the enigmatic phenotype: relevant signs and symptoms in...

Eur. J. Psychiat. Vol. 19, N.° 4, (215-230)2005

Key words: Schizophrenia, Signs, Symptoms, Dimensions

The enigmatic phenotype: Relevant signs andsymptoms in schizophrenia

F.W.H.M. Wijers*,**W.M.A. Verhoeven*,**S.Tuinier*

*Vincent van Gogh Institute for Psychiatry,Venray, The Netherlands

**Erasmus University Medical Centre,Department of Psychiatry, Rotterdam

ABSTRACT – Ever since schizophrenia was conceptualized by Kraepelin and Bleuler,attempts have been made to rearrange signs and symptoms in order to achieve an useful dis-ease concept with consequences for outcome, prognosis, treatment response and etiology.Several procedures were used to describe relevant phenotypes of the disease. In the begin-ning, famous psychiatrists conceptualized definitions of schizophrenia which was followedby a consensus about the operational criteria of schizophrenia. Later, more emphasis wasplaced on the statistical analyses of symptoms present in patients with psychotic disorderswhich resulted in a great variety of symptom clusters. In another approach, investigators tryto deconstruct psychiatric diagnoses in search for so called endophenotypes of which covertsymptoms like cognitive deficits in schizophrenia, are an example.

The value of all these endeavours ultimately depends on the external validity whichmeans that a relationship has to be established with the etiology, treatment response andoutcome. The premises of all these research efforts is, however, the idea that the patho-genic agent of schizophrenia or a subtype will be found.

In this paper an outline of the literature about the ordening of overt and covert symp-toms in schizophrenia is presented. It is concluded that the different approaches are essen-tial analogue and that research into the delineation of cognitive deficits and their treatmentis at present most promising.

Introduction

Although the psychopathological pictureof Kraepelins’ dementia praecox with a gen-eral weakening of mental processes resulting

in a defect as cornerstone, has been describedmore than a century ago, the diagnosis stilldepends on the subjective experiences of thepatient, the history and course of symptomsand the observation of behaviour and is basedtherefore on observable symptoms. With

respect to symptomatology, however, it has tobe stressed that symptoms of schizophreniaencompasses the entire spectrum of psy-chopathology with a substantial interindivid-ual variation and that virtually any combina-tion of symptoms may be present in anindividual patient. Despite the critics onschizophrenia as a disease entity (Van Praag,1976, Kendell 1982, 1989), it is, however,generally accepted that the disorder can beidentified in different cultures and nations andhas a worldwide prevalence of 1 percent andthat the diagnosis is rather stable over time(WHO 1973, 1979, Kendell et al. 1979,Schwartz et al. 2000). Furthermore a widevariety of outcomes can be observed inpatients with similar initial symptom charac-teristics (Jablensky et al. 1992, Leff et al.1992).

Although symptoms and signs are crucialfor the diagnosis of schizophrenia, there isan ongoing debate since Kraepelin abouthow to group symptoms or to subtype thisdisorder with the aim of discovering thenature of schizophrenia and its outcome andprognosis (Strauss et al. 1974). The searchfor the ideal phenotype deals with compos-ing ‘Idealtypen’, relevant subtypes, delin-eation of symptom clusters by means of sta-tistical procedures, the description ofunderlying cognitive deficits and the identi-fication of so called endophenotypes. Thepresent paper reviews these differentapproaches and tries to answer the simplequestion what approach is the most relevantfor outcome and prognosis.

Diagnostic typing and subtyping

Since the original description by Krae-pelin of the dementia praecox with its sub-types and the longitudinal outcome as diag-nostic criterion, various attempts have been

made to arrange the manifold symptomsand signs of schizophrenia. In 1911 EugenBleuler introduced the so called ‘fundamen-tal’ and ‘accessory’ symptoms which com-prise loosening of associations, ambiva-lence and autism on the one hand, andhallucinations, delusions and catatonicsigns on the other hand. According toBleuler (1911) fundamental symptoms areobligatory for the diagnosis. In the fifties,Kurt Schneider (1950, 1957) formulated, onan entirely pragmatic base, the so calledfirst rank symptoms of schizophrenia thatwere believed to have a crucial significancefor the diagnosis. They included elevensymptoms such as audible thoughts, thirdperson auditory hallucinations, interferencewith the thought process or delusional per-ception. Schneider himself, however, neverreferred to these symptoms as pathogno-monic for schizophrenia. The emphasis onSchneider-like symptoms was reinforced bythe effects of neuroleptics in alleviatingthem. Despite the clinical effects of thesecompounds, a majority of patients was stilldisabled due to persistent Bleulerian funda-mental symptoms.

Kraepelins’ original distinction of defec-tive and productive symptoms was in theseventies revived by the positive and nega-tive symptom distinction. This dichotomywas described in some form in most theoret-ical constructs before that time. Accordingto Berrios (1985) this terminology, thatstems from observations in epilepsy, wasfirst mentioned by John Russell Reynolds in1858 and elaborated subsequently by JohnHughlings-Jackson in the eighties of thenineteenth century. The concept of Jackson(1887) is based on the doctrine of the disso-lution of higher nervous functions. His theo-ry of a hierarchy of levels of functionalorganisation in the nervous system impliedthat positive symptoms such as delusions

216 F.W.H.M. WIJERS ET AL.

and hallucinations represented release phe-nomena, arising when a higher cortical reg-ulator has been lost and the activity from alower level therefore emerged unchecked.Negative symptoms were due to ‘dissolu-tion’, that is they represented a diffuse andgeneralised loss of higher centres.

Until the present day the positive-nega-tive symptom polarity is used in the dissec-tion of schizophrenia and this was givenagain impetus by Crow (1980a,b) who pro-posed to group the symptoms and signs ofschizophrenia as either positive or negative,the so called type I and type II schizophre-nia. According to Crow, type I is charac-terised by positive symptoms like delusions,hallucinations and formal thought disorderthat occurs usually in the setting of an acuteillness, while type II is defined by negativesymptoms such as blunting of affect andpoverty of speech as well as indices ofstructural cerebral abnormalities which gen-erally shows a chronic course (Crow 1985).He hypothesized that these types representtwo etiological distinct subtypes. Subse-quent factor analytical studies suggestedthat these types represent the two ends of acontinuum (Andreasen and Olsen 1982,Lewine et al. 1983). It should be stressed,however, that the placement of symptoms ineither category is purely descriptive andrather arbitrary. In reviewing the literature,Walker and Levine (1988) concluded thatonly six symptoms were consistently classi-fied as either negative or positive that areincluded in de widely used scales. In addi-tion, Carpenter et al. (1988) proposed todistinguish primary from secondary nega-tive symptoms in which the primary deficitsymptoms are enduring traits that includeanhedonia, flattening of affect, poverty ofspeech and lack of motivation. To the non-deficit negative symptoms belong psy-chomotor slowness, anergia and social with-

drawal that depend on mood state and sideeffects of medication.

The ambiguity of the negative-positivedichotomy is best illustrated by symptomslike thought and speech disorder as well ascatatonic features which are difficult toplace in either group. The difficulties in theappreciation of motor symptoms can beinferred from the specific history of catato-nia, originally recognised as a separate dis-ease entity by Karl Ludwig Kahlbaum andlater considered to be a subtype of schizo-phrenia or an accessory symptom in variousneuropsychiatric disorders (review: Van derHeijden et al. 2005).

The two-factor model

As elegantly described by Jablensky(2001), grouping of symptoms has been doneon the basis of expert clinical impression likethe fundamental and accessory symptoms asdescribed by Bleuler or the hierarchical con-tinuum as proposed in later works by Krae-pelin, and the frequency profiles of symp-toms. By applying statistical procedures todiscover latent variables or factors, Liddle(1987a) found a three factor structure ofsymptomatology instead of the previouslydescribed positive and negative dimensions.Symptoms, assessed in a relatively smallsample of stable patients with schizophrenia,segregated into three syndromes: psychomo-tor poverty, disorganisation and reality dis-tortion, of which the first two were associatedwith social and occupational impairment.Later, Peralta et al. (1994) proposed on thebasis of a larger patient group a four syn-drome model including positive, negative,disorganisation and relational dimensions. Itshould be stressed, however, that the resultsof this kind of studies are highly dependenton the input, in that the number of factors

THE ENIGMATIC PHENOTYPE: RELEVANT SIGNS AND SYMPTOMS IN SCHIZOPHRENIA 217

required to explain the variance is greaterwhen a wider range of symptoms is used.Furthermore, the results are influenced by thepatient population investigated, sample size,age, duration, course and outcome of illness,response to treatment and the applied diag-nostic criteria. In addition, the stability offactors over time is still questionable (Arndtet al. 1995, Eaton et al. 1995, McGuffin &Farmer 2001).

In the first decades of the past century,several subtypes of schizophrenia weredescribed that ultimately resulted in eightcategories in the ICD-9: simple, he-bephrenic, catatonic, paranoid, schizoaffec-tive, latent and residual and acute, whereasthe DSM-III recognised five categories: dis-organised, catatonic, paranoid, undifferenti-ated and residual. Others emphasized thatthis subdivision is based on the predominantclinical picture at evaluation (Kendell 1987,McGlashan & Fenton 1991). Many othersubgroups based on clinical pictures havebeen proposed of which those of Kleist andLeonhard are examples of clinical ideo-graphic classifications (Leonhard 1995,review: Van der Heijden et al. 2002). Theserather detailed subdivisions, however, areflawed by the observation that many patientsdo not lie within any particular subgroup andthat changes to another subgroup frequentlyoccur during the course of the illness (Fen-ton & McGlashan 1991)

Starting in the sixties, several studies havebeen performed in order to regroup psychoticsymptoms (Wing 1961, 1978, WHO 1973).This type of research was promoted by theavailability of rating scales like the Scale forAssessment of Negative Symptoms (SANS)and the Scale for Assessment of PositiveSymptoms (SAPS) (Andreasen 1983, 1984),as well as the introduction of modern statisti-cal programs. These scales were developedon the assumption that there are two major

syndromes that account for schizophrenicphenomena (Klimidis et al. 1993). In theearly eighties Crow as well as Andreasen andco-workers published their data on the posi-tive-negative symptom polarity in schizo-phrenia. Andreasen and Olsen (1982) con-firmed the polarity between positive andnegative symptoms and described a mixedgroup comprising symptoms that either donot meet the criteria for positive or negativesymptoms or are in agreement with the crite-ria for both. These three groups differed on anumber of variables such as premorbidadjustment, the overall functioning, impairedcognitive function and indications of cerebralstructural abnormalities. In a review of theliterature, Walker and Levine (1988) con-clude that, in accordance with the originalconcept from 1858 by Reynolds, the twosymptom dimensions in schizophrenia arerelatively independent and that the negativesymptoms are associated with premorbiddysfunction and cognitive impairments. In anattempt to amend the homogeneity of nega-tive symptoms, Carpenter et al. (1988) madea distinction between the primary or endur-ing negative symptoms termed deficit symp-toms and the more transient non-deficit nega-tive symptoms secondary to other factors likedrug effect, dysphoric mood and absence ofsocial stimulation.

Factor analytical studies basedon the two-syndrome model

As mentioned above a three dimensionmodel of schizophrenia was originallydescribed by Liddle (1987a,b). The symp-toms obtained in a sample of 40 chronicschizophrenic patients selected for persis-tence of symptoms and a duration of illnessof at least 3 years without an exacerbationof symptoms or changes in drug treatmentduring the previous 6 months. The symp-


toms segregated into three syndromes ‘psy-chomotor poverty’ (poverty of speech, lackof spontaneous movement and variousaspects of blunting affect), ‘disorganisation’(inappropriate affect, poverty of content ofspeech and disturbances of the form ofthought) and ‘reality distortion’ (particulartypes of delusions and hallucinations). Thelatter did not correlate with cognitive orneurological dysfunction. In a subsequentstudy, Liddle and Barnes (1990) replicatedthese results and found that the syndromes‘psychomotor poverty’ and ‘disorganisa-tion’ are linked to neuropsychologicaldeficits such as conceptual reasoning, long-term memory, concentration and new learn-ing. In contrast to the classical subtypingthat attempts to identify discrete types of ill-ness, it was demonstrated that the three syn-dromes may coexist in the same patient.Similar observations in various samples ofschizophrenic patients were reported byArndt et al. (1991) and in a later study byAndreasen et al. (1995). A comparable threecomponent model was found in a sample ofpatients with chronic schizophrenia (Brown& White 1992) and in a random sample ofschizophrenic patients with at least sixmonths of symptoms (Johnstone & Frith1996). In the study with chronic patients,only the ‘psychomotor poverty’ dimensionwas associated with neuropsychologicalimpairments. In this large group of unselect-ed patients, cognitive deficits appeared to beunrelated to the dimension of ‘reality distor-tion’. In subsequent studies by Van der Doesand co-workers in patients with recent-onsetschizophrenia, also three clusters of symp-toms could be established. As a result of theuse of different symptom scales, a fourthfactor emerged: ‘depression’. Only ‘disor-ganisation’ was correlated with cognitiveperformance deficits (Van der Does et al.1993 a,b, 1995, 1996). The above mentionedstudies that are reviewed by Buchanan and

Carpenter (1994) show that the positive-neg-ative symptom dichotomy is too restrictedand should be expanded to at least a three-dimensional model. This was replicated insome later studies (Löffler & Häfner 1999,Peralta et al. 2001, John et al. 2003). Itshould be stressed, however, that studies thatfound three syndromes did not included theentire range of symptoms in schizophrenicpatients such as the common motor features(Peralta & Cuesta 2001).

As already stipulated in 1994 by Liddle,two additional syndromes, depression andpsychomotor excitation, can be identified ifaffective items and features of overarousalare included too (Liddle et al. 1994). Fur-thermore, it has been demonstrated that thethree psychopathological domains are notunique for schizophrenia and can also befound in other diagnostic categories(Ratakonda et al. 1998).

The generalizability of the results of thestudies that demonstrated two or threedimensions is, however, limited since theyincluded samples composed of patients withDSM-core schizophrenia and the analysesare mostly based on SAPS and SANSscores. The majority of the models asdescribed in the seventies and eighties havebeen obtained by exploratory factor analysisof these two scales in patients who met acategorical diagnosis of schizophrenia(review: Peralta et al. 1994). As the SAPSand the SANS were designed to measurenegative and positive symptoms it is not sur-prising that factor analysis of their ratingsresults in negative and positive dimensions.The outcome reflects the underlying con-cepts especially if other symptoms that forman integral part of schizophrenia such asaffective and motor symptoms are excluded.

In later years, factor analytical studieswere performed that use a great variety of


scoring instruments. As reviewed by VonKnorring and Lindström (1995) and con-firmed by other investigators (Lykouras etal. 2000), principal component analysis ofthe Positive and Negative Syndrome Scale(PANSS, Kay et al. 1987) revealed a fivefactor model comprising: negative, excite-ment, depression, positive and cognitiveimpairment. A later study demonstratedfour factors: negative symptoms, disorga-nized thought, hostility/excitement anddelusions/hallucinations (Hwu et al. 2002).A four or five factor structure was alsofound with the Comprehensive Psy-chopathological Rating Scale (CPRS,Asberg et al. 1978) that resembled thedimensions of the scale itself (Arora et al.1997, Salokangas 1997, Van Os et al. 1999).With the AMDP-system (Scharfetter 1983),even a 10-dimensional model was found(Cuesta & Peralta 2001, Cuesta et al. 2003).With other scales a 4 to 5 factor structurehas been described (Kitamura et al. 1995,McGorry et al. 1998).

It should be kept in mind that the decisionas to whether the dimensions found arevalid, must be based on external criteriasuch as e.g. outcome and treatment responseas well as pathophysiological and etiologi-cal parameters. As pointed out by Lieber-man (1995), symptom clusters should beconsidered as purely descriptive and dotherefore not differ essentially from the tra-ditional qualitative subtypes of schizophre-nia. The great discrepancies in the reportson the number of dimensions underlyingpsychosis can be explained by the inclusionof categorical defined schizophrenicpatients, the use of global rating of theSAPS/SANS or the PANSS only and theinstrument dependency of the results (Cues-ta & Peralta 2001). In addition, Stuart et al.(1999) demonstrated that studies that indi-cated low numbers of syndromes suffered

from severe limitations such as exclusion ofmany items from the analyses, samplesrestricted to chronic schizophrenia and apoor fit of the symptom model to the data.

Operational criteria andpolydiagnostic approach

Since the early sixties of the past centuryan epistemological discussion about the sci-entific quality of psychiatry is ongoing(Hempel 1961, Kendell 1975a, Van Praag1978). The specificity of so called schizo-phrenic symptoms has also been challengedby Pope and Lipinski (1978). This debate ismainly focussed on the concept of schizo-phrenia with its controversial definitions andits problems of taxonomy and has resulted ina series of explicit operational criteria for thediagnosis (Brockington et al. 1978, Stephanset al. 1982). All these systems, however, arebased on a more or less accurate recording ofsigns and symptoms and should thereforestill be regarded as a set of clearly statedworking hypotheses. It is therefore difficultto determine whether one definition of schiz-ophrenia has a greater validity than any other.Different operational definitions may have adifferential utility in terms of external validi-ty. This is illustrated by the results of the twinstudies from the Maudsley Hospital whichshowed that some definitions, includingDSM schizophrenia, defined a syndrome ofhigh heritability while a definition based onSchneider’s first rank symptoms defined asyndrome of zero heritability (McGuffin etal. 1984, Farmer et al. 1987). As shown byBrockington et al. (1978) who applied 10definitions of schizophrenia to two samplesof psychotic patients, only four definitionsemerged as relatively effective predictors ofsocial and clinical outcome, whereas Schnei-der’s symptoms proved weak in all areas ofprediction. In a large long-term study using 9


different sets of criteria it was demonstratedthat quite different groups of schizophrenicpatients were obtained by applying differingdiagnostic criteria. The correlation with long-term follow-up status in these differentlydefined patients with schizophrenia appearedto be related to the number of variables hav-ing prognostic significance that are used inmaking the diagnosis (Stephans et al. 1982).

Given the low diagnostic concordancebetween several definitions of functionalpsychoses and the absence of an adequatecriterion validity, none of the diagnostic sys-tems can claim superiority over an other(McGorry et al. 1992, Van der Heijden et al.2004). It was therefore advocated to use apolydiagnostic approach that includes mixedand atypical psychotic disorders as well,assuming that psychoses form a continuumwithout clear boundaries between syn-dromes. Based on these premises, McGuffinet al. (1991) developed an operational criteriachecklist for recording and scoring informa-tion from a variety of sources while main-taining sufficient flexibility to apply multipletypes of operational criteria, the so calledOPerational CRITeria (OPCRIT) diagnosticsystem. This checklist is a 90-item schedulegiving basic demographic information,indices of disease scores and severity, andratings of psychotic and affective symptomswhich generates reliable diagnoses accordingto 12 operational diagnostic systems (Crad-dock et al. 1996, Azevedo et al. 1999,McGuffin & Farmer 2001). The OPCRIT canbe considered as the European response tothe array of phenomena in the psychoses. Inthe United States a parallel development wasstarted by Andreasen in 1985 that resulted inthe construction of the ComprehensiveAssessment of Symptoms and History, theCASH (Andreasen, 1985; Andreasen et al.,1992). The OPCRIT is in use as the standard

to make diagnoses in genetic studies in schiz-ophrenia.

Factor analytical studies with theOPCRIT

Cardno and co-workers (1996) were thefirst to compare data from factor analysis ofschizophrenic symptoms by means of 21psychosis items of the OPCRIT with thoseof previous factor analytical studies inDSM-schizophrenia. They found that a fivefactor model with the predominant symp-tom types: paranoid, negative, disorganisa-tion, first rank delusions and first rank hal-lucinations, accounted best for the data,instead of the three factor solution of posi-tive, negative and disorganisation.

Since then a few studies using the OPCRIThave been performed to identify symptomdimensions in patient populations with psy-chotic disorders (Table I). By using 20 items,Van Os et al. (1996) demonstrated sevenunderlying structures that accounted for 63%of the variance. The first includes bizarrebehaviour, catatonia, inappropriate affect anddifficult rapport (inappropriate-catatonia), thesecond delusions of passivity, bizarre delu-sions, thought interference and hallucinations(delusions-hallucinations), the third mania,grandiose delusions and relationship psychot-ic/affective symptoms (mania), the fourthinsidious onset, blunting of affect and age ofonset (insidious-blunting), the fifth depres-sion and depressive delusions (depression)and the last two lack of insight and paranoiddelusions respectively. In a study including 66patients with schizophrenia, Cardno et al.(1997) found even eight factors that are tosome extent quite different from the sevendescribed by Van Os et al. (1996). In a mixedsample of psychotic and depressed patients,Serretti et al. (1996) identified on the basis of


38 items three psychosis-factors (excitement,disorganization and delusion) and one affec-tive factor (depression). In an extension studyusing 46 items, Serretti et al. (2001) con-firmed their previous four factor model.Comparable results were obtained by McIn-tosh et al. (2001). In a twin study aimed toelucidate useful phenotypes for genetic stud-ies, Cardno et al. (2001) described six psy-chotic dimensions, comprising a disorgan-ised, a negative and 4 positive factors. In avery heterogeneous patient group, schizo-phrenic psychoses could be characterized byfour dimensions: positive, negative, dyspho-ria and mania (Rosenman et al. 2003). In agroup of patients with functional psychoses,Serretti and Olgiati (2004) performed a fac-tor analysis on 29 items and found five fac-tors: mania, positive, disorganization, depres-sion and negative. In a subsequent analysis,Serretti and co-workers (2004) confirmed thepresence of a depression dimension in schiz-ophrenia. Finally, Matsuura et al. (2004)described a four structure model in schizo-phrenic patients.

Although the OPCRIT is more compre-hensive with respect to the included items,its value in research on functional psy-choses is still dependent on factors thatdetermine the external validity. Further-more, the usefulness of this method is limit-ed. Different syndromes may exist in thesame patient, correlations between symp-tom factors have demonstrated to be some-times high and subtypes or dimensions havea modest stability over time.

Neurocognitive functions ascovert symptoms

Apart from the symptomatologicaldomains that can be ascertained by standard-ized clinical instruments like the PANSS and

the OPCRIT, it is widely accepted that cog-nitive deficits such as inattention, memoryand executive function, are core features ofschizophrenia and can be considered ascovert symptoms. In general, the results ofcognitive tests indicate that this disorder ischaracterised by a broadly based cognitiveimpairment. Although the pattern of thesedeficits is highly variable, there is someempirical evidence that cognitive perfor-mance tends to be related to negative symp-toms (Bilder et al. 1985, Rund 1998, Ale-man et al. 1999, Bozikas et al. 2004). Itshould be stressed, however, that any selec-tive deficits in specific functions are relativeand exist against the background of generaldysfunction (Heinrichs et al. 1998) and thatthe relationship between cognitive impair-ments and symptom dimensions in general isweak (Mohamed et al. 1999, Bilder et al.2000, O’Leary et al. 2000, Nieuwenstein etal. 2001, Donohoe & Robertson 2003).

As reviewed by Green (1996), certainneurocognitive deficits like vigilance, verbalmemory and executive functioning seemmore predictive for functional outcome thanare psychotic symptoms. In a subsequentmeta-analysis Green and co-workers (2000)confirmed that these aspects of neurocogni-tion are involved in the functional outcomeindeed and that composite measures explain20 to 60% of the variance. They suggestedthat measures such as social cognition andlearning potential may be more fundamentalfor the neurocognitive assessment of patientswith schizophrenia. Other investigators havefocussed on attention impairment as animportant predictor of outcome (review:Michie et al. 2000). It has to be emphasizedagain that correlations between cognitiveperformance and severity of psychoticsymptoms are generally absent and that thecorrelation between negative symptoms andcognitive performance is not very large



Table IFactor analytical studies with the OPCRIT in patients with psychotic disorders

Author Number Number Mean Age Diagnosis Inclusion Dimensionsof patients of items age of onset criteria

Cardno 102 21 45.1 24.7 Schizophrenia DSM-III-R 1) paranoidet al. 1996 2) negative

3) disorganisation4) first-rank delusions5) first rank hallucinations

Van Os 191 20 26.4 24.4 Functional Psychotic 1) inappropriate-catatoniaet al. 1996 Psychoses disorder 2) delusions-hallucinations

3) mania4) insidious-blunting5) depression6) lack of insight7) paranoid delusions

Serretti 1004 38 42.1 29.4 Major Psychotic 1) excitementet al.1996 psychoses disorder 2) depression

3) disorganisation4) delusion

Cardno 66 19 36.6 30.3 Schizophrenia Research 1) positive formal thought disorderet al. 1997 Diagnostic 2) first rank delusions

Criteria 3) first rank hallucination4) inappropriate affect and

bizarre behaviour5) negative symptoms6) grandiose/bizarre

delusions7) delusions of influence8) other hallucinations

Serretti 2241 46 41.7 28.5 Major Psychotic 1) excitementet al. 2001 psychoses disorder 2) depression

3) disorganisation4) delusion

Rosenman 980 64 39.3 39.3 Psychotic Psychotic 1) positiveet al. 2003 (mean age) disorder disorder 2) negative

3) dysphoria4) mania

Serretti and 1294 29 41.7 28.5 Schizophrenia DSM-IV 1) maniaOlgiati 2004 Bipolar disorder 2) positive

Delusional 3) disorganizationdisorder 4) depression

5) negative

Matsuura 116 60 39.2 29.9/24.6 Epileptic Not 1) maniaet al. 2004 psychoses/ mentioned 2) negative

Schizophrenia 3) depressivespectrum disorde 4) vegetative

5) positive

(Goldberg et al. 1993, Mohamed et al. 1999,Bilder et al. 2000, Green et al. 2004a).

It is as yet unclear whether the replace-ment of symptom profiles by cognitivedeficits or other so called endophenotypeswill be of significance for insight in the etiol-ogy of functional psychoses (Gottesman &Gould 2003, Zobel & Maier 2004). Delin-eation of phenotypes on the (sub)symptoma-tological level with the ultimate aim to distin-guish etiological or pathogenetic factors isseverely hampered by the phenotypical vari-ability that is the rule even when etiology isknown (Goldberg & Weinberger 1995, Baron2001).

Diagnoses and syndromes aspredictors of course andoutcome

The usefulness of the delineation of diag-noses, syndromes and dimensions highlydepends on external validation whichimplies that, apart from consensus aboutoperationally defined categories and theirreliability, a relationship should be presentwith etiology, pathophysiology, treatmentresponse or outcome. With respect to theoperational definitions, it is well establishedthat they include different patient groupsand show a considerable variation in pre-dicting functional outcome (Brockington etal. 1978, Kendell et al. 1979, McGorry etal. 1992). As can be inferred from theprospective WHO studies, the initial symp-tom characteristics are associated with avery heterogeneous outcome and variableslike insidious onset, premorbid functioning,age at onset and gender are consistentlyrelated to poor prognosis albeit that theirrelevance for later social functioningremains uncertain. Furthermore, the futuredisability depends on the level of function-

ing in the early course of the illness andmuch less on sociodemographic or illnesscharacteristics (Jablensky et al. 1992,Wiersma et al. 2000, Häfner 2000).

Factor analytic studies have yielded amodest association with course and outcomeof illness. Although the relationship betweensymptoms and outcome has been extensive-ly studied, the results are still inconclusive.There are some indications that negativesymptoms moderately predict poor qualityof life in the early course of schizophrenia(Wieselgren et al. 1996, Ho et al. 1998). Thefew results obtained with the OPCRIT indi-cate that several symptom dimensions corre-late with outcome measures, albeit that thepercentage explained variance is rather low(Van Os et al. 1996, Rosenman et al. 2003).

The results of these symptom-based stud-ies are confounded by several factors likethe natural course of the disease, treatmentregimen, compliance, substance abuse aswell as the availability and quality of health-care services. Whether the duration of theuntreated symptomatic period is indepen-dently connected with treatment responseand prognosis is still a matter of debate(Verdoux et al. 2001, Norman & Malla2001, Fuchs & Steinert 2004).

Deficits in cognitive and social capacitiesin children and adolescents have beenshown to be associated with the later devel-opment of schizophrenia (Olin et al. 1998,Yung et al. 1998, Kremen et al. 1998,Davidson et al. 1999). Although cognitiveimpairments are a core feature of schizo-phrenia and of considerable significance forcommunity outcome, it should be stressedthat a host of factors apart from cognitionsuch as psychosocial rehabilitation and edu-cational/vocational opportunities are modi-fying these associations (Ragland 2003,Green et al. 2004a).


Despite the awareness that psychoticsymptoms do not predict social and func-tional outcome measures, all antipsychoticsare targeted at the reduction of positivesymptoms as measured with rating scales.So far there is no convincing evidence thateither classic or so called atypical antipsy-chotics are effective in the improvement ofnegative or cognitive symptoms (Stip 2002,Awad & Voruganti 2004, Mishara and Gold-berg 2004, Verhoeven et al. 2005). Thisobservation has stimulated the NIMH tostart the so called Measurement And Treat-ment Research to Improve Cognition inSchizophrenia (MATRICS) initiative aimedat the development of new compounds forthe cognitive deficits of schizophrenia(Green et al. 2004b).

In conclusion

The rearrangement of symptoms andtypes of patients has been the leitmotiv eversince schizophrenia was conceived as a dis-ease. Both Kraepelin and Bleuler consid-ered the accompanying negative symptomsas crucial for the diagnosis of schizophreniathat was confirmed by a poor outcome. Therecognition of schizophrenia as an impre-cise concept that frequently resulted in dis-agreements, has led to the development of avariety of operational definitions of the dis-order. In the seventies of the past century atleast 10 sets of diagnostic criteria wereprevalent, a situation characterised byBrockington and co-workers (1978) as “areplacement of inarticulate confusion in thediagnosis of schizophrenia by a babble ofprecise but differing formulations of thesame concept”. The debate on the diagnoseswas virtually finished by the developmentof the ICD and DSM criteria, while at the

same time others advocated a polydiagnos-tic or flexible diagnostic approach (Carpen-ter et al. 1973, Kendell 1975b). Althoughthe categorical taxonomies identify severalsubtypes of schizophrenia, other approachesto distinguish psychopathological syn-dromes have been pursued. In 1963 Lorr etal. recognised in the first quantitative studythat the symptoms of psychotic disorderscould be grouped into ten major syndromesof which seven were manifestations ofschizophrenia. About 25 years later Liddle(1987a) proposed a three syndrome modelof chronic schizophrenia that was subse-quently widely accepted for schizophreniain general. Most of the studies that foundthree factors used for analysis the global rat-ings of the SANS/SAPS. This method, how-ever, leads to an artificial outcome since theanalysis of individual items of these scalesdemonstrate the existence of at least 11 syn-dromes (Stuart et al. 1999). With othersymptom checklists like the OPCRIT, 4 to 8dimensions have been described of whichthe number depends on the statistical proce-dures. Covert symptoms like cognitivedeficits are most probably more informativethan overt psychotic symptoms since theyare consistently related to outcome mea-sures (Milev et al. 2005). Symptom clustersand subtypes of schizophrenia should beconsidered purely descriptive until theirrelationship to other lines of evidence suchas response to treatment, course of illness,etiology and pathophysiology can bedemonstrated.

These endeavours are essentially similarand can be defined as an attempt to discoverrelevant phenotypes on the basis of phenom-enology, which for the time being willremain the cornerstone of the diagnosis andresearch methods of schizophrenia. Recent-ly, Kendler (2005) stated: ‘Our strongly helddesires to find the explanation for individual


psychiatric disorders are misplaced andcounterproductive’ and advocated explana-tory pluralism as a research attitude.

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