Schizophrenia: refining the phenotype, resolving endophenotypes

BEHAVIOUR RESEARCH AND THERAPY

PERGAMON

Behaviour Research and Therapy 37 (1999) 281±295

Invited Essay

Schizophrenia: re®ning the phenotype, resolving endophenotypes Mark F. Lenzenweger a, b, * a

Laboratory of Experimental Psychopathology, Cornell University, USA b Department of Psychiatry, Cornell University Medical College, USA Received 7 July 1998

Abstract The conceptual history of the diagnosis of schizophrenia is reviewed and the current de®nition of the illness is examined (e.g. DSM-IV). A dimensional alternative to the traditional categorical model of diagnosis is discussed with a speci®c emphasis on the four dimensions of psychopathology represented by reality distortion (hallucinations, delusions), disorganization (positive formal thought disorder, bizarre behavior), negative symptoms (¯attened a€ect, avolition, alogia, asociality), and premorbid social functioning. Also discussed is the development of structured psychiatric interviews that emerged from the clinical/research context that gave rise to explicit (i.e. operational) diagnostic criteria for schizophrenia. The general methodological approach used to detect valid endophenotypes for schizophrenia liabilityÐi.e. indicators of liability not visible to the unaided naked eyeÐas well as their potential diagnostic and research utility is presented in overview. The rationale for linking such indicators to schizophrenia liability, which is conceptualized as a latent construct, is also reviewed. Future directions in the development and re®nement of the diagnostic approach to schizophrenia and schizophrenia liability are highlighted. # 1999 Elsevier Science Ltd. All rights reserved.

1. Schizophrenia: re®ning the phenotype, de®ning endophenotypes Schizophrenia remains one of the most devastating forms of psychopathology known to humankind and its pathogenesis continues to elude those seeking to fully understand its etiology and development (Lenzenweger & Dworkin, 1998). In short, the syndrome of schizophrenia remains an enigma with an unknown origin and a pathophysiology that is yet to be well delineated. What is well-known clinically regarding schizophrenia is that it is a * Correspondence to Mark F. Lenzenweger PhD, Department of Psychology, Harvard University, 33 Kirkland Street, Cambridge, Massachusetts 02138, USA. E-mail: [email protected] 0005-7967/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 0 0 5 - 7 9 6 7 ( 9 8 ) 0 0 1 3 8 - 7

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psychotic illness (characterized by hallucinations, delusions, and thought disorder as well as negative symptoms) that begins early in life for many and frequently results in a life-long disabling of psychosocial and cognitive functioning in those so a€ected. The prevalence of schizophrenia is commonly estimated to be about 1%, a€ecting over two million people in the US alone, and costing the US economy over $70 billion annually (Wyatt, Henter, Leary & Taylor, 1995). Any investigation of schizophrenia must take as its fundamental unit of analysis those diagnosed cases of the illness and, as such, the diagnosis of schizophrenia remains a focus of considerable discussion and research. However, and thankfully so, long gone are the days when schizophrenia was thought to be a ``myth'', merely a ``label'', or a ``sane reaction to an insane world''. Furthermore, as research into the nature and causes of schizophrenia has advanced over the past 20 years or so, there has been an increasing interest in (a) alternative approaches to the traditional psychiatric diagnostic approach to the illness (e.g. dimensional symptom models), (b) methods of e€ectively detecting schizophrenia liability that do not rely on the clinical phenotype (i.e. endophenotypes), and (c) operationalizing the assessment of those signs and symptoms of the emerging schizophrenic illness that may aid early detection and, perhaps, intervention. This Invited Essay will, therefore, focus on matters related to the history and current conceptualization of the schizophrenia phenotype and contemporary explorations aimed at improving the detection of schizophrenia liability (also known as schizotypy, see Meehl, 1990). 1.1. Big facts in schizophrenia Although the precise origins and pathophysiology for schizophrenia remain unresolved, there are a number of what might be termed ``big facts'' with respect to this disorder. A review of these facts, in brief, will provide a context into which this discussion of diagnosis may be placed. It is now unambiguously established that schizophrenia is known to be subject to very considerable genetic in¯uences (Gottesman, 1991; Moldin & Gottesman, 1997) with heritability estimates ranging from .74 to .89. It is also understood at this date that the disorder is not entirely genetically determined as the median concordance rate for schizophrenia observed among monozygotic (MZ) (or identical) twin pairs is 46%, a feature that implicates nongenetic factors (Moldin & Gottesman, 1997; cf. McGun, Asherson, Owen & Farmer, 1994). As yet there is no known genetic locus for schizophrenia susceptibility although the optimism for the detection of such a locus is running high with interesting leads pointing towards chromosomal region 6p (Gottesman & Moldin, 1998). The precise nature and relative importance of the environmental contribution to the etiology of schizophrenia remains unresolved (McGun, Asherson, Owen & Farmer, 1994). Just as the reality of substantial genetic in¯uences for the disorder has taken on the status of scienti®c fact in the study of schizophrenia, so has the prospect that several neurotransmitter systems within the central nervous system are integrally related to the emergence of the disorder. Although early models of the neurobiological dysfunction of central relevance to schizophrenia principally focused on the excessive functional activity of one neurotransmitter (i.e. dopamine, see Snyder, 1976; Carlsson, 1978), contemporary models of the neurobiology of schizophrenia emphasize several neurotransmitter systems that include but are not limited to dopaminergic (DA) activity (e.g. serotonin, glutamate) [see Csernansky & Grace (1998)Ðentire

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issue) for an extensive review]. The role of dopamine in schizophrenia remains an area of active research interest and contemporary models of the disturbance in the various DA pathways in the brain are now considerably more complex than previously considered, with some DA pathways displaying DA overactivity and others showing underactivity in schizophrenia (cf. Grace & Moore, 1998). Models have moved from simply suggesting neurobiological imbalances, to more complex interactive models emphasizing neural circuitry and multiple neurotransmitter systems (Csernansky & Grace, 1998), many having a particular focus on cortico-limbic circuitry. On a related note, although there is as yet no pathognomonic brain abnormality that has been reliably identi®ed and demonstrated to have causal signi®cance in schizophrenia, there is considerable interest in prefrontal, temporal, and midbrain (e.g. ventral striatum) areas as well as the crucial neural developmental events that may be related to the development of the illness itself or a liability for the disorder (cf. Akbarian et al., 1993; Benes, 1998). It is also now well established that although the quality of one's familial environment is related to one's likelihood to relapse (cf. Hooley & Hiller, 1998; Butzla€ & Hooley, 1998), it is not likely that the quality of one's rearing homelife (Gottesman, 1991) or one's socio-economic class causes schizophrenia (Dohrenwend et al., 1992). Finally, the rigorous methodologies of the experimental psychology laboratory have also aided researchers in establishing a number of important features of schizophrenia-related cognitive and personality functioning as worthy of extensive research and inclusion in research studies with a genetic, neurobiological, and/or brain functioning orientation. Well replicated phenomena found in the study of schizophrenia patients such as sustained attention de®cits (Cornblatt & Keilp, 1994), eye movement dysfunction (Levy, Holzman, Matthysse & Mendell, 1994), psychometric deviance (Lenzenweger, 1994, 1998), and working memory de®cits (Park & Holzman, 1992) are now thought to tap into the underlying liability for schizophrenia. Extensive reviews of the contemporary research approaches to schizophrenia, particularly those from an experimental psychopathology vantage point, may be found in Lenzenweger and Dworkin (1998). 1.2. The breadth of the schizophrenia construct: a brief historical excursus Accounts of schizophrenia as an illness are not readily available through historical documents or descriptions, a feature of the history of the illness that has led some to suggest it may be a disorder of relatively recent origin (cf. Gottesman, 1991). The de®ning features of the illness have been proposed variously over the past 100 years and may be reviewed in a brief and necessarily selective historical fashion as follows (see Hoenig, 1983 for greater detail). Emil Kraepelin (1856±1926) is usually credited with describing the condition he termed dementia praecox (Kraepelin, 1919)1, which emphasized an early onset as well as a chronic, deteriorating course for the disorder. In his focus on early onset, deterioration in cognitive and personality functioning over time, and a generally poor prognosis, Kraepelin de®ned a relatively narrow 1

It is now established that Kraepelin had been substantially in¯uenced by Ewald Hecker's (1871) classic paper on hebephrenia, which described a psychosis of early onset with a deteriorating course characterized by a ``silly a€ect'', behavioral peculiarities, and formal thought disorder (Sedler, 1985).

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construct. The second major ®gure in the early history of schizophrenia description was the Swiss psychiatrist Eugen Bleuler (1857±1939). Bleuler (1911/1950) actually named the illness and de®ned it in such as manner so as to de-emphasize the age at onset and course of the illness. His focus was not so much on the psychotic symptoms (e.g. hallucinations, delusions), but rather on the ``breaking of associative threads'' that underpinned integrated psychological functioning (e.g. thought, emotion, behavior). Bleuler (1911/1950) came to emphasize disturbances in a€ect, associations, autism, and ambivalence (his so-called ``4 As'') as the fundamental symptoms of schizophrenia, whereas phenomena such as hallucinations, delusions, and bizarre behaviors were considered ``accessory symptoms''. His view of the illness began a shift in focus from the ¯agrant forms of psychotic phenomenology to de®cit symptoms as well as less reliably de®ned intrapsychic processes in the de®nition of schizophrenia. In doing so, Bleuler expanded the schizophrenia construct beyond that proposed by Kraepelin. Bleuler's view of the illness would serve to guide diagnostic practice, particularly American practice, in the ensuing decades. The breadth of the schizophrenia construct would continue to expand well into the 1960s due in large part to the in¯uence of psychodynamically oriented conceptualizations of the illness (e.g. Sullivan, 1924±1925) as well as the introduction of less psychotic variants of the condition (cf. Hoch & Polatin, 1949). The expansion of the schizophrenia construct was evident in the ocial diagnostic nomenclature of the American Psychiatric Association as contained in DSM-I and DSM-II (American Psychiatric Association [APA], 1968). In addition to the changes in the breadth of the schizophrenia construct from the late-1890s until the late1970s, there were a number of attempts to meaningfully parse the domain of schizophrenia signs and symptoms, including sub-type distinctions (e.g. paranoid vs. non-paranoid, process vs. reactive schizophrenia, good vs. poor premorbid schizophrenia, and acute vs. chronic schizophrenia). With the dawn of the neo-Kraepelian revolution in psychiatry (e.g. Feighner et al., 1972; Robins & Guze, 1970; Spitzer, Endicott & Robins, 1978) in the late-1960 s/early1970 s as well as the increasing awareness of the utility of careful diagnosis for studies of schizophrenia conducted in the experimental psychopathology laboratory (cf. Lenzenweger & Dworkin, 1998), a sea change occurred in the ocial de®nition of the illness as contained in the DSM-III (APA, 1980). This change re¯ected, in part, some of the in¯uential ideas of Kurt Schneider (1959) and Feighner et al. (1972) regarding the diagnostic utility of explicitly de®ned phenomenology. Once again, now in the interest of reliability and increasing validity, a narrow, more ``Kraepelinian'' de®nition of schizophrenia was adopted for both clinical and research usage. The DSM-III (APA, 1980), in contrast to its predecessors, contained relatively explicit criteria for the signs and symptoms of schizophrenia, with a particular emphasis on the positive (psychotic) symptoms such as delusions, hallucinations, and thought disorder as well as diagnostic rules regarding onset and duration of illness. The impact the change in nomenclature had on the rate at which the diagnosis of schizophrenia was made was documented persuasively by Loranger (1990). He found a nearly 50% reduction in the diagnosis of schizophrenia in a series of over 10,000 admissions to a university hospital by comparing the rates for the schizophrenia diagnosis for the ®ve years prior to and ®ve years after the introduction of the DSM-III system. Although the return to a systematic and operational approach to the diagnosis of schizophrenia was welcomed in many quarters, the relative absence of emphasis on negative (i.e. de®cit, defect) symptoms, such as avolition,

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¯attened a€ect, asociality, in the DSM-III de®nition of schizophrenia was seen as a shortcoming of the content of the de®nition (see Dworkin & Lenzenweger, 1984). Thus, in review, the de®nition of schizophrenia began as a narrowly de®ned entity (Kraepelin), went through a period of expansion (cf. Bleuler, Sullivan, Hoch & Polatin), endured a period of attack (e.g. the ``label-myth'' period of the 1960s), and then returned to a more narrowly de®ned entity (DSM-III, DSM-IV). 1.3. The contemporary signs and symptoms approach to diagnosis: the DSM-IV criteria The diagnostic criteria for the current de®nition of schizophrenia as contained in the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (4th edition; DSM-IV, 1994) can be seen in Table 1. As can be seen from Table 1, the contemporary diagnostic criteria are relatively explicitly described, there are fundamental thresholds de®ned for the number of symptoms required for diagnosis, information regarding both social/occupational dysfunction and duration are well speci®ed, and other diagnostic rules are explicated. A noteworthy feature of the Criterion A Table 1 DSM-IV diagnostic criteria for schizophrenia A. Characteristic Symptoms: Two (or more) of the following, each present for a signi®cant portion of time during a one-month period (or less if successfully treated): (1) delusions (2) hallucinations (3) disorganized speech (e.g. frequent derailment or incoherence) (4) grossly disorganized or catatonic behavior (5) negative symptoms, i.e. a€ective ¯attening, alogia, or avolition Note: Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other. B. Social/occupational dysfunction: For a signi®cant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement). C. Duration: Continuous signs of the disturbance persist for at least six months. This six-month period must include at least one month of symptoms (or less if successfully treated) that meet Criterion A (i.e. active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A present in attenuated form (e.g. odd beliefs, unusual perceptual experiences). D. Schizoa€ective and mood disorder exclusion: Schizoa€ective disorder and mood disorder with psychotic features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods. E. Substance/general medical condition exclusion: The disturbance is not due to the direct physiological e€ects of a substance (e.g. a drug of abuse, a medication) or a general medical condition. F. Relationship to pervasive developmental disorder: If there is a history of autistic disorder or another pervasive developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).

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symptoms and signs is the predominance of positive (i.e. psychotic) phenomena, namely four of the ®ve criteria are positive symptoms. Negative symptoms, which received considerably less attention in the DSM-III (APA, 1980) and DSM-III-R (APA, 1987), are considered collectively as an individual criterion under the Criterion A category. The inclusion of the negative symptoms in Criterion A represents the impact of the past 15 years worth of research indicating that negative symptoms do represent a reliably identi®able (Lenzenweger, Dworkin, & Wethington, 1989; Andreasen, Arndt, Alliger, Miller & Flaum, 1995) aspect of schizophrenia phenomenology that is linked to important criteria of validity for the disorder (e.g. genetic in¯uences, Dworkin & Lenzenweger, 1984; see Earnst & Kring, 1997 for an extensive review). Unlike some conceptualizations of schizophrenia that were dominant during the earlier part of this century (e.g. Bleuler), the DSM-IV de®nition of schizophrenia does not contain an emphasis on psychological processes that are more subjective in nature. Finally, the DSM-IV has retained the concept of the clinical sub-type in schizophreniaÐthe disorganized, catatonic, and paranoid subtypesÐthat is similar to the one proposed originally be Kraepelin. This brief review is not intended to suggest that there is now complete agreement on what constitutes the best de®nition of schizophrenia (a ``gold'' standard) or that there are no lingering thorny issues nagging at the current operational de®nition of schizophrenia as embodied in the DSM-IV. Indeed, on the contrary, investigation into the phenomenology of schizophrenia seems to be alive and well (Mortimer, 1992) and workers continue to seek important common ground among varying operational de®nitions of schizophrenia (e.g. OPCRIT system, McGun, Farmer & Harvey, 1991). There remain multiple unresolved issues in the de®nition of the schizophrenia phenotype from the traditional categorical psychiatric perspective. A number of pressing issues, though clearly not an exhaustive listing, requiring further illumination in the diagnosis of schizophrenia would include (a) determination of the incremental value provided by clinical sub-types of schizophrenia to basic science research and treatment, (b) consideration of a larger role for negative symptomatology in the traditional phenotype (cf. Fenton & McGlashan, 1992; McGlashan & Fenton, 1992), (c) development of symptom hierarchies in an e€ort to reduce heterogeneity in the phenotype, and (d) consideration of potential biological indexes or laboratory measures for inclusion as possible diagnostic criteria in the future. 1.4. An alternative approach to organizing schizophrenia phenomenology The relative instability of schizophrenia sub-types as well as their somewhat inconsistent utility for clinical treatment of the disorder were facts that came to trouble many interested in the classi®cation of schizophrenia through the 1970s and early 1980s. Moreover, the heterogeneity of schizophrenia symptomatology seemed to be an aspect of the disorder's presentation that could not be e€ectively addressed through simple sub-typing schemes, which sought to create mutually exclusive, clinically homogenous categories. This state of a€airs set the stage for the emergence of one of the more powerful approaches to organizing the phenomeonology of schizophrenia, namely the positive±negative symptom distinction. The positive±negative symptom distinction represents an approach to schizophrenia symptoms that stands apart from sub-typing strategies as it has held out the promise of organizing symptomatology at both the phenotypic level as well as providing suggestions for potential

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pathologies underlying the positive and negative symptom dimensions. The positive±negative symptom distinction generated a considerable amount of discussion and research through the 1980s and into the 1990s, resulting in a dimensional model that now consists of at least three, and possibly four dimensions of schizophrenia symptomatology (Lenzenweger & Dworkin, 1996). The potential utility of a dimensional approach to organizing schizophrenia symptoms was, as a result of the collective work on the positive±negative distinction, acknowledged in the DSM-IV and an alternative set of dimensional descriptors of schizophrenia was listed in the manual (Appendix B: Criteria sets and axes provided for further study, see pp. 710±711). The positive±negative distinction had its roots originally in neurology, speci®cally in the work of J.R. Reynolds, J. Hughlings-Jackson, and others (Berrios, 1985). Positive symptoms were thought to represent the presence of phenomena not normally present in the healthy state, whereas negative symptoms were taken to re¯ect the absence of abilities or functions that were normally present in the healthy state. The most well-known initial application of the distinction to schizophrenia can be traced to the work of Strauss, Carpenter and Bartko (1974). They hypothesized that three independent pathological processes might underlie the observed occurrence of three general classes of schizophrenic signs and symptoms, namely positive symptoms (hallucinations, delusions, formal thought disorder, and bizarre behavior), negative symptoms (¯attened a€ect, alogia, anhedonia, and avolition-apathy), and disordered personal/ social relationships. Although the precise etiologies of the three putative disease processes remained unspeci®ed, Strauss, Carpenter & Bartko (1974) argued persuasively that the patterning of phenotypic manifestations in schizophrenia might be re¯ective of the actual pathological processes. Thus, Strauss, Carpenter and Bartko (1974) proposed a model of three functional processes in schizophrenia that consisted of two distinct components: (1) at the descriptive level, three separate symptom dimensions (or clusters) were hypothesized to characterize the phenotypic manifestations of the illness and (2) at the level of pathogenesis, the three symptom dimensions were hypothesized to be re¯ective of three relatively distinct etiologies and/or pathophysiologies. Two of the three symptom classes emphasized by Strauss, Carpenter and Bartko (1974), positive and negative symptoms, became the focus of model development and extensive research in the 1980s (Crow, 1980; Andreasen & Olsen, 1982). Crow's (1980) view of positive and negative symptoms was that each represented an independent dimension of pathology, with positive symptoms related more to dopaminergic abnormalities and negative symptoms related to neurological and brain abnormalities. Andreasen and Olsen (1982) initially argued for positive and negative types of schizophrenia, a view they would eventually discard some years later in favor of a dimensional conceptualization guided by factor analytic results (Andreasen, Arndt, Alliger, Miller & Flaum, 1995; e.g. Lenzenweger, Dworkin & Wethington, 1989). In general, the construct validity of negative symptomatology became relatively well-established as a function of the extensive research on the positive±negative symptom distinction (Earnst & Kring, 1997; Pogue-Geile & Zubin, 1988), whereas the validity of positive symptomatology as a relatively homogeneous domain of psychopathology had been established previously through decades worth of research on psychotic symptomatology (cf. Blash®eld, 1984). As early as 1987, however, there were hints that even the positive±negative symptom distinction might require revision if the taxonomy were to be driven by results obtained from the actual analysis of schizophrenia symptom covariation. For example, Liddle (1987), based

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on the results of an exploratory factor analysis, proposed that positive symptomatology could be further reduced to ``reality distortion'' (hallucinations, delusions) and ``disorganisation'' (tangentiality, derailment, bizarre behavior) components and thereby suggested that three dimensions might more accurately describe the latent organization of schizophrenia phenomenology (i.e. reality distortion, disorganisation, and negative symptoms). Working from a con®rmatory model-guided perspective, Lenzenweger and colleagues (1989, 1991, 1996) also sought to determine if the latent organization of schizophrenia phenomenology could be speci®ed by more than two factors. We argued that if the content and number of dimensions that appear to best account for the phenotypic manifestations of the illness could be speci®ed reliably, then the likelihood of resolving those pathological processes hypothesized to be re¯ected in each of those dimensions would be enhanced a priori. Stimulated in large part by the seminal theoretical conjectures of Strauss, Carpenter and Bartko (1974) as well as the heuristic model proposed by Crow (1980), we conducted a con®rmatory factor analytic (CFA) study to determine if three relatively independent symptom dimensions, namely positive symptoms (e.g. delusions, hallucinations, formal thought disorder, bizarre behavior), negative symptoms (e.g. ¯attened a€ect, asociality, apathy, alogia), and disordered interpersonal relationships could account well for the latent organization of phenotypic schizophrenic symptomatology. We (Lenzenweger, Dworkin & Wethington, 1991) reported that indeed a dimensional approach to understanding the latent organization of schizophrenic symptomatology was warranted and, moreover, our con®rmatory methodology allowed us to empirically contrast alternative theoretical formulations in an e€ort to determine the model providing the best ®t to schizophrenic symptoms. Based on our 1991 con®rmatory study, using a relatively large sample of schizophrenic cases, we argued that the three broad dimensions, as hypothesized by Strauss, Carpenter and Bartko (1974), did best characterize the phenotypic manifestations of schizophrenia. This program of research was extended with a ®nal study that sought to determine if the positive symptom component of this three-process model might actually be reliably parsed to re¯ect Liddle's ``reality distortion'' and ``disorganisation'' subcomponents (Lenzenweger & Dworkin, 1996). Indeed, in the 1996 con®rmatory study, we found that in our relatively large series of schizophrenia cases, it appeared that a fourdimensional model best ®t the observed data and supported a reliable latent organization consisting of ``reality distortion'', ``disorganisation'', ``negative symptoms'', and ``premorbid social relations/adjustment''. Currently, it appears that the phenomenology of schizophrenia can be organized in a reliable fashion that takes into account the natural structure of the signs and symptoms and allows for a dimensional conceptualization of the full range of schizophrenia phenomenology. Furthermore, it appears that a dimensional system may have greater utility in application in both the research and clinical realm as it imparts an increased sensitivity to measures of schizophrenia symptoms not feasible with sub-types. For example separate symptom dimensions can be explored in relation to various research criteria (e.g. genetic in¯uences, neurobehavioral processes, areas of brain activation) as well as clinical indexes (e.g. drug response, prediction of relapse). In other words, the dimensional approach does not necessitate placing schizophrenia cases into mutually exclusive sub-types, a process that serves to lose valuable symptom information through potentially arbitrary assignment. In the course of our work on the latent structure of schizophrenia phenomenology we were struck

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by the importance the current de®nition of schizophrenia (i.e. DSM-IV) has for future studies of schizophrenia symptoms from a methodologic standpoint. That is, future research must attend to the possibility that contemporary de®nitions of schizophrenia (e.g., DSM-IV) have still allowed negative symptoms only a somewhat diminished role with respect to the central diagnostic criteria for the illness. As noted in Table 1, in the DSM-IV, whereas negative symptoms are included, the diagnosis of schizophrenia is necessarily conditioned on the presence of at least one of the other four primary criteria (i.e. Criterion A), all of which are positive symptoms. All symptom data derived from diagnoses made using systems like the DSM-IV will bear the imprint of the relationship that negative symptoms must have vis aÁ vis positive symptoms. In practical terms, this feature of the newer operational de®nitions may, in fact, substantially reduce observable variation in negative symptoms among study populations. Such a reduction could a€ect obtained correlational relationships between negative and positive symptomatology as well as latent structure analyses exploring these symptoms. Any future study of the latent structure of schizophrenia symptomatology that involves cases diagnosed according to DSM-IV must keep this issue in mind.

1.5. Current standards of assessment for schizophrenia In addition to the clearer speci®cation of the diagnostic criteria for schizophrenia, the research trends that culminated in the development of the DSM-III criteria (and its successors) for mental disorders also gave rise to the emergence of structured interviews for the assessment of schizophrenia symptoms. The structured interview brought an organizational focus to the traditional psychiatric interview that provided a strict format and directions to the interviewer. This level of structure assured that the interviewer would systematically assess all those criteria relevant to the diagnosis of any particular mental disorder. In the case of schizophrenia, where diagnostic criteria had been relatively vaguely de®ned in early systems (e.g. DSM-II), this level of organization for the diagnostic interview was a welcome change. The utility of the structured interview approach was immediately appreciated in terms of reliability, which especially helped to facilitate communication within the schizophrenia treatment and research community. Moreover, having a consensually shared set of diagnostic criteria (e.g. DSM-III) as well as a structured assessment device helped to ensure a more common unit of analysis in research across centers. Though most workers would hail the operationalization of diagnostic criteria as an advance, there remain concerns about the impact that an unbridled quest for increased diagnostic reliability might have on validity (cf. Farmer, Jones, Williams & McGun, 1993; see also Carey & Gottesman, 1978). In this context it should be noted that although the development of alternative dimensional systems for symptom organization has gained momentum in the past ten years, it is safe to say that the traditional psychiatric diagnostic approach, with its reliance on categorical diagnoses, remains the mainstay of clinical and research work on schizophrenia. However, it should be emphasized that the information necessary for dimensional organization of schizophrenia symptoms is precisely the same as that required for a diagnosis of schizophrenia, for the most part (see below).

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1.5.1. Diagnosing schizophrenia: the structured interviews Thus, the standard for assessment of schizophrenia remains the qualitative (i.e. categorical) diagnostic approach (e.g. DSM-IV) and this approach is best implemented with the structured interview methodology. Perhaps the most well-known of the early structured interviews designed for use in the assessment of schizophrenia is the Present State Examination (PSE) (Wing, Cooper & Sartorious, 1974), an instrument that received extensive usage in both the US±UK Cross National Project (Cooper et al., 1972) and the International Pilot Study of Schizophrenia (IPSS) (World Health Organization, 1973). The PSE was carefully tested and modi®ed through nine editions and, in a sense, it set the standard at a high level for future interviews to meet. The PSE was recently revised for use with both the DSM-IV and ICD-10 diagnostic criteria for mental disorders and it is now known as the SCAN/PSE-10 (Wing, Sartorius & UÈstuÈn, 1998). In the United States, Spitzer and Endicott (1978) developed the well-known Schedule for A€ective Disorders and Schizophrenia (SADS) in order to have a structured interview tool to accompany their Research Diagnostic Criteria (Spitzer, Endicott & Robins, 1978). The SADS received extensive usage as it allowed for the elicitation of information from patients that would allow also for the diagnosis of schizophrenia consistent with the newly revised diagnostic criteria present in the DSM-III, which appeared in 1980. Upon the introduction of the DSM-III-R (APA, 1987), the SADS was extensively revised into a branching-style interview known as the Structured Clinical Interview for DSM-III-R (SCID) (Spitzer & Williams, 1985; Spitzer, Williams, Gibbon & First, 1990). The SCID was modi®ed in 1997 to conform to the new DSM-IV system of diagnosis (First, Spitzer, Gibbon & Williams, 1997). Finally, in an e€ort to allow for multiple diagnostic systems to be applied during assessments in a simultaneous fashion McGun, Farmer and Harvey (1991) have developed the polydiagnostic methodology that is implemented through their OPCRIT system (see also Farmer, Wessely, Castle & McGun, 1992 for a discussion of caveats). 1.5.2. Assessing positive and negative symptoms in schizophrenia At the level of positive and negative symptom assessments, the assessment standards in the ®eld have emerged from Andreasen's work. The Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1984a) and the Scale for the Assessment of Positive Symptoms (SAPS) (Andreasen, 1984b) can be used for detailed assessments of negative and positive symptomatology respectively. The SANS assesses the negative symptoms of avolition±apathy, anhedonia±asociality, a€ective ¯attening or blunting, alogia, and inattention. The SAPS assesses hallucinations, delusions, bizarre behavior, positive formal thought disorder, and inappropriate a€ect (i.e. not simply ¯at or blunt, but incongruous). The SANS and the SAPS can be used separately or accessed through the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen, Flaum & Arndt, 1992). An extensive discussion of symptom data derived from the use of the SANS and SAPS can be found in Andreasen, Arndt, Alliger, Miller and Flaum (1995). 1.5.3. Focal assessments of thought disorder in schizophrenia Finally, it should be noted that thought disorder, as a psychotic symptom not necessarily speci®c to schizophrenia, has also received considerable attention in terms of assessment

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methodologies. Principally, thought disorder is assessed either through speech samples obtained in the course of a psychiatric interview or thought disorder is coded from an individual's speech produced in response to a standard set of stimuli. Interview-based assessments of thought disorder have utilized a technique such as Andreasen's (1979) Scale for the Assessment of Thought, Language, and Communication, whereas stimuli-based assessment of thought disorder is best exempli®ed in the Thought Disorder Index (TDI) developed by Philip Holzman and coworkers (Holzman, Shenton & Solovay, 1986; Johnston & Holzman, 1979). 1.6. The role of latent liability and endophenotypes in contemporary schizophrenia research Finally, no discussion of assessment issues in schizophrenia would be complete without some mention of attempts to better re®ne methods for detecting actual liability to the illness, even if that liability is never expressed in a given person (i.e. a latent liability). That a latent schizophrenia liability construct is defensible and worthy of empirical investigation is supported by multiple lines of research data, such as (1) non-psychotic forms of psychopathology, known as schizotypic conditions, are known to be related to an increased familial risk for schizophrenia; (2) unexpressed genotypes for the illness are known to exist (Gottesman & Bertelsen, 1989); (3) well-established biobehavioral markers, which have no discernible phenotypic connection to overt schizophrenia, are known to be associated with a latent diathesis for the illness; and (4) the likelihood is that the prevalence of genuine schizophrenia liability, which may be about 10% in the general population (Meehl, 1990), greatly exceeds the rate of observed clinical illness (i.e. about 1%) and suggests that many persons carrying the liability for schizophrenia may never show any (or, perhaps, only slightly) discernible evidence of the liability. Taken together, both theoretical and empirical considerations argue strongly for the plausibility of a complex latent liability construct in schizophrenia. Given that most persons vulnerable to schizophrenia may never show ¯agrant psychosis or easily diagnosed signs and symptoms of schizotypic personality functioning, researchers have sought ways to detect such a latent liability (often termed ``schizotypy'') using more sensitive detection approaches (i.e. various laboratory and psychometric measures). E€orts have been made to discover valid objective indicators of latent liability (schizotypy) that function eciently across a range of clinical compensation as well as mental state and are capable of detecting liability even in clinically unexpressed (non-symptomatic) cases. Such indicators, psychometric and otherwise, are thought to assess an endophenotype (a feature not visible to the unaided, ``naked'' eye; see Gottesman, 1991; see also Gottesman & Moldin, 1998) and their inclusion in research investigations of the genetics and familiality of schizophrenia is likely to enhance the power e€orts even when the putative indicators are only modestly correlated with the latent liability (Matthysse & Parnas, 1992; Smith & Mendell 1974). Identi®cation of valid endophenotypes of schizophrenia liability could also be useful in reducing the heterogeneity observed in clinically expressed cases of schizophrenia (e.g. those schizophrenia patients with vs. without eye movement dysfunction) and such a clarifying role for the endophenotypes may serve to increase signal and reduce noise when a research focus is on a subtle neural circuit or neurobiological pathway. Finally, objectively assessed endophenotypes could be used to augment clinical e€orts that have emerged in recent years that are geared to very early

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detection of schizophrenia (e.g. Loebel et al., 1992; see also McGlashan (1996) Schizophrenia Bulletin, volume 22, ]2, Issue theme: Early Detection and Intervention in Schizophrenia). To date the most well-established of these endophenotypic measures are de®cits in sustained attention (Cornblatt & Keilp, 1994), eye movement dysfunction (Levy et al., 1993; Levy, Holzman, Matthysse & Mendell, 1994), schizotypy-related psychometric deviance (Lenzenweger, 1994, 1998), working memory de®cits (Park & Holzman, 1992), and schizophrenia-related personality disorders (i.e. schizotypal and paranoid personality disorders). Typically endophenotypic markers (or indicators) of schizophrenia liability have been discovered through the study of actual patients a€ected with the illness and then a putative marker is studied among the ®rst-degree biological relatives of schizophrenia patients or children at-risk for schizophrenia. Additional validation of putative endophenotypic markers has come from the study of such markers in non-psychotic schizotypic subjects (e.g. Lenzenweger, 1998). Current and future studies in this area should begin to move to the study of putative endophenotypic markers in general unselected population studies as well as among, speci®cally, the siblings of schizophrenia-a€ected persons. Studies of the general population and sib-pairs can be augmented through the use of appropriate latent class statistical procedures to scan the multivariate space for meaningful natural sub-groups (e.g. taxometrics, Waller & Meehl, 1998) and meaningful components within performance indexes (e.g. Rubin & Wu, 1997). 1.7. Summary Schizophrenia remains one of the most dicult forms of psychopathology to de®ne in a manner acceptable to all clinical and research workers. However, great strides have been made in recent years that have brought about a convergence on a de®nition of the illness as well as excellent methods of assessment that are acceptable to many workers. Lively debate continues regarding the utility of the classic subtypes of schizophrenia, which has given rise to considerable interest in alternative dimensional conceptualizations of schizophrenia phenomenology, especially the dimensions of reality distortion, disorganisation, negative symptoms, and premorbid social functioning. E€orts will necessarily continue to be directed at (a) reduction of heterogeneity within the schizophrenia diagnosis, (b) moving toward more biologically-based diagnostic criteria, (c) validation of endophenotypes and their application in complex family and genetic studies, (d) revision of current diagnostic criteria to better demarcate the boundaries of the illness from other psychotic conditions, (e) discovery of those symptom/sign combinations that predict treatment compliance and outcome, and (f) ongoing longitudinal assessment of populations at-risk for schizophrenia (i.e. o€spring of schizophreniaa€ected parents, siblings of a€ected persons, and clinically [schizotypal personality disorder], psychometrically [psychosis-prone], or laboratory-index [e.g. eye movement dysfunction] identi®ed persons). Research into the fundamental causes and nature of schizophrenia remains an exciting area of scienti®c inquiry, drawing upon the talents of many scienti®c disciplines beyond psychology. The e€ective diagnosis and treatment of schizophrenia also remains an important priority due not only to the cost of the illness, but also because the su€ering of those a€ected with the illness as well as their families cannot be quanti®ed.

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Acknowledgements I would like to thank the following individuals for sharing their thoughts regarding the current status of the assessment of schizophrenia: John F. Clarkin, PhD, Robert H. Dworkin, PhD, Irving I. Gottesman, PhD, William M. Grove, PhD, Jill M. Hooley, DPhil, Deborah L. Levy, PhD, Paul E. Meehl, PhD, Steven O. Moldin, PhD, David Silbersweig, MD, and Emily Stern, MD. The author, of course, takes responsibility for all views and opinions expressed in this article.

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