Development of liability syndromes for schizophrenia: Where did they come from and where are they going?


  • William S. Stone,

    Corresponding author
    1. Department of Psychiatry, Massachusetts Mental Health Center, Division of Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
    • Correspondence to:

      William S. Stone, Massachusetts Mental Health Center, 75 Fenwood Road, Boston, MA 02115.


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  • Anthony J. Giuliano

    1. Department of Psychiatry, Massachusetts Mental Health Center, Division of Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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  • Disclosures: The authors report no financial disclosures or conflicts of interest.


Three decades after Paul Meehl proposed the term “schizotaxia” to describe a conceptual framework for understanding the liability to schizophrenia, Ming Tsuang et al. at Harvard University reformulated the concept as a clinical syndrome with provisional research criteria. The reformulated view relied heavily on more recent data showing that many non-psychotic, un-medicated biological relatives of individuals with schizophrenia showed difficulties in cognitive and other clinical functions that resembled those seen in their ill relatives. The reformulation raised questions about both whether and when liability could be assessed validly in the absence of psychosis, and about the extent to which symptoms of liability are reversible. Both questions bear on the larger issue of early intervention in schizophrenia. This article reviews the efforts of Tsuang et al. to conceptualize and validate schizotaxia as one such syndrome of liability. Towards this end, liability is considered first more generally as an outcome of interactive genetic and environmental factors. Liability is then considered in the context of endophenotypes as a concept that is both broader and is potentially more specific (and predictive) than many DSM or ICD diagnostic symptoms. Liability syndromes are then considered in the context of their proximity to illness, first by reviewing prodromal syndromes (which are more proximal), and then by considering schizotaxia, which, as it is currently formulated, is pre-prodromal and, therefore, less proximal. Finally, challenges to validation and future directions for research are considered. © 2013 Wiley Periodicals, Inc.


Professor Ming Tsuang has devoted a lifetime of pioneering and innovative research to furthering our understanding of psychopathology. Many of his efforts have focused on the identification of the core features of major mental illnesses such as schizophrenia, and their subsequent integration into syndromes and diagnosable disorders. The purpose of these efforts has been to facilitate our understanding of their genetic, biological, cognitive, social, and clinical etiologies, in the service of the even larger goal of developing effective intervention and treatment strategies. One of Professor Tsuang's—and psychiatry's—most basic goals has been to initiate therapeutic interventions as early as possible, both to avoid or minimize the host of adverse consequences that are associated with chronic psychosis, and to promote or maximize the more positive outcomes associated with treating people who have not yet suffered critical declines in function. While prevention of major mental illness, which is the ultimate goal of these efforts, has yet to appear on the horizon, Professor Tsuang et al. proposed a strategy to facilitate its development by defining one or more “liability syndromes” that could help identify individuals at high risk for schizophrenia.

This article reviews the work that resulted from this initiative by embedding it in the context of broader notions of liability, with an emphasis on the prodrome, which often precedes the first psychotic episode. We will then consider pre-prodromal liability in the context of another important conceptual and methodological development over the last 25 years, the identification and study of endophenotypes, before reviewing the provisional development of one such liability syndrome, based originally on a Paul Meehl's conception of “schizotaxia.” We will then review the validity and utility of the provisional syndrome, and current and future challenges to syndromal development.


Liability to schizophrenia and to other mental disorders may be conceptualized along multiple dimensions. Some of the most important of these includes underlying etiological dimensions such as genetic and environmental factors, and also phenotypic dimensions that focus as much on the identification of liability as its causes. The notion of liability to schizophrenia itself dates back at least as far as the early “modern” views of the disorder at the beginning of the twentieth century [Kraepelin, 1919/1971]. Bleuler [1911/1950] reported, for example, that patients who developed schizophrenia often showed abnormalities (e.g., dysfunctional or otherwise unusual social functions) early in life, prior to the development of psychosis. Family, twin and adoption studies have since provided compelling evidence that close biological relatives of individuals with schizophrenia show elevated risks for developing schizophrenia and other disorders compared to the general population [Gottesman, 1991; Tsuang et al., 1999a; Gottesman and Hanson, 2005]. Both behavioral genetic and molecular biological approaches provide equally compelling evidence that a significant portion of this liability reflects a genetic etiology [Tsuang and Winokur, 1975; Kendler, 2001; Gottesman and Hanson, 2005; Harrison and Weinberger, 2005; Glatt et al., 2007; Allan et al., 2008; Craddock et al., 2009], as does the view that “unaffected” biological relatives (who share many genes in common with their ill relatives) also share an elevated liability to develop related illnesses and other abnormalities [Gottesman and Gould, 2003].

Similarly, environmental contributions to the etiology of schizophrenia and other mental disorders are well established [Tsuang et al., 2008, 2011]. Evidence has accrued to implicate a variety of environmental factors that may produce adverse biological consequences that, in turn, increase vulnerability to schizophrenia or other psychiatric disorders. Some of these factors may be relatively distal etiologically to the disorder(s) they influence, and might be considered as proxies for other factors. Detrimental effects of migration or season of birth, for example, could be viewed in this context [Bhui, 2008; McGrath and Parker, 2008]. Other environmental factors may be more proximal to their detrimental effects. Meta-analyses show, for example, elevated rates of schizophrenia in adulthood following a range of abnormalities during pregnancy and delivery (e.g., contracting the flu, smoking during pregnancy, vitamin D deficiency, poor neonatal conditions, decreased birth weight, eclampsia and/or premature delivery) [Geddes and Lawrie, 1995; Cannon et al., 2002]. Notably, non-psychotic relatives of people with schizophrenia also show elevated rates of obstetric problems compared to healthy controls without family histories of schizophrenia [McGrath, 2003], and are associated with reduced gray matter volumes in first-degree relatives [Scott et al., 2003], suggesting they may contribute to vulnerability in people with genetic high risk for schizophrenia or related disorders.

The nature of the relationships between environmental events and biological liabilities, however, remains uncertain and are likely to involve a range of etiological relationships. Generalities are difficult to establish. While pregnancy and obstetric complications may contribute to the risk of developing schizophrenia, for instance, it should be emphasized that most offspring of mothers who developed schizophrenia did not develop schizophrenia themselves, even if their mothers had pregnancy or obstetric complications [Preti et al., 2012; Suvisaari et al., 2012]. Moreover, the rate of obstetric complications is itself at least partly a function of whether mothers had already developed schizophrenia, with some studies noting that obstetric complications only occurred when mothers developed schizophrenia prior to the birth of their offspring [Jablensky et al., 2005]. Similarly, most individuals whose mothers (and other first-degree, biological relatives) did not develop schizophrenia, but did experience obstetric complications, did not develop schizophrenia [Zornberg et al., 2000].

Thus, while it is essential to distinguish causal factors in schizophrenia from markers of vulnerability for schizophrenia (e.g., do obstetric abnormalities contribute to the risk for schizophrenia, or do they both reflect the influence of other factors?), it is also critical to identify the circumstances that govern or modulate the actions of those factors. This latter finding exemplifies a point about genetic and environmental causation of schizophrenia and many other mental disorders that has attained an increasingly broad consensus: they are frequently complex disorders with genetic and environmental etiological liabilities that interact with each to produce better or worse outcomes [Tsuang et al., 2008]. This point is exemplified by the Finnish adoption studies, which have compared adopted-away biological children who are at high genetic risk (i.e., a parent had schizophrenia) with adopted-away biological children who are at low genetic risk (i.e., a parent did not have schizophrenia), in rearing environments that are more or less dysfunctional. Taken together, these studies showed that elevated risks for subsequent schizophrenia and for schizophrenia spectrum conditions in the adopted children were related to a combination of genetic (i.e., high risk) and environmental (i.e., dysfunctional rearing environments) factors [Tienari, 1991; Tienari et al., 1994; Wynne et al., 2006]. Notably, high risk adoptees that were exposed to better rearing environments did not show elevated rates of subsequent schizophrenia. This relationship was also reported by a separate group that showed elevated rates of schizophrenia in genetic high risk adoptees who were raised in disadvantaged socioeconomic circumstances [Wicks et al., 2010].

The Finnish studies showed that this interactive relationship extended beyond the issue of schizophrenia diagnosis and into more specific clinical domains. One of these domains included aspects of thought disorder, which were more likely in the high risk adoptees when they were raised by adoptive mothers who themselves showed elevated levels of “communication deviance” [Wahlberg et al., 1997]. High risk adoptees that were raised by adoptive parents with low levels of communication deviance were less likely to show thought disorder. Consistent with these findings, no significant relationships between thought disorder and communication deviance were obtained in low risk adoptees.

Moreover, high-risk adoptees in high communication deviant environments were more sensitive to problems in their adoptive environments than low-risk adoptees [Tienari et al., 2004], demonstrated problems that were more predictive of clinical outcomes for those who developed schizophrenia spectrum conditions [Tienari et al., 2004], and showed elevated scores on the MMPI Social Maladjustment scale [Siira et al., 2007]. A recent analysis of premature death over a period of 28 years in the adoptee sample showed that while overall mortality did not differ between the high risk and low risk groups, suicides and other unnatural causes of death were associated with the high risk group and the high communication deviance rearing environment [Hakko et al., 2011]. These studies emphasize evidence of both environmental responsibility and environmental susceptibility to abnormal functions based on genetic predisposition.


Although increases in the reliability of DSM diagnoses for schizophrenia and other psychiatric disorders started to facilitate genetic studies in the 1980s and 1990s, a broad consensus emerged about the limited utility of DSM or ICD diagnostic criteria to facilitate efforts to identify genes and genetic mechanisms involved in specific mental disorders [Tsuang et al., 1999a, 2000]. This problem emphasized the point that schizophrenia is broader than the diagnostic criteria or syndromes that are required for its diagnosis, and it turned increasing attention to symptoms and abnormalities that might be related to the disorder, but were not associated with its formal diagnostic criteria. The concept of “endophenotypes” (e.g., schizophrenia-related social, psychophysiological or neuropsychological abnormalities), which was first applied to psychiatric disorders and then elaborated further by Gottesman [Gottesman and Shields, 1982; Gottesman, 1991; Gottesman and Gould, 2003], reflected this growing awareness that multidimensional expressions of psychiatric disorders can advance the search for underlying etiological, diagnostic or modulatory factors [Gottesman and Gould, 2003; Gur et al., 2007; Turetsky et al., 2007; Allan et al., 2008; Chan and Gottesman, 2008; Allen et al., 2009; Eack et al., 2010]. Moreover, specific endophenotypes (e.g., a particular level of difficulty on a particular measure of verbal learning and memory) may be more amenable to objective measurement than symptoms, possibly reflecting variation among smaller numbers of genes than is the case for more distal clinical symptoms [Braff and Freedman, 2002; Gottesman and Gould, 2003; Braff et al., 2007], show elevated rates of occurrence in non-psychotic biological relatives, and heritability [Greenwood et al., 2007; Husted et al., 2009]. Although it is questionable whether endophenotypes reflect simpler genetic architectures than other phenotypes [Flint and Munafo, 2007], their potential reliability and validity support the utility of endophenotypes in conceptualizing and assessing liability [Gottesman and Shields, 1972; Tsuang, 1994; Faraone et al., 1995b, 2003; Tsuang et al., 2000; Braff and Freedman, 2002; Gottesman and Gould, 2003; Seidman and Wencel, 2003; Braff et al., 2007].

Attempts to identify useful endophenotypes have focused largely on abnormalities in the central nervous system (e.g., structural brain differences or psychophysiological dysfunctions), or from abnormalities presumed to derive from it (e.g., deficits in cognition). While this is a reasonable presumption, the possibility that common pleiotropic genes would also produce endophenotypes for mental disorders outside the central nervous system is a viable one as well [Stone et al., 2007]. Regardless of which dimensions of function are emphasized by particular endophenotypes, however, several broad issues in their conceptualization and utilization should be emphasized. Some of these include proposed criteria for putative endophenotypes, such as the need to establish their: (1) relationships to particular illnesses or conditions; (2) state independence; (3) heritability; and (4) elevated levels in biologically, “unaffected” relatives [Gottesman and Gould, 2003; Gur et al., 2007]. A second general issue underlying the utility of proposed endophenotypes involves the extent to which they discriminate between affected and non-affected samples. These questions are not answered solely by demonstrating significant differences, but also by assessments of sensitivity, specificity and other epidemiological measures of function [Faraone et al., 1995a]. Ultimately, however, one of the greatest clinical benefits of identifying endophenotypes or other non-DSM or ICD measures of liability will be to understand how they combine into syndromes that will increase both our ability to identify which individuals will develop psychosis and other problems, and which aspects of that liability are most amenable to therapeutic interventions. The following discussion addresses this critical issue by considering the most proximal expressions of liability, as exemplified by prodromal states, and then by considering pre-prodromal expressions of liability, as exemplified by an evolving conception of schizotaxia.


The concept of a prodrome to schizophrenia was introduced in the early 20th century [Sullivan, 1994], but it is only in the last two decades that it became a focus of international clinical research with the goals of characterizing its features, developing prediction models of conversion to psychosis, and measuring impacts of early intervention strategies [Fusar-Poli et al., 2012a]. The inception of prodromal research programs was galvanized by the intersection of two other research strategies and began to close the gap between them. The first involved behavioral genetic research programs that established compelling evidence for genetic contributions to schizophrenia, the liability to develop schizophrenia, and for multiple clinical, cognitive, and functional features of schizophrenia. The identification of these features contributed to the development and rapid growth of the endophenotype concept. The second significant influence was related to the growing momentum of first-psychotic-episode research programs in the late 1980s and early 1990s that focused on characterizing early manifestations of the diagnosable illness, and of interventions designed to reduce the duration of untreated psychosis and facilitate improved functional outcomes. First-episode research programs provided evidence that much of the impact of the illness is established by the first episode phase, including its cognitive signature. Specialized first episode intervention programs have shown some reason for optimism in terms of facilitating relatively better symptomatic and functional recovery, though sustained positive outcomes remain very difficult to achieve [Penn et al., 2005; Addington, 2007; Bertelsen et al., 2008, 2009; Addington and Heinssen, 2012]. From this perspective, prodromal research moves back in the illness course to a pre-psychotic stage with the hope that earlier intervention might be better still. At present, early detection and intervention are regarded as the field's best hope for realizing substantive improvements in the outcome of individuals with schizophrenia and related disorders.

Over the past 15 years, there has been substantial effort devoted to the detection of individuals at true risk of developing a psychotic illness. Given that a large majority of people who develop psychotic illnesses experience a prodrome (or some period marked by changes from a person's premorbid mental state and level of functioning), efforts to understand and intervene in the pre-psychotic stage might be expected to have a broad salutary impact. This work has largely been organized around the development and testing of operational criteria for the prospective assessment of psychosis liability over time. These research efforts have also yielded considerable information about the nature of the prodrome, including its clinical, functional, and biological features, and have contributed to the development of prediction and treatment models [Fusar-Poli et al., 2012a].

While there are a variety of methods for assessing the prodrome, each preferentially emphasizes the recent onset or worsening of attenuated positive symptoms, brief intermittent psychotic states, and/or significant functional deterioration in the context of genetic-familial risk (i.e., having a first degree relative with a psychotic disorder) in adolescence or young adulthood. Among these methods are the comprehensive assessment of at-risk mental state (CAARMS) [Yung and McGorry, 1996a-1996c; Yung et al., 2003]; the structured interview of prodromal symptoms/scale of prodromal symptoms (SIPS/SOPS) [Miller et al., 2002, 2003; Yung et al., 2005]; and the basel screening instrument for psychosis (BSIP) [Riecher-Rossler et al., 2007]. In the SIPS, for example, information is gathered on family history, global functioning, the presence of schizotypal personality disorder, and the presence and severity of 19 symptoms across four domains of psychopathology, including positive, negative, disorganization, and general symptoms [Miller et al., 2002; McGlashan et al., 2010]. Operational criteria are provided for ruling in or out the presence of psychosis and three putative prodromal syndromes including brief intermittent psychotic symptoms (but at a frequency too brief to meet diagnostic criteria for a psychotic disorder), attenuated positive symptoms, and/or genetic risk and deterioration. Initial studies documented that for individuals demonstrating one or more putative prodromal syndromes, the risk of developing a psychotic disorder increased from the expected rate of approximately 10% in genetic-familial high risks studies to about 30–50% in clinical high risk samples followed for up to 2 years. In the largest clinical high risk sample followed to date (within the North American Prodromal Longitudinal Study; NAPLS; n = 291), approximately 25% of individuals who met criteria for a prodromal risk state developed a psychotic illness within 1 year, and 35% within 2 years [Cannon et al., 2008]. Interestingly, recent studies have shown a pattern of declining conversion rates in prodromal individuals, which implicates some combination of earlier identification and treatment, or increased numbers of false positive cases [Addington and Heinssen, 2012].

The clinical, functional, and cognitive characteristics of the prodrome to psychosis have also been elucidated. By definition, a majority of individuals demonstrate some degree of concerning attenuated positive symptoms, and are help-seeking. Studies have also shown, however, that many have comorbid diagnoses including anxiety, mood, and substance use disorders that are themselves clinically relevant and in need of treatment [Yung et al., 2007, 2008; Woods et al., 2009]. Many have high levels of negative symptoms that have worsened, and many demonstrated significant social, educational, and vocational impairments. Notably, some studies have documented levels of social and role dysfunction that are comparable to those in the early stages of diagnosable illness [Lencz et al., 2004; Niendam et al., 2006; Ballon et al., 2007; Cornblatt et al., 2007; Addington et al., 2008; Yung et al., 2008; Fusar-Poli et al., 2009], lending credibility to the notion that much of the disability associated with the diagnosable illness develops during the prodromal period.

From a cognitive perspective, two meta-analyses have documented that the clinical high risk state for psychosis is associated with significant and widespread impairments in neurocognitive functioning and social cognition that are intermediate between healthy control and first-episode psychosis samples [Fusar-Poli et al., 2012b; Giuliano et al., 2012]. These impairments were evident on measures of general intelligence, executive function, verbal and visual memory, verbal fluency, attention and working memory, and social cognition. Moreover, subsequent transition to psychosis was particularly associated with deficits in verbal fluency and memory functioning. Interestingly, clinical high risk individuals who demonstrated significant deficits on processing speed and memory tasks also showed a level of functional disability that was similar to those with established psychotic illness [Niendam et al., 2006].

Although there is variability among the prediction models employed to understand conversion to psychosis in clinical high risk samples (in terms of the specific variables tested), severity and duration of attenuated positive symptoms (e.g., unusual thought content, suspiciousness, and bizarre thinking) are the strongest predictors of conversion and time to conversion [Cannon et al., 2008; Yung et al., 2008]. Negative symptoms are also predictive, but to a lesser extent. Dramatic declines in functioning are also predictive of conversion [Velthorst et al., 2010], and substance use history adds incremental (though weak) predictive value [Cannon et al., 2008].

Although rates of conversion to psychosis have dominated prodromal research, clinical high risk states produce a variety of other outcomes. Some individuals demonstrate symptomatic recovery, while others (up to 40% in one study) [Addington et al., 2011] show a stable symptom pattern along with compromised social and role functioning. Schlosser et al. [2012] reported that 36% experience symptom remission and 30% experience limited functional recovery. Many continue to show a range of psychiatric problems and nonpsychotic Axis I diagnoses, such as mood and anxiety disorders. These figures emphasize that while many individuals do not go on to develop primary psychotic disorders, they are often not well, either, and experience significant psychiatric disorders [McGorry et al., 2011; Weiser, 2011; Addington and Heinssen, 2012; Fusar-Poli et al., 2012a].

To an extent, the diversity of clinical outcomes is also a reflection of the diversity of underlying etiological factors. Prodromal symptoms such as attenuated psychotic symptoms are not specific to one disorder or spectrum. They may reflect, for example, disorders in the schizophrenia or the bipolar spectrums, or unipolar depression. Similarly, different SIPS syndromes (e.g., attenuated psychotic symptoms, brief limited intermittent psychotic episode with psychosis, and genetic risk and deterioration syndrome) have different diagnostic criteria and likely “capture” diverse underlying disorders. This point underscores the importance of identifying the nature and symptoms of schizophrenia illness (and other disorders) at stages that precede the prodrome, both to assess more specific symptoms and syndromes, and to identify potential treatment targets prior to the development of positive symptoms. Initial efforts to identify one such syndrome are described below.



The emergence of, or increase in, positive symptoms in the prodrome or the first episode of psychosis signifies a transition to a clinical state that is close to schizophrenia. An important question is whether liability could be identified earlier, prior to the prodrome and the emergence of attenuated positive symptoms. As noted earlier, unusual behaviors in non-psychotic relatives of patients with schizophrenia were also observed frequently. Rado [1953, 1960] noted that “schizotypes” and “schizotypal behaviors” resulted from a genetic liability to schizophrenia, which was integrated into a model proposed by Meehl [1962, 1989] in which a major gene (a “schizogene”) produced a “neural integrative defect” that he referred to as “schizotaxia.” The underlying neural defect produced an observable phenotype called “schizotypy,” which is a type of personality organization that interacted with environmental variables such as social learning and other, polygenic factors (e.g., a predisposition to high or low anxiety, or to different types of temperament). When the environment and other genetic circumstances were favorable in individuals who carried the schizogene, the observable phenotype would consist of only minor clinical symptoms (e.g., “compensated schizotypy”), but when other genetic and/or environmental circumstances were less favorable, then more severe, decompensated conditions would result, including schizophrenia.

Over the next 3–4 decades, schizotaxia was used as a general term to describe the premorbid, neurological liability for, and basis of, schizophrenia. In part because schizotaxia was unobservable directly in Meehl's conceptualization, it was not defined operationally or studied as a clinical syndrome. In contrast, Meehl's conception of the most direct consequence of schizotaxia—schizotypy—was considered observable, and that concept did enter the psychiatric nosology in the modified form of “schizotypal personality disorder.” By the 1990s, however, a growing body of literature showed that a subset of non-psychotic relatives of people with schizophrenia showed a broad range of measurable abnormalities in brain structure and function, neurophysiological aspects of information processing such as eye tracking and various sensory gating paradigms, neuropsychological function, and social functioning, among others [Faraone et al., 2001; Seidman and Wencel, 2003; Gur et al., 2007; Turetsky et al., 2007]. These findings supported the view that the notion of liability might be amenable to operational definitions, whereas it had not been previously.

Other factors contributed to the development of this idea. The focus on non-psychotic relatives, who could be studied without the confounding effects of psychosis, medication or chronic illness, produced a paradigm shift in the field [Thaker, 2007], away from formal diagnostic clinical symptoms in patients, and towards biological, neuropsychological, social and other markers of schizophrenia disease. This shift focused renewed attention on endophenotypes, which helped to provide a conceptual understanding of the schizophrenia-related abnormalities that were identified in relatives [Braff et al., 2007]. As the focus shifted away from diagnostic criteria for schizophrenia, it also shifted away (somewhat) from psychosis, and towards problems (e.g., neuropsychological deficits and social functioning deficits) that onset earlier than psychosis that might reflect the liability to develop schizophrenia. Tsuang et al. (Stephen V. Faraone, Larry J. Seidman, and William S. Kremen) were instrumental in emphasizing the distinction between presumably more specific neurodevelopmental aspects of liability and the less specific nature of psychosis [Tsuang et al., 2000; Faraone et al., 2001]. Longitudinal findings from genetic high risk studies showing neuropsychological, social/interpersonal and motor and abnormalities in the children of parents with schizophrenia that were associated with the development of subsequent psychosis, for example, were also major contributors to this research [Stone et al., 2005; Tsuang et al., 2010]. In the same period, replications of genetic linkage studies gave new hope that eventually, susceptibility genes for schizophrenia might be identified, and would contribute to the early identification of individuals most at risk for developing schizophrenia [Tsuang et al., 1999a]. Early identification, in turn, would facilitate early intervention efforts, and hopefully, at some point, prevention.

Each of these lines of research promoted a broader view of schizophrenia than the DSM or ICD symptoms required to diagnose it. No strong, single predictor of schizophrenia emerged from this research, however, to predict the development of the disorder reliably [Dazzan et al., 2004]. Many abnormalities that show predictive power when studied retrospectively are non-specific, and are likely to contribute to elevated false positive rates and lower levels of specificity [Faraone et al., 1995a]. Moreover, even subjects who demonstrated positive symptoms (as demonstrated by elevated scale of prodromal symptoms (SOPS) scores, for example) may remit or otherwise not progress to develop schizophrenia [Simon et al., 2007; Cannon et al., 2008; Simon and Umbricht, 2010]. A more accurate approach may involve the use of multiple measures or combinations of measures [Erlenmeyer-Kimling, 2001; Mortensen et al., 2010], but the prediction of schizophrenia still remains at an early stage of development.


In this broad context, Tsuang et al. reformulated the term schizotaxia in the 1990s to integrate newer data [Faraone et al., 2001]. Our conception of schizotaxia was consistent with Meehl's view of it as the underlying liability among people predisposed to schizophrenia, though aspects of his view were modified. Perhaps most importantly among these differences, we proposed a provisional, operational definition of schizotaxia [Tsuang et al., 1999b] that allowed the concept to be validated or disconfirmed experimentally. At this point, the proposed syndrome only applies to adult, non-psychotic, biological, first-degree relatives of individuals with schizophrenia. This reflects the view that the etiology of schizophrenia contains significant genetic components that may interact with the biological consequences of adverse environmental factors (e.g., gestational diabetes or pre-eclampsia) to produce an underlying biological vulnerability [Faraone et al., 2001].

Among the reasons for starting with adults were the assumptions that they could cope better than children or adolescents with either the “label” of schizotaxia, or with a planned intervention involving drug administration (described below) to reduce schizotaxia symptoms. The initial research criteria involved a subset of theoretically important symptoms/deficits that were relatively well-studied at the time, including negative symptoms and specific deficits in neuropsychological functioning. Negative symptoms were included because they (flat affect and avolition especially) are often elevated in families with a schizophrenic member, in contrast to positive symptoms, which often are not [e.g., Tsuang et al., 1991]. In this view, negative symptoms in schizotaxia are essentially the same as negative symptoms in DSM-IV schizotypal personality disorder. In this sense, they represent a “negative schizotypy” dimension, without the positive (or disorganized) dimension that together constitutes the DSM-IV disorder [Tsuang et al., 2002]. In our pilot studies, anhedonia (e.g., few interests or sources of pleasure) and asociality (e.g., few romantic relationships or close friends) were among the most common negative symptoms observed in individuals who met provisional criteria for schizotaxia [Tsuang et al., 1999b].

Our initial criteria for schizotaxia also included neuropsychological deficits in specific measures of verbal memory, attention and/or executive functions. Deficits in these neuropsychological domains are core features of schizophrenia that also occur frequently in relatives [Kremen et al., 1994; Abdolmaleky et al., 2004; Sitskoorn et al., 2004; Snitz et al., 2006; Gur et al., 2007; Mesholam-Gately et al., 2009]. In addition to negative symptoms and cognitive deficits, multiple inclusion and exclusion criteria were intended to minimize false positive diagnoses (e.g., negative symptoms or cognitive problems due to known neurological or medical conditions, current substance dependence, history of electroconvulsive treatment, or English spoken as a second language), and subjects with any lifetime history of a psychotic disorder [Tsuang et al., 1999b]. Using these provisional, conceptually-based criteria, we assessed a group of 27, non-psychotic, first degree relatives of individuals with schizophrenia [Stone et al., 2001]. Eight subjects met criteria for schizotaxia, and 19 did not. Comparisons between the two groups were made on several relatively independent, non-criterion clinical measures, including the Social Adjustment Scale (SAS) [Weissman and Bothwell, 1976], the DSM-IV Global Adjustment Scale (GAS) [American Psychiatric Association, 1994], and the Symptom Checklist—90—Revised (SCL-90-R) [Derogatis, 1993], among others. The groups did not differ in age, education, paternal education, IQ or number of ill relatives. The comparisons demonstrated evidence of concurrent validity for the concept by showing that relatives who met criteria for schizotaxia also showed poorer functioning on these non-criterion, relatively independent clinical measures than did relatives who did not meet criteria, regardless of whether the measures were self-rated or rated (blindly) by the researchers.

As part of an attempt to determine whether symptoms of schizotaxia were amenable to intervention, we also administered a low dose of risperidone (0.25–2.0 mg) to six of the eight subjects who met the schizotaxia criteria, and who agreed to a 6-week, open-label course of the drug. Institutional oversight was provided by the Institutional Review Board (IRB) of the Massachusetts Mental Health Center (Boston, MA). All subjects completed the protocol. Side effects were temporary and mild, and no abnormal movements were observed. Five of the six subjects showed improvement on a demanding test of auditory-verbal working memory, and showed reductions (25–50%) in the number of negative symptoms rated as at least moderate (i.e., scores of 3 or higher) on the Scale for Assessment of Negative Symptoms (SANS) [Andreasen, 1983].

The results of the pilot validation study and the response to the pharmacological probe were encouraging, and led to a larger investigation designed to replicate or modify the proposed liability syndrome in adult, non-psychotic, first-degree biological relatives. Although the pilot study was conducted in Boston, the subsequent study was conducted at the Mental Health Institute, Second Xiangya Hospital of Central South University, Changsha, Hunan Province, People's Republic of China, and will be referred to as the “Changsha Study” [Stone et al., 2012a, 2012b]. The change in location reflected both the challenges involved in recruiting subjects locally who met our provisional criteria, and the opportunity to recruit appropriate subjects through collaborators who were working with larger numbers of schizophrenia families.

The clinical (negative symptoms) and neuropsychological domains used to assess schizotaxia were the same in the Changsha study as they were in the Boston pilot study. Individual neuropsychological tests, however, were changed, because most of the criterion tests used in Boston lacked normative values for Chinese samples. The criteria used in the pilot study were stringent, but were effective in identifying almost a third of the first group of relatives we assessed (8/27) as meeting provisional criteria for schizotaxia. These criteria identified a much lower percentage of relatives in the Chinese sample, however, using the modified battery of tests with Chinese norms. Consequently, we modified the criteria to make them less stringent and more consistent with the Boston cutoff values, but we also performed cluster analyses to determine whether our two-group classification of relatives into schizotaxic and non-schizotaxic groups cohered empirically. In addition to the criterion measures, subjects also received additional measures of clinical, social, neuropsychological, and medical function.

One hundred eighty-nine relatives were assessed, along with 30 community comparison subjects (CCS) [Stone et al., 2012b]. Using the modified, conceptually-based criteria, 86 subjects were classified as having schizotaxia (45.5%), while 103 were not. In general, relatives classified as non-schizotaxic performed similar to the CCS group. Relatives classified as schizotaxic showed significantly lower/poorer performance on a variety of criterion-related and non-criterion-related neuropsychological, clinical, and social measures, including the GAF and the SAS. Results of the cluster analysis confirmed the two-group solution (as did a discriminant function analysis), and confirmed the classification of most of the subjects. It did, however, reduce the number of subjects classified as schizotaxic from 86 to 53 (28.0%), making it similar to the percentage we obtained in our pilot study in Boston, and it increased the non-schizotaxic relatives group to 135. The cluster-derived groups showed the same pattern of relationships as the conceptually determined groups, but the effect sizes of several group differences increased, including the GAF and the SAS.

Subjects classified with schizotaxia were also recruited into a 6-week intervention trial that involved administration of low doses of risperidone (0.25–2.0 mg) [Stone et al., 2012a]. Unlike our open-label pilot study, the trial utilized a double-blind, placebo-controlled design. Thirty-six of the 86 subjects who met criteria for schizotaxia agreed to enter the trial, of whom 20 were randomized to the risperidone group, and 16 were randomized to the placebo group. Side effects were mild and well-tolerated generally, but one subject receiving risperidone did stop taking it 2 days before the completion of the protocol. The first set of data analyses focused on the criterion measures for schizotaxia, the non-criterion neuropsychological measures, and some of the non-criterion clinical measures, including the GAF and the SAS. The results showed significant improvement in the risperidone group in the criterion measures for executive function (i.e., fewer perseverative errors on the Wisconsin Card Sorting Test), and better self-rated social function on the SAS. The GAF scores did not change. The SANS scores did not change, either, as they did in the pilot study, which emphasizes the importance of following-up initial findings obtained using open-label designs with more rigorous, double-blind protocols.

Overall, these results are encouraging, and emphasize the potential importance of cognition in the assessment of liability for schizophrenia. It should also be underscored, however, that progress towards the identification of a liability syndrome for schizophrenia remains in the early stages of development, as is discussed further in the following section. The use of different neuropsychological tests in the Boston and the Changsha samples, and the results of the cluster analysis, emphasize the provisional nature of the criteria at this point. The results of the risperidone study also require caveats. Only some measures changed with treatment, which could have occurred by chance, and which will necessitate additional replication. Although our findings are potentially significant in showing that neuropsychological and other symptoms related to the liability for schizophrenia may be amenable to intervention, they do not provide sufficient justification for the clinical use of antipsychotic medications—and their potential medical and psychosocial side effects—in preventive roles at this time.


It is now over a decade since Tsuang et al. published the first proposed research criteria for a schizotaxia reliability syndrome [Tsuang et al., 1999b]. In that time, several studies, as reviewed above, provided concurrent evidence for schizotaxia. Moreover, at least one other group has studied non-psychotic relatives using similar classification criteria [Rybakowski et al., 2007]. They identified a putative schizotaxia syndrome in seven adult (aged 17–44), never-psychotic, first- or second-degree biological relatives of patients with schizophrenia. Unlike our subjects, these subjects reported a decline in function over the previous year, and neuropsychological problems, though they did not meet DSM-IV diagnostic criteria for any schizophrenia-related spectrum disorder. These classification criteria thus shared features with the prodromal “genetic risk and deterioration” syndrome [Miller et al., 2003; McGlashan et al., 2010]. Subjects took low doses of risperidone for periods of 3–7 years. Similar to our findings, all subjects demonstrated improvements in at least some neuropsychological functions. They also showed improvement in social and vocational function, and in negative symptoms.

Research conducted to date generally supports the view advanced by Tsuang et al. that putative liability syndromes could be defined, though schizotaxia and its criteria remain in early stages of development. At least several factors contribute to this state-of-the-field. One is that schizotaxia, or any pre-prodromal syndrome of liability is, by definition, further away from the development of overt illness than is, for example, the prodrome, and is thus more vulnerable to different outcomes and developmental trajectories. Moreover, schizotaxia, as it has been formulated thus far, is likely to remain stable in most people and not progress, which complicates attempts to establish predictive validity. The magnitude of this problem is substantial, particularly in light of findings showing that predictions of good or poor outcomes are far from certain even in subjects who meet formal criteria for prodromal syndromes [Cannon et al., 2008; Addington and Heinssen, 2012; Fusar-Poli et al., 2012a; Schlosser et al., 2012].

Uncertainty about the clinical significance of a schizotaxia “diagnosis” contributes to related ethical and pragmatic difficulties in recruiting research subjects to participate in schizotaxia-related studies. The ethical concern involves the cost-benefit analysis of classifying individuals as meeting criteria for the syndrome, even in a provisional manner. While the potential benefits of identifying either risk for future problems or providing an understanding of current problems could be significant clinically if they are linked to therapeutic interventions, these outcomes are not yet established for schizotaxia. Consequently, potentially negative outcomes of diagnosis, including stigmatization by others, dysphoric reactions to receiving the diagnosis and societal repercussions such as problems getting insurance, all become more prominent. These potentially negative outcomes are also likely to complicate recruitment efforts in schizophrenia families, as members of the family may have already observed or experienced effects of stigmatization and/or fear the possibility that they will be viewed in the same light as their ill relatives. Ethical concerns should also be considered in relation to possible interventions, as noted above in the caveats concerning the use of antipsychotic medications to reduce symptoms of schizotaxia.

Conceptually, numerous issues will require resolution for the utility of liability syndromes, including schizotaxia, to increase. One of these will involve the incorporation of additional dimensions of function in the syndrome and in the diagnostic criteria. Despite the encouraging results obtained thus far, the limited provisional criteria were intended to serve as starting points for the development of more comprehensive and predictive syndromes. In part, this means exploring the most useful measures and cutoff points for existing criteria, and the most useful combinations of measures [Kremen et al., 2004; Stone et al., 2012a, 2012b]. It also involves the inclusion of different dimensions of function, however, including biological, social, genetic and other clinical and neuropsychological measures. Other, less evident measures than those related to psychiatric, psychological or neurobiological measures function, such as other medical measures, should also be considered as endophenotypes related to schizotaxia, and assessed for empirical validation [Stone et al., 2007]. Overall, this view of liability is consistent with recent proposals emphasizing the need for better and fuller definitions of the architecture of liability states prior to the prodrome, and including multiple dimensions of function such as genetic and epigenetic biomarkers, and cognitive and physiological indicators, among others [Insel, 2010]. Moreover, in addition to incorporating multiple dimensions of function, schizotaxia research will benefit from a developmental psychopathology perspective that emphasizes the identification of multiple trajectories over time, particularly empirically identified trajectories towards serious mental illness. Such a program of research could help identify common versus specific liabilities to schizophrenia spectrum disorders (and possibly other disorders), including genetic liability markers and candidate endophenotypes, each of which may vary as a function of developmental stage or status. Identifying trajectories may help to illuminate the multiple etiological pathways that underlie the development of schizophrenia. Ultimately, these lines of research may lead schizotaxia research well beyond its current conceptualization as a single putative syndrome, and towards the identification and validation of multiple liability syndromes. While the likelihood of, and the time frame for, such an evolution is uncertain, the current formulation of schizotaxia contributes to an empirical foundation for pre-prodromal liability research that, in turn, has the potential to contribute significantly to the development of early intervention strategies for schizophrenia-related disorders.