schizotaxia clinical implications and new directions for research

7/27/2019 Schizotaxia Clinical Implications and New Directions for Research

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"Schizotaxia": Clinical Implications andNew Directions for Researchby Stephen V. Faraone, Alan I . Qreen, Larry J . Seidman,and Ming T. Tsuang

The At Issue section of the Schizophrenia Bulletin con-tains viewpoints and arguments on controversial issues.Articles published in this section may not meet the stricteditorial and scientific standar ds that are applied tomajor articles in the Bulletin. In addition, the viewpointsexpressed in the following article do not necessarily rep-resent those o f the staff or the Editorial Advisory Board ofthe Bulletin The Editors.

AbstractWe sought to show that (1) schizotaxia (Meehl's termfor the predisposition to schizophrenia) is a clinicallyconsequential condition, and (2) distinguishing it fromschizotypal personality disorder may be useful fromboth clinical and scientific perspectives. We review thefeatures of schizotaxia that may be relevant in clinicalsettings and discuss their implications for the diagno-sis, psychosocial functioning, family intervention andtreatment of people in schizophrenia families . Ourreview indicates that prior work finds some of thenonpsychotic and nonschizotypal relatives of schizo-phrenia patients to have a psychiatric syndrome char-acterized by negative symptoms, neuropsychologicalimpairment, and psychosocial dysfunction. FollowingMeehl, we call this constellation of clinical and neuro-biological features schizotaxia. The studies we reviewsuggest it may be worthwhile to consider schizotaxiaas a separate diagnostic class. Doing so would alertclinicians to a neurobehavioral syndrome not ade-quately covered by current diagnostic criteria andwould motivate researchers to develop diagnostic andtherapeutic approaches aimed at helping schizotaxicindividuals and, perhaps , prevent ing the onset ofschizophrenia.

Keywords: Schizophrenia, schizotaxia, genetics,prevention, spectrum

Schizophrenia Bulletin, 27(1):1-18,2001.

In 1962, Paul Meehl used the term "schizotaxia" todescribe the genetic predisposition to schizophrenia(Meehl 1962). Schizotaxic individuals, he surmised,would deve lop e i ther schizotypy or schizophrenia ,depending on environmental circumstances. Eventually,schizotypy (in the form of schizotypal personality disor-der) entered the diagnostic nomenclature. Schizotaxia didnot. It was used in research to ind icate the premorbid neu-rological substrate of schizophrenia, but it was not exam-ined as a clinically meaningful syndrom e.Now, almost 4 decades later, research suggests thatschizotaxia may be a clinically consequential condition.This work describing abnormalities in affect, cognition,and social functioning among the nonschizotypal andnonpsychotic relatives of schizophrenia patients shows

that schizotaxia is not merely a theoretical construct; ithas psychiatric and neurobiological features that m ay jus -tify further research about its nosologic validity.Although our use of the term schizotaxia is consistentwith Meehl's view of it as the underlying defect amongpeople genetically predisposed to schizophrenia, we donot endorse other aspects of his theory if we have notexplicitly done so in this article. For example, havingwritten his theory before molecular genetic data wasavailable, Meehl favored a single major gene theory ofschizophrenia, which has since been proven false bygenetic linkage studies. Also, Meehl view ed schizotypy as

the only clinical phenotype of schizotaxia. This articlesuggests that, when not expressed as schizotypy, schizo-taxia results in neuropsychological deficits and negativesymptoms.There have already been comprehensive reviews ofthese schizotaxic fea tures (see , e .g . , the issue of

Schizophrenia Bulletin (20(1), 1994) edited by Moldinand Erlenmeyer-Kimling). In this article, we seek not toreproduce that information but to inform clinicians about

Send reprint requests to Dr. M. Tsuang, Harvard Dept. of Psychiatry,Massachusetts Mental Health Center, 74 Fenwood Road, Boston, MA02115; e-mail: [email protected].


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the clinical features of schizotaxia and to motivateresearchers to develop diagnostic and therapeuticapproaches aimed at helping those with schizotaxia.Clinical Features of SchizotaxiaThe clinical descriptions of most psychiatric conditionsoriginally derived from reports of patients who presentedwith a specified cluster of signs and symptoms. In con-trast, clinical descriptions of schizotaxia come from stud-ies of people genetically predisposed to schizophrenia: therelatives of schizophrenia patients. Such studies infer aclinical or neurobiological abnormality to be a potentialfeature of schizotaxia if it is elevated among these rela-tives and among schizophrenia patients. In this section weconsider three clinically relevant areas of research: psy-chiatric signs and symptoms, neuropsychological per-formance, and psychosocial functioning.Psychiatric Signs and Symptoms. Because family,adoption, and twin studies firmly support the idea thatrelatives of schizophrenia patients are at high risk forsc h iz o typa l pe r sona l i ty d i so rde r (Torge r se n 1985 ;McGuffin and Thapar 1992; Battaglia and Torgersen1996) , severa l s tudies have a t tempted to de te rminewhich schizotypal symptoms are most common amongthe relatives of patients with schizophrenia. For exam-ple , Gunderson, et al. (1983) found that relatives ofschizophrenia patients were at high risk for social isola-tion, interpersonal dysfunction, and impoverished affec-tive experiences. In that study, mild psychotic like symp-toms such as recurrent illusions and magical thinkingwere more common in relatives who were themselvesdiagnosed with borderline personality disorder. Tsuanget al. (1991) reported that negative symptoms (especiallyflat affect and avolition) were significantly elevated inthe schizophrenia families, while positive symptomswere not. In the Roscommon family study, odd speech,social dysfunction, and negative symptoms strongly dis-criminated relatives of schizophrenia patients from con-trols. In contrast, positive symptoms, suspicious behav-ior, and avoidant symptoms were less discriminating(Kendler et al. 1995).

Consistent with these studies, psychometric assess-ments of schizotypa l symptoms among re la t ives ofpatients with schizophrenia have found a predominance ofnegative rather than positive symptoms. For example,Grove et al. (1991) showed that relatives of schizophreniapatients have greater deficits on the Physical AnhedoniaScale (which measures negative schizotypal features) thanon the Perceptual Aberration Scale (which measures posi-tive schizotypal features). Although we must consider thepossibility that artifacts of self-report scales such as

defensiveness might have led to these results, their consis-tency with direct interview studies is com pelling.In summary, the literature to date provides firm sup-port for the idea that nonpsychotic relatives of schizophre-nia patients are at risk for schizotypal personality traits.The literature also shows that the relatives in schizophre-nia families are more likely to express negative symptomsthan positive symptoms, although, as the Roscommonstudy showed, positive schizotypal symptoms are alsofound among nonpsychotic relatives of schizophreniapatients.These studies have focused on positive and negativeschizotypal traits because several studies suggested thatschizotypal symptoms fell along two dimensions: cogni-tive-perceptual and interpersonal, or positive and negative(Raine and Allbutt 1989; Kendler et al. 1991). But three-and even four-dimensional solutions have also beenreported by others (Muntaner et al. 1988; Bentall et al.

1989; Hewitt and Claridge 1989; Raine et al. 1994; Chenet al. in press). These studies suggest that, as is the casefor schizophrenia, we may need a third dimension, disor-ganization, to adequately describe schizotypal signs andsymptoms. Thus, a more complex view of clinical schizo-typal traits should be examined in future studies ofschizotaxia.Given that negative schizotypal symptoms are promi-nent among relatives of schizophrenia patients, we would

expect these relatives to also show an excess of schizoidpersonality disorder. But relevant data are mixed. In aDanish adoption study, the biological relatives of schizo-phrenia patients did not show an excess of schizoid per-sonality (Kety et al. 1994). Similar results were reportedin a family study by Maier et al. (1994a; 19946) and atwin study by Torgersen et al. (1993). In contrast, twofamily studies found higher rates of schizoid personalityamong relatives of schizophrenia patients compared withrelatives of controls (Dorfman et al. 1993; Kendler et al.1993). Because there are no syste ma tic differencesbetween studies that do and do not find schizoid personal-ity in schizophrenia families, further work is needed toclarify the nature of the negative symptoms of schizotaxiaand to determine why these are expressed in negativeschizotypal, but not schizoid traits.Neuropsychological Performance. When the genes forschizophrenia do not lead to frank psychosis, will theynonetheless affect the brain and lead to neurobiologicalabnormalities and neuropsychological deficits? Severaldecades of research suggest that the answer is "yes"(Seidman 1997). Abnorm alities found among relatives ofschizophrenia patients include eye tracking dysfunction(Levy et al. 1994), allusive thinking (Catts et al. 1993),neurologic signs (Erlenmeyer-Kimling et al. 1982), char-ac te r is t ic audi tory evoked potent ia ls (Fr iedman and


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Squires-Wheeler 1994), neuropsychological impairment(Kremen et al. 1994), and structural brain abnormalitiesassessed by magnetic resonance imaging (Seidman et al.1997). Although each of these domains of research hasprovided valuable data about the neurobiological featuresof schizotaxia, we focus here on the neuropsychologicalfindings because they describe deficits that have clinicallymeaningful implications for members of schizophreniafamilies.

Two research paradigmsstudies of children ofschizophrenia patients and studies of adult relatives ofschizophrenia patientshave provided data about theneuropsychological features of schizotaxia. It is useful todistinguish studies of child and adult relatives because,unlike children, adults have lived through some, or all, ofthe risk period for schizophrenia. Thus, both types of rela-tive groups will include some schizotaxic individuals butstudies of children are more likely to include cases thatwill eventually develop schizophrenia.

One neuropsychological function that differentiateschild relatives is motor ability. Impaired motor ability pre-sents in children as soft neurological signs such as dis-turbed gait, poor balance, uncoordination, motor im persis-tence and impaired mirror drawing (Lifshitz et al. 1985;Asarnow and Goldstein 1986). In contrast, motor func-tioning has been less consistently impaired among adultrelatives of schizophrenia patients (Kinney et al. 1986;Cannon et al. 1994; Faraone et al. 19956; Kinney et al.1991; Rosen etal. 1991).

Perceptual-motor speed tests assess the ability to per-ceive stimuli and react to them quickly in an appropriatemanner. Among the children of schizophrenia patients,there is consistent evidence for deficits on such tests(Er lenmey er-Kimlin g e t a l . 1982; Nuech ter le in andDawson 1984). Similar results have also been foundamong adult relatives. For example, in studies from twodifferent research groups, nonpsychotic relatives were sig-nificantly slower on the Trail Making Test (Pogue-G eile etal . 1991; Keefe et al. 1992; Keefe et al. 1994). Similartrends were reported by others (Goldberg et al. 1990;Condray and Steinhauer 1992).

Tests of short-term mem ory assess the ability to retaininformation in memory for a brief duration (e.g., recallinga phone number after finding it in the directory). In most(Mednick and Schulsinger 1968; Sohlberg 1985; Landauet al. 1989) but not all (Worland and Hesselbrock 1980)studies, children of schizophrenia patients showed poorshort-term memory as measured by oral arithmetic scores(which require short-term memory to manipulate mathe-matical concepts). They are not consistently impairedwhen asked to recall a string of digits (Mednick andSchu ls inge r 1968; Worland and Hess e lbrock 1980;Cornblatt and Erlenmeyer-Kimling 1985; Lifshitz et al.

1985), but they do show deficits if distracted during digitrecall (Harvey et al. 1 981; Winters et al. 1 981; Cornblattand Erlenmeyer-Kimling 1985; Spring 1985). Short-termdigit recall has not been impaired in studies of adult rela-tives (Roxborough et al. 1993; Faraone et al. 19956),probably because of the lack of a distraction componentin those studies.

Impaired vigilance (often referred to as sustainedattention) is usually measured with a continuous perform-ance test (CPT), which presents a long series of stimuliand asks the subject to respond whenever a rare targetstimulus appears. Cornblatt and Keilp's (1994) review of40 studies using the CP T shows that vigilance deficits areevident among both the adult and child relatives of schiz-ophrenia patients.

There has been little neuropsychological evaluationof verbal ability and language among children of schizo-phrenia patients. Most studies of adult relatives have notfound differences in general verbal ability, although therewas some evidence for poorer vocabulary scores in onesample (Faraone et al. 19956). Notably, three studiesfound significant impairments in speed and ease of verbalproduction (Pogu e-Geile et al. 1991 ; Keefe et al. 1992;Roxborough et al. 1993; Keefe et al. 1994) and Cannon etal. (1994) found deficits in language abilities.

Difficulties with language have also been docu-mented in studies of communication deviance, which havefound unclear, amorphous, disruptive, or fragmented com-munication among the parents of schizophrenia patients(Wynne and Singer 19636; Singer and Wynne 1965;Doan e et al. 19 81 ; Rund 1986 ; Velligan et al. 199 0;Docherty 1993; Docherty 1994; Miklowitz 1994; Rund1994; Velligan et al. 1995; Docherty et al. 1996; Velliganet al. 1996). Given these communication problems, it isnot surprising that relatives of schizophrenia patients alsoshow signs of thought disorder (Lidz et al. 1962; Wynneand Singer 1963a; Wynne and Singer 19636; Rosman etal. 1964; Singer and Wynne 1965; Schopler and Loftin1969; Arboleda and Holzman 1985; Saccuzzo et al. 1988;McConaghy 1989; Shenton et al. 1989; Romney 1990).Indeed, communication deviance and thought disorder areusually associated with one another (Docherty 1994). Thethought disorder observed among relatives is never assevere as that seen among schizophrenia patients, but itdoes share qualitatively similar characteristics such aslooseness of associations, autistic logic, word finding dif-ficulties, perseveration, and conceptual disorganization.

Studies of children of schizophrenia patients haveprovided scant information about the ability to learn andrecall verbal material. Adult relatives, however, have dif-ficulties recalling the details of a short story (Roxborou ghet al. 1993; Cannon et al. 1994; Faraone et al. 19956;Faraone et al. in press;) or using the semantic sim ilarities


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of words to aid in their recall (Lyons et al. 1995). In con-trast, deficits in simple visual-spatial learning and mem-ory tasks are not usually found in schizotaxic adults(Orvaschel et al. 1979; Driscoll 1984; Neuchterlein andDawson 1984; Cannon et al. 1994), although some posi-tive findings have been reported (Faraone et al. 19956;Faraone et al., in press).

Executive functions are essential for planning, forprocessing abstract concepts and for using retained infor-mation in other cognitive tasks. Children of people withschizophrenia do poorly on measures of concept forma-tion (Asarnow et al. 1978) but not on object sorting teststhat require them to abstract a rule from a series of stimu-lus presentation s (W inters et al. 1981). Adult relatives alsodo poorly on concept formation tests (Pogue-Geile et al.1989; Condray and Steinhauer 1992) and, although thereis some contrary evidence (Condray and Steinhauer 1992;Keefe et al. 1992; Rox boro ugh et al. 19 93; Keefe et al.1994), most studies have found adult relatives to beimpaired on sorting tests (Pogue-Geile et al. 1991; Frankeet al. 1992; Mirsky et al. 1992; Faraone et al. 19956).Consistent with these findings of executive dysfunction,adult relatives are impaired on tests of working memorythat assess the ability to remember information over ashort period of time so that it can be used in a subsequenttask (Park et al. 1995; Farao ne et al. in press).

Table 1 summarizes the neuropsychological studiesof child and adult relatives. It renders a clear conclusion:in schizophrenia families, some relatives have neuropsy-chological deficits in multiple domains. The domainsimpaired in these relatives are consistent with the cogni-tive dysfunctions thought to be central to schizophreniapatients themselves. This consistency supports the ideathat som e relatives in schizophrenia families have a famil-

ially transmitted syndromeschizotaxia, which manifestsas abnormalities in neuropsychological performance.Psychosocial Functioning. If schizotaxia is a clinicallysignificant condition, it should be associated with disabil-ity at work, in school, or with interpersonal relationships.For adult relatives, one might infer such disability fromtheir profile of neuropsychological impairments. Forexample, at work and in school, impaired executive func-tions will jeop ardi ze successful achievemen t, wh ichrequires planning and organizational skills and the abilityto process abstract concepts. Moreover, impairments invigilance will make it difficult for schizotaxic people tosucceed in settings that require concentration over longperiod s. One might infer interpersonal dysfunction fromthe subtle thought disorder and comm unication associatedwith schizotaxia.

Although these neuropsychological inferences arecompelling, few studies of adult relatives have directlyexamined psychosocial functioning. One exception is thework of Toomey et al. (1997), who reported adult rela-tives to have deficits in the social perception of nonverbalcues; these deficits were associated with poor vigilance.We also know that schizotaxia leads to negative symp-toms, which include indexes of psychosocial failure suchas impersistence at school or work, recreational interestsand activities, sexual activity, and relationships withfriends and peers.

In contrast to the dearth of psychosocial informationabout adult relatives, psychosocial dysfunction has beendocumented among the children of schizophrenia patients("child relatives" for short). For example, data from theNew York High-Risk Project found child relatives to havepoorer social functioning and more restricted interests

Table 1. Neuropsychological functions impaired in child and adult relativesType of Relative

Neuropsychological domain Children/adolescents AdultsMotor abilityPerceptual-motor speedShort-term memorySustained attentionVerbal ability and languageVerbal learning and memoryVisual-spatial learning and memoryExecutive functionsNote.+ = impaired ; - = not impa ired; +/- = variable results; ? = not sufficiently studied.


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than psychiatric or normal controls (Small 1990). Thesocial competence of child relatives decreased betweenchildhood and early adolescence but rem ained stable fromearly to late adolescence (Dw orkin et al. 1994).

In the Israeli high risk study, Auerbach et al. (1993)found boys of schizophrenia parents to be more with-drawn than boys of nonschizophrenia parents. The boyswho developed schizophrenia-related disorders had beenshy and withdrawn or aggressive and antisocial (Hans etal . 1992). In the Danish high risk study, child relativeswere described by teachers as passive and socially iso-lated, and by mothers as both passive and aggressive.When compared with controls, teachers described childrelatives as less socially competent and more aggressive;peers described them as more aggressive, withdrawn,and unlikable (Ledingham 1990). Notably, Asarnow'sreview (1988) determined that all studies of adolescentrelatives have found them to have significant social dys-function.

Thus, like neuropsychological impairment, there isconsistent evidence for psychosocial dysfunction amongchildren at risk for schizophrenia. Moreover, studies ofchildren link these two domains of dysfunction. Forexample, in Auerbach et al.'s (1993) study, the sociallywi thdra wn c h i ld re n a l so ha d motor a bnorma l i t i e s .Walker and Lewine (1990) rated videotapes of childrenwho subsequently developed schizophrenia. These chil-dren had neuropsychological impairments (poor fine andgross motor coordination) and evidence of social dys-function (poor eye contact, more negative affect and lowsocial responsiveness). In the New York High-RiskProject, a ttentional problems in childhood predictedsocial dysfunction in adolescence and social isolation inadulthood (Dworkin et al. 1993). Notably, an associationbetween neuropsychological performance and functionalimpairment is a lso seen for schizophrenia pa t ients(Green 1996).Because neuropsychological impairment is evident

at an early age (e.g., Fish and Hagin 1973) and typi-cally emerges prior to social dysfunction (Dworkin etal. 1993), it is intriguing to speculate about a causallink between these two features of schizotaxia. As sug-gested by Cornblatt and Keilp (1994), an early atten-tional deficit could impair the processing of interper-sona l in fo rma t ion a nd le a d to f a i lu re in soc ia linteractions.

Cornblatt and Keilp's model predicts that interper-sonal interactions will frequently fail, leading to increasedstress and a repeated cy cle of increased psycho social dif-ficulties and stress. We would extend this model toinclude other neuropsychological deficits as potentialcauses of psychosocial dysfunction. Future confirmationof these causal links would suggest that treatment of neu-

ropsychological deficits might improve the psychosocialfunctioning of schizotaxic people.Clinical Implications of SchizotaxiaTo recap, schizotaxia is a subtle syndrome of brain dys-function expressed, in part, as negative symptoms andneuropsychological deficits, but not as psychosis. Thissyndrome is qualitatively similaryet less severethanthat observed among schizophrenia patients. In this sec-tion we address questions that these findings pose for clin-ical practice: How does one diagnose schizotaxia and dif-f e re n t ia te i t f rom sc h iz o typa l pe r s ona l i ty? Doe sschizotaxia have implications for family interventions forschizophrenia? What are the treatment options for schizo-taxic people?How Does One Diagnose Schizotaxia and DifferentiateIt From Schizotypal Personality? For schizotaxia to be auseful diagnostic class, requires the formulation of specificdiagnostic criteria is required. But specifying diagnosticcriteria is not currently possible given that this issue has notbeen directly examined in prior research. We expect suchcriteria to evolve as future research assesses the concurrentand predictive validity of schizotaxia criterion sets.Moreover, such research will need to document the diver-gent validity of schizotaxia: Is the syndro me sufficientlydifferent from other disorders to warrant a separate cate-gory? Here we address the most difficult differential diag-nost ic hurdle for schizotaxia: is it sufficiently different fromschizotypal personality to warrant a separate category?

Notably, in a reformulation of his theory, Meehl(1989) conceded the possibility that some schizotaxic per-sons might not develop schizotypal personality. Althoughhe thought this outcome would require "a sufficientlywell-managed prophylaxis" (p. 938), subsequent datahave shown tha teven without inte rvent ionmanyschizotaxic persons will neither become schizotypal nordevelop schizophrenia. The core features of schizotaxia(nega t ive symptoms and neuropsychologica l impair-ments) occur in 20 percent to 50 percent of such relatives(Faraone et al. 1995a, 1995fc), but less than 10 percent ofadult family members of schizophrenia patients will bediagnosed with schizotypal personality disorder. Thus,unlike schizotypal personality, schizotaxia appears to becommon among re la t ives of schizophrenia pa t ients .Because schizotypal personality should be evident byadulthood, finding that many schizotaxic adults are notschizotypal shows that the former condition does notalways evolve into the latter.

There is another reason to demarcate schizotaxiafrom schizotypal personality: The latter is a heteroge-


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neous disorder. This heterogeneity stems from the twomethods used to study it: The "clinical method" has iden-tified personality disordered patients who seem to exhibita mild form of schizophrenia symptoms; the "familyresearch method" has identified relatives of patients withschizophrenia who exhibited subtle schizophrenia likepsychopathology (Kendler 1985). Although the peoplerecruited by these two methods show some clinical simi-larities, several studies suggest that "clinical" and "famil-ial" schizotypal personality may be different disorders(Kendler 1985).

F o r e x a m p l e , a m o n g s u b j e c t s d i a g n o s e d w i t hschizotypal personality, Torgersen (1985) reported thatthe negative symptoms of social withdrawal and impair-ment were genetically related to schizophrenia whilepositive, psychotic-like symptoms were not. Thaker etal. (1993&) found clinical schizotypal subjects to showmore e v ide nc e o f ma gic a l ide a t ion a nd pe rc e p tua lideation than familial schizotypal subjects. The twogroups, however, did not differ in either physical orsocial anhedonia.

A family study reported elevated rates of schizotypalpersonality among relatives of patients with mood disor-der (Squires-Wheeler et al. 1989), but compared withschizotypal relatives in schizophrenia families, the schizo-typal relatives in mood-disordered families were morelikely to show symptoms of anxiety and depression at afollow up assessment (Squires-Wheeler et al. 1992).Similarly, Lyons et al. (1994) compared schizotypal rela-tives of schizophrenia probands with schizotypal relativesof mood disordered probands. The former group had moreinadequate rapport and anxiety whereas the latter hadhigher rates of impulsive-dramatic personality disorders.

Biological studies also find evidence for two types ofschizotypal personality. An early review by Siever (1985)concluded that a subgroup of schizotypal subjects exhib-ited biological abnormalities that were similar to thoseseen in schizophrenia patients. This subgroup manifestednegative symptoms and neuropsychological impairment(two features of schizotaxia), but rarely exhibited positivesymptoms. Moreover, Condray and Steinhauer (1992)found impaired language comprehension among schizo-typal subjects with a family history of schizophrenia, butnot among those without such a history and Kendler et al.(1991) showed that among schizotypal subjects, negativesymptoms predicted attentional and eye-tracking dysfunc-tion (likely features of schizotaxia) but the positive syn-drome did not . Resul ts cons is tent with these werereported by Thaker et al. (1996), who assessed eye track-ing among subjects with paranoid, schizoid, and schizo-typal personality. Eye-tracking abnormalities were associ-ated with these disorders, but only for subjects with afamily history of schizophrenia.

The view that schizotypal personality is heteroge-neous finds further support from family studies. Forexample, Thaker et al.'s review (1993a), shows that moststudies of clinically derived schizotypal probands did notfind elevated rates of schizophrenia among the probandrelatives. Subsequent reports have also supported thatassertion (Battaglia et al. 1995). These findings suggestthat many clinically ascertained schizotypal patients donot carry the genetic predisposition to schizophrenia (i.e.,they do not have schizotaxia).

In figure 1, schizotaxia (the left circle) and schizo-typal personality (the right circle) are shown as conditionsthat sometime co-occur. The lack of complete overlapbetween the two circles illustrates the notion that schizo-taxia is a broader construct than the subset of schizotypalpersons who have predominantly negative symptoms. Thearea of overlap between the circles corresponds to peopleshowing both schizotaxic and schizotypal symptoms.These people have been described as having "familial"schizotypal personality in the research literature. The por-tion of the schizotypal personality circle not overlappingwith the schizotaxia c irc le conta ins those pa t ientsdescribed as having "clinical" schizotypal personality.

We leave to future research the goal of parsing thecomorbidity between schizotypal personality and schizo-taxia. Because comorbidity is a common feature of psy-chiatric illness, recognizing both conditions and theircomorbidity might be a reasonable solution. In contrast, itmay be preferable to sharpen diagnostic criteria with thegoal of separating schizotaxia from schizotypal personal-Figure 1. Overlap betwee n sch izotax ia andschizotypal personality

Schizotaxia= Schizotypal Personality

Familial Schizotypal PersonalityClinical Schizotypal Personality


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treat schizotaxia? Although there is no specific therapy forthe condition, here we speculate on potential psychologi-cal and pharmacological approaches, which may not bemutually exclusive.

The treatment of schizotaxia may benefit from meth-ods effective in the psychotherapy of other neurodevelop-mental conditions (e.g., adult attention deficit hyperactiv-ity disorder), which share some clinical features withschizotaxia. As discussed by Seidman (1994), therapistswho treat patients with subtle neuropsychological impair-ments should attend to several issues.First, the therapist should have an objective under-standing of the patient's neuropsychological strengths and

weaknesses. This knowledge helps patients and the signif-icant people in their lives to reformulate their view of thebehavioral consequences of cognitive dysfunction. Forexample, schizotaxic people with deficits in attention andverbal memory may view themselves as "stupid" becausethey cannot learn in the many educational settings thatrequire these skills. Therapy can help them reinterpretthese difficulties and develop cop ing strategies. Moreover,teaching schizotaxic people about their neuropsychologi-cal profile might help them develop realistic expectationsand better plan their occupational and educational pur-suits.

Clinicians could also help schizotaxic people developcognitive-behavioral strategies to cope with specificdeficits . For example, relatives with memory deficitswould benefit from learning mnemonic strategies; thosewith abstraction deficits could be taught systematic meth-ods of planning and organizing their activities. Thus, stan-dard tools used to aid recall (e.g., appointment books, cal-endars) could be part of the therapeutic toolbox.Therapists can also use neuropsychological informa-tion to facilitate an empathic approach to the issues ofshame, inferiority and performance anxiety that oftenarise in patients with neurocognitive disorders (Seidman1994). Such maladaptive emotions may stem directly

from the experiences of failure caused by the schizotaxic,neuropsychological syndrome. They may be reactions tothe stress and stigma of having a relative with schizophre-nia. Or, they may derive from the relative's fear of devel-oping schizophrenia. Furthermore, the language and self-regulation deficits of schizotaxic people may make itdifficult for them to articulate their awareness of thesefeelings. Without therapeutic attention, these emotionalconsequences might worsen cognitive performance andlead to a down ward spiral toward further dysfunction.Although psychologica l in te rvent ions , as notedabove, would appear to be appropriate, research is needed

to clarify which psychotherapeutic approaches are mosteffective and whether pharmacotherapy would also beuseful. Of course, there are no known medications for

schizotaxia, and no clinical guidelines can be sugg ested atthis time. It is worthwhile, however, to examine the impli-cations for future pharmacotherapeutic research suggestedby the data reviewed in this article. These data suggestthat schizotaxia shares causal and pathophysiologicalcomponents with schizophrenia. Thus, the data raise aprovocative question: Would schizotaxic traits respond tomedications used in the treatment of schizophrenia?

Answering this question is not straightforward. Theanswer m ust assume that antipsychotic m edications are ofvalue in treating negative symptoms and improving neu-ropsychological functions. Although treatment with lowdoses of typical neuroleptic drugs has shown some effi-cacy for schizotypal personality (e.g., Hymowitz et al.1986), these drugs may not effectively treat the schizo-taxic syndrome of negative symptoms and neuropsycho-logical impairment. Moreover, studies of schizotypalpatients suggest that neuroleptic side effects lead to med-ica t ion discont inua t ion ra tes as high as 50 percent(Hymowitz et al. 1986).

The atypical or novel antipsychotic drugs may bemore promising for the treatment of schizotaxia. Althoughnot all studies agree, and the relative effects of theseagents on "primary" and "secondary" symptoms is underdebate (Carpenter et al. 1995; Meltzer 1995), severalreports suggest that the first of the atypical agents, cloza-p i n e , improve s a t l e a s t some ne ga t ive symptoms(Carpenter et al. 1995; Meltzer 1995) and some neurocog-nitive deficits (Mortimer and Dye 1997; Potkin et al.1997; Stone et al. 1997) in severely ill, treatment-refrac-tory patients. Although the toxicity of clozapine pro-scribes its use in the absence of clear psychotic symp-toms, the post-clozapine agentsrisperidone, olanzapine,and quetiapinemay all improve negative symptoms inpatients (Marder and Meibach 1994; Beasley et al. 1996;Small et al. 1997), and risperidone appears to improvesome neurocognit ive def ic i ts (Green e t a l . 1997;Lindenmayer et al. 1997).

Clearly, knowledge about the effects of these novelagents in patients is nascent, but the intriguing hints abouttheir effects on negative symptoms and neurocognitivedeficits, coupled with their acceptable safety profile, sug-gests that they might be reasonable candidates for a thera-peutic trial in schizotaxic relatives. Moreover, otherexperimental agents may also be appropriate after more islearned about their properties.Currently, however, there are several obstacles to thetreatment of schizotaxia with atypical antipsychotic med-ica t ions . In pr ior s tudies of schizophrenia pa t ients ,improvements in neuropsychological functioning were

modest. Moreover, the response of negative symptomsrelative to that observed for conventional neurolepticscould have been due to the milder side effects of the atyp-


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ical drugs, which lead to fewer secondary negative symp-toms. Thus, because of the limitations of extant work,strong conclusions about the value of atypical antipsy-chotics for the treatment of schizotaxic traits must awaitfuture studies using more sensitive m easures.

If pharmacological treatment studies of schizotaxiaproceed, careful pilot investigations would need to assessthe potential occurrence of side effects and clarify thedose and titration schedules suitable for schizotaxic peo-ple. A very cautious approach to this potential use ofantipsychotics is especially warranted given reports ofspontaneous dyskinesias in schizotypal subjects (Cassadyet al. 1998), and widespread neurological abn ormalities innonpsychotic relatives of patients with schizophrenia(Kinney et al. 1986; Kinney et al. 19 91; Ismail et al.1998). Assuredly, proposed studies of antipsychotic treat-ment w ould need to weigh the potential benefits of reduc-ing schizotaxic symptoms against the risks for drug-induced side effects.

Developing treatments for schizotaxia could haveseveral implications. Effective therapies, be they psycho-logical or psychopharmacologic, might improve the neu-ropsychological deficits and negative symptoms typicallyfound in relatives. If Cornblatt and Keilp's (1994) modelis correct, improvements in these domains should lessenthe distress of the individuals themselves and allow themto function better in family, occupational, and societalroles. Moreover, improving the welfare of schizotaxicfamily members would indirectly benefit their relativeswith schizophrenia by decreasing stress in the home andfacilitating the progress of family interventions.

Our discussion of the treatment of schizotaxia raisesan additional question: Do schizotaxic persons seek treat-ment for themselves other than around dealing with a rel-ative with overt schizophrenia? Because of the dearth ofdata on this issue, a definitive answ er awaits futureresearch. Such research should consider several possibili-ties. Many relatives of schizophrenia patients will denypathology in themselves, either to avoid identifying withtheir schizophrenia relative or because they do not experi-ence disability or distress from schizotaxic phenomena.When viewed in contrast to the intense adverse outcomesof schizophrenia, the experience of schizotaxia may notfeel much different from normal. We will not know ifthese people want or need treatment until appropriateresearch is completed.

We must also consider that many schizotaxic peopledo not have a relative with schizophrenia. This occursbecause of the play of chance: If a family transmits schiz-ophrenia genes, members are at increased risk for schizo-phrenia, but not all such families will have a member withschizophrenia. Although, such schizotaxic people shouldtheoretically exist, they have never been studied. Thus, weawait future research to answer a variety of intriguing

questions: Do schizotaxic people show up in mentalhealth clinics? If so, are they diagnosed with schizotypalpersonality d isorder? Or do their attentional difficultieslead to a diagnosis of attention deficit hyperactivity disor-der? Do life failures associated with schizotaxic deficitslead to depression?

The treatment of schizotaxic adolescents: Canschizophrenia be prevented? It is intriguing to wonderwhether our clinical reformulation of schizotaxia hasimplications for the primary prevention of schizophre-nia, although speculative. To move from speculation to apreventive trial, we would need to establish at least twofacts: (1) that it is possible to accurately define the popu-lation at risk for schizophrenia, and (2) that there is acompelling rationale for the proposed preventive treat-ment.Can the onset of schizophrenia be predicted?Because a primary prevention trial would target personsat high risk for schizophrenia, its success presupposes amethod of defining that risk. A simple method would beto choose adolescent children or siblings of schizophre-nia patients. This group has a ten-fold elevated risk forthe disorder and is entering the age period of greatestrisk for the onset of psychosis. But even though the ele-vation in risk for this group is substantial, only 10 per-cent would be expected to develop schizophrenia or arelated psychotic disorder. This magnitude of risk is notsufficient for defining the at risk population for preven-tive trials (unless there was a low-risk treatment that wasinexpensive to adm inister).

Fortunately, research suggests that measures ofschizotaxia may improve risk prediction to the levelwhere it would be useful in defining populations at veryhigh risk for schizophrenia. For example, in two inde-pendent studies of children of schizophrenia patients,Fish (1992), described a syndrome of motor abnormali-ties that predicted subsequent schizophrenia or relateddisorders. Similarly, in both the Copenhagen and NewYork high risk projects, neuromotor impairment pre-dicted the onset of schizophrenia (Olin and Mednick1996; Erlenmeyer-Kim ling 1997). These findings areconsistent with Walker and Lewine's (1990) finding ofpoorer fine and gross motor coordination in videotapesof children who subsequently developed schizophrenia.In a dd i t ion to ne uromotor impa i rme nt , a t t e n t iona ldeficits also have been found to predict subsequentschizophrenia and related disorders (e.g., L. Erlenmeyer-Kimling, personal communication, 1997).

Given the established link between neuropsychologi-cal and social impairment in child relatives, it is not sur-prising that psychosocial dysfunction also predicts subse-quent schizophrenia and related disorders. In the Israelihigh risk study, subjects who eventually developed schiz-ophrenia-related disorders had been shy and withdrawn or


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aggressive and antisocial as children (Hans et al. 1992).Walker and Lewine's (1990) videotape study describedthe children who developed schizophrenia as having hadpoorer eye contact, more negative affect, and diminishedsocial responsiveness. Similarly, in the Copenhagen highrisk study, teacher-rated social behaviors were predictiveof subsequent schizophrenia (Olin and Mednick 1996).

Thus , among chi ldren of schizophrenia pa t ients ,schizotaxic traits may predict subsequent psychosis. Yet,more needs to be known about the diagnostic accuracy ofschizotaxic traitsthat is, their sensitivity and specificityas predictors of psychosis (Faraone and Tsuang 1994)before they can be used in prevention trials. Many of thestudies reviewed above are difficult to interpret becausethe outcome they predict is rather broad (i.e., schizophre-nia and related disorders). Because trials with antipsy-chotics would not be warranted for prevent ing somerelated disorders (e.g., schizotypal personality), futurework needs to precisely estimate the degree to whichschizotaxia can predict schizophrenia. Moreover, becauseno diagnostic criteria are available for schizotaxia, it isnot possible to compare the diagnostic accuracy of schizo-taxia and schizotypal personality as predictors of psy-chosis. Future work will need to address this issue.Theoretically, risk prediction should dramaticallyimprove after molecular genetic studies discover genesfor schizophrenia. Notably, linkage studies have discov-

ered regions of the genome that may harbor schizophreniagenes. Four promising chromosomal regions are: 22qll-q l 3 , 6p23, 8p22-21, 15ql3-ql4, and 10pl4-pl2 (Pulveret al. 1994; Straub et al. 1995, 1998; Wang et al. 1995;S c h i z o p h r e n i a C o l l a b o r a t i v e L i n k a g e G r o u p( C h r o m o s o m e 2 2 ) 1 9 9 6 ; S c h i z o p h r e n i a L i n k a g eCollaborative Group for Chromosomes 3 6 and 8 1996;Freedman et al. 1997; Faraone et al. 1998; Leonard et al.1998; Schwab et al. 1998). Although these findings arepromising, no schizophrenia gene has yet been found.After geneticists identify the mutations leading to schizo-phrenia, these results can be used in combination withschizotaxic signs to delineate a group at very high risk forthe disorder.

Is there a compelling r ationale for a preventive inter-vention? Although a reasonably accurate ability to predictwho will develop schizophrenia is a necessary precondi-tion for prevention trials, it is far from sufficient. Therealso needs to be a compelling rationale to support anattempt at preventive treatment. In this section we exam-ine possible rationales for psychosocial and psychophar-macologic interventions but emphasize that more researchis needed to clarify the potential efficacy of eitherapproach.

The ore t ic a l ly , psyc hosoc ia l in te rve n t ions c ou ldchoose two foci for intervention: the at-risk individual andthe individual's environment. On one hand, such interven-

tions might help the at-risk person withstand the stressfulsituations that are inherent in life but may be toxic to peo-ple predisposed to schizophrenia. On the other hand, sincesome data, albeit controversial, suggest that the nature offamily relationships may be a risk factor for symptoms ofschizophrenia (e.g., Goldstein 1987), family interventionsmight reduce stressors that affect vulnerable family mem-bers.

But studies of family interaction must be interpretedcautiously. Rather than being causes of subsequent schiz-ophrenia, family relationships may be influenced by thenegative symptoms, neurocognitive dysfunction or psy-chosocial impairments of the at-risk schizotaxic individ-ual or by the effects that these features produce amongother family members who may never themselves developschizophrenia. If a higher genetic risk for schizophrenialeads to a greater expression of schizotaxic traits, thenmeasures of stress in the family might well be correlatedwith the level of genetic vulnerability in the family. If so,then any apparent causal link between the nature of fam-ily relationships and subsequent schizophrenia in familymembers might be spurious.Clearly, further research is needed to create a scien-tific foundation for potentially preventive psychosocialinterventions. In addition, the possibility that psychophar-macologic approaches might improve the stress toleranceof a t- r isk persons should a lso be cons idered. As

researchers begin to address this lacuna in the literature,they will likely develop several research strategies. Oneidea would be to consider the possibility that treatmentstudies of schizotaxic adults might inform prevention tri-als for schizotaxic adolescents.This research strategy assumes that (1) adult schizo-taxia provides a suitable model of the pathophysiology ofpremorbid schizophrenia, and (2) treatments that amelio-rate adult schizotaxia do so through neural mechanismsinvolved in the onset of psychosis in schizotaxic adoles-cents. If neurobiological studies can verify this hypothe-

sis, then an effective medication for adult schizotaxiamight be the logical choice for a primary prevention trialof schizophrenia.

That psychopharmacologic treatment might preventthe onset of schizophrenia is a logical extension ofWy att's (1995) idea that early intervention for schizophre-nia might alter the course of the illness. His review of 21controlled studies found that patients who had beentreated with antipsychotic medication during their first orsecond hospitalization had a better outcome than patientswho had not been treated early in the course of the illness.Others have suggested that early treatment, especiallywith newer agents, might preserve brain plasticity andreduce the clinical deterioration of chronic schizophrenia(Gre e n and Sc h i ld kra u t 1995 ; L ie be rma n 1996 ;McGlashan and Johannessen 1996). It is also possible

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that, rather than having a neuroprotective effect, earlytreatment mitigates the social consequences of schizo-phrenia psychopathology, which may result in better out-come by allowing for the easier re-integration of patientsinto their social netw orks. This line of reasoning has m oti-vated the creation of early detection and intervention pro-jects seeking to treat schizophrenia patients during theirprodrome or first episode (Green and Schildkraut 1995;Falloon et al. 1996; McGlashan 1996; McGlashan andJohan nessen 1996; Mc Go rry e t a l . 1996; Olin andMednick 1996; Vaglum 1996; Yung et al. 1996).

More work is needed to determine if early treatmentwith novel antipsychotics exerts a neuroprotective effect orif its success is mediated through social factors. If neuropro-tective effects can be shown for first episode schizophreniapatients, is it possible that ph armacological treatment wouldhave neuroprotective effects for schizotaxic adolescents. Ifso, would the medications protect them from the first onsetof psychosis? Although this possibility is intriguing, it ishypothetical and faces several obstacles. Although the ben e-fits of preventing psychosis are clear, a case must be madethat they outweigh the risks of treating schizotaxic adoles-cents with antipsychotic medication. These medicationshave some side effects in adults, and their effects on adoles-cent development are unknown. For these reasons, any pro-posed preventive intervention for schizotaxic adolescentswould demand a high level of ethical scrutiny and wouldpresuppose a compelling rationale for any proposed treat-ment along with the ability to accurately predict who willand who will not develop schizophrenia.

ConclusionOur inquiry into schizotaxia yields clear conclusions fromprior work and intriguing hypotheses for future study.Schizotaxia, we conclude, is not merely a theoretical con-struct describing the unknown neural substrate of schizo-phrenia. Almost 4 decades after Meehl first coined theterm, an accumulation of research reveals schizotaxia tobe a clinically consequential condition. Indeed, the nega-tive symptoms, neuropsychological deficits and psychoso-cial disabilities of the schizotaxic person constitute achronic syndrome that may compromise quality of lifeand goal attainment.

Because some schizotaxic people meet criteria forschizotypal personality disorder, one might argue forincorporating the former into the latter. But that wouldblur the meaning of schizotypal personality, which isalready a heterogeneous diagnosis. Moreover, cleavingschizotypal personality into groups with and without afamily history of schizophrenia creates subgroups that dif-fer on etiologic, neurobiological, and clinical features.Thus , we propo se to join schizoph renia -re la ted

schizotypal personality disorder with other cases of

schizotaxia. This leaves future research the goal of refin-ing diagnostic criteria to accent the distinction betweenschizotaxia and schizotypal personality disorder. In partic-ular, although negative symptoms and neuropsychologicalimpairments appear to be hallmarks of schizotaxia, somepositive symptoms such as mild thought disorder mightalso be considered as diagnostic criteria. The validity ofproposed diagnostic criteria could be examined in familystudies of schizophrenia, but family studies of schizotaxiawould also be needed to fully clarify the familial relation-ship between the two conditions.

Our reformulation of schizotaxia has several clinicalimplications. In family interventions for schizophrenia,knowledge of schizotaxic deficits should help cliniciansrefine their clinical approach to relatives of schizophreniapatients. Likewise, the psychotherapy of schizotaxia wouldbenefit from the clinical insights of those who work withother neuropsychological disorders. There are, of course,no protocols for the psychosocial therapy of schizotaxia.Their invention is another goal for future research .

Our conclusions are limited in several ways. Becausethere are no agreed upon diagnostic criteria for schizo-taxia, studies that have examined this construct amongrelatives of schizophrenia patients have not used compa-rable samples. Many of these studies have examined puta-tive indicators of schizotaxia in samples that include sub-jec ts with persona l i ty disorders , thus obscur ing therelative contributions of schizotaxia and known clinicalc ond i t ions to the e xpre s s ion o f s c h iz o ta x ic t r a i t s .Moreover, we have also drawn inferences from studies ofschizotypal personality disorder which, as we have dis-cussed in this paper, is itself heterogeneous.Assuredly, our comments regarding the pharma-cotherapy of schizotaxic adults and the prevention ofschizophrenia are speculative. We view these as clinicalhypotheses rooted in a nascent scientific literature. Theycall for studies of schizotaxia: to describe its geneticroots, to delineate its risk factors, to detail its pathophysi-ology, and to determine why its outcome is not solelyschizophrenia.

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AcknowledgmentsPreparation of this article was supported in part bythe Na t iona l Ins t i tu te o f Me nta l He a l th Gra n ts1 R 0 1 M H 4 1 8 7 4 - 0 1 , 5 U O 1 M H 4 6 3 1 8 , a n d1 R37MH43518 to Dr . Ming T. Tsuang as well asR01MH49891 and R01MH52376 to Dr. Alan I. Green; bygrants from the Stanley Foundation to Dr. Larry J.Seidman; and by the Commonwealth Research Center ofthe Massachusetts Department of M ental Health.

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Schizophrenia Bulletin, Vol. 27, No . 1, 2001 S.V. Faraone et al.

The AuthorsStephen V. Faraone, Ph.D., is Associate Professor at theHarvard Medical School, Boston, MA. Alan I. Green,M.D., is Associate Professor at the Harvard Medical,Boston, MA. Larry J. Seidman, Ph.D., is AssociateProfessor at the Harvard Medical School, Boston, MA.Ming T. Tsuang, M.D., Ph.D ., is the Stanley CobbProfessor of Psychiatry at the Harvard Medical School,Boston, MA.

schizotaxia clinical implications and new directions for research

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