Schizoaffective Disorder: Concept and Reality - Schizophrenia Bulletin

14 Schizoaffective Disorder:Concept and Reality

by Ming T. Tsuang andJohn C. Simpson

Abstract

A wide variety of concepts have beenproposed to account for schizo-affective psychoses. Presenting amixture of schizophrenic andaffective symptoms, these psychoseshave long defied classification in theusual scheme of the two majordiagnostic categories, schizophreniaand major affective disorder.Empirical findings are often contra-dictory, and have sometimessupported the classification of schizo-affective disorder with schizophrenia,and, more recently, with majoraffective disorders. An alternativehypothesis is that schizoaffectivedisorder is fundamentally hetero-geneous, and that research effortsshould be directed toward the identi-fication of homogeneous subtypes.To illustrate the latter researchstrategy, we describe our currentresearch program of long-termfollowup and family studies ofpatients with schizoaffectivepsychoses and other atypicalpsychoses. Extensive data have beenobtained using blind, structuredpsychiatric interviews with probandsafter 30 to 40 years of followup, andwith their first degree relatives. Inthe same way, followup and familydata were obtained for patients whomet research criteria for schizo-phrenia, mania, and depression, andfor matched surgical controls. Bycomparing these groups of "typical"psychotic patients with the schizo-affective patients, we can selecthomogeneous subgroups of schizo-affective patients and analyze theircharacteristics to refine clinical andresearch criteria for the differentialdiagnosis of schizoaffective subtypes.

The purpose of this article is todiscuss diagnostic concepts of schizo-affective disorder and the relation ofthose concepts to the reality of

psychotic disorder in patients whohave schizoaffective features. Thistopic is of interest for severalreasons. First, it addresses the clini-cally important question of theappropriate diagnosis and treatmentof substantial numbers of "atypical"psychotic patients, i.e., those who donot unambiguously satisfy diagnosticcriteria for schizophrenia or majoraffective disorder. In particular, weare concerned here with theoccurrence in individuals of bothschizophrenic and affective features,e.g., delusions, hallucinations,thought disorder, or bizarrebehavior, accompanied by strikingmanic or depressive sympto-matology, acute onset, and goodrecovery.

Secondly, the issue of the validityof the concept of schizoaffectivedisorder lies at the heart of the majorenduring controversy in modernpsychiatry: the classification ofpsychotic patients and, specifically,the differential diagnosis of schizo-phrenia from bipolar disorder(manic-depression) and majordepression.

In view of the daunting complexityof these problems and the relativelyprimitive state of empirical research,we argue throughout this review forthe continuing need to consider allrelevant factors in order to avoidpremature and oversimplifiedconclusions. Following a discussionof diagnostic concepts related to theissue of schizoaffective disorder, weselectively review the empiricalsupport for various diagnosticmodels, and describe recent researchtrends in this field. We also presentour own reasons for adopting aresearch strategy based on a search

Reprint requests should be sent to Dr.M.T. Tsuang at Butler Hospital, 345Blackstone Boulevard, Providence, RI02906.

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for homogeneous subgroups ofschizoaffective patients.

The Concept ofSchizoaffective Disorder

Although the introduction of theterm "schizoaffective psychosis" canbe traced back 50 years to an influ-ential presentation by Kasanin(1933), concern with forms ofpsychosis showing mixed features ofschizophrenia and affective disordershas been a prominent fixture ofpsychiatric discourse for far longer,due to the fundamental importanceof the differential diagnosis of schizo-phrenia and manic-depression. AsKasanin (1933, p. 99) himselfacknowledged after characterizingschizoaffective patients, "Bleulermany years ago recognized suchcases." It is instructive to considerBleuler's position in some detailbecause of its historical importanceleading to the concept of schizo-affective disorder as a form ofschizophrenia.

Bleuler (1911/1950) devotedconsiderable attention to the differ-ential diagnosis of schizophrenia and"manic-depressive psychosis" and, indoing so, discussed the conjunctionof schizophrenia and manic-depressive symptoms. His theoreticalposition was that all manic-depressive symptoms can also occurin schizophrenia, and furthermore,that "hallucinations and delusions arepartial phenomena of the most varieddiseases." Hence the presence of thesesymptoms "is often helpful in makingthe diagnosis of psychosis, but not indiagnosing the presence of schizo-phrenia" (p. 294).

To make the differential diagnosis,Bleuler relied on the presence orabsence of specific schizophrenicsymptoms, namely, those "funda-mental" symptoms that defined theschizophrenic splitting of cognition

from emotion and behavior: formalthought disorder, flat or bluntedaffect, autistic tendencies, andambivalence. In view of recentconcern with overreliance on nonspe-cific schizophrenic symptoms forpurposes of diagnosis (e.g., Pope andLipinski 1978), it is instructive tonote the theoretical distinction thatBleuler made between these"fundamental symptoms" and lessspecific "accessory" symptoms suchas delusions and hallucinations. Inpractice, however, Bleuler appears tohave relied heavily on accessory aswell as fundamental symptoms fordifferential diagnosis. Thus, althoughhe acknowledged the occurrence ofdelusional states in manic-depression,and was careful to distinguishbetween formal thought disorder inschizophrenia compared to mania(schizophrenic "incoherence" vs.manic "flight of ideas") and inschizophrenia compared todepression (schizophrenic "blocking"vs. depressive "inhibition"), hebelieved that many cases of"melancholia and mania," "especiallythose with hallucinatory mania ormelancholia, or with manic ormelancholic delusions, respectively,belong to schizophrenia" (p. 287).

Differences in the course of theillness were also used by Bleuler todistinguish between schizophrenia(typically leading to deterioration)and manic-depression (with almostfull recovery between episodes).However, atypical cases were alsopossible: 'The periodic or cycliccourse may be absent in manic-depressive psychosis whereas, on theother hand, it may occur in schizo-phrenia" (p. 311). The decisivefactors in such cases were again thepresence or absence of "distinct signsof schizophrenia."

In summary, Bleuler's basicposition was that the combination ofschizophrenic and manic-depressive

features usually represented schizo-phrenia, and that the presence of"fundamental" schizophrenicsymptoms unambiguously indicatedcases of schizophrenia, regardless ofthe extent of affective sympto-matology.

In contrast to Bleuler, Kasanin's(1933) concern in describing schizo-affective patients was to delineatehomogeneous subgroups of psychoticpatients, and in particular, to differ-entiate a specific type of atypical casefrom a homogeneous group of"constitutional schizophrenics." Assuch, his concept of "schizoaffectivepsychosis" was primarily descriptiveand does not clearly indicate therelation of this syndrome to schizo-phrenia and manic-depression.However, by virtue of describing adistinct homogeneous group ofpsychotic patients, his concept leads •readily to the concept of a diagnosticentity different from schizophreniaand from manic-depression, butsharing features of both.

The primary value of Kasanin's1933 report was his precisedescription of what he believed to bea homogeneous group of patients, hisisolation of the primary features, andhis felicitous choice of the term"schizoaffective" to label thissyndrome by highlighting theatypical yet characteristic blending ofschizophrenic and affectivesymptoms. Other defining featuresincluded:

• Ages 20-39;

• Usually a history of a previousattack in late adolescence;

• Normal premorbid personality;

• Good social and work adjustment;• Very sudden onset in a setting of

marked emotional turmoil with adistortion of the outside world andpresence of false sensory impres-sions in some cases;

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• Definite and specific environmentalstress;

• Absence of any passivity orwithdrawal;

• Duration of a few weeks or monthsand followed by recovery.

Not surprisingly, subsequentinvestigators have not always beencontent to adopt Kasanin's termi-nology or definition, but haveproposed various terms and defini-tions in line with their own clinicalinterests and theoretical orientations.Nor did that process begin afterKasanin. Reports by Kasanin (1933)and other investigators as far back asBell (1849) have been described byVaillant (1965) as "the efforts ofpsychiatry to rename the recoveredschizophrenic." Among the 16eponyms that Vaillant lists are"mixed conditions of manic-depressive insanity" (Kraepelin 1913),"hysterical twilight state" (Bleuler1924), "schizophreniform state"(Langfeldt 1937), and "cycloidpsychoses" (Leonhard 1961). Procci(1976) compiled a similar list,updated to include Vaillant's (1965)own "remitting schizophrenia," aswell as "recovered schizophrenics"(Stephens, Astrup, and Mangrum1966), "good prognosis schizo-phrenia" (Fowler et al. 1972), and"reactive psychoses" (McCabe andStromgren 1975).

In the face of this profusion ofstudies, systematic progress towardunderstanding schizoaffectivepsychoses has been slowed by a lackof agreement on diagnosticterminology, and the resultant diffi-culty of comparing study samplesand results, and of replicatingprevious findings. A particularsource of confusion is the widespreaduse of the term "schizoaffective" tocover a variety of samples, usuallywithout specific diagnostic criteria.This situation persists in DSM-1II

(American Psychiatric Association1980), with its emphasis on theinclusion of patients with mixedschizophrenic and affectivesymptoms within the diagnosticcategories of "schizophrenia with asuperimposed atypical affectivedisorder" and "major depression orbipolar disorder with mood-congruent or mood-incongruentpsychotic features." "Schizoaffectivedisorder" survives only as adiagnostic category of last resort,and is defined as psychotic illnesswith a mixture of schizophrenia andaffective symptoms that fails tosatisfy diagnostic criteria for schizo-phrenia, major affective disorders, orschizophreniform disorder. Incontrast, the Research DiagnosticCriteria (RDC) of Spitzer, Endicott,and Robins (1978) include specificdiagnostic criteria for schizoaffectivedisorder and even for manic anddepressed subtypes.

That both DSM-III and RDCretain the term "schizoaffective"emphasizes the dominant concernwith the combination of schizo-phrenic and affective features,whether they occur concurrently orin distinct episodes. The choice ofterminology is important becausediagnostic labels serve as convenienthighly abbreviated descriptions. Forexample, "dementia praecox"emphasized early onset and deteri-oration (poor prognosis); "schizo-phrenia" emphasizes the splitting(lack of coordination) of the mentalprocesses of cognition, emotion, andbehavior; and "affective disorder"emphasizes mood disruption. Theamount of distortion caused by suchabbreviated description is offset, onehopes, by selection of the mostsignificant or salient features. Fortu-nately, the recent widespreadadoption of operational definitionsusing specific diagnostic criteria hasreduced the import of diagnostic

terminology, although the choice ofterminology still plays a major rolein our thinking and discourse.

Faced with the mounting confusionattributable largely to conceptualvagueness and the lack of uniformdiagnostic criteria, several investi-gators have attempted directly toclarify the diagnostic puzzle ofschizoaffective disorder. Vaillant(1965) systematically compared thecommon features observed by hisselected list of 16 studies of remittingschizophrenics. There was goodagreement across most studies aboutthe salient features, which included:

• An acute picture resembling schizo-phrenia but with symptoms ofpsychotic depression;

• Acute onset;• Confusion or disorientation during

the acute onset;• Good premorbid adjustment;• A clear precipitating event; and

• Remission to the best premorbidlevel of adjustment.

Comparison with Kasanin's (1933)list of defining features for schizo-affective psychoses (given above)shows a close correspondence.

Procci (1976) updated Vaillant'scomparison and found continuedgood agreement across studies on thesalient features of patients who are"neither clearly schizophrenic norclearly bipolar affective." In additionto the features listed above, Procci'sreview found evidence that suchpatients characteristically have afamily history of depression (alsostressed by Vaillant 1965, 1978) andpsychomotor excitation (hypomanicfeatures). Having isolated aconsistent subtype, Procci proceededto review the response to lithiumcarbonate therapy, followup studies,and family studies of schizoaffectivepatients. He concluded that schizo-affective psychosis encompasses a

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heterogeneous group of disorders,but that the relatively homogeneousgroup defined above probablyrepresents "a variant of affectivedisorder or an independent entitybearing a similarity to affectivedisorder" (p. 1176).

This conception of schizoaffectivedisorder corresponds nicely withKasanin's (1933) emphasis onhomogeneous subgroups of psychoticpatients. If schizoaffective disorder isfundamentally heterogeneous, itcould be that several diagnosticconcepts will be needed to describehomogeneous subgroups of schizo-affective patients. Mention hasalready been made of the manic anddepressive subtypes of schizoaffectivedisorder described by the RDC.Tsuang (1979) hypothesized thatthere are three distinct schizoaffectivesubtypes: a schizophrenic subtypeclosely related to schizophrenia, anaffective subtype closely related toaffective disorder, and an undiffer-entiated subtype that is distinct fromboth schizophrenia and affectivedisorder. A fourth possible subtype,of unknown significance at present,would represent the more-or-lessrandom occurrence of schizophreniaand affective disorder in the sameperson, corresponding to Bleuler's"mixed forms of manic-depressivepsychosis and schizophrenia," e.g.,"manic-depressive attacks released byschizophrenia" (Bleuler 1950, p. 269).

A relatively recent and highlyinfluential conception of schizo-affective disorder is that it represents(in many or most cases) a form ofaffective disorder, primarily bipolaraffective disorder. This viewpoint hasbeen forcefully argued in criticalreviews by Ollerenshaw (1973) andby Pope and Lipinski (1978). Centralto this argument is the nonspecificityof schizophrenic symptoms,contrasted with the predictive utilityof affective symptoms. We will

discuss the empirical support forthese points below. We merely notehere that this conception represents astriking reversal from the Bleulerianposition that patients with schizo-phrenic and affective symptoms areprobably schizophrenic. If the morerecent position is correct, it willmark a major landshift in psychiatricthought.

Nevertheless, the concept ofschizoaffective disorder as a form ofaffective disorder agrees with theKraepelian (and Bleulerian) two-entities tradition—that schizophreniaand affective disorder are the twoprimary and distinct forms ofpsychosis. This tradition has alsobeen challenged by the view thatthere is a continuum or spectrum ofpsychotic illness running from schizo-phrenia to affective disorder (Beck1967). In this view, the mixture ofschizophrenic and affective featuresdoes not represent a distinctdiagnostic entity, but rather an inter-mediate region of the continuumwhere schizophrenic psychosis shadesinto affective psychosis. In contrastto the two-entities tradition, forwhich the existence of schizoaffectivepatients poses a major puzzle andsomething of an embarrassment,schizoaffective syndromes fitnaturally into the schema of acontinuum model. An interestingvariant of the continuum model,leading to a similar conception ofschizoaffective disorder as anintermediate form of psychosis, is thehierarchical model of Foulds andBedford (1975).

We close this section with mentionof an empirical comparison byBrockington and Leff (1979) of eightalternative definitions of schizo-affective psychosis and relatedsyndromes, including the definitionsof Kasanin (1933), Stephens, Astrup,and Mangrum (1966), Welner,Croughan, and Robins (1974), the

Catego system (Wing, Cooper, andSartorius 1974), and the RDC. Ingeneral, the agreement across defini-tions was low. Values of Kappa (ameasure of concordance corrected forchance agreement) ranged from — .03to .50 (for Kasanin vs. Stephens),and the mean value of Kappa acrossthe diagnostic comparisons was .19(or, less conservatively, .27). In viewof the generally acceptable reliabilityof most of these definitions, theauthors attributed this lowconcordance to substantivedisagreement about the definingcharacteristics of schizoaffectivedisorder. This contrasts sharply withthe conclusions of Vaillant (1965)and Procci (1976) that studies ofschizoaffective-like patients haveusually studied similar individualswith a readily identifiable syndrome.

In this section, we have reviewedsome of the major concepts of schizo-affective disorder, and pointed upseveral areas of contention. Unfor-tunately, as demonstrated by Brock-ington and Leff (1979), there is stillconsiderable disagreement about thevalidity of different concepts ofschizoaffective disorder. What makesthe issue so difficult to resolve is thateach concept, by virtue of being adiagnostic concept, entails uniquediagnostic criteria that result inselecting patients for study whodiffer to some degree from patientsdefined by an alternative concept.Hence, reports based on differentdiagnostic concepts inevitablyproduce different findings. The onlyapparent way out of this "unnervingcircularity" is through "a continuousprocess whereby increasingly refineddiagnoses allow more definitivestudies of inheritance, outcome,response to treatment, etc., which inturn shape diagnostic concepts"(Brockington and Leff 1979, p. 97).To aid in this process, we nowsurvey empirical findings relevant to

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the major concepts of schizoaffectivedisorder.

Empirical Studies ofSchizoaffective Disorder

Schizoaffective Disorder as a Form ofSchizophrenia. Historically, thisconcept has been based largely on theBleulerian position that certainschizophrenic symptoms havepathognomonic importance for thedifferential diagnosis of schizo-phrenia, whereas affective symptomsare nonspecific (Bleuler 1950).Uncritical application of this positionevidently resulted in the overdiag-nosis of schizophrenia in Americaand a tendency to lump any patientswith even relatively nonspecificschizophrenic symptoms (such asdelusions and hallucinations) togetherwith more typical cases of schizo-phrenia (Pope and Lipinski 1978).Though a trend away from viewingschizoaffective disorder as a subtypeof schizophrenia is discernible in therecent literature on the subject,Croughan, Welner, Robins, andassociates (Croughan, Welner, andRobins 1974; Welner et al. 1977;Welner, Welner, and Fishman 1979),in a series of articles reporting thefindings arising from their extensivestudy of schizoaffective patients,conclude that schizoaffective disorderis an expression of schizophrenia anddoes not merit the status of a distinctdiagnostic entity.

Historically, a commonplace ofschizoaffective research has been theobservation that patients presentingsymptoms of both schizophrenia andaffective disorder are more likely torecover than those presenting schizo-phrenic symptoms alone (Vaillant1965; Procci 1976; Pope and Lipinski1978). The findings of Welner et al.(1977) do not support this traditionalassociation of schizoaffective disorder

and good prognosis. In their study,over 70 percent of the 114 patientsdiagnosed as suffering from schizo-affective or related psychoses had achronic course of illness, and over 80percent of these chronic cases deteri-orated. This is not an isolatedfinding, but agrees with severalrecent longitudinal studies of goodprognosis or remitting schizophrenicsthat have shown little or noprognostic significance for affectivesymptoms in patients with markedschizophrenic symptomatology(Hawk, Carpenter, and Strauss 1975;Vaillant 1978; Gift et al. 1980). SinceKraepelin's time, a chronic, deterio-rating course has been considered asign of schizophrenia. Thus, Welneret al. (1977) conclude that "whenschizoaffective illness is used todescribe a psychosis whose cardinalsymptoms are both schizophrenicand affective, the psychosis should beregarded as schizophrenia" (p. 420).In a subsequent article, Welner,Welner, and Fishman (1979)attempted to validate this finding ina family study of 20 probands whosefirst degree relatives had a history orpresence of affective or psychoticsymptoms. Twenty-seven of the 30relatives who had psychoticsymptoms also had a chronic deterio-rating course of illness which wasconsistent with a diagnosis of schizo-phrenia. The authors recommendedthat patients presenting a confusingadmixture of acute schizophrenic andaffective symptoms be labeled"undiagnosed" rather than "schizo-affective" because there is insufficientevidence for the validity of schizo-affective disorder as a distinct diag-nostic entity.

Recently, Himmelhoch et al. (1981)published a report coinciding withthe conclusions of Welner et al. at anumber of significant points. After748 patients were examined withrigorous diagnostic criteria, only 39

were identified as schizoaffective.The authors concluded that schizo-affective disorder, when defined bystringent longitudinal standards, is arare diagnosis. The diagnostic criteriaused by Himmelhoch et al. aresimilar to, but not identical with,those of Welner et al., with the mostsignificant difference being theformer group's requirement of inter-episodic thought disorder. Amongpatients who suffered thoughtdisorders between acute psychoticepisodes marked by prominentaffective features, a significantdifference was noted between patientslabeled "schizoaffective" and thoselabeled "affective" on clinical,demographic, and prognosticvariables. Clinically, schizoaffectivepatients were less likely thanaffective patients to abuse drugs.Based on demographic information,schizoaffective patients were morelikely than affective patients never tohave married, and, as for prognosis,schizoaffective patients were morelikely than affective patients torelapse. These data suggested asimilarity between schizoaffectivedisorder and schizophrenia.However, Himmelhoch et al. werenot willing to go as far as Welner etal. and dismiss schizoaffectivedisorder as a useful diagnostic entity.They concluded that although it maybe a category only rarely invoked,"schizoaffective" retains its diagnosticfunction by pointing to an affectiveelement that is not part of our usualconception of schizophrenia.

Schizoaffective Disorder as a Form ofAffective Disorder. Beginning in thelate 1960s, a number of recent studieshave argued that schizoaffectivedisorder is actually misdiagnosedaffective disorder. Stephens, Astrup,and Mangrum (1966) eschewed thecomplexities of diagnosing schizo-affective disorder as a subtype of

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schizophrenia, in favor of a simplerrating on a prognostic scale. Fromstudies of "good prognosis schizo-phrenics," McCabe et al. (1972) andFowler et al. (1972) suggested thatthe disorder they studied might be avariant of affective disorder ratherthan a subtype of schizophrenia.Similar conclusions were reached byClayton, Rodin, and Winokur(1968), based on family history data.McCabe and Cadoret (1976) alsonoticed a clear dissimilarity betweenschizoaffective disorder and schizo-phrenia in their review article, whichexamined age-corrected morbidityrisks for the first degree relatives ofpatients with atypical psychoses. Thestudies they analyzed consistentlyreported that relatives of patientswith atypical psychoses are morelikely to suffer from remittingpsychoses than from nonremittingpsychoses. In their summary McCabeand Cadoret maintained that "thegenetic evidence would suggest thatthe relationship of atypical psychosesto schizophrenia is minor" (p. 352).

A number of recent studies havesuggested that in many cases, schizo-affective patients would be moreaccurately classified as having amajor affective disorder. Thesestudies view "schizoaffectivedisorder" as a misnomer, as a labelinappropriately applied to a purelyaffective disorder because ofconfusing symptomatology. Readersof these studies are frequentlyreminded that acute episodes ofmania sometimes manifest symptomssuggestive of schizophrenia. Thewell-documented tradition of givingprecedence to schizophrenicsymptoms, especially in the UnitedStates, explains why a large numberof difficult-to-diagnose cases ofbipolar affective disorder may havebeen falsely labeled "schizoaffective."

• Sovner and McHugh (1976)concluded from a chart followup of

27 schizoaffective patients thatbipolar patients are sometimesmistakenly diagnosed as schizo-affective because of the time-honoredpractice of giving more weight toschizophrenic symptoms when theclinical picture is ambiguous. Abramsand Taylor (1976), using the RDC,were unable to find any significantdifference between groups of patientswith mania and schizoaffectivedisorder, manic type, compared forsymptoms, demographic charac-teristics, individual or family history,or treatment response. Brockington,Wainwright, and Kendell (1980)likewise observed close similaritiesbetween "schizomania" and "manic-depressive psychosis" in a 1- to4-year followup study of 32"schizomanic" patients. Theyconcluded that consideration shouldbe given to expanding the definitionof typical mania to encompasspatients whose manic sympto-matology is complicated bydelusions, hallucinations, andpassivity phenomena.

Pope and Lipinski (1978), in anoverview of the use of schizophrenicsymptoms in diagnosis, argued thatthe subordination of schizoaffectivedisorder to schizophrenia is the resultof a misguided tendency to attach thelabel "schizophrenic" to any disorderwhich manifests hallucinations,delusions, or emotional blunting,despite the fact that one or more ofthese can appear in cases of affectivedisorder. They appeal to' phenom-enologic studies, prognostic studies,family history studies, treatment-response studies, and combinationstudies to buttress their conclusionthat "the entire range of 'schizo-phrenic' symptoms is recorded, notin a few cases of MDI [manic-depressive illness], but in about 20percent to 50 percent of both manicand depressed patients" (p. 813).Hence, although they do not rule out

the possibility of a distinct disorderseparate from schizophrenia andaffective disorder, Pope and Lipinskiargue that the data which point inthis direction can be more convinc-ingly and economically explained byassuming that many, if not all, caseslabeled "schizoaffective" are actuallycases of affective disorder.

However, not all studies whichposit a close relationship betweenschizoaffective and affective disorderlead to the conclusion that the twodisorders should be collapsed intoone. Tsuang, Dempsey, and Rauscher(1976) and Tsuang and Dempsey(1979) examined a group of 85schizoaffective patients from a seriesof 310 consecutive "atypical" schizo-phrenic admissions at the Universityof Iowa Psychiatric Hospital between1934 and 1944. All these patientsreceived hospital diagnoses of schizo-phrenia, but failed to meet theWashington University diagnosticcriteria for schizophrenia (Feighner etal. 1972) because of short duration ofsymptoms or the presence of affectivesymptoms at admission. Ninety-eightpercent of the 85 schizoaffectivepatients had depressive symptoms (75percent had four or more depressivesymptoms), and 80 percent hadmanic symptoms (58 percent hadthree or more manic symptoms)(Tsuang, Dempsey, and Rauscher1976). The schizoaffective patientswere compared with 200 schizo-phrenics and 325 affective disorderpatients (100 bipolar, 225 unipolar)selected according to the WashingtonUniversity diagnostic criteria. Atadmission the schizoaffective patientsmost resembled the bipolar groupexcept for a significantly higherproportion of precipitants and anearlier age of onset in the schizo-affective group. At followup 30 to 40years later, the schizoaffective groupfared significantly better than thegroup of schizophrenics, but signif-

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icantly worse than the affectivedisorder groups. Taken together,these findings indicate that schizo-affective disorder is in some waysmore closely related to affectivedisorder than to schizophrenia andshould clearly be excluded fromstudies of schizophrenia. However,the complexity of the overall picturealso argues against a simple reclassi-fication of schizoaffective disorder asa form of affective disorder.

Schizoaffective Disorder as a Distinctor Heterogeneous Illness. Leonhard(1961) described three acute onsetpsychoses with good prognosis underthe heading of "cycloid" psychoses,which he claimed were neitherschizophrenic nor affective disorders,but constituted a distinct diagnosticentity. The work of otherinvestigators has subsequentlysupported this conclusion. Kaij(1967) and Walinder (1972) reportedtwo families with a history of schizo-affective psychosis. The maincharacteristics of relatives with thispsychosis were a strong affectivecomponent—predominantlydepression, swings in mood betweenelation and despondency, someparanoid delusions, confusion, andan acute, sometimes sudden onsetand complete recovery. Morerecently, Perris (1974) usedLeonhard's classificatory system andconcluded that the cycloid psychosesdo, in fact, represent a distinctnosological entity based on theoutcome of 60 patients. Thesepatients were characterized by acuteonset, periodic recurrence,termination free from residualdefects, and an array of other illness-related factors. McCabe (1975)examined 40 patients from Denmarkwho had psychoses specificallyrelated to a precipitating stressaccording to the criteria ofStromgren (1968), and concluded

that these patients could be distin-guished as a third functionalpsychosis after manic-depressivepsychosis and schizophrenia.

Mitsuda (1965, 1967, 1974) focusedattention on the relationship between"atypical psychosis" and epilepsy.Mitsuda pointed out that atypicalpsychosis, with both schizophrenicand affective features, carries aparoxysmal or "ictal" stamp, and isnearly always characterized bydisorders of consciousness. He alsonoted a higher incidence of epilepsyrather than schizophrenia or manic-depressive psychosis among thefamilies in his study. Mitsuda arguedthat "atypical psychosis" is a distinctnosological entity which could betransmitted as a dominant or as arecessive trait. Since there is no clearevidence of the mode of inheritance,however, a cautious attitude shouldbe adopted toward these results.

Studies of psychiatric illness inrelatives of schizoaffective patientsprovide a useful source of infor-mation about distinctiveness ofschizoaffective disorder. If schizo-affective disorder is geneticallydistinct, we would expect to find anincreased risk of schizoaffectivedisorder in families of schizoaffectivepatients compared to families ofpatients with schizophrenia or majoraffective disorder. We would alsoexpect to find less schizophrenia inrelatives of schizoaffective patientsthan in relatives of schizophrenicpatients, and less affective disorder inrelatives of schizoaffective patientsthan in relatives of patients withaffective disorders.

Recently, a number of studies havebeen made of psychiatric illness inrelatives of schizoaffective patients.Abrams (1984, this volume) reviewedthis topic in detail and concludedthat the empirical data provided bythese recent studies do not supportthe status of schizoaffective disorder

as a separate and distinct diagnosticentity. The reader is referred toAbrams' article for a detaileddiscussion of this research. Thegeneral pattern is that schizoaffectivedisorder is uncommon in families ofprobands with schizoaffectivedisorder, schizophrenia, and affectivedisorder (Angst, Felder, andLohmeyer 1979a; Mendlewicz,Linkowski, and Wilmotte 1980;Baron et al. 1982). Gershon et al.(1982) found a greater familial riskfor schizoaffective disorder withschizoaffective probands compared toprobands with affective disorders,but this effect was nonspecific andreflected increased risks for schizo-phrenia and for affective disorders infamilies of schizoaffective patients.

In a record study of the morbidityrisk for psychosis in over 1,000 firstdegree relatives of 150 schizoaffectivepatients, Angst, Felder, andLohmeyer (1979a) found that themorbidity risk for affective disorderamong relatives was somewhatgreater than the risk for schizo-phrenia. Although the authorsconcluded that "from a geneticviewpoint schizoaffective disordertakes an intermediate positionbetween schizophrenia and affectivedisorders," no direct comparisonswere made with relatives of probandswith schizophrenia or affectivedisorders. Hence, these results aresubject to various interpretations.Other researchers have found thatthe risk for affective disorders issimilar in relatives of schizoaffectiveand affective disorder probands(Tsuang, Dempsey, and Rauscher1976; Tsuang et al. 1977; Abramsand Taylor 1980; Mendlewicz,Linkowski, and Wilmotte 1980;Baron et al. 1982; Gershon et al.1982). The morbidity risk for schizo-phrenia in first degree relatives ofschizoaffective patients has beenreported to be either as great as the

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risk in relatives of schizophrenics(Tsuang, Dempsey, and Rauscher1976), or intermediate between therisk in relatives of schizophrenics andthe risk in relatives of affectives(Tsuang et al. 1977; Mendlewicz,Linkowski, and Wilmotte 1980;Baron et al. 1982). Taken together,these family data are more consistentwith a hypothesis of diagnosticheterogeneity than with thehypothesis that schizoaffectivedisorder is a distinct diagnosticentity.

Since it is generally acknowledgedthat the terms "schizophrenia" and"affective disorder" designate familiesof illnesses with a broad range ofdefining characteristics rather thansingle, homogeneous diseases, thequestion of heterogeneity naturallyarises in studies of schizoaffectivepatients. For example, using the sameprobands and relatives as in theirstudy cited earlier, Angst, Felder,and Lohmeyer (1979b) attempted toanswer the question: Are schizo-affective psychoses heterogeneous?They subdivided the probands bysex, age at first episode, number ofepisodes, schizophrenic subtypes,affective subtypes, and schizo-affective subtypes, but they wereunable to detect any significantdifferences in the morbidity riskamong relatives of probands. Theonly indication of heterogeneity wasfound when probands were dividedaccording to age of onset: relativesof schizoaffectives were at a higherrisk for schizoaffective disorder if thepatient became ill between the agesof 20 and 29 years. Although theyinterpreted their data as confirmingthe existence of schizoaffectivedisorder as a third diagnostic entityalongside schizophrenia and affectivedisorder, their findings did not allowthem to distinguish between schizo-affective subgroups using the external

criterion of morbidity risk amongrelatives.

The family and linkage study ofMendlewicz, Linkowski, andWilmotte (1980), on the other hand,did suggest that schizoaffectivedisorder is heterogeneous. Theyconcluded that there is a genetic linkbetween schizoaffective disorder andaffective disorder on the basis of thehigh morbidity risk for manic-depressive illness in relatives ofschizoaffective patients. However,other factors, such as theunexpectedly high prevalence ofschizophrenia in relatives, suggestedthat some cases of schizoaffectivedisorder may be traced to genesrelated to schizophrenia. Proccisurveyed the literature in 1976 acrossa variety of dimensions, includingacute symptomatology, response tolithium carbonate therapy, followupstudies, family history, and genetics.He concluded that, most likely,schizoaffective psychosis is a hetero-geneous entity that includes anumber of different pathologicalstates.

Similar results were obtained in astudy of 35 psychotic sib pairsconducted by Tsuang (1979). Tsuangcompared the actual combinations ofpsychoses in sib pairs with thecombinations that would be expectedif schizoaffective disorder weregenetically independent, a variant ofaffective disorder, or a variant ofschizophrenia. Results wereconsistent with the conclusion thataffective disorder and schizophrenia,but not schizoaffective disorder, aregenetically distinct. Furthermore,these analyses indicated that schizo-affective disorder is geneticallyheterogeneous, with at least twosubtypes: an affective subtype and aschizophrenic subtype. A third,undifferentiated, subtype was alsoproposed as a means of accountingfor patients whose disease resists

classification into the schizophrenicor affective subtype, or because of anadmixture of strong schizophrenicand affective features, or in caseswith insufficient information.

Another approach to analyzing theheterogeneity of schizoaffectivedisorder is to subtype patientsaccording to the polarity of theiraffective features. This is the schemeadopted by Spitzer, Endicott, andRobins (1978) in the RDC. Clayton(1982) argued for the usefulness ofthis approach in a review of studiesof schizoaffective manic and schizo-affective depressed patients. Claytonalso presented preliminary findingsfrom a small sample of 36 schizo-affective patients indicating that thesesubgroups can be distinguished onthe basis of symptomatology andespecially family history. Brock-ington, Kendell, and Wainwright(1980) and Brockington, Wainwright,and Kendell (1980) reported similarresults, and also found distinct differ-ences in the course and outcome,although the depressive subgrouptended to be highly heterogeneous.The family history comparisonsmade by Angst, Felder, andLohmeyer (1979b), on the otherhand, provided no evidence for thesubtyping of schizoaffective disprderon the basis of polarity or along thelines of the Kraepelinian two-entitiestradition.

More recently, Baron et al. (1982)conducted a study of schizoaffectiveillness, schizophrenia, and affectivedisorders in first degree relatives ofschizoaffective patients who weresubdivided according to theirsymptom patterns into schizophrenicand affective subtypes. The affectivesubgroup was further subdivided intomanic and depressed subtypes usingthe RDC. Comparisons of thefamilial patterns of psychotic illness,using matched groups of schizo-phrenic, unipolar, and bipolar

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probands, showed that the schizo-phrenic subgroup was geneticallysimilar to the schizophrenic group,whereas the affective subgroupresembled the unipolar and bipolarprobands. Additional analyses basedon small samples suggested that theaffective subtype can be meaningfullysubdivided into manic and depressivesubtypes along the lines of the RDC.In particular, relatives of the schizo-affecrive-manic subgroup were atgreater risk for unipolar and bipolaraffective disorders than relatives ofthe schizoaffective-depressedsubgroup, although the differenceswere not statistically significant. Thisstudy clearly demonstrates "thepotential utility of diagnosticsubtyping in sorting out homoge-neous subgroups from among theschizoaffective psychoses" (Baron etal. 1982, p. 259).

Conclusion

Despite the large number of investi-gations of schizoaffective patientsthat have been conducted, theprincipal research problems remainunresolved: the validity of theconcept of schizoaffective disorder,and the similarity of schizoaffectivepatients to patients with typicalforms of schizophrenia and majoraffective disorders. As this surveyhas indicated, empirical studies canbe cited to support several divergentconcepts of schizoaffectivedisorder: that this "disorder" isactually (a) a form of schizophrenia,(b) a form of major affectivedisorder, or (c) qualifies as a distinctand possibly heterogeneousdiagnostic entity.

Evidence can also be cited tosupport the hypothesis that schizo-affective disorder actually identifiesan intermediate region on aunidimensional or hierarchicalcontinuum of psychotic illness. This

hypothesis was suggested in part bysuccess in differentially predictingoutcome using prognostic scales(Stephens, Astrup, and Mangrum1966). The blending of schizophrenicand affective symptoms in schizo-affective patients, and the inter-mediate position (between schizo-phrenia and major affectivedisorders) reported by Tsuang andDempsey (1979) in a study of long-term outcome, are also consistentwith the continuum hypothesis. Thishypothesis has also been suggested asa means of explaining intransigentproblems in the classification ofschizoaffective patients whencomparisons are made on the basis ofhistory, clinical picture, and outcome(Brockington and Leff 1979; Brock-ington, Kendell, and Wainwright1980). In this sense, the concept of apsychotic continuum provides avaluable alternative to diagnosticconcepts derived from theKraepelinian two-entities tradition.

The widespread divergence ofempirical findings in this area ofresearch does not necessarily indicatethat certain studies need to becompletely discounted. Analternative and more promisingapproach is to accept these repeateddifferences as evidence for the hetero-geneity of schizoaffective disorder.Together with differences in selectioncriteria (arising from differentdiagnostic concepts) and theinevitable selection factors in hospitalstudies (Himmelhoch et al. 1981),this heterogeneity could help accountfor a number of discrepant findings.Faced with evidence of substantialheterogeneity, an appropriateresearch strategy is to search forhomogeneous subgroups of schizo-affective patients (e.g., see Angst,Felder, and Lohmeyer 1979b; Tsuang1979; Brockington, Kendell, andWainwright 1980; Brockington,Wainwright, and Kendell 1980;

Clayton 1982). This research strategymakes clinical sense as well, becausedifferential diagnosis of schizo-affective patients is needed fortreatment choice (e.g., neurolepticsvs. lithium) and prognosis (e.g.,chronic course vs. episodic orremitting course).

In order to identify and analyzehomogeneous subtypes of schizo-affective disorder, it is helpful toincorporate information abouthomogeneous subtypes of schizo-phrenia and major affectivedisorders. Our current researchprogram—in which schizoaffectivepatients have been studied using thesame procedures for studying thelong-term outcome and family dataof strictly defined groups of schizo-phrenics, manics, and depressives—will now be described to illustratethis research strategy.

We have already briefly describedthe selection of a sample of 85schizoaffective patients forcomparison with 525 patients (the"Iowa 500" sample) meeting theWashington University researchcriteria (Feighner et al. 1972) forschizophrenia (n " 200), mania(n = 100), and depression(n = 225). The Iowa 500 Study alsoincluded a matched group of 160surgical controls in order to ensureblindness during followup and familyinterviews, and to providecomparison groups for analyzingoutcome and mortality. Additionaldetails are given elsewhere (Tsuang,Dempsey, and Rauscher 1976;Tsuang et al. 1977, 1979).

The schizoaffective sample of 85patients is a subset of 310 "atypicalschizophrenics," who, like the Iowa500 probands, were hospitalized atthe University of Iowa PsychiatricHospital between 1934 and 1944. Ofthe 3,800 original admissions duringthis decade, 510 had received a chartdiagnosis of schizophrenia. Of these,

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the 310 who did not meet theresearch criteria of Feighner et al.(1972) were collectively called"atypical" schizophrenics. Using thesame blind procedures employed forthe Iowa 500 Study, we collected 30-to 40-year followup and family datafor these "atypical" schizophrenics,along with a matched control groupof 176 surgical patients admitted tothe University of Iowa GeneralHospital during the same period oftime (to show the comparison withthe earlier study, we have termedthis the Iowa Non-500 Study).

We reported above the results ofcomparing the subgroup of 85 schizo-affective patients with the Iowa 500Study groups after comparisons weremade on the basis of sex, age atadmission, precipitating factors,outcome, and a family history ofschizophrenia or affective disorder.Briefly, we found that the schizo-affective group differed greatly fromthe schizophrenics, and most closelyresembled the mania group whenallowance was made for a youngerage at onset and a higher frequencyof precipitants (Tsuang, Dempsey,and Rauscher 1976). Comparisons oflong-term outcome showed thatschizoaffective patients fared betterthan schizophrenics, but significantlyworse than patients with affectivedisorders (Tsuang and Dempsey1979).

In our current research, we arecontinuing the analysis of these 85schizoaffective patients in order todevelop more precise diagnosticcriteria for schizoaffective disorderand to determine if subtypes can beidentified for purposes of diagnosisand treatment. Additional compar-isons are being made with the typicalgroups of psychotics from the Iowa500 Study using the variablesmentioned above, plus clinicalfeatures (rated from admission

hospital charts) and family data fromblind structured psychiatric inter-views with first degree relatives(Tsuang, Woolson, and Simpson1980). Previous analyses have shownthat our groups of schizophrenic andaffective disorder patients representtwo different nosological conditions(Tsuang, Woolson, and Fleming1979; Tsuang, Winokur, and Crowe1980). Furthermore, these groups arerelatively homogeneous with respectto lifetime psychiatric diagnoses(Tsuang, et al. 1981) and family data(Tsuang, Winokur, and Crowe 1980).At present, therefore, we are investi-gating index admission variables thatdiscriminate between schizophreniaand major affective disorder(according to the final studydiagnosis, which incorporates allrelevant information including long-term course and family data) to seehow well these same variablessubclassify schizoaffective patientsinto "schizophrenic" and "affective"homogeneous subgroups. Othertaxonomic procedures are also beingused to validate these analyses.Then, by analyzing the character-istics of such subgroups, we areattempting to develop clinical andresearch diagnostic criteria for thedifferential diagnosis of schizophrenicpatients. The subtyping criteria willbe tested and refined by applicationto the larger study sample of 310atypical schizophrenics. In the future,we plan to conduct a prospectivecohort and family study based on adifferent population of psychoticpatients to test the generality ofdifferential diagnostic criteriadeveloped using our Iowa studysamples. We also expect thatbiological and psychosocial researchwill eventually play a major role indeciding how to classify and treatpatients with schizoaffective features.

In closing, it is worth noting thatthe continuing research interest in the

concept of schizoaffective disorder isan indication of the incompletenessand inadequacy of current conceptsof schizophrenia and major affectivedisorders. For this reason, researchconcerning schizoaffective disorderhas the potential to make a majorcontribution to our understandingand clinical management of the entirespectrum of major psychoticdisorders.

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Acknowledgment

The research reported was supportedin part by funds from the NationalInstitute of Mental Health, UnitedStates Public Health Service GrantsMH-24189, MH-31673, andMH-38079. Jerome A. Fleming,M.S., assisted in the preparation ofthis article.

The Authors

Ming T. Tsuang, M.D., Ph.D.,D.Sc, is Professor and ViceChairman, and John C. Simpson,Ph.D., is Assistant Professor(Research), Department of Psychiatryand Human Behavior, BrownUniversity. In addition, Dr. Tsuangis Director, and Dr. Simpson isResearch Scientist, PsychiatricEpidemiology Research Unit, ButlerHospital, Providence, RI.

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