativesymptoms (after emotionalwithdrawal was excluded as a"secondary" negative symptom)showed little response to either drug(Angrist, Rotrosen, and Gershon1980a).

3. Are negative symptomsassociated with poor long-termoutcome? Are they more persistentthan positive symptoms7

This issue is addressed by Pogue-Geile and Harrow (this issue). Alsorelevant is the study of Pfohl andWinokur (1982) of 52 institu-tionalized patients from the Iowa-500sample followed for the presence orabsence of negative and positivesymptoms over a period of 35 years.Included as negative symptoms weresocial impairments as well as povertyof speech, flattening of affect, andhypoactivity or catatonic motorbehavior. An overall analysis (table2) indicates that in general negativesymptoms are of later onset andmore persistent than positivesymptoms. In this study a highprevalence of cognitive impairmentwas noted as in previous studies(Crow and Mitchell 1975; Crow andStevens 1978; Owens and Johnstone1980), and these impairments, likenegative symptoms, were of lateonset and tended to persist. Also ofinterest is the finding that impair-ments of self-care were more likely toresolve than some negativesymptoms (e.g., flat affect) andcognitive and memory deficits.

4. Are negative symptomsassociated with structural brainchanges7 A number of CT scanstudies have now been completed.With one or two exceptions, they arein agreement with the originalfinding that, by comparison withage-matched controls, some patients

with chronic schizophrenia have adegree of ventricular enlargement(for review, sec Crow and Johnstone,in press).

Some studies (e.g., Johnstone et al.1976, 1978b; Rieder et al. 1979;Donnelly et al. 1980; Golden et al.1980) have found ventricular size tobe significantly related to intellectualimpairment, others to poorpremorbid personality (Weinberger etal. 1980b) or treatment resistance(Weinberger et al. 1980a).

However, in a recent study (Owenset al. 1985) of 110 patients withchronic schizophrenia, lateralventricular enlargement was notsignificantly related to negativesymptoms and intellectualimpairment (in both cases there wasa U-shaped relation, with somepatients with either feature havingsmall ventricles) but was significantlyassociated with behavioral deterior-ation (as in Haug 1962, 1982),absence of positive symptoms, andthe presence of abnormal involuntarymovements. Ventricular enlargementwas unrelated to past insulin coma,electroconvulsive therapy, or neuro-leptic medication.

Although some studies (e.g.,Takahashi et al. 1981; Gross, Huber,and Schuttler 1982; Kling et al. 1983;Williams et al. 1985) have foundventricular enlargement to beassociated with negative symptoms.

Table 2. Time of onset and persistence of positive and negativesymptoms in chronic schizophrenia1

Symptom classificationPositiveNegative

p value(Fisher's exact)

Early

104

Onset

0.004

Late

110

Persistence

No Yes

7 41 13

0.0071 Reprinted, with permission, from Pfohl and Winokur (1982).



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this has not been a consistentfinding. Rather, there is a generaltendency for ventricular enlargement(as assessed by CT scans) to berelated in different studies to one ormore of the components of the typeII syndrome—behavioral impairment,intellectual loss, negative symptoms,and abnormal involuntarymovements.

One possibility is that, assuggested strongly by a recent post-mortem study (Brown et al., inpress), lateral ventricularenlargement, as seen on CT scan,reflects only indirectly moresubstantial structural changes takingplace in the temporal lobe. If thesecould be directly assessed, bettercorrelations with clinical variablesmight be obtained.

S. Are there neurochemicalcorrelates of the two syndromes7Because a number of patientsincluded in the Owens and Johnstone(1980) survey have subsequentlydied, we have been able to examinethe relationships between positiveand negative symptoms assessed inlife and a number of neurochemicalvariables. The principal findings todate are:

•D2 receptors (assessed by 3H-spiperone binding) are significantly(p < .01) related to positive but notto negative symptoms (Crow et al.1981b).

•The enzymes dopamine-0-hydroxylase and choline acetyltransferase are not reduced inpatients with negative symptoms(Crow et al. 1981a). Thus, the type IIsyndrome differs from Alzheimer'sdisease in which both of theseenzymes (markers of adrenergic andcholinergic neurons, respectively) arereduced (this is relevant to thepredictions discussed by Carpenter,Heinrichs, and Alphs, this issue.

•In a study of six neuropeptides(Ferrier et al. 1983; Roberts et al.1983), there were no striking overalldifferences between patients withschizophrenia and controls, but inpatients with negative symptomscholecystokinin (CCK) content wasfound significantly reduced inhippocampus and amygdala, andsomatostatin content reduced inhippocampus. Since CCK andsomatostatin are located inamygdalo-hippocampal projections,and in hippocampus in small inter-neurons in the pyramidal cell layer,these changes may reflect localneuronal losses.

6. Are there electroencephalo-graphic (EEG) correlates of the typeII syndrome? Itil et al. (1975) reporta study that apparently is relevant tothis issue. On the basis of a compu-terized analysis of EEG recordings,they concluded:

"Therapy resistant" schizophrenicpatients were characterized by alesser degree of very fast betaactivity, more alpha waves andslow waves, higher amplitudes incomputer EEG and a lesser degreeof acute (florid) psychotic sympto-matology but more "negative"symptoms such as motor retar-dation and blunted affect.

A Revision of theTwo-Syndrome Concept

In the light of recent findings, and torender the concept more challengingas a hypothesis, some modest exten-sions are indicated (table 3). Theseinclude particularly the notion thatthe structural changes that are postu-lated to underlie the type IIsyndrome are located in the temporallobe. This is suggested by the recentpost-mortem study (Brown et al., inpress) and also accommodates thefindings of the investigation of

neuropeptide content (Ferrier et al.1983; Roberts et al. 1983).

The suggestion is also added thatabnormal involuntary movementsrather than being (as is oftenassumed) a late effect of neurolepticmedication (implicit in the concept of"tardive dyskinesia") are acomponent of the type II syndrome.The notion that such movements arenecessarily related to neurolepticmedication has already beenchallenged (Brandon et al. 1971;Owens, Johnstone, and Frith 1982),as has the view that an irreversiblecomponent of such movements isattributable to such medication(Crow et al. 1982b, 1983). The viewproposed here that they are part ofthe type II syndrome is consistentwith Kleist's concept of parakineticcatatonia (Waddington and Crow, inpreparation), and with observationsthat these symptoms correlate withother components of the type IIsyndrome, e.g., intellectualimpairment, negative symptoms(Owens and Johnstone 1980;Waddington et al., in press), andventricular enlargement (Owens et al.1985) that cannot be attributed topast neuroleptic medication.

The type II syndrome is referred toas the Pinel-Haslam syndromebecause these authors were probablythe first to provide clear descriptionsof what we would now recognize asschizophrenia (Pinel 1809; Haslam1809). In each case they describeillnesses in which negative symptomsand intellectual decline rather thanpositive symptoms are prominent.The type I syndrome, on the otherhand, is attributed, perhaps a littlefacetiously, to E. Bleuler as it washe, more so than Kraepelin, whoasserted that true intellectualimpairment does not occur in the"group of schizophrenias" (Crow andJohnstone 1980).



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Different Syndromes, NotDifferent Diseases

Andreasen (this issue) makes much ofthe distinction between diseases andsyndromes, and writes:

Early formulations of the positivevs. negative distinction failed todiscuss the issue of the "mixed"patient. Positive and negativesymptoms were treated as if theywere distinct entities . . . . (p.385]

These strictures appear to applyparticularly to Andreasen (1982)entitled "Negative vs. PositiveSchizophrenia: Definition andValidation." 3

Such attempts to subdivide schizo-phrenia are not apparent in the workof Wing, Strauss, and theircolleagues referred to earlier, and inCrow (1980) is the following:

Episodes of type I symptoms maybe followed by development of thetype II syndrome and both may bepresent together. Type IIsymptoms, however, define agroup of illnesses of graverprognosis. They occasionally occurin the absence of the type Isyndrome (for example in "simpleschizophrenia) . . . . [p. 68]

The view that a negative symptomcomponent can either precede orsucceed episodes of positivesymptoms and that it is a morestable, and less readily reversiblecomponent of the manifestations ofschizophrenia is implicit in the

3 The view (Andreasen, this issue) thatpositive symptoms are related to anexcess, and negative symptoms to adeficit, of dopaminergic transmission, is indifficulty in explaining how patients canhave both types of symptom at the sametime. This problem is recognized(Andreasen, p. 383) but no solutionoffered. It appears the difficulty is fata]for the single dimension dopaminergichypothesis.

formulations of Snezhnevsky, Wing,Strauss, and their colleagues. Strauss,Carpenter, and Bartko (1974) alsodrew attention to the relationshipbetween the presence and absence ofthe negative symptom componentand the process-reactive, amorphous-fragmented, good-poor premorbid,and schizophrenia-schizophreniformpsychosis distinctions of otherauthors. I have attempted toillustrate the possible temporalrelationships between the twosyndromes and their correspondenceto other concepts by a scheme of

overlapping circles in a Venndiagram (figure 2).

In this figure, the arrows indicatepossible progression of symptomswith the passage of time. Thus, someillnesses present with positivesymptoms as in the left segment ofthe figure. If they remit, they tend tobe labeled as "schizophreniform,""schizoaffective," or "reactive." Ifthey persist and no negativesymptoms appear, they can beconsidered as chronic paranoidillnesses (according to the paranoid-nonparanoid dichotomy of Tsuang

Figure 2. Relationship between types I and II syndromes asoverlapping constellations of symptoms, and changes that canoccur with time (Indicated by arrows)

Typel Typ«lE

Kraepelin

Bleuler

WinokurLangfeldt

Kasanin

Leonhard)Pern's )Vaiflant

paranoia :

paranoia .-

paranoid .-schizophreniform

psychosis :schizo-affective

psychosis .-cycloidpsychosis :

good- prognosisschizophrenia:

dementia praecox ("classical Kraepelinianschizophrenia")

hebephrenia : simple schizophrenia.- the "defect state"

non-paranoid schizophrenia

Also shown are possible relations of the 3 symptom patterns (defined by the Intersection ofthe circles) to other diagnostic subclasslflcatlons of schizophrenia (from Crow 1983).



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VOL. 11, NO. 3, 1985 481

and Winokur 1974). Illnesses inwhich negative symptoms alsoappear (or are already present) willtend to be labeled as "nonparanoid,""true," "process," or "classicalKraepelinian" schizophrenia. In someof these illnesses, positive symptomswill remit (as Pfohl and Winokur,1982, have documented) leaving the"pure deficit" type II syndrome(right-hand segment of Venndiagram). In some cases, positivesymptoms reappear. However, thecrossed arrow between the middleand left-hand segments of thediagram is intended to indicate therelative resistance to remission of thecomponents of the type II syndrome,i.e., primary negative symptoms andintellectual impairment.

It seems likely that negativesymptoms do sometimes remit.Goldberg (this issue), Pogue-Geileand Harrow (this issue), and Pfohl

and Winokur (1982) provideexamples. If such symptoms aredefined loosely and include those thatwould be regarded by Carpenter,Heinrichs, and Alphs (this issue) assecondary, this is not surprising. Themore interesting question is whetherprimary negative symptoms andintellectual impairments ever remit. Isuspect that they occasionally do, butit is a relatively unusual event, andone which deserves to be welldocumented. A problem is to definesuch symptoms as "true" (orprimary) negative symptoms. Oneapproach is that of Huber andcolleagues (Huber 1966; Gross,Huber, and Schiittler 1982) to whatthey refer to as the "irreversible puredefect syndromes." These are definedas irreversible when they have beenpresent without change for 3 years.Such a definition, of course, limitstheir use as prognostic indices but, as

with the DSM-II1 (AmericanPsychiatric Association 1980)definition of schizophrenia, perhapsfor some purposes it is necessary totake into account duration.

Etlologlcal Implications

Since negative symptoms, or moregenerally the type II syndrome,define a group of patients withschizophrenia who are doing badlyrather than a separate disease entity,the distinction does not have clearetiological implications. Perhaps asWinokur and colleagues havesuggested, genetic factors are relevantto the development of nonparanoidtypes of illness as well as to schizo-phrenia in general. In other words, itmay be that patients with particulargenes in addition to those whichpredispose to schizophrenia are liable

Table 3. Modified two-syndrome concept1

Type I Type II

Characteristic symptoms

Response to neuroleptics

Outcome

Intellectual Impairment

Abnormal Involuntarymovements

Postulated pathologicalprocess

Delusions,hallucinations(positive symptoms)

Good

Potentiallyreversible

Absent

Absent

Increased Didopamlne receptors

Flattening of affect,poverty of speech(negative symptoms)

Poor

Irreversible?

Sometimes present

Sometimes present

Cell loss (Includingpeptlde-contalnlngInterneurons) Intemporal lobe structures(hippocampus, amygdalaand parahlppocampalgyrus)

Eponym E. Bleuler Plnel-Haslam1 Modified from Crow and Johnstone (1985).



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to develop negative symptoms andintellectual defects. I have argued(Crow 1984) that the retrovirus/transposon hypothesis is moreparsimonious than a gene-environ-mental factor interaction inexplaining the etiology of schizo-phrenia, and have put forward a casefor a common etiology for schizo-phrenia and manic-depressivepsychosis. According to this view,the type II form of schizophreniamight be seen as at one end of acontinuum of severity of outcome,i.e., as that subgroup of patientswith psychosis who either have themost severe structural changes in thebrain or have lesions located in siteswhere they are least easilycompensated.

Solomon Goldberg (this issue)offers the alternative hypothesis thata subgroup of patients with schizo-phrenia have a quite different("organic") etiology from themajority of patients and that it is thisgroup who show ventricularenlargement, intellectual impair-ments, and poor response to neuro-leptic medication. He also argues(along with R.M. Murray andcoworkers) that this group have aless genetic form of the disease. Thisview encounters several problems,among which are: (1) the relativelyhigh prevalence of severe cognitiveimpairments in patients with chronicschizophrenia (Stevens et al. 1978;Owens and Johnstone 1980), (2) thestrong association between negativesymptoms and cognitive deficits(table 2), and (3) the fact that therelation between family history andventricular enlargement depends criti-cally upon the (arbitrary) line that isdrawn between normal andabnormal ventricular size (Owens etal. 1985).

Two articles in the present issue(Sommers and Carpenter, Heinrichs,and Alphs) refer to the concept that

negative symptoms are due to institu-tionalization. This was examined inthe study of Johnstone et al. (1981) inwhich it was established that whenage and duration of illness are takeninto account, negative symptoms areas common in patients (defined bythe Feighner criteria) who have beendischarged into the community afterinpatient admission as in patientswho have remained in hospital. Intel-lectual impairments, however, weregreater in the latter group. A furtherinvestigation (Johnstone et al. 1985)established that in a small group ofinstitutionalized patients with chronicmanic-depressive psychoses (definedby the Feighner criteria), negativesymptoms did occur (although lessfrequently than in a comparablegroup of patients with schizo-phrenia), and cognitive impairmentswere present in both groups. Thus,some components of the defect stateare present in psychoses other thanschizophrenia.

Conclusions

The concept of two syndromes inschizophrenia arose from thenecessity to postulate more than onedimension of pathology underlyingthe disease—a reversible (and poten-tially neuroleptic-responsive)component and a sometimesprogressive and relatively irreversiblecomponent associated with the deficitstate and poor long-term outcome.Negative symptoms (narrowlydefined as in the modified Krawieckascale) appear to be more closelyrelated to the latter component, asalso are cognitive impairments(which are common in chronicschizophrenia), abnormal involuntarymovements, and behavioral deterior-ation. These are components of thetype II syndrome (which correspondsto the "defect state" or "deficit

syndrome") that is postulated asmore closely related than positivesymptoms (the type I syndrome) tothe structural brain changes describedin pneumoencephalographic, CTscan, and recent post-mortemstudies. The type I syndromerepresents the potentially neuroleptic-responsive and reversible component,and may be associated with adisturbance of dopaminergic trans-mission. In post-mortem brain tissuefrom patients assessed in life forpositive and negative symptoms,numbers of D2 receptors are signifi-cantly correlated with positive butnot negative symptoms, and CCKand somatostatin content of hippo-campus and CCK content inamygdala are reduced in patientswith negative symptoms. The type IIsyndrome may be a consequence ofstructural changes occurring in thetemporal lobe.

The two syndromes are regardedas relatively independent processeswhich may coexist in the samepatient but follow different timecourses; they are assumed to bedifferent manifestations of theactivity of a single pathogen.

References

Andreasen, N.C. Negative v.positive schizophrenia: Definitionand validation. Archives of GeneralPsychiatry, 39:784-788, 1982.Andreasen, N.C. Positive vs.negative schizophrenia: A criticalevaluation. Schizophrenia Bulletin,11:380-389, 1985.

Angrist, B.; Rotrosen, }.; andGershon, S. Positive and negativesymptoms in schizophrenia—Differ-ential response to amphetamine andneuroleptics. Psychopharmacology,72:17-19, 1980a.



ownloaded from


VOL 11, NO. 3, 1985 483

Angrist, B.; Rotrosen, J.; andGershon, S. Responses to amphet-amine, apomorphine and neurolepticsin schizophrenic subjects. Psycho-pharmacology, 67:31-38, 1980b.Asano, N. Pneumoencephalographicstudy of schizophrenia. In: Mitsuda,H., ed. Clinical Genetics inPsychiatry. Tokyo: Igaku-Shoin,1967. pp. 209-219.

Berrios, G.E. Positive and negativesymptoms and Jackson: Aconceptual history. Archives ofGeneral Psychiatry, 42:95-97, 1985.

Bleuler, E. Dementia Praecox, or TheGroup of Schizophrenias. NewYork: International UniversitiesPress, 1950.

Brandon, S.; McClelland, H.A.; andProtheroe, C. A study of facialdyskinesia in a mental hospitalpopulation. British Journal ofPsychiatry, 118:171-184, 1971.

Brown, R.; Colter, N.; Corsellis,J.A.N.; Crow, T.J.; Frith, CD.;Jagoe, R.; Johnstone, E.C.; andMarsh, L. Post-mortem evidence forstructural brain changes in schizo-phrenia: Differences in brain weight,temporal horn area and parahippo-campal gyrus by comparison withaffective disorder. Archives ofGeneral Psychiatry, in press.

Carpenter, W.T., Jr.; Heinrichs,D.W.; and Alphs, L.D. Treatment ofnegative symptoms. SchizophreniaBulletin, 11:440-452, 1985.

Carpenter, W.T., Jr.; Wagman,A.M.I.; and Heinrichs, D.W. 'TheDeficit and Non-deficit Forms ofSchizophrenia." Submitted for publi-cation, 1984.

Cornblatt, B.A.; Lenzenweger, M.F.;Dworkin, R.H.; and Erlenmeyer-Kimling, L. Positive and negativeschizophrenia symptoms, attention,and information processing. Schizo-phrenia Bulletin, 11:397-408, 1985.

Crow, T.J. Molecular pathology ofschizophrenia: More than onedimension of pathology? BritishMedical Journal, 280:66-68, 1980.

Crow, T.J. Schizophrenic deteri-oration (discussion). British Journalof Psychiatry, 143:80-81, 1983.

Crow, T.J. A re-evaluation of theviral hypothesis: Is psychosis theresult of retroviral integration at asite dose to the cerebral dominancegene? British Journal of Psychiatry,145:243-253, 1984.

Crow, T.J.; Corsellis, J.A.N.; Cross,A.J.; Frith, CD.; Johnstone, E.C.;Owen, F.; Bloxham, C ; Ferrier,I.N.; and Owens, D.G.C. The searchfor changes underlying the type IIsyndrome of schizophrenia.In: Penis, C ; Struwe, G.; andJansson, B., eds. BiologicalPsychiatry 1981. Amsterdam:Bsevier/North-Holland, 1981a.pp. 727-731.

Crow, T.J.; Cross, A.J.; Johnson,J.A.; Johnstone, E.C.; Joseph, M.H.;Owen, F.; Owens, D.G.C; andPoulter, M. Catecholamines andschizophrenia: An assessment of theevidence. In: Usdin, E.; Carlsson,A.; Dahlstrom, A.; and Engel, J.,eds. Catecholamines: Neuropharma-cology and Central NervousSystem—Therapeutic Aspects. NewYork: Alan R. Liss, 1984. pp. 11-20.

Crow, T.J.; Cross, A.J.; Johnstone,E.C; and Owen, F. Two syndromesin schizophrenia and their patho-genesis. In: Henn, F.A., andNasrallah, H.A., eds. Schizophreniaas a Brain Disease. NewYork: Oxford University Press,1982a. pp. 196-234.

Crow, T.J.; Cross, A.J.; Johnstone,E.C; Owen, F.; Owens, D.G.C; andWaddington, J.C Abnormal invol-untary movements in schizo-phrenia: Are they related to thedisease process or its treatment? Are

they associated with changes indopamine receptors? Journal ofClinical Psychopharmacology,2:336-340, 1982b.

Crow, T.J., and Johnstone, E.C.Dementia praecox and schizo-phrenia: Was Bleuler wrong? Journalof the Royal College of Physicians,14:238-240, 1980.

Crow, T.J., and Johnstone, E.C.Schizophrenia: The nature of thedisease process and its biologicalcorrelates. In: Montcastle, V.B., andPlum, F., eds. Handbook ofPhysiology. American PhysiologicalSociety, in press.

Crow, T.J., and Mitchell, W.S.Subjective age in chronic schizo-phrenia: Evidence for a subgroup ofpatients with defective learningcapacity? British Journal ofPsychiatry, 126:360-363, 1975.

Crow, T.J., and Stevens, M. Agedisorientation in chronic schizo-phrenia: The nature of the cognitivedeficit. British Journal of Psychiatry,133:137-142, 1978.

Crow, T.J.; Owens, F.; Cross, A.J.;Ferrier, N.; Johnstone, E.C;McCreadie, R.M.; Owens, D.G.C;and Poulter, M. Neurotransmitterenzymes and receptors in post-mortem brain in schizo-phrenia: Evidence that an increase inDj receptors is associated with thetype I syndrome. In: Riederer, P.,and Usdin, E., eds. TransmitterBiochemistry of Human Brain Tissue.London: Macmillan, 1981b. pp.85-96.

Crow, T.J.; Owens, D.G.C;Johnstone, E.C; Cross, A.J.; andOwen, F. Does tardive dyskinesiaexist? Modern Problems inPharmacopsychiatry, 21:206-219,1983.

de Clerambault, G. OeuvrePsychiatrique. Paris: PressesUniversitaires de France, 1942.



ownloaded from



Donnelly, E.F.; Weinberger, D.R.;Waldman, I.N.; and Wyatt, R.J.Cognitive impairment associated withmorphological brain abnormalities oncomputed tomography in chronicschizophrenic patients. Journal ofNervous and Mental Disease,168:305-308, 1980.

Ferrier, I.N.; Roberts, G.W.; Crow,T.J.; Johnstone, E.C.; Owens,D.G.C.; Lee, Y.C.; O'Shaughnessy,D.; Adrian, T.E.; Polak, J.M.; andBloom, S.R. Reduced cholecysto-kinin-like and somatostatin-likeimmunoreactivity is associated withnegative symptoms in schizophrenia.Life Sciences, 33:475-482, 1983.

Fish, F.J. Schizophrenia.Bristol: John Wright, 1962.Gibbons, R.D.; Lewine, R.R.J.;Davis, J.M.; Schooler, N.R.; andCole, J.O. An empirical test of aKraepelinian vs. a Bleulerian view ofnegative symptoms. SchizophreniaBulletin, 11:390-396, 1985.

Goldberg, S.C. Negative and deficitsymptoms in schizophrenia dorespond to neuroleptics. Schizo-phrenia Bulletin, 11:453-456, 1985.

Goldberg, S.C; Klerman, G.L.; andCole, J.O. Changes in schizophrenicpsychopathology and wardbehaviour as a function of pheno-thiazine treatment. British Journal ofPsychiatry, 111:120-133, 1965.

Golden, C.J.; Moses, J.A.;Zelazowski, R.; Graber, B.; Zatz,L.M.; Horvath, J.B.; and Berger,P.A. Cerebral ventricular size andneuropsychological impairment inyoung chronic schizophrenics.Archives of General Psychiatry,37:619-623, 1980.

Gross, G.; Huber, G.; and Schiittler,R. Computerized tomography studieson schizophrenia diseases. Archiv furPsychiatrie and Nervenkrankheiten,231:519-526, 1982.

Haslam, J. Observations on Madness

and Melancholy. London: J. Callou,1809.

Haug, J.O. Pneumonencephalo-graphic studies in mental disease.Ada Psychiatrica Scandinavica,38:Supplement No. 165, 1962.

Haug, J.O. Pneumoencephalographicevidence of brain atrophy in acuteand chronic schizophrenic patients.Ada Psychiatrica Scandinavica,66:374-383, 1982.

Huber, G. Pneumoencephalo-graphische Bilder bei EndogenPsychosen. Berlin: Springer Verlag,1957.

Huber, G. Reine defekt syndromeund Basistadien endogenenPsychosen. Fortschritte derNeurologie und Psychiatrie,34:409-426, 1966.Huber, G.; Gross, R.; and Schiittler,R. Schizophrenie. Eine verlaufs - undsozialpsychiatrie Langzeitstudie.Monographien aus dem Gesamte-gebiet der Psychiatrie. Vol. 21.Berlin: Springer, 1979.

Itil, T.M.; Marasa, J.; Saletu, B.;Davis, S.; and Mucciardi, A.N.Computerized EEG: Predictor ofoutcome in schizophrenia. Journal ofNervous and Mental Disease,160:188-203, 1975.

Johnstone, E.C. Schizo-phrenia: Measurement andassessment. In: Burrows, G.D., ed.Handbook of Schizophrenia Studies.Amsterdam: Elsevier/North-Holland,in press.

Johnstone, E.C; Crow, T.J.; Frith,CD.; Carney, M.W.P.; and Price,J.S. Mechanism of the antipsychoticeffect in the treatment of acuteschizophrenia. Lancet, 1:848-851,1978a.

Johnstone, E.C; Crow, T.J.; Frith,CD.; Husband, J.; and Kreel, L.Cerebral ventricular size andcognitive impairment in chronic

schizophrenia. Lancet, 11:924-926,1976.

Johnstone, E.C; Crow, T.J.; Frith,CD.; Stevens, M.; Kreel, L.; andHusband, J. The dementia ofdementia praecox. Acta PsychiatricaScandinavica, 57:305-324, 1978b.

Johnstone, E.C; Owens, D.G.C;Frith, CD.; and Calvert, L.M.Institutionalisation and the outcomeof functional psychosis. BritishJournal of Psychiatry, 146:36-44,1985.

Johnstone, E.C; Owens, D.G.C;Gold, A.; Crow, T.J.; andMacmillan, J.F. Institutionalisationand the defects of schizophrenia.British Journal of Psychiatry,139:195-203, 1981.Kling, A.S.; Kurtz, N.; Tachiki, K.;and Orzeck, A. CT scans in sub-groups of chronic schizophrenics.Journal of Psychiatric Research,17:375-384, 1983.

Kraepelin, E. Dementia Praecox andParaphrenia. Translated by R.M.Barclay and G.M. Robertson. NewYork: R.E. Krieger, 1919.

Krawiecka, M.; Goldberg, D.; andVaughan, M. A standardisedpsychiatric assessment for ratingchronic psychiatric patients. ActaPsychiatrica Scandinavica,55:299-308, 1977.

Letemendia, F.J.J., and Harris, A.D.Chlorpromazine and the untreatedchronic schizophrenic: A long termtrial. British Journal of Psychiatry,113:950-958, 1967.Lewine, R.R.J.; Fogg, L.; andMeltzer, H.Y. Assessment of negativeand positive symptoms in schizo-phrenics. Schizophrenia Bulletin,9:368-376, 1983.

Mackay, A.V.P.; Iversen, L.L.;Rossor, M.; Spokes, E.; Bird, E.;Arregui, A.; Creese, I.; and Snyder,S.H. Increased brain dopamine and



ownloaded from


VOL. 11, NO. 3, 1985 485

dopamine receptors in schizophrenia.Archives of General Psychiatry,39:991-997, 1982.Owen, F.; Cross, A.J.; Crow, T.J.;Longden, A.; Poulter, M., and Riley,G.J. Increased dopamine receptorsensitivity in schizophrenia. Lancet,11:223-226, 1978.

Owens, D.G.C., and Johnstone, E.C.The disabilities of chronic schizo-phrenia: Their nature and the factorscontributing to their development.British Journal of Psychiatry,136:384-395, 1980.

Owens, D.G.C.; Johnstone, E.C;Crow, T.J.; Frith, CD.; Jagoe, J.R.;and Kreel, L. Cerebral ventricularenlargement in schizophrenia:Relationship to the disease processand its clinical correlates.Psychological Medicine, 15:27-41,1985.Owens, D.G.C; Johnstone, E.C;and Frith, CD. Spontaneousinvoluntary disorders of movement.Archives of General Psychiatry,39:452-461, 1982.

Pfohl, B., and Winokur, G. Theevolution of symptoms in institu-tionalised hebephrenic/catatonicschizophrenics. British Journal ofPsychiatry, 141:567-572, 1982.

Pinel, P.H. Traite Medico-Philoso-phique sur I Alienation Mentale.Paris: Anton Brosson, 1809.Pogue-Geile, M.F., and Harrow, M.Negative symptoms in schizophrenia:Their longitudinal course andprognostic importance. SchizophreniaBulletin, 11:427-439, 1985.

Reynolds, J.R. On the pathology ofconvulsions, with special reference tothose of children. Liverpool Medico-Chirurgical Journal, 2:1-14, 1858.

Rieder, R.O.; Donnelly, E.F.; Herdt,J.R.; and Waldman, I.N. Sulcalprominence in young chronic schizo-phrenic patients: CT scan findingsassociated with impairment on

neuropsychological tests. PsychiatryResearch, 1:1-8, 1979.Roberts, G.W.; Ferrier, I.N.; Lee, Y.;Crow, T.J.; Johnstone, E.C; Owens,D.G.C; Bacarese-Hamilton, A.J.;McGregor, G.; O'Shaughnessy, D.;Polak, J.M.; and Bloom, S.R.Peptides, the limbic lobe and schizo-phrenia. Brain Research,288:199-211, 1983.

Russell, B. History of WesternPhilosphy. London: George Allenand Unwin, 1946.

Snezhnevsky, A.V. Thesymptomatology, clinical forms andnosology of schizophrenia. In:Howells, J.G., ed. ModernPerspectives in World Psychiatry.Edinburgh: Oliver & Boyd, 1968. pp.425-447.

Sommers, A.A. "Negativesymptoms": Conceptual andmethodological problems. Schizo-phrenia Bulletin, 11:364-379, 1985.

Stevens, M.; Crow, T.J.; Bowman,M.; and Coles, E.C Age disorien-tation in chronic schizophrenia: Aconstant prevalence of 25% in amental hospital population? BritishJournal of Psychiatry, 133:130-136,1978.Strauss, J.S.; Carpenter, W.T., Jr.;and Bartko, J.J. The diagnosis andunderstanding of schizophrenia: III.Speculations on the processes thatunderlie schizophrenic symptoms andsigns. Schizophrenia Bulletin, 1(Experimental Issue No. ll):61-69,1974.

Takahashi, R.; Inaba, Y.; Inanaga,K.; Kato, N.; Kumashiro, H.;Nishimura, T.; Okuma, T.; Otsuki,S.; Sakai, T.; Sato, T.; andShimazono, Y. CT scanning and theinvestigation of schizophrenia. In:Perris, C; Struwe, G.; and Jansson,B., eds. Biological Psychiatry 1981.Amsterdam: Elsevier/North-Holland,1981. pp. 259-268.

Tsuang, M.T., and Winokur, G.Criteria for subtyping schizophrenia.Archives of General Psychiatry,31:43-47, 1974.

Waddington, J.C., and Crow, T.J."Abnormal Involuntary Movementsin the Pre-neuroleptic Era and inUnmedicated Patients: Implicationsfor the Concept of TardiveDyskinesia.' " In preparation.

Waddington, J.L.; Youssef, H.A.;Molloy, A.G.; O'Boyle, K.M.; andPugh, M.T. Association ofintellectual impairment, negativesymptoms and aging with abnormalinvoluntary movements ("tardivedyskinesia"). Journal of ClinicalPsychiatry, in press.

Weinberger, D.R.; Bigelow, L.B.;Kleinman, J.E.; Klein, S.T.;Rosenblatt, J.E.; and Wyatt, R.J.Cerebral ventricular enlargement inchronic schizophrenia: Associationwith poor response to treatment.Archives of General Psychiatry,37:11-14, 1980a.

Weinberger, D.R.; Cannon-Spoor,E.; Potkin, S.G.; and Wyatt, R.J.Poor premorbid adjustment and CTscan abnormalities in chronic schizo-phrenia. American Journal ofPsychiatry, 137:1410-1413, 1980b.

Williams, A.O.; Reveley, M.A.;Kolakowska, T.; Ardern, M.; andMandelbrote, B.M. Schizophreniawith good and poor outcome: II.Cerebral ventricular size and itsclinical significance. British Journalof Psychiatry, 146:239-246, 1985.

Wing, J.K. Clinical concepts ofschizophrenia. In: Schizo-phrenia: Toward a New Synthesis.London: Academic Press, 1978. pp.1-30.

Wing, J.K., and Brown, G.W.Institutionalism and Schizophrenia.Cambridge: Cambridge UniversityPress, 1970.



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The Author

Timothy J. Crow, Ph.D., F.R.C.P.,F.R.C. Psych., is Head, Division ofPsychiatry, Clinical Research Centre,Northwick Park Hospital, Harrow,England HA1 3UJ.

World Congressof BiologicalPsychiatry

The World Federation of Societies ofBiological Psychiatry (WFSBP) andthe Society of Biological Psychiatry(U.S.A.) announce the Fourth WorldCongress of Biological Psychiatry, tobe held in Philadelphia, on September8-13, 1985. The program willencompass every aspect of biologicalpsychiatry. It will consist of lectures,symposia, and free communications(oral and poster). An extensive socialand leisure time program is planned.

Officials of the Congress are:George N. Thompson, M.D.,

Honorary Chairman and ConvenorCharles Shagass, M.D., President,

WFSBP, ChairmanGeorge M. Simpson, M.D.,

Secretary-GeneralRichard A. Roemer, Ph.D.,

Treasurer

Wagner H. Bridger, M.D., Chairmanof Program Committee

Announcements and registrationmaterials for the Congress may beobtained by writing to theConference Management:

Anthony F. Jannetti, Inc.North Woodbury Road/56Pitman, NJ 08071 U.S.A.

Communications concerning theScientific Program should beaddressed to:

Wagner Bridger, M.D., or GeorgeM. Simpson, M.D.

Medical College of Pennsylvania atE.P.P.I.

Henry Avenue & Abbottsford RoadPhiladelphia, PA 19129 U.S.A.



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