Clinica Fenomenologica.

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VOL. 14, NO. 3, 1988 Clinical Phenomenology

CHAIRPERSONNancy C. Andreasen

CO-CHAIRDavid Shore

MEMBERSJack D. Burke, Jr.William M. GroveJeffrey A. LiebermanThomas F. Oltmanns

Jay W. PettegrewAnn E. PulverLarry J. SieverMing T. TsuangRichard Jed Wyatt

The authors appreciate the as-

sistance of Ma ry Ellen Wlvel, M.A.,

Science Writer, National Institute

of Mental Health, In the prepara-

tion of this report.

The ability to advance our knowl-edge about schizophrenia has beenpartially handicapped by our inabili-ty to define it precisely and consis-tently. There is no question thatschizophrenia is a "real disord er"that produces severe and often per-sistent disabilities. For a variety ofhistorical and conceptual reasons,however, there has been disagree-ment among clinicians and investi-

gators as to the best ways to definethis disorder. The principal and ab-solutely fundamental contributionthat phenomenology and nosologycan make is to identify some of thecontroversial issues so that their ef-fect on research is recognized and tomake a useful group of suggestionsconcerning these definitional issues.If we are to make any substantialprogress in understanding thepathophysiology and etiology ofschizophrenia or in developing im-

proved treatments for it, knowinghow to describe, define, and recog-nize it is a necessity.

One major controversy concernsthe boundaries of the concept ofschizophrenia. Should it be definednarrowly or broadly? In the late1800's, Kraepelin chose a narrowdefinition, describing this illness asone with early onset and withprogressive deterioration and cogni-tive impairment ("dem entia prae-cox"). In 1911, Bleuler introduced

the term "schizophrenia." He be-lieved that the characteristic featureof schizophrenia was "splitting" orfragmenting of thinking processes inschizophrenia, a symptom that hereferred to as "associative loosen-ing ." He believed tha t this abnor-mality was the distinguishingcharacteristic of schizophrenia andthat certain other features such asaffective blunting, ambivalence, anddisordered attention were also of

great significance. He did not be-lieve that the illness necessarily ledto deterioration, but he did thinkthat schizophrenia w as a heteroge-neous group of disorders, referringto it as the "group of schizophre-nias." Bleuler's concept was there-fore quite broad. Although earlywork in schizophrenia tended to fol-low Kraepelin's definitions, thebroad-based Bleulerian concept waswidely adopted in research conduct-ed in the 195O's and 1960's.

A further change in thinking cameabout in the early 1970's whenSchneiderian concepts w ere pop u-larized and som e researchers ado pteda narrower definition of schizophre-nia. The main impetus for theimplementation of narrower defini-tions was a desire to objectify thediagnostic process through the in-troduction of diagnostic criteria orcomputerized diagnostic system s.

The Bleulerian concepts, whileimportant, were difficult to opera-tionalize and ap ply reliably. Themovement toward narrower defini-tions culminated in the publicationof DSM-II1 in the United States in1980. The DSM-III definition is rela-tively narrow, requiring 6 months ofsymptoms before a diagnosis ofschizophrenia can be m ade. Thisnarrow definition was chosen to de-fine a "co re" gro up of schizophren-ic patients for research and to pre-

vent the overdiagnosis ofschizophrenia in everyday clinicalpractice. The nosologists who devel-oped the definition recognized it asa provisional compromise, a neces-sary step required until our under-standing could be advance dsufficiently to identify causes.

As this historical survey indicates,any review of research in schizo-phrenia conducted during thiscentury must take these changing



346 SCHIZOPHRENIA BULLETIN

definitions into account. Unfortu-

nately, several decades ago, investi-

gators did not realize how important

it was to specify how they identified

a particular cohort of patients as

schizophrenic. Consequently, inter-

preting and generalizing research

findings of the past has been

difficult.

In this report, we attempt to

review our collective experience in

research and to make concreterecommendations and suggestions

about the way that research in

schizophrenia can advance in the fu-

ture. In this context, it is important

to keep the basic purposes of the

study of phenomenology and nosol-

ogy in mind. The ultimate goal of

any system for diagnosis or clinical

description is to provide insights

into the etiology and pathophysi-

ology of a given disorder. With a

clear understanding of etiology and

pathophysiology, effective therapyand ultimately prevention can take

place. However, before meaningful

insights can be acquired, well-

defined homogenous populations of

the disorder need to be identified for

study. This is a particular problem

for the study of schizophrenia be-

cause the diagnosis is made on the

basis of clinical findings that are not

unique to schizophrenia. Taking the

course of the illness into considera-

tion can increase the diagnostic ac-

curacy, but difficulties still remain.

Considering biological as well as

clinical measures in combined cross-

sectional and longitudinal studies

should enhance diagnostic accuracy

even further.

Schizophrenia appears to encom-

pass a spectrum of neuropsychiatric

disorders with a spectrum of clinical

phenotypes. Within the clinical

spectrum are dusters of phenotypes

that can be identified for more fo-

cused study. The causes of schizo-

phrenia are presumably due to a

number of differing etiologies: some

purely genetic, some purely ac-

quired or "environmental," with

most cases of schizophrenia proba-

bly due to a combination of genetic

and acquired etiologies. These

different etiologies presumably

operate through a number of neuro-

chemical and psychobiological

mechanisms to provide the resulting

clinical spectrum of the disorder

(figure 1).

Figure 1. Pathogeneses and spectrum of schizophrenia

GENETIC

BACKGROUND

ENVIRONMENTAL

STRESSORS

NEURO- PSYCHO-

BIOLOQICALV/ BIOLOGICAL

MECHANISMS

CLINICAL SPECTRUM OF SCHIZOPHRENIA



VOL. 14, NO. 3, 1988 347

Clinical Description andDiagnosis

Current Knowledge. Enormousprogress has been made in the areaof clinical description and diagnosisduring the past 15-20 years. As theabove historical review h as indicat-ed, research in schizophrenia beforethe early 1970's, while often imag-

inative and creative, was alsoplagued by serious definitionalproblems. During the late 1%0'sand early 1970's, multinationalstudies such as the InternationalPilot Study of Schizophrenia andthe United States/United KingdomStudy led to widespread recognitionof inconsistencies in clinical descrip-tion and diagnosis both in the Unit-ed States and throughout the world.This awakened interest in develop-ing improved method s, which ledeventually to the development ofstandardized instruments such asthe Present State Examination andattempts to develop compu ter-basedmethods for making diagnoses. Byand large, computer-based ap -proaches to diagnosis have nowbeen abandoned in the UnitedStates, and a number of alternatestrategies for making diagnoses andcharacterizing patients haveemerged.

This early work has stressed the

crucial importance of reliability inclinical assessment. Reliability refersto the capacity of two observ ers toagree on whether symptoms arepresent or absent, or whether aspecific diagnosis should be made.Since the m id-1970's, increasinglysophisticated strategies have beendevelop ed to assess reliabilitystatistically and to employ a varietyof designs, such as evaluations us-ing multiple raters who differ inbackground and training, assess-

ments of interrater versus test-retestreliability, and examination of thereliability of symptoms and diag-noses assessed retrospectively. It isaxiomatic in science that progresscannot be made without measure-ment, and that measurement ispointless if it cannot be stabilizedand made repeatable or reliable. Be-cause of this progress during thepast several decades, we now have astrong group of techniques for as-sessing the clinical picture ofschizophrenia in a reliable manner.

The initial step that was taken wasthe development of criteria for mak-ing diag noses. The first set of widelyused criteria was developed by agroup of investigators at Washing-ton University in St. Louis. Thesecriteria have well-docum ented relia-bility and continue to be widelyused, although they have often been

supplanted or supplemented by al-ternate criteria. They were followedby the development of the ResearchDiagnostic Criteria (RDC), which ex-panded the diagnostic coverage ofthe St. Louis criteria. For schizo-phrenia, the RDC provided a broad-er range of definitions, includingrelatively brief forms of schizophre-nia (of less than 2 weeks' duration)as well as relatively more chronicforms (those that have lasted morethan 2 years). In addition, the RDCprovided criteria for schizoaffectivedisorder. The RDC also are widelyused in current research, primarilybecause of the system's breadth anddetail. The most recent contributionto the development of diagnosticcriteria was made by DSM-111 andDSM-III-R. These have added relia-ble definitions of schizophreniaspectrum disorders, such as schizo-typal personality, paranoid person-ality, and the various forms of para-noid disorders.

Diagnostic criteria represent onlytentative formulations, since we arestill uncertain as to the boundariesand the various subtypes ofschizophrenia. Such criteria do,nevertheless, provide a useful stan-darized base upon which researchcan proceed. They also provide amethod for studying comparativenosology in schizophrenia, since theeffects of varying the breadth of

definitions and the effects of differ-ent definitions can be applied.Several such studies comparingRDC versus St. Louis versus DSM-III diagnostic systems have beendone with informative populationssuch as identical twins to explorethe power of various diagnostic sys-tems for detecting discrete biologicalsubtypes.

The development of diagnosticcriteria was quickly followed by the

development of instruments torecord current symptoms and pasthistory in a reliable way. Th ese in-struments usually take the form ofstructured interviews that requireinvestigators to ask essentially th esame questions in a systematic man-ner and to collect the same sympto-matic data base. The earliest of th esestructured interviews was thePresent State Examination, devel-oped in Great Britain, which focusesprimarily on symptoms that have

occurred during the previousmonth. Because many psychiatric ill-nesses, and particularly schizophre-nia, are best understood byexamining past history over a longertimeframe, additional structured in-terviews were subsequently devel-oped that attempt to describe thecourse of illness beginning with theearliest symptoms. The Schedule forAffective Disorders and Schizophre-nia (SADS) is one such instrumentthat is at present widely used. It




includes a current section thatdescribes cross-sectional phenomen-ology, as well as a section thatrecords a broad range of symptomsthat occurred in the past. It is or-ganized to permit diagnoses to bemade using the RDC. The SADS is ahighly reliable, widely used stan-dardized instrument that has provedvery valuable in the study of schizo-phrenia; its major limitation is that

its coverage of some sy mpto ms ofschizop hrenia is relatively incom-plete, particularly negative symp-toms. W ith the development ofDSM-II1, investigators felt there wasa need to have a structured inter-view with broader symptomaticcoverage that would permit investi-gators to inquire about all the sym p-toms that are included in theDSM-III criteria. Several additionalinterviews have been developed tomeet this need. One is the Struc-

tured Clinical Interview for DSM-III(SCTD) and a second is the Compre-hensive Assessment of Symptomsand History (CA SH). The former issomewhat briefer and has less ex-tensive symptom coverage, whilethe latter is more time-consumingbut also provides a broader informa-tional data base.

Although the available structuredinterviews vary in their psychomet-ric prop erties, all four instrum entscertainly m eet the m inimum criteri-

on of good interrater reliability.Several have been extensivelystudied to evaluate the effects of col-lecting information from multiplesources and multiple informants,the validity of retrospective recall,and other important aspects of inter-viewing that can affect validity inaddition to reliability. Cons equently,at present investigators who wish toconduct research in schizophreniahav e a stro ng range of choices avail-

able to them w hen they proceed toselect instrumentation for clinicaldescription and diagnosis.

The third major step during thepast several decades has been thedevelopment of rating scales to as-sess symptoms more briefly and tomeas ure change s over time. Instru-me nt d esign for clinical descriptionmust meet a broad range of needs .These include the need to make a di-

agnosis, the need to describe currentand past symptoms comprehensive-ly, and the need to make brief dailyor weekly assessm ents in a repeatedmea sures design. The latter need isparticularly important for studiesdesigned to assess response to treat-ment. The Brief Psychiatric RatingScale (BPRS) was the earliest scale toenjoy wid e use in such research,and it remains an important clinicalstandard. It has been supplementedby a number of additional instru-

ments that increase coverage andprovide more detailed description,such as the Scale for the Assessmentof Thought, Language, and Com-mu nication ; th e Scale for the As-sessment of Negative Symptoms(SANS) and its complementaryscale, the Scale for the Assessmentof Positive Symptoms (SAPS); theAbnormal Involuntary MovementsScale (AIMS); and the Global As-sessm ent Scale (GAS). The psycho-metric stability of all these scales hasalso been well docum ented.

A fourth important step has beenthe development of scales to assessmild or "spectrum" forms of schizo-phrenia. Interest in such scales hasgrown particularly during the past5-10 years as investigators have be-come increasingly concerned that ahighly restrictive or narrow defini-tion may not be the most powerfulone to use in some forms of research(e.g., genetic and family studies).

Some of the more recent structuredinterviews, such as the SCID or theCASH, contain sections that assessthe spectrum disorders in detail. Inaddition, several free-standing inter-views, such as the Schedule for In-terviewing Borderlines (SIB), havebeen developed. An interview hasalso been developed to assess abroad range of personality disor-ders, including paranoid, schizoid,and schizotypal: the Structured In-terview for DSM-III Personality Dis-orders (SIDP).

Future Needs. The development ofthese various instruments and scalesrepresents a substantial body ofwork in the area of phenomenologyand diagnosis during the past sever-al decades. It has provided the psy-chiatric community with a verysound base on which to build fur-ther research. Nevertheless, a

num ber of important future need sremain. As subsequent sections ofthis report indicate in more detail,future work in schizophrenia willmove into new areas that willrequire additional clinical in-strumentation.

One clear future need is morecareful longitudinal and prospectivestud ies, particularly of informativepatient populations such as first-episode patients, patients early inthe illness, or patients who have

never been medicated. As yet, nolong-term prospective study thatemploys the type of standardized in-strumentation described above toidentify index cases has been com-pleted. We nee d to know a greatdeal more about the course and out-come of schizophrenia to plan treat-ment, to advise families aboutprognosis, and to make long-termpublic policy plans. We needrigorous scientific studies that will



VOL 14, NO. 3, 1988 349

tell us definitively how frequentlypatients with various forms ofschizophrenia recover, have partialremission, develop a chronic stablecondition, or deteriorate into severeincapacity. In particular, it would beuseful to determine whether futureoutcome can be predicted early inthe illness. To conduct such studies,specific instruments must be

developed for the collection of infor-mation at regular standardized inter-vals (e.g., 6-month intervals). Somepreliminary work h as been don e inthis area, but considerably moreneeds to be done. In particular, thereliability and validity of such lon-gitudinal information must be care-fully assessed.

We also need to determine the ac-curacy of symptomatic and diagnos-tic information that is collectedcross-sectionally but attempts to

evaluate clinical history retrospec-tively. This type of clinical evalua-tion has formed the basis for mostepidemiological research, which de-pends on a single contact with anindividual who describes his pastpsychiatric history to an interviewerwho is "bl in d" (i.e., makes the di-agnosis without any prior informa-tion to bias his judgment). Patientswith schizophrenia may have diffi-culty in recalling their past symp-toms and course. It seems likely

that the best way to make a defini-tive diagnosis of schizophrenia andschizophrenia spectrum disorders isto obtain as much information aspossible from a wide variety ofsources, although this is much moredifficult and time consuming. Therelative value of these differentstrategies must b e assessed, as wellas the ability of patients to recallpast symptoms. This methodologicalwork will become increasingly im-portant as more and more effort is

put into collecting large pedigreesthat contain many members likely tobe either mildly ill or well, such asoccurs whe n extended pedigrees arecollected for molecular geneticstudies. For these studies, we needstrong lifetime diagnostic instru-ments, as well as instrum entstargeted to collecting screeninginformation through the family his-tory method. The Family HistoryResearch Diagnostic Criteria(FHRDC) have good reliability andhigh sensitivity and specificity forcore schizophrenia but are consid-ered weaker for the evaluation ofmilder spectrum disorders. Anotherinstrument that is not as widelyknown was developed at the NewYork S tate Psychiatric In stitute. Thisfamily informant schedule generatesDSM-III diagnoses with questions tobe asked for each diagnosis andspecific criteria for "probable" and

"certain" within each diagnosticcategory.

As such studies of samples thatmay contain some mild "subclinicalcases" contin ue, there will be an in-creasing need for subtle measures ofpsychopathology. This will requireexploration in several directions.One approach has been the develop-ment of subjective rating scales.Examples of this type that have al-ready proved useful include the

Scale for Physical Anhedonia, theScale for Perceptual Aberrations andPsychotic-like Phenomena, and theScale for Social An hedo nia. To date,these have been used to detect mildsymptomatology in populations ofcollege students, and they are cur-rently being applied in several fami-ly and genetic studies. While thepredictive validity of these scalesstill needs considerable work, theymay poten tially be useful as sensi-tive measures of clinical phenomena

that might otherwise be ignored inclinical interviews or direct obser-vation.

Yet another area of future need isfor laboratory-based microanalysesof behavior that may prove useful insolving some of the problems inher-ent in studying milder forms of ill-ness. Some work in this area hasalready been completed. One exam-

ple involves the use of automatedassessment of the acoustical proper-ties of speech to develop an objec-tive measure of affective blunting. Ithas been shown that patients whoare rated clinically as having affec-tive blunting tend to show adecrease in the frequency and am-plitude of their intonational pat-terns. Patterns of hesitation in thepatient's speech or possible associ-ations between subvocal speechand elect romyographic recordings

of patients with auditory hallucina-tions are other possible avenues ofinvestigation. The development ofsuch objective empirical measures isrelatively labor-intensive, but it isalso potentially q uite useful inproviding an objective physiologicalvalidator of clinically observedphenom enology. It may ultimatelylead to increased und erstand ing be-tween clinical phenomena and basicbiological processes.

A final area into which research is

likely to advance is the developmentof post-mortem tissue banks. Workwith post-mortem samp les in thepast has been seriously ha ndicappedby a lack of appropriate clinical in-formation. A s prospective efforts areorganized to collect post-mortembrains, it will be very important todevelop an agreed-upon clinicaldescriptive base for such tissuebanks. Since this data base will col-late information from living rela-tives, hospital records, and other



35 0 SCHIZOPHRENIA BULLETIN

sources, it provides a major in-strumentationaJ challenge.

Specific Symptoms VersusCharacteristic Symptoms

Current Knowledge. When Kraepe-lin originally described the syn-drome of dementia praecox, hecharacterized it by a broad range of

symptoms. Bleuler, who gave us theterm "schizophrenia," modified thecom prehens ive clinical descriptionprovided by Kraepelin and sug-gested that some symptoms werespecific to schizophrenia and patho-gnomonic of it. Bleuler's influenceon the concept of schizophrenia waspervasive for many years, leadinginvestigators to believe tha t charac-teristic symptoms of schizophreniacould be identified that would occurin this disease alone.

Bleuler suggested that the patho-gnomonic symptom of schizophre-nia was thought disorder, which hedescribed as "associative loosen-ing." Many years of research havebeen devoted to attempting to de-velop highly specific methods for as-sessing thought disorder, but whenthese attempts w ere pursued care-fully, they usually led to the conclu-sion that thought disorder (definedeither as disorganized speech or asdifficulty in organizing concepts)

might also occur in other d isorderssuch as mania, depression, ordementia. A type of thinking distur-bance highly specific to schizophre-nia has not been identified.

Other indicators of schizophreniainclude psychotic symptoms such ashallucinations and delusions. How-ever, patients with other disorderssuch as mania or depression mayalso manifest these symptoms dur-ing an acute phase of illness,

although psychotic symptoms dotend to resolve as the mood disorderepisode itself resolves. Schneider'sfirst-rank symptoms, specific typesof delusions and hallucinationsthought for a time to be specific toschizophrenia, have also been foundto occur in other disorders. Like-wise, negative symptoms such asblunted affect or poverty of speechare quite common in other d isorders

such as depression. It seems clear atpresent that symptoms unique toschizophrenia have no t been identi-fied. No single symptom can be con-sidered pathognom onic of thisdisorder. Rather, it is characterizedby a polythetic cluster of symptoms,usually expressed in a particularcourse or pattern.

Since schizophrenia is a perplex-ing disease characterized by multi-ple symptoms of very differenttypes, the b est clinical de scriptions

of schizophrenia and the bestresearch data bases must be compre-hensive. They must give majorweight to the very broad range ofsymptoms that are carefully andreliably d efined. This is the beststrategy as long as we must resolvemajor issues such as the bo undariesof the concept, delimitation fromother disorders, and the evaluationof a variety of possible mechanismsand etiologies.

Many of the diagnostic criteria and

structured interviews currentlyavailable give a strong emphasis topsychotic symptom s such as delu-sions or hallucinations, also some-times referred to as positivesymptoms. An emphasis on the im-portance of positive symp toms wasa natural and logical strategy at atime when psychiatrists were strug-gling to achieve objective and relia-ble descriptions that could be widelyused in clinical and research set-

tings. Positive symp toms such asdelusions and hallucinations arestriking and usually clearly presentor absent.

Unfortunately, however, for atime a strong emphasis on positivesymptoms led to a deemphasis onthe importance of negative or deficitsymptom s. The reemergence of aninterest in negative symptom s h asbeen an important step forward

during the past few years. Whilepositive sym ptoms represent an ex-aggeration or distortion of normalfunction (i.e., hearing voices whenthey are not there), negative symp-toms represent a diminution or lossof normal function. Negative symp-toms include affective blunting (lossof the ability to exp ress emo tionsfluently), alogia (impoverished non-fluent speec h), avolition (loss ofdrive), anhedonia (loss of the abilityto feel emotional attachment or

experience pleasure), and attention-al impairment. These negativesymptoms account for a great dealof the emo tional and social morbidi-ty of schizophrenia, since they leadto social isolation and withdrawal,difficulty in holding a job or remain-ing in school, and impaired ability torelate to others.

The distinction between positiveand negative symptoms has beenuseful bo th as a way of organ izingand simplifying clinical thinking,

and as a way of beginning to explorethe underlying mechanisms behindsymptoms. One widely discussedhypothesis during recent years hasbeen the "two-syndrome hypothe-sis" of schizophrenia. This hyp othe-sis suggested that there are twomain subtypes of schizophrenia.Type 1 or positive schizophreniawas characterized by good premor-bid adjustment, acute onset, promi-nent positive symptom s, a good



VOL. 14, NO. 3, 1988 351

response to neuroleptic treatment,and hyperdopaminergic transmis-sion. Type 2, or the negative syn-drome, was characterized by poorpremorbid adjustment, insidious on-set, prominent negative symptoms,cognitive impairment, structuralbrain abnormalities (as opposed toneurochemical abnormalities) asmanifested by ventricular enlarge-ment, and a poor response to treat-ment. It now seems clear that thisdichotomy, while heuristic andhypothesis-generating, was an over-simplification. Its value has b een togenerate such questions as: Arenegative symptoms due to sometype of specific neural mechanism?Can positive symptoms be related tohyperdopaminergic activity in spe-cific brain regions such as limbicstructures? Do negative symptom ssuggest a more irreversible course ora poorer response to treatment?

These all represent questions thatare still in need of an answer.

Future Needs. Future research onthe characteristic sym ptom s ofschizophrenia should focus on anumber of different areas. One areais the definition and significance ofnegative symptoms. These effortsshould continue to focus on the bestway to identify them, to determinetheir relationship to positive

symptoms, and to identify their lon-gitudinal course. Confound ing vari-ables, such as the tendency ofneuroleptic medication to produceakinesia or the effects of institution-alization or psychotic symptomsthemselves, must be disentangled inthe study of negative symptom s sothat we can determine important is-sues such as prognostic significance,response to treatment, and underly-ing mechanisms. The relationshipbetween negative symptoms and the

deficit syndrome (an enduring formof negative symptoms) must be ex-plored to isolate primary fromsecondary negative symptoms andto clarify the many physiologicalprocesses that can lead to the finalcommon pathway of negativesymptoms.

Isolating a relatively pure sub-group of patients with primary

negative symptoms, which mayperhap s be done at this point byidentifying patients with persistentnegative symptoms and the absenceof positive symptoms, is probablythe best strategy at present. Oncesuch a set of patients has been iden-tified, the underlying neuralmechanisms should be explored,particularly with techniques thatpermit direct examination of thecentral nervous system such as invivo brain imaging.

Anoth er clinical issue in n eed offurther exploration is the responseof negative symptom s to treatm ent.It is sometimes assumed that nega-tive symptoms, whenever present,will not improve with treatment.This belief is potentially dangeroussince it could lead to therapeutic ni-hilism. To address this issue, a ser-ies of well-designed treatmentstudies using careful definitions andstandard neuroleptic therapy shouldbe undertaken. In addition, a search

for alternate treatments that may bemore powerful or more specificshould be initiated, w hether they benew classes of neuroleptic drugs ortactics involving social rehabili-tation.

In addition to controlled treatmentstudies, naturalistic prospectivestudies of patients identified rela-tively early in the illness are alsoneeded to docum ent the course ofboth positive and negative symp-toms over time.

Finally, investigators must alsocontinue to pursue the search forthe mechanisms that are responsiblefor the various symptoms of mentalillness. For this work, the study ofboth normal individuals and animalmodels is important and fundamen-tal. For example, we need to unde r-stand the mechanisms that governnormal auditory perception and en-coding of auditory information inlong-term memory stores to developneural models that might explainthe production of auditory halluci-nations. As is discussed in more de-tail below, the development oftechniques such as brain imagingis particularly useful in this pur-suit, since they permit in vivo evalu-ation of brain function in norm alindividuals throug h the use ofcognitive challenges and permit in-vestigators to determine if thesefunctions are abnormal in patients

suffering from schizophrenia. Otherstrategies involve the use of physio-logical measures such as elecrroen-cephalographic (EEG) techniques orsmooth pursuit eye movements.

Biological Subtyping ofSchizophrenia

Current K nowledg e. The stud y ofphenomenology and nosology is notan end in itself. The primary goal of

nosology is to identify a method forclassifying illnesses that subdividesthem on the basis of pathoph ysio-logical mechanisms and ultimatelyetiology. This means that we ulti-mately seek a nosology of schizo-phrenia that will be based onneurochemical, neuropathological,genetic, and environmentalmechanisms.

Current nosologies are basedprimarily on phenomenology— thatis, the cross-sectional clinical picture




of the illness and its evolution overtime. Our nosologies tend to subdi-vide schizophrenia into acute andchronic, disorganized and paranoid,and more recently positive andnegative subtypes. Phenomenologyis a reasonable place to begin, partic-ularly when powerful biologicalmeasures are not available. It will al-ways remain an important founda-tion for n osology , e ven a biologically

based nosology, since a clinical dis-cipline such as medicine usuallyseeks to unde rstan d biological sub-types in terms of clinical correlates.

The most likely working hypothe-sis concerning schizophrenia is thatit is not a single illness produced bya single pathophysiological or etio-logical mechanism, or even by a sin-gle clear clustering of mechanisms,but rather a heterogeneous group ofdisorders that share some clinicalcharacteristics in com mon but are

etiologically diverse. One model thatwe can borrow in clarifying theproblem of identifying etiologicalsubtypes is the example of mentalretardation. Mental retardation is asyndrome characterized by impairedintellectual functioning beginningrelatively early in life. We nowknow that some types of mentalretardation, such as phenylketon-uria (PKU), are due to an abnormalgene that produces an inborn errorof metabolism. Yet some disordersthat are "genetically" caused, suchas rrisomy-21, are not explicable onthe basis of classic Mendelianpatterns of transmission (but are in-stead influenced by environmentalrisk factors such as increased mater-nal age). Some forms of mentalretardation, such as lead en-cephalopathies or cerebral palsy ac-companied by mental retardation,are due to a very prominent en-vironmental component. Further,

the mechanisms producing thesymptoms of mental retardationrange from neurochemical andmetabolic to structural, and they canbe either irreversible or reversible ifdiagnosis is achieved at an earlystage.

Parkin son's disease provides asimilar model that perha ps brings useven closer to an illness like schizo-phrenia. Patients with Parkinson's

disease have a very similar phenom-enology, with variable amounts oftremor, rigidity, akinesia, affectiveblunting, an d cognitive impairment.This syndrome is produced by a sin-gle mechanism, neuronal loss of thecell bodies of dopamine-producingneurons in the substantia nigra, andwe therefore know that the mechan-ism producing the Parkinsoniansyndrome is a functional hypoactivi-ty in the dopam ine system. Substan-tial clinical improvement of

symp toms is produced if this dys-functional system receives ex-ogenous supplements of dopaminein the form of L-dopa. Thus, Parkin-son 's disease repres ents a clearclinical syndrome with a singlerecognized pathophysiologicalmechanism. Yet we know that theetiology of Parkinson's disease isheterogeneous. Some people havedeveloped this syndrome as a conse-quence of having encephalitis dur-ing major epidemics of influenza.

Others, as in the case of Parkinsoni-an complex of Guam, have been ex-pos ed to a relatively isolatedenvironmental agent. Yet others de-velop Parkinso n's disease on afamilial and hereditary basis. As wegrow to understand more about thevarious biological mechanisms thatproduce the variable sym ptoms ofschizophrenia, we may discover thata variety of different etiologicalagents are producing this syndrome

by acting on crucial brain regionssuch as the frontal lobes or limbicsystem.

Other models are, of course, pos-sible. Many medical illnesses, partic-ularly those affecting the centralnervou s system (CNS), have a varia-ble clinical picture from time to time,depe nding primarily on the brainregion involved. Multiple sclerosis(MS) and syphilis are both exam-

ples. In these cases, although thesymp toms and course are variable,the illness is single rather than het-erogeneous. The phenomenologysuggests m ultiple illnesses, whenthis is in fact not the ca se. The varia-ble symptoms in schizophreniacould, as is the case with MS, reflectCNS lesions that wax and waneover time.

This review of various possiblemodels for biological subtyping,which indicates that there are manyareas of uncertainty and ambiguity,should not be taken to indicate thatwe have failed to make substantialprogress in our understanding ofschizophrenia d uring recent dec-ades. As subsequent sections of thispanel report indicate, and as otherpanel reports also demonstrate,major achievements have alreadyoccurred and improved our under-standing of the interplay of neurobi-ological, environmental, and geneticmechanisms in schizophrenia.

Genetic studies, such as those oftwins or adopted offspring, have in-dicated that genetic factors dearlyoperate in producing some cases ofschizophrenia. Research combiningthe study of twins with the use ofbrain-imaging techniques has sug-gested that environmental factors,such as perinatal complications, mayinteract with an underlying geneticsubstrate to produce the schizophre-nia syndrome in vulnerable in-



VOL. 14, NO . 3, 1988 353

dividuals, while those who arespared these environmental insultsare also spared from having the ill-ness. The examination of ventricularenlargement, as assessed by com-puted tomography in high-riskindividuals who h ave also beenevaluated prospectively for early en-vironmental insults such as birth in-jury, has led to similar conclusions.Careful exploration of the dopamine

hypothesis has made it dear that ab-normalities in this neu rotransmittersystem may explain certain symp-toms of schizophrenia. Imaging an dneuropathological studies have fo-cused increasingly on specific brainregions such as the hippocampus orthe prefrontal cortex and attemptedto examine the interaction betweenaffected brain regions and clinicalpicture. All of this work provides afirm foundation for future initiativesthat attempt to identify biological

subtypes of schizophrenia.

Future Nee ds. Future efforts shouldcontinue to explore the v ariousnosological and mechanistic modelsdescribed above, attempting to com-bine careful phenomenologicaldescription of samples with intelli-gently selected biological correlates.Since we are not certain which ofthe various nosological models actu-ally applies to schizophrenia, we

must maintain an open mind and beprepared to explore a variety ofhypotheses. In a practical sense, thismeans that while the possibility thatschizoph renia is a single illnessmust be entertained, biological het-erogeneity is more likely, and weshould attempt to address thisproblem in future research.

Two strategies for dealing withthis complex task are probablyappropriate. On the one hand,relatively small, well-designed,

hypothesis-driven studies of singlebiological mechanisms are highlyappropriate. Examples indudemolecular generic studies of singlelarge multigeneration pedigreesdensely affected with schizophreniaand related psychoses which mightassist us in identifying a form ofschizophrenia analogous to PKU.Another example would be in vivoneurotransmitter studies to examine

dopaminergic abnormalities inyoung never-medicated patientswith dassic dementia praecoxphenomenology who are then fol-lowed at regular intervals for a peri-od of years. Small, elegantlydesigned, hypothesis-driven studiesconcerning specific subtypes mustbe complemented, however, withrelatively large sample studies thatcombine comprehensive clinicaldescription with multifaceted biolog-ical descriptions. "Biological subtyp-ing" in which a single biologicalcorrelate is examined in relationshipto a minimally describedphenomenological base is not likelyto be very useful. Of course, mul-tifaceted large sample studies mustalso be informed by multiplehypotheses, or they are likely toproduce large data sets that areuninterpretable d ue to problems ofstatistical analysis.

Nonreplication is a serious

problem in biological studi es ofschizophrenia. This is no dou bt duein part to the heterogeneityproblems just described. Two p ointsare appropriate in this regard. First,when ever possible, investigatorsshould themselves conduct theirown replication studies instead ofleaving replication to other centers.This pred ud es easy recourse to ex-plaining nonreplication as "due to adifference in sample." Second, topermit comparison of results collect-

ed in different cente rs, it is impor-tant that investigators who focus onbiological correlates also pay closeattention to dinical, phen omen ologi-cal, and diagnostic correlates. It isnot sufficient to dismiss clinicaldescription with the statem ent thatall subjects are "RDC schizophren-ic" or "DSM-II1 schizophrenic." In-formation is needed in all studiesconcerning average age, duration of

hospitalization, type of treatmentreceived, and types of symptomspresent. Even when such informa-tion is provided, it is difficult todetermine whether samples arecomparable, but information aboutchronicity, types of sym ptom s, pasttreatment, and o ther relevant varia-bles represents a reasonable mini-mum. It is also important to identifythe source of information, since verydifferent data might be collected de-pending on whether the patient, a

family member, a clinician, or otherinformant is being u sed.

Conceptual Boundaries andGenetic Approaches

Current Know ledge. The bound-aries of the schizophrenia spectrumhave been another fundamentalproblem in schizophrenia research.Not only must we determinewhether this disorder is in fact a het-

erogeneous group of subtypes, butwe must determine how broad thisrange of subtypes actually is. Somedefinitions of schizophrenia havebeen relatively narrow, includingonly patients with severe longstand-ing incapacity. Since Bleuler in-troduced the concept of the "groupof schizophrenias," however, mostinvestigators have worked from abroader concept and included pa-tients who combine psychotic fea-tures with affective features, as well




as patients with mild nonpsychoticdisorders characterized predomin-antly by eccentric behavior and avariety of negative symptoms.

Generic and family studies haveprovided one useful tool for deter-mining the breadth of the schizo-phrenia spectrum. Although theresults of such stud ies are not con-clusive, they tend to suggest thatthe concept of schizophrenia should

be relatively broad and should in-clude a spectrum of disorders.

Family studies were among theearliest investigations of genetic fac-tors in schizophrenia. These studieshave consistently indicated that therelatives of schizophrenic patientshave a higher risk for schizophreniathan the approximately 1 percentobserved in the general population.In addition to documenting thatschizophrenia has a genetic compo-nent, family studies have also been

used to explore the boundaries ofthe schizophrenia spectrum. Thesestudies have shown that the rela-tives of schizophrenic patients alsohave a relatively increased rate ofboth schizoaffective disorder andschizotypal personality, suggestingthat these disorders may have somerelationship to narrowly definedschizophrenia.

In one of the largest family studiesof schizophrenic probands, the rela-tives of schizophrenic patients n ot

only had an increased morbid riskfor chronic schizophrenia itself andfor schizophrenia-related personalitydisorders, but also for other psy-chotic disorders including schizoaf-

fective disorder, atypical psychosis,schizophreruform psychosis, andpsychotic affective disorder. There-fore, it appears that there may begenetic factors shared betweenschizophrenia and many other psy-chotic disorders.

Twin studies have also been usedto explore both the genetic compo-nent in schizophrenia and theboundaries of the schizophreniaspectrum. Concordance rates inmonozygotic twins range from a lowof 38 percent to a high of 72 percentfor schizophrenia or probableschizophrenia. If other related dis-orders, such as schizoid personalityare also included, then the concor-

dance rates are higher. Thus, theschizophrenic phenotype appears tobe both variable and broad, evenwhen genetic factors appear to beidentical. The Genain quadrupletsprov ide a particularly informativeinsight in this context. They showedno single phenomenologic or biolog-ic profile characteristic of allschizophrenic patients, but insteadranged from mild to severe.

Study of the adopted children ofschizophrenic mothers is yet a third

strategy that has been used to evalu-ate genetic components in schizo-phren ia. This strategy is a particularlypowerful one, since it isolates rela-tively pu re genetic factors andexcludes role modeling in the de-velopment of schizophrenia. Adop -tion studies have supported a majorgenetic component in schizophre-nia. The adoption studies conductedin Denmark have also indicated thatschizotypal personality appears tobe genetically related to core

schizophrenia.Much less work has been don e

on the relationship between schizo-phrenia and relatively pure paranoiddisorders. The available data sug-gest that these disorders may be lessclosely related to core schizophre-nia, but considerably more workneeds to be done in this area.

Other methods apart from genetictechniques have also been used toexamine the relationship between

the various disorders on the schizo-phrenia spectrum. For example, insome studies, patients with bothschizophrenia and schizotypal per-sonality share an impairment insmooth pursuit eye movements(SPEM) and poor performance on abackward masking task, suggestingbiological comm onalities between atleast a subgroup of schizotypal pa-tients and chronic schizophrenic pa-

tients. Investigators have also usedresponse to treatment as a methodof exploring the schizophrenia spec-trum; they have shown that somepatients with schizotypal features orborderline personality respond toneuroleptic medication.

Future N eed s. It is clear that in thefuture the boundaries of the schizo-phrenia spectrum should be ex-plored further using the above

methods and other techniques aswell. This exploration should bedone with an appreciation thatgenetic factors implicated in schizo-phrenia may be expressed variablyand with the recognition that morethan one set of generic determinantsmay be involved in the pathogenesisof schizophrenia. In addition tonuclear, core, or chronic schizophre-nia, other related disorders shouldalso be evaluated, including schizo-typal personality disorder, paranoid

disorders, psychotic affective disor-ders (noting features such as mood-congruent vs. incongruent symp-toms), atypical psychoses, andschizophreniform, schizotypal,schizoid, and borderline personalitydisorders.

Most family studies conducted todate have begun by ascertaining pa-tients suffering from schizophrenia.Only rarely have such studies in-dexed the milder or spectrum forms



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to determine their relationship.Given the relative rarity of chronicschizophrenia in the relatives ofchronic schizophrenic patients andthe possibility that the various spec-trum disorders are less geneticallyloaded variants, larger sample sizesthan those currently reported maybe required to establish or rule out arelationship between core schizo-phrenia and the spectrum disorders.

Definitive family studies of schizo-typal patients or other patients w ith-in the schizophrenia spectrum,using direct interviews of their rela-tives are still needed.

Biological studies of the schizo-phrenia spectrum disorders are intheir infancy. As noted previously,however, some biological correlatesof schizophrenia have been ob-served in schizotypical patients.Such studies need to be extended.

Far more work needs to be doneon the interaction between geneticfactors and both organic and psy-chosocial environmental factors.When schizophrenic patients arecompared to patients with schizo-rypal personality, for example,perinatal complications are morepromin ent in the patients with coreschizophrenia. Other environmentalinsults have not yet been systemati-cally examined in these two popula-tions. In addition, psychosocialfactors that might modify the genet-ic predisposition to schizophrenia-related disorders, either toward oraway from the more severe chroniccore schizophrenia, also need to bestudied.

Molecular genetics is, of course,an especially promising area for fu-ture re search. It is also an areawh ere careful clinical evaluation a nddiagnosis may play a crucial role. In-formation about pedigrees collectedfor the purpose of seeking possible

genetic markers will require a com-prehensive clinical data base thatlends itself to determining the effectof broad versus narrow definitionson identifying linkage. Since molec-ular genetic studies are especiallylikely to require cooperation be-tween individuals working in a vari-ety of centers, it is particularlyimportant to develop standardizedassessment techniques for such

studies. These assessment tech-niques shou ld not only meet the re-quirement of good reliability, butthey should contain a detaileddescription of the broad range ofclinical symptoms and other infor-mation such as age of onset andexposure to environm ental riskfactors.

Neurotransmltters, Neuroendo-crine Systems, and the Selec-

tion of Informative PopulationsCurrent Knowledge. The search forneurochemical abnormalities inschizophrenia h as been substantiallyassisted by the dev elopment of thedopamine hypothesis and increasingknowledge concerning the mechan-ism of action of neuroleptic drugs.The dopamine hypothesis postulatesthat functional hyperactivity of thedopamine system at crucial anatom-ic locations in the brain is an impor-

tant mechanism that produces atleast some of the symptoms ofschizophrenia. T his hypo thesis issupported by two major lines of evi-dence: (1) Antipsychotic drugsproduce their behavioral effectsthrough dopaminergic blockade;most of the antipsychotic medica-tions currently in use have variableeffects on serotonin, D, receptors,and D 2 receptors, but the bulk of ex-isting evidence implicates the D 2

receptor in psychotic sym ptomatolo-

gy. (2) Psychostimulant d rugs withdopamine agonist effects canproduce or exacerbate psychoticsymptoms of schizophrenia.

The exploration of possible rea-sons for functional hyperactivity ofthe dopamine system are notreviewed in detail here, since it iscovered more fully in other panelrep orts . Briefly, one line of researchhas focused on the study of dopa-

mine metabolites, particularlyhomovanillic acid (HVA), whichcan serve as a measure of d opam ineneural activity. Several studies havebeen completed, but they are diffi-cult to interpret because of variabili-ty in patient samples, insufficientknowledge about the long-term ef-fects of prior medication, and thescarcity of samples of drug-naive pa-tients or patients who have been offmedications for very long periods oftime. Nevertheless, the major thrustof these efforts appears to suggestthat the neurochemical abnormalityin schizophrenia is neither excessivedopamine production nor failure tometabolize it. The study of post-mortem bTains has suggested in-stead that patients with schizophre-nia may have an increase in D 2

receptors on postsynaptic neurons,thereby producing a functionalhyperactivity. While this finding hasbeen consistently repo rted by a

num ber of investigators working indifferent centers throughout theworld, the results of such stud iesmust be interpreted cautiously, be-cause of the possibility that long-teim neuroleptic medication may in-duce postsynaptic receptor prolifera-tion as a consequence of chronicblockade.

The development of in vivo imag-ing of neuroreceptor systems duringthe past several years has providedan important contribution to our un-




derstanding of the dopam ine systemin schizophrenia. Several differentresearch groups have worked outhighly sophisticated methods forquantifying numbers of receptors,and two studies concerning D2

receptor density (B ma x) inschizophrenia have been reportedduring the past year. Unfortunately,the results of these two studies arein conflict. At present, it is not dearwhether this conflict is a conse-quence of differences in patientselection or differences in methodol-ogy. The patient sample in which anincreased number of D 2 receptorswas found tends to be considerablyolder and more chronically ill thanthe patients with normal D 2 recep-tors. Both of these studies were con-ducted using schizophrenic patientswho had never been medicated.These studies highlight both the im-portance of studying special rare buthighly informative populations andthe importance of carefulphenomenologic description so thatdifferences in findings can be inter-preted intelligently.

The use of dopamine agonistprobes has been an alternate strategydesigned to identify special sub-populations of patients withschizophrenia an d to attempt toidentify patients particularly vulner-able to subsequent psychoticrelapses. This strategy is based onthe recognition that amphetaminesmay produce a psychosis resemblingparanoid schizophrenia in a normalperson. If this person is given neu-roleptic medication, the psychosisabates. Further , dopam ine agonistpsychostimulants can provoke or ex-acerbate psychotic symptoms inschizophrenic patients at subpsy-chotogenic doses. The psy-chostimulants do not superimpose adrug psychosis on the schizophre-

nia, but instead exacerbate the pa-tient's preexisting condition. Thiseffect a ppe ars to be selective an ddoes not occur in depressed or man-ic patien ts. The behav ioral effectsare believed to be mediated via braincatecholamines by directly releasingthem into the synaptic cleft orpreventing their inactivation by re-uptake into the presynaptic terminalfrom which they were released.

The neuroendocrine system isanother approach to studying dopa-mine neuronal physiology in schizo-phrenia. T here is a neuroanatomicalrelationship of the pituitary gland,the hypothalamus, and their extra-hypothalamic CNS connections.Horm ones secreted by the pituitarycan be measured in the peripheralcirculation. Since the secretory pat-terns of the anterior pituitary hor-mones are to an extent under CNScontrol, it is inferred that these hor-mones reflect CNS neurochemical

activity and that this could serve asan indirect measure of dopaminefunction.

One neuroendocrine abnormalitythat has been observed in schizo-phrenia is in growth horm one secre-tion. As with the dopam ine agonistchallenge studies of symptom ex-acerbation, the growth hormoneresponse to pharmacological stimu-lation also shows considerable diver-sity. The majority of schizophrenicpatients show a blunting of growthhormone response, but there aresome patients in all studies withnormal or exaggerated growth hor-mone responses. Further complicat-ing interpretation of these studies isthe fact that blunted growth hor-mone response to pharmacologicalchallenge is not obviously consistentwith the dopamine hypothesis. Ithas been suggested by some investi-gators that a blunted growth hor-

mone response is associated withchronicity and clinical deterioration ,while exaggerated response s occurin younger patients with florid psy-chotic symptomatology. This line ofthinking is consistent with the sug-gestion put forward by several in-vestigators that hy podopam inergicactivity actually characterizes latestages of the illness or is associatedwith prominent negative symptoms,

while functional h yperactivity ismore characteristic of acute formsand associated with positivesymptoms.

Future Needs. For such neurochem i-cal investigations, the study of spe-cial informative g roup s is especiallyimportant. Of highest priority is thestudy of drug-naive patients. Thelong-term effects of neurolepticdrugs on the dopamine system arenot known at present, but it is

definitely possible that effects couldremain for months or even years.Most of the work completed to datehas involved patients who havebeen withdrawn from medicationsfor only a few weeks and who hadpreviously been under treatment forvariable amounts of time. Muchmore careful attention needs to begiven to the differential effects ofduration of treatment an d durationof the withdrawal period in suchstudies. Until such information iscarefully collected, however, the

study of drug-naive patients in asmany centers as possible is crucial.This strategy is important in manytypes of investigation, but it is par-ticularly imperative in the study ofneurochemical systems, since thedrugs used to treat schizophreniaact directly on these systems.

As the above review of recentachievements has indicated, resultsare sometimes difficult to interpret



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because samples often mix patientswith acute and chronic duration andwith prominent positive or negativesymptomatology. Future studiesshould focus on discrete "purified"subgroups of patients such as first-episode acute patients versuschronic end-stage pa tients, orgroups with clearly defined positivesymptoms versus dearly definednegative symptoms. In neurochemi-

cal studies conducted to date, clini-cal description of patients has oftenlagged behind the laboratorytechnology.

As techniques for studying neuro-receptor systems with positronemission to mog raphy (PET) con-tinue to evolve, it will also becomeincreasingly important to attempt tounderstand abnormalities in thedopam ine system no t only in rela-tion to clinical pheno meno logy butalso in relation to specific brainsubregions. For example, severalreports during the last year have in-dicated that hyperactivity (either asmeasured by glucose use or byblood flow using oxygen-15) occursin subcortical brain regions. Thesefindings provide an interesting com-plement to earlier reports of hypo-frontality in schizophrenia seen withboth glucose use as measured byPET and regional blood flow asmeasured by the xenon inhalationtechnique. These findings suggest

that a possible imbalance may occurin different functional componentsof the dopam ine system (i.e., frontalprojections v s. nigrostriatal or limbicprojections), which could producemarked differences in clinical symp -toms and in the course of the ill-ness. As this anatomical dissectionof the neural circuitry involved inschizophrenia continues, it will be-come increasingly im portant to pro-vide detailed cross-sectional and

longitudinal descriptions of patients.Ultimately, it will be important tomap possible shifts in chemical andmetabolic balances in patients overtime in relation to cha nge s in clinicalphenomenology.

These neurochemical studies re-quire special clinical settings. Sincesuch studies must be done either ondrug-naive patients or patients who

have been withdrawn from medica-tion for long periods of time, theymust be conducted in settings wheresuch patients can be managed withcareful clinical supervision and sen-sitive and compassionate support.The patients themselves and third-party payers cannot be expected tosupport research endeavors that in-volve the absence of treatment. Inorder to support such neurochemi-cal research, the development ofspecial clinical research settings willbe required.

Neuropathology and StructuralApproaches

Current Kno wled ge. Since Kraepe-lin's original description of thedisorder, investigators have hypoth-esized that many schizophrenicsymptom s could be explained bysome type of brain abnormality. Ear-ly work in this area, such as that

conducted by m embers of Kraepe-lin's own colleagues (including Alz-heimer, Nissl, and Brodmann),failed to yield conclusive results,although they diligently sought neu-ropathological abnormalities in boththe frontal and the temporal lobes.

More recently, however, there hasbeen a resurgence of interest in neu-ropathology which has suggested avariety of different types of abnor-malities. For ex amp le, in a series ofpost-mortem studies of the basal

ganglia and limbic system, a 20 per-cent decrease in the size of the inter-nal pallidum was noted, as well as a20-40 percent decrease in the limbicportions of the temporal lobe,including the dentate gyrus, subicu-lum of the hippocampus, parahip-pocampal gyrus, and amygdala. Thetemporolimbic abnormalities havebeen most consistently reported,with at least four different gro up s of

investigators noticing some type ofabnormality in the hippocampus orparahippocampal gyrus. In addition,cytoarchitectonic studies havedemonstrated reduced numbers ofneurons in layers 2, 3, and 4 of theprefrontal cortex, as well as abnor-malities in the cingulate gyrus,which are consistent with a develop-mental abnormality rather than neu-ronal loss later in life.

These neuropathological findingsare important because they point tospecific brain regions that could beinvolved in producing the symp-toms of schizophrenia. Limbicsubstructures, such as the hip-pocampus, play an important role inencoding and storing memory.Other limbic structures have func-tional importance for regulating af-fect and em otional respo nsiven ess,as does the cingulate gyrus and theprefrontal cortex. One persistentproblem in post-mortem studiesconducted to date has been thedifficulty in relating site of abnor-mality to clinical features of the ill-ness before death. This limitationhas unfortunately partiallydiminished the resolving po wer ofsuch post-mortem neuropathologicalstudies and highlights the impor-tance of collecting prosp ectively, ifpossible, detailed clinical informa-tion about those w hose b rains aredonated to post-mortem tissuebanks.




In vivo brain-imaging techniqueshave also been applied to the studyof brain structure in schizophrenia.Computer tomography (CT scan-ning) was the earliest technique tobe used, and during the past 10years many CT studies have beenconducted. Abnormalities describedincluded an increased ventricle:brain ratio (VBR), cortical atrophy asmeasured by enlarged sulci, cerebel-

lar atrophy, and reversed cerebralasymmetry.

By far th e mo st consistent findinghas been ventricular enlargement asmeasured by an increased VBR. Thisfinding has been consistently repli-cated in a large number of studiesconducted throughout the world.Important issues in interpretingthese studies include the effects ofmedication, chronicity, and institu-tionalization; the selection of controlsamples; and the prognost ic and

pathop hysiologic significance ofventricular enlargement. Some par-tial answers to these questions havebeen provided. Studies examiningventricular size in young first-episode patients have indicated thatthey show a high rate of ventricularenlargement, suggest ing that thefinding is probably not a conse-quence of chronicity, treatment, orinstitutionalization. Investigatorshave applied a variety of statisticalmetho ds to more chronic pat ientsstudied with CT scanning to deter-

mine whether confou nding factorsassociated with chronic illness couldexplain an increase in ventricularsize; quite consistently, th e an alyseshave shown little or no relationshipbetween type of treatment, durationof treatment, or effects of institu-tionalization. When ventricular sizeis plotted over time in a cohort ofschizophrenic patients of varyingages and a group of normal subjects

of varying ages, the lines of bothgroups have parallel slopes; ventric-ular size increases steadily with agein both samples, but the schizo-phrenic p atients have a larger ven-tricular size at onset.

Attem pts have also been made tocorrelate ventricu lar size w ith clini-cal picture and response to treat-men t. There is some suggestion thatventricular enlargement is associat-

ed with poor premorbid adjustment,negative sym ptom s, cognitive im-pairment, and a poor response toneuroleptic drugs. Much more workneeds to be don e in this area, how-ever, particularly research using im-proved clinical definitions.

Future Need s. The thrust of thisresearch has been to suggest thatmorphological chang es occur in asubgroup of schizophrenic patients.Many important questions remain

about the significance of thesefindings.

While structural abnormalitieshave often been found, eitherthrough neuropathological tech-niques or throu gh in vivo imagingtechniques such as CT, they haveonly been consistently found in asubg roup of patients. For example,the frequency of ventricular enlarge-ment ranges from as low as 5 per-cent in some studies to as high as40-50 percent in others. It is neverfound in all patients. Much morework needs to be done to determinethe meaning of this finding and itsrelationship to genetic and/or en-vironmental risk factors. The twinand high-risk stud ies describedearlier, which applied CT scanningto informative populations such asmono zygotic twins discordant forschizophrenia or the children ofschizophrenic mothers for whombirth records were available, illus-

trate especially po werful applica-tions of such imaging techniques tothe evaluation of mechanisms.Other exam ples include longitudinalprospective studies of first-episodepatients and evaluation of ill andwell memb ers of multiply affectedfamilies.

In the present and future, it seemslikely that in such structural studiesCT scanning will be largely sup-

planted by the us e of m agneticresonance imaging (MRI). MRI has anum ber of advantages over CT scan-ning. It does not involve the use ofionizing radiation, p rovides superbgray/white resolution, and is able toimage in multiple planes, includingsagittal and coronal in addition totransaxial planes. Thus, it permitsthe evaluation of a number of im-portant brain regions which cannotbe seen readily w ith CT scanning,such as the hippocampu s and amyg-

dala, basal ganglia nuclei, and areasof the prefrontal cortex. Investiga-tors are currently attem pting to de-velop software that will providesemiautom ated volumetric assess-men ts. These methodological de-velopments should significantlyadvance the sensitivity and accuracyof in vivo structural imaging tocharacterize the neu ropathology ofschizophrenia.

It is also quite important to sup-plement the structural techniques

with functional or dynamic tech-niques, including the measurementof regional cerebral blood flow witheither cortical probes or single pho-ton emission computed tomography(SPECT), as well as PET. Anotherarea that needs particular attentionis the development of in vivonuclear magnetic resonance (NMR)spectroscopy w hich can provide awealth of metabolic information thatis not available with any other tech-



VOL. 14, NO. 3, 1988 35 9

nique. At least in their initial stages,these dynamic techniques must beused in unmedicated (and prefera-bly never-medicated) patients to ruleout confounding effects of drugs oncerebral blood flow and metabolism.The potential resolving power ofsuch techniques for the study ofphenomenology is substantial. Theypermit the determination of whetherthere is indeed a correlation

between prominent negative symp-toms and hypoactivity in thefrontal lobes, the relationship be-tween specific limbic subregions anda variety of positive symptoms, andthe capacity of the schizophrenic pa-tient to respond to a wide variety ofcognitive challenges. These tech-niques will draw us much closer tothe possibility of relating clinicalphenomena to their underlying n eu-ral mechanisms.

The development of post-mortemtissue banks is also a high priority.As efforts increase to identify poten-tial don ors prospectively, it will be-come very imp ortant to developstandardized methods for evaluatingdonors during life and carefullydocumenting their clinical picture,course of illness, history of med ica-tion, birth history, and the manyother variables that can lead to the "development of cerebral patholog y.

Medication Versus DisorderIssues

Current Knowledge. Treatmentwith neuroleptic dr ugs h as a con-founding effect on the pathophysi-ology of schizophrenia. This effectmay vary depending on the type ofvariable under investigation. It isnot likely that neuroleptics will af-fect genomic DNA or gross anatomicbrain structure. On the other hand,

antipsychotic medications can con-taminate most physiological, be-havioral, and biochemical measures.For example, abnormalities in dopa-mine transmission (as reflected bydopamine receptor density and af-finity) can be obscured or evencaused by treatment with neurolep-tics. Studies in animals have demon-strated that the administration ofantipsychotic medications increasesthe number of brain dopaminereceptors. Medications also in-fluence brain electrical activity andcan potentially influence a variety ofneurophysiological measu res. Theyaffect the extrapyTamidal system inparticular, producing a Parkinsoniansyndrome, thereby affecting theclinical assessment of phenomenolo-gy, especially negative symptoms.Of course, antipsychotic drugs arehighly effective for diminishing

positive symptoms. Thus, studiesthat attempt to evaluate intercorrela-tions between clinical and biologicalvariables will be subjected to man yconfounders when patients arestudied on medication.

Investigators have tried to grapplewith this problem in a variety ofways. Statistical corrections haveoften been applied to data to covaryeffects of treatment. The use of ex-tended washout periods so that pa-tients can be studied while free of

medication has been more valuable.These studies are logistically difficultto accomplish and therefore fre-quently involve relatively smallsamples. As has already been m en-tioned, the study of never-medi-cated patients repre sents the idealsituation, but such patients are par-ticularly rare. Therefore, samplesmust necessarily be quite small, andnever-medicated patients may be anatypical sample of schizophrenicsubjects.

Future Needs. To interpret the ef-fects of neuroleptic medication onthese various parameters, we need aseries of well-designed drug with-drawal studies that will provideinformation concerning the relation-ship between medication, clinicalsymptom s, blood levels of the drug,and ideally some measure of chemi-cal activity in the brain. Such studieswou ld give us a relatively definitive

answer to the following impo rtantquestions: How long is long enoughfor drug withdrawal? On whichvariables do drugs h ave the greatesteffect? What is the relationship be-tween blood level, receptor oc-cupancy, and clinical symptoms?How do these measures correlatewith other variables such as brainelectrical activity, cerebral perfusion,and o ther commonly u sed biologicalcorrelates? The selection of th e ap -propriate type of sample for such

studies remains a persistentproblem. For expensive complexstudies that necessarily involvesmall samples (such as the study ofdrug-naive patients), two differentstrategies are possible. One is to usea very narrow definition of schizo-phrenia that will help purify thesample. Narrow definitions typicallyrely on specifying chronicity (dura-tion of 6 months or longer). This ap-proach has the adv antage ofensuring that the diagnosis is rela-

tively certain, but the disadvantagethat informative patients who onlyrecently became ill may be excluded.An alternative strategy, which maybe preferable in some instances(e.g., the study of drug-naive pa-tients) , is to collect a series ofphenomenologically typical schizo-phrenic patients who do not neces-sarily have established chronicityand follow them longitudinally toidentify those with sufficient chro-




nicity to meet relatively narrow defi-nitions.

In general, a longitudinal ap-proach to studying selected patientgroups is highly desirable. Groupsthat can be particularly informativein determining the effect of medica-tion include young schizophrenicpatients (less than 5 years' durationof illness), never-medicated andfirst-episode patients and adolescent

high-risk individuals (e.g., off-spring of schizophrenic p atients and,perhap s, psychostimulant and hal-lucinogenic drug abusers). This ap-proach permits investigators toidentify patients either before theyreceive medication or relatively earlyin the course of treatment. It permitsdiagnosis to be validated prospec-tively over time instead of cross-sectionally in a narrow timeframe.It also allows correlations to bemade between baseline phenomeno-

logical and biological variables, aswell as a variety of outcome varia-bles such as treatment response andcourse of illness.

Since such prospective longitudi-nal studies can be costly and labor-intensive, they are best performedin patient groups that have the max-imum likelihood to yield significantresults. Young nonchronic patientshave the advantage of having hadrelatively less treatmen t ex posureand may still be on the linear por-

tion of their evolution of illnesscurve as compa red to more chronicpatients who have had longer treat-ment and whose illness may have"leveled off" and clinically ceasedto change.

Gaps In Present Knowledge

A substantial number of gaps in ourpresent knowledge of schizophreniahave already been enumerated un -

der the heading Future Needs ineach of the previous sections. Inaddition, there are a number ofother areas that require further ex-ploration.

There are many promising areas ofinvestigation in which abnormalitiesin schizophrenia have been demon-strated, but w hich have not beenrelated to clinical heterogeneity inschizophrenia. Examples include

SPEM, abnormalities in vestibularfunctioning, and neurological softsigns. These kinds of abnormalitiesneed to be related to clinical varia-tion both within patients themselvesand within their family members(preferably using designs that willpermit the identification of spectrumdisorders or subclinical phenom enain family members). Using this ap-proach, investigators can generatehypotheses to help "slice u p " theschizophrenias into more clinically

and biologically homogeneousgroup s, mak ing pathophysiologicaland etiological research morefruitful.

Much more work needs to bedone on the personality disordersthat may be within the schizophre-nia spectrum. For example, it is notclear whether both paranoid person-ality and schizotypal personalitybear the same relationship to coreschizophrenia. Further, observationof relatives of schizophrenic patients

has indicated that these relativesmay have num erous peculiaritiesthat are not actually diagnosable aseither type of personality disorder,although they do have some impor-tant subsyndromal features such asodd ideation or asociality.

As this example indicates,research in schizophrenia m ustwork at m ultiple levels. Too fre-quently, conceptualization has beenonly at th e d iagnostic level or

perha ps at the syndromal level. Infact, investigators must both thinkand code their data at multiple lev-els, including diagno ses, syn-dromes, symptoms, and signs. Thisis important because our current di-agnostic systems are only provision-al . We have not yet identified"true" diagnoses which, by defini-tion, represent disorders for whichwe know the mechanism or cause.

The evaluation of subsyndrom aldegrees of schizophrenia-likepatholog y is particularly challeng-ing. Our ability to measure delu-sions exceeds our grasp of mildlyaberrant personal beliefs (e.g., su-perstition s, beliefs about clairvoyance,peculiar ideas about bodily health).Our assessment of affective bluntingand inap propriateness is also muchcruder than needed for assessingsubclinical defects. Promising begin-nings in this area include the analy-

sis of vocal inflections from recordedvoice samples and work on the abili-ty of schizophrenic patients to inter-pret facial expressions as denotingemotional states. A multifaceted ap-proach using structured interviewsand rating scales, self-report ques-tionnaires, special test situationssuch as facial recognition assess-ment, and mechanical methods suchas voice analysis m ay be required tocover the full range of relevantphenomena.

Analyses in future studies need tostay closer to original data. T he in-ternal cohesiveness of a symptom orassessment picture may afford valu-able clues for isolating new syn-dromes, thereby assisting inevaluating the heterogeneity ofschizophrenia. But such dissection ispossible only under the followingconditions: A wide array of mea-surements is needed. These mustinclude not only clinical phenomena



VOL 14, NO. 3, 1988 361

such as hallucinations, delusions,and abnormal affective and motorphenomena, but also measuresrelated to cerebral status such as IQ,cognitive performance, and hand ed-ness. Social pathology such as an-hedonia and asociality should alsobe assessed, and thorough and stan-dardized neurological examinationsshould be conducted for all subjects.

All these measures need to bereadily retrievable and not doneaway with at some intermediatestage of data coding. Uncoded dataare unanalyzable data. Ideally, suchdata should be collected so that theyprovide a long-term repository forinformation that can be available forlater investigations as new hypoth-eses arise 4-5 years into a project,and that will also be available toother investigators who wish tocross-check hypotheses and estab-lish continuing standardization. In

addition to standard techniques ofassessment such as structured inter-views, several other approaches areparticularly useful and promising.Ideally, one should videotape as-sessment sessions of patients to ar-chive clinical phen om ena in a visibleliving library. Later stud ies can th enprofitably reanalyze existing ar-chives, rediagnosing patients inmore subtle ways than are possiblewith structured interviews or evencase histories. Such archives are also

useful in comparing results in dif-ferent centers and determiningwhether differences in results maybe du e to differences in patien tpopulations. For example, suchvideotape libraries would be veryuseful to compare the patients instudies that produce conflictingresults in different schizophrenicpatient samples.

Detailed records summarizing casehistories should also be maintained,

however, in addition to videotapelibraries and structured interviews.They provide a compact and easilyconveyed method for describing pa-tients in greater detail than is ob-tained through checking and listingsymptom criteria.

The intercenter (and not merelyintracenter) reliability of m easu re-ments needs to be continuallyassessed. If this is not done, a con-fusion of tongues results and non-replications are given greater weightthan they deserve, producing un-warranted pessimism. The readyavailability of videotape equipmentmakes such intercenter reliabilitystudies much easier to do.

Specific Recommendations

In addition to the recomm endationscontained in the body of the Panel

Report, the group reached an overallconsensus about several majorneeds that are described below:

• There is a need for im prov emen tin standardization and definition ofclinical sam ples. This need covers abroad range of issues and includes anum ber of specific recom men dations.

1. There is a continuing need forimproved clinical assessment tech-niques. These may vary, dependingon the goal of the study, but areas ofneed include comprehensive evalua-tion of patients at index admissionor assessment, sensitive techniquesto assess change in treatmentstudies, and methods to map thelongitudinal course of the illness. Atthe moment, acceptable instrumentsare available for cross-sectionalevaluation and possibly for past his-tory, but acceptable instruments arenot available to map longitudinalcourse at regular intervals over time.

The instruments currently used toassess change in treatment studiesshould be updated and m ore specifi-cally targeted to schizophrenia.

2. There is a need for a consensusas to the "bare minimum" whichshould appear in the publisheddescription of any patient sampleand in any clinical data base tha t isused to study schizophrenic patientsin research settings. We do not

make specific recommendations asto this "bare minimum," but itmight be appropriate to convene aconsensus conference to u ndertak ethis task. It is quite clear tha t thebare minimum should not be toobare. Studies that invest heavily inthe collection of biological or out-come measures are penny wise andpound foolish if they scrimp on thephenomenological description of pa-tients. This is particularly importantbecause we do not know the defini-

tion or boundaries of schizop hrenia.The process of understan ding thedefinition and bo undaries m ustresonate back and forth betweengood phenomenology and good bio-logical measure s.

3. There is a need to collect ar-chival resources and to have multi-ple groups study the same patients.Whenever possible, the same pa-tient populations should be studiedby more than one research group.This will optimize the use of limitedpatient resources and also addressissues of replication in a timelyfashion. More objective measures(such as audio and video recordingwith frequency analysis) need to bedeveloped for the recording and ar-chiving of clinical data which canthen be analyzed by more than oneresearch group .

4. There is a need to identify anddesignate research facilities that arewell equipped to train other investi-




gators in clinical assessment andphenomenology. Such trainingcenters could be used to raise thegeneral level of sophistication con-cerning the difficult issues involvedin phenomenology and nosology, aswell as to create improved con-sistency in definition and assess-ment across a variety of researchsites in the United States. This is es-sential if we are to be able to com-

pare results from various centersand to understand why replicationsdo or do not occur.

• Studies of schizophrenia shouldinclude both cross-sectional and lon-gitudinal components insofar as thisis possible. They also should includeboth clinical (including medicationdata) and biological measures.Schizophrenic patients will need tobe compared to both normal con-trols and patients with other non-schizophrenic neuropsychiatric

disorders with and without similarmedication usage. The assessmentof both clinical and biologicalparameters in combined cross-sectional and longitudinal studiesshould increase the scientific powerof the studies and make the studiesmore economical in long term.

• The various definitional andboundary issues described in thisreport have not yet been resolved.The best way to resolve them isthrough careful research. Therefore,

there should be no prematureclosure on definitional or boundaryissues. Some studies may requirebroad definitions (e.g., epidemiolog-ical studies and possibly familystudies), while other studies may re-quire relatively narrow definitions(e.g., expensive biological studies onsam ple s th at are difficult to collect).

• Increasingly, studies shouldtailor their study of populations andtheir definitions of schizophrenia to

specific h ypoth eses an d q uestions.There is no "best" definition ofschizophrenia, but there may be a"best" sample to address a particu-lar question. For example, drug-naive patients are the ideal popula-tion to study abnormalities in neu-rorransmitter systems. Multiplexfamilies and extended pedigrees arethe best population to explore issuesin molecular genetics. Other unique

populations are also valuable—e.g.,twins and high-risk samples.

• There is a need for continuingbasic research in both phenom enolo-gy and nosology. Research inpheno meno logy at a descriptive lev-el is useful, but it is also importantto try to tie phenomenology to ob-jective measures. Additionalresearch instrum ents need to bedeveloped that empirically andaccurately assess some of the abnor-mal clinical features of schizophre-

nia such as abnormal thou ghtprocesses, affect, and social inter-actions.

• It is also very important to un-derstand phenomenology better byinvesting in research in normal in-dividuals and animals. Since thestudy of the phenomenology ofmental illness looks at abnormalbehavior, cognition, and emotionalresponse, we need careful defini-tions of the normal if we are to iden-tify and understand the abnormal.

For example, greater knowledgeabout aud itory perceptual systemsmay improve our understanding ofthe mechanisms that produce abnor-mal perceptions such as auditoryhallucinations. Improved under-standing s of normal brain structureand function will permit us to recog-nize and define neural abnormalitiesin schizophrenia. Mapping normalpatterns of neural circuitry or neuro-chemical system s will assist us in

identifying neurochemical aberra-tions in schizophrenia.

• Ultimately, research in nosologyand phenomenology must integrateneurob iology. There is little point instudying phenomenology alone,despite the need for good basicresearch in phenom enology. The ul-timate goal of clinical definition is tounderstand mechanisms and causes.In the case of schizophrenia, a major

portion of the etiology is clearly neu-ral. As this report has indicated,many areas are promising. These in-clude research to explore relation-ships between clinical symptomsand brain structure and function(neuroimaging and in vivo neuro-chemical studies), work usingmolecular genetics and other emerg-ing approaches and technologies,and growth of special resource facili-ties such as brain banks. In suchstudies, the very best phenomenolo-gy must be joined to the very bestneurobiology.

• To perm it these efforts to un itephenomenology and neurobiology,investment in research infrastruc-ture in psychiatry is necessary. Qin-ical research facilities that willpermit the study of drug-naive andnever-medicated patients are need-ed. Post-mortem tissue banks mustbe assembled to study the neuro-pathology of schizophrenia. DNAbanks are needed for molecular

genetic studies. In some instances,expensive technological equipmentmust be pu rchased. The various invivo brain-imaging techniques arean important example. At present,many investigators have difficulty inobtaining access to MRI, NMRspectroscopy, SPECT, or PET equip-ment. Since these imaging tech-niques have great resolving powerfor interrelating phenomenologyand neurobiolo gy, as well as for dis-



VOL 14, NO. 3, 1988 36 3

secting clinical h eterogen eity,searching for metabolic and neuro-chemical mechanisms, and develop-ing improved approaches totreatment, support is needed for im-aging centers emphasizing researchon psychiatric patients, particularlythose suffering from schizophrenia.

• To achieve the kind of integra-tive clinical research that is neede d,increased opportunities for interac-

tion between basic neurobiologistsand phenomenologists must be en-couraged. Over the short term, eachof these disciplines must learn moreabout the needs and goals of theother so that the rich developmentsin neuroscience that are emergingdurin g the 1980's an d 1990's can beimple men ted in clinical research inpsychiatry. The National Institute ofMental Health should use its con-vening pow er to facilitate suchopportunities whenever possible,

and it should continue to emphasizethe importance of this interactionthrough the development of neuro-science clinical research centers tar-geted to the study of schizophrenia.Ultimately, the Institute's long-termgoal should be to make the interac-tion so strong that neurobiology andclinical phenomenology are integrat-ed in single individuals and thestudy of schizophrenia is pursuedby a sophisticated new generation of"clinical neurobiologists"—individ-

uals who combine clinical excellenceand commitment to patient carewith a strong grounding in basicneuroscience.

Suggested Readings

Alpert, M., ed. Controversies inSchizophrenia: Changes and Constan-cies. New York: Guilford, 1985.

American Psychiatric AssociationWork Grou p to Revise DSM-HI.

DSM-IH-R. 2nd ed. Washington,DC: American Psychiatric Press,Inc., 1987.

Andrea sen, N.C . The diagnosis ofschizophrenia. Schizophrenia Bulletin,13:9-22, 1987.

Andreasen, N .C , and Olsen, S.Negative v positive schizophrenia.Archives of General Psychiatry,39:789-794, 1982.

Carp enter, W .T., Jr.; Bartko, J.J.;Strauss, J.S.; and Hawk, A.B. Signsand symptoms as predictors of out-come: A report from the Internation-al Pilot Stud y of Sc hizophrenia.American Journal of Psychiatry,135:940-945, 1978.

Chapman, L.J., and Chapman, J.P.Scales for physical and social an-hedonia. Journal of Abnormal Psychol-ogy, 85:374-382, 1976.

Feighner, J.P.; Robins, E.; andGuze, S.B. Diagnostic criteria foruse in psychiatric research. Archivesof General Psychiatry, 26:57-63, 1972.

Go ttesma n, 1.1.; Shields, J.; andHanson, D.R. Schizophrenia: TheEpigenetic Puzzle. Cambridge: Cam-bridge U niversity Pre ss, 1982.

Johnston, M.H., and Holzman, P.S.Assessing Schizophrenic Thinking. Sa nFrancisco: Jossey-Bass, 1979.

Kendler, K.S. Diagnostic ap-

proaches to schizotypal personalitydisorder: A historical perspective.Schizophrenia Bulletin, 11:538-553,1985.

Knight, R.A.; Roff, J.D.; Barrnett, J.;and M oss, J.L. Concurrent and pre-dictive validity of thoug ht disorderand affectivity: A 22-year followupof acute schizophrenics. Journal ofAbnormal Psychology, 88:1-12, 1979.

Levin,S.; Hall, J.; Knight, R.; andAlpert, M. Verbal and nonverbal ex-pression of affect in speech ofschizophrenic and depressed pa-tients. Journal of Abnormal Psychology,94:487-497, 1985.

Neale, J.M., and Oltm anns, T.F.Schizophrenia. New York: John Wiley& So ns, 1980.

Pfohl, B., and Winokur, G. The

evolution of symptoms in institu-tionalized hebephrenic/catatonicschizophrenics. British Journal of Psy-chiatry, 141:567-572, 1982.

Siever, L.J. Biological markers inschizotypal personality disorder.Schizophrenia Bulletin, 11:564-575,1985.

Silverman, J.M.; Mohs, R.C.;Siever, L.J.; Kendler, K.S.; Breitner,J.C.S.; and Davis, K.L. Heritabilityfor schizophrenia-spectrum disorders

in schizophrenic and schizophreniarelated personality disorder pa-tients. Clinical Neuropharmacology, 9(Suppl. 4):271-273, 1986.Spitzer, R.L.; Endicott, J.; andGibbon, M. Crossing the border intoborderline personality and border-line schizophrenia: The develop-ment of criteria. Archives of GeneralPsychiatry, 36:17-24, 1979.

Spitzer, R.L.; Endicott, J.; andRobins, E. Research D iagnosticCriteria: Rationale and reliability.Archives of General Psychiatry,35:773-782, 1978.

Strauss, J.S., and C arpenter, W .T.,Jr. Schizophrenia. New York: PlenumFVess, 1981.

Torgersen, S. Relationship ofschizotypal personality disorder toschizophrenia: Genetics. Schizophre-nia Bulletin, 11:554-563, 1985.

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