"Schizotaxia": clinical implications and new directions for research

We sought to show that (1) schizotaxia (Meehl's term for the predisposition to schizophrenia) is a clinically consequential condition, and (2) distinguishing it from schizotypal personality disorder may be useful from both clinical and scientific perspectives. We review the features of schizotaxia that may be relevant in clinical settings and discuss their implications for the diagnosis, psychosocial functioning, family intervention and treatment of people in schizophrenia families. Our review indicates that prior work finds some of the nonpsychotic and nonschizotypal relatives of schizophrenia patients to have a psychiatric syndrome characterized by negative symptoms, neuropsychological impairment, and psychosocial dysfunction. Following Meehl, we call this constellation of clinical and neurobiological features schizotaxia. The studies we review suggest it may be worthwhile to consider schizotaxia as a separate diagnostic class. Doing so would alert clinicians to a neurobehavioral syndrome not adequately covered by current diagnostic criteria and would motivate researchers to develop diagnostic and therapeutic approaches aimed at helping schizotaxic individuals and, perhaps, preventing the onset of schizophrenia.     

Schizophrenia: vulnerability versus disease

One of the most important trends in the treatment of schizophrenia involves its early diagnosis and intervention. The ultimate goal of research is the prevention of the disorder, A major impediment to the development of prevention strategies, however, is that we do not yet know what the liability for schizophrenia is before the onset of psychosis. Consequently, early treatment attempts are focused on the "prodrome," which involves the early symptoms of psychosis. In a companion paper, we recently suggested that prevention work should focus not only on the prodrome, but also on "schizotaxia," which is a clinically meaningful condition that may reflect the vulnerability to schizophrenia in the absence of psychosis. Because schizotaxia can be assessed prior to the prodrome, studies of schizotaxia might lead to more effective prevention programs. We continue the characterization of schizotaxia in this paper by focusing on the etiological roots of schizotaxia, plus its likely neurodevelopmental course, clinical expression, and treatment. Finally, the importance of including neurobiological variables in the conceptualization and eventual diagnosis of schizotaxia is reviewed.     

Conceptualization of the liability for schizophrenia: clinical implications

Historically, the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for schizophrenia have emphasized several features, including symptoms of psychosis, a dissociation of symptoms from their etiology, a reliance on clinical symptoms, and a categorical approach to classifying the disorder. Although these emphases are quite useful, they have limitations. We review these here, and stress the importance of incorporating recent data on the genetic /biological and neurodevelopmental origins of schizophrenia into current conceptions of the disorder. We also review "schizotaxia, " which is a concept thai embodies this point of view, occurs before the onset of psychosis, and is hypothesized to represent the liability for schizophrenia. If our hypothesis on this point is correct, the identification of schizotaxic individuals will eventually facilitate the development of prevention strategies by identifying a premorbid (but clinically significant) condition for schizophrenia. Moreover, the identification of biological or neuropsychological components of schizotaxia will provide more specific bases for developing novel treatment interventions. Our initial attempts to develop protocols for the assessment and treatment of schizotaxia are encouraging, and will be reviewed.     

Schizophrenia: family studies and treatment of spectrum disorders

A substantial part of the contribution of genetic studies to the treatment of schizophrenia involves its emphasis on reliable and valid diagnoses. One consequence of this focus is the recognition that schizophrenic illness is broader than the diagnostic entity of schizophrenia itself, and instead consists of a "spectrum" of related disorders. Because some of the symptoms in these disorders differ from each other, they provide an opportunity to determine which ones reflect a common etiology. To the extent that such symptoms are identifiable, they may provide a foundation for treatment and even prevention strategies. In this paper, we focus on a clinical condition - "schizotaxia" - that may reflect the liability for schizophrenia. To characterize the nature and extent of this proposed syndrome, we will review results from family studies in our laboratory, and consider conceptual foundations and criteria for assessment. A more general consideration of treatment strategies for schizophrenia spectrum disorders follows, along with suggestions for future research. Our initial attempts to treat and validate schizotaxia are encouraging, and raise the possibility that early treatment might eventually prevent or attenuate the development of other, more severe disorders in the schizophrenia spectrum, including schizophrenia itself.     

Toward reformulating the diagnosis of schizophrenia

OBJECTIVE: The authors assess implications of DSM criteria for schizophrenia by reviewing the criteria's 1) emphasis on psychotic features, 2) dissociation of symptoms from their etiology, 3) exclusive reliance on clinical features but exclusion of biological indicators, and 4) classification of schizophrenia as a discrete category. The authors then discuss alternative conceptions of schizophrenia that take into account recent data concerning its genetic and neurodevelopmental origins and its pathophysiological substrates. METHOD: The historical development of diagnostic criteria for schizophrenia is reviewed in the context of recent published data on the biology and development of schizophrenia. RESULTS: Growing evidence suggests that symptoms of psychosis may be a common end-state in a variety of disorders, including schizophrenia, rather than a reflection of the specific etiology of schizophrenia. Features occurring before the advent of psychosis that are clinical, biological, and/or neuropsychological in nature may constitute evidence of a genetic predisposition toward schizophrenia ("schizotaxia") and may provide more specific information about the genetic, pathophysiological, and developmental origins of schizophrenia. CONCLUSIONS: The success of efforts to treat and prevent schizophrenia will depend to an important extent on an accurate understanding of its causes. This goal can be furthered by conducting field trials to develop research criteria to assess the value of a developmentally sensitive, biologically informed approach to classification that would consider schizotaxia with psychosis (schizophrenia) and schizotaxia alone as distinct diagnostic conditions.     

An integration of schizophrenia with schizotypy: identification of schizotaxia and implications for research on treatment and prevention

The liability to schizophrenia (schizotaxia) is associated with deficits in a variety of domains, including negative symptoms and neuropsychological deficits, even in the absence of psychosis or pre-psychotic prodromal symptoms. Conceptually, this view of schizotaxia is similar to negative schizotypy (i.e., schizotypal personality disorder minus the positive symptoms). It is broader than DSM-IV schizotypal personality disorder (SPD), however, in that more relatives of patients with schizophrenia show core symptoms of schizotaxia than meet the diagnostic criteria for SPD. Three lines of evidence support the validity of schizotaxia. First, evidence of concurrent validation was obtained by showing that schizotaxic subjects were more impaired than non-schizotaxic subjects on a variety of independent clinical scales. Second, schizotaxic subjects showed higher levels of negative symptoms on the Structured Interview for Schizotypy than non-schizotaxic subjects, but did not differ on positive symptoms. Third, subjects who met predetermined criteria for schizotaxia (i.e., negative symptoms and neuropsychological deficits) showed positive effects following treatment with low doses of risperidone (0.25-2.0 mg). Thus, clinical deficits in schizotaxia may be identifiable, and to a significant extent, reversible. Implications for the conception of schizotypy and the prevention of schizophrenia will be discussed.     

Concurrent validation of schizotaxia: a pilot study.

BACKGROUND: Many first-degree relatives of patients with schizophrenia show deficits in clinical, neuropsychological, neurobiological and social domains, in the absence of psychosis. We recently reformulated Meehl's concept of schizotaxia to conceptualize the liability to schizophrenia, and we proposed preliminary criteria based on the presence of negative symptoms and neuropsychological deficits. Here we investigate the concurrent validity of schizotaxia by comparing a group of subjects who met criteria for schizotaxia with a group who did not on independent measures of clinical function, and on lifetime rates of selected comorbid psychiatric disorders. METHODS: Twenty-seven adults who were first-degree, biological relatives of patients with schizophrenia were evaluated for schizotaxia based on our predetermined criteria involving negative symptoms and neuropsychological deficits. Subjects also received portions of the Diagnostic Interview for Genetic Studies, the Structured Interview for Schizotypy, the Family Interview for Genetic Studies, the DSM-IV Global Assessment of Functioning, the Physical Anhedonia Scale, the Social Adjustment Scale and the Symptom Checklist-90-Revised. Subjects who met criteria for schizotaxia were compared with those who did not on each of the clinical measures, and on their rates of comorbid DSM-IV psychiatric diagnoses. RESULTS: Eight subjects met criteria for schizotaxia, and 19 did not. Subjects with schizotaxia showed significantly lower levels of function on each of the clinical scales. Differences in comorbid psychiatric diagnoses were not significant, although the rate of lifetime substance abuse diagnoses in the schizotaxic group (50%) approached levels that are often seen in schizophrenia. CONCLUSIONS: These findings provide the first evidence of concurrent validation for a proposed syndrome of schizotaxia. They are also consistent with the view that the vulnerability to schizophrenia may be defined, at least partially, although larger studies to assess both the concurrent and predictive validity of schizotaxia will be required to confirm these results.     

Schizotaxia--theoretical construct or a tool for clinical research?

From Kretschmer's trials binding personality traits with risk of psychoses have been described in literature. Still there is lack of one theory linking genetic factors with schizophrenia. In 1962 Meehl, introducing the term "schizotaxia", had been trying to find an answer to such a question. He described schizotaxia as subtle neuronal integration deficit caused by a single genetic factor, which depending on conditions, can give schizotypy or schizophrenia. Actually, this theory has only historical meaning. Recently Tsuang and Faraone reformulated the concept of schizotaxia used in clinical studies. Preliminary results lead to a conclusion that presence of schizotaxia has a detrimental influence on social functioning, which is improving after neuroleptic therapy. Studies confirmed that the risk of schizophrenia in persons with schizotaxia was higher as compared to persons without such characteristics. It is supposed, that paying attention to traits of schizotaxia will improve the possibility of early diagnosis of schizophrenia.     

Pre-psychotic states--contemporary diagnostic and therapeutic issues. Part I. Clinical identification of pre-psychotic states

Early intervention in psychotic disorders, particularly schizophrenia, has been increasingly recognized as important by clinicians. The benefits of early intervention in schizophrenia to patients include prevention of neurobiological changes, minimization of secondary morbidity and prevention of relapse. Other benefits of prepsychotic intervention include the capacity to research the onset phase of psychosis. We would like to support in our paper a statement by Maeres: What is needed is not diagnosing the early stages of schizophrenia but the diagnosis of prepsychotic schizophrenia. We are interested in recognizing the schizophrenia 'prodrome' prospectively using to concepts: subjects 'at risk mental state' (ARMS) and subjects from 'ultra high risk' (UHR) group. For clinical reasons that involves both some clinical features of pre-psychotic states (attenuated psychotic symptoms) and some "trait factors", i.e. schizotypal personality or family predisposition factors. Recent data revealed that some characteristics of pre-psychotic states had stronger predictive value: longer symptoms duration, lower level of GAF (< 40), and presence of attenuated psychotic symptoms. The possibility of providing intervention prior to the onset of psychosis has risen from recent interest in early intervention in these pre-psychotic states.     

A unitary model of schizophrenia: Bleuler's "fragmented phrene" as schizencephaly

inding a unifying concept behind the diversity of signs and symptoms in schizophrenia is a central challenge to contemporary research. A neo-Bleulerian unitary model is described, which defines the illness as a neurodevelopmentally derived "misconnection syndrome," involving connections between cortical regions and the cerebellum mediated through the thalamus (the cortico-cerebellar-thalamic-cortical circuit [CCTCC]). An abnormality in this circuitry, normally used to coordinate both motor and mental activity, leads to misconnections in many aspects of mental activity, or "cognitive dysmetria." As Bleuler originally proposed, "thought disorder" is the primary defining feature of schizophrenia, rather than the more obvious signs and symptoms such as delusions and hallucinations. Cognitive dysmetria, or a disorder in the CCTCC, may provide a heuristic theoretical framework for strategies to explore etiology, pathophysiology, intervention, or prevention.     

Searching for the liability to schizophrenia: concepts and methods underlying genetic high-risk studies of adolescents

Conceptualizations of the liability for schizophrenia help guide the development of research protocols, which, in turn, provide empirical confirmations or disconfirmations of the conceptualization's tenets. This paper focuses on a conception of liability and its relationships to genetic adolescent high-risk studies. Specifically, the derivation and nature of a proposed multidimensional syndrome of liability to schizophrenia ("schizotaxia") are outlined, followed by a representative review of features reported in previous high-risk studies that may be related to schizotaxia, and a perspective on future high-risk investigations. Overall, genetic high-risk studies generally confirm the concept of liability in the offspring of parents with schizophrenia, as expressed by deficits or abnormalities in multiple dimensions. It is concluded that high-risk studies on the liability to schizophrenia provide an important tool with which to explore the etiology and development of schizophrenia, in part by contributing to the identification and validation of specific liability syndromes.     

Trait vs. State Markers for Schizophrenia: Identification and Characterization through Visual Processes

One central issue in schizophrenia research is to identify and characterize behavioral and biological markers that are intrinsic to the complex psychiatric disorder and that can serve as targets for detection, treatment, and prevention. A trait marker represents the properties of the behavioral and biological processes that play an antecedent, possibly causal, role in the pathophysiology of the psychiatric disorder, whereas a state marker reflects the status of clinical manifestations in patients. Certain visual functions, while deficient in schizophrenia, may be independent of psychosis. The question of what types of visual functions can serve as trait or state markers is beginning to be understood. Examining clinically unaffected relatives of schizophrenia patients and patients with bipolar disorder can provide information about the relationship between a schizophrenic disposition and visual response traits. In this effort, researchers found that motion integration is dysfunctional in schizophrenia patients but not in their relatives or bipolar patients, whereas motion discrimination is dysfunctional in schizophrenia patients and their relatives, but not in bipolar patients. By synthesizing these findings, this review suggests that distinguishing enduring trait markers from transient state markers for schizophrenia through visual processes is helpful for developing neurobiologically and psychologically based intervention strategies.     

Cognitive therapy for schizophrenia: from conceptualization to intervention.

OBJECTIVES: To outline the cognitive understanding of symptoms of schizophrenia, such as delusions, hallucinations, and emotional withdrawal, and to review the cognitive therapy approach to ameliorating these symptoms. METHOD: We identified studies examining cognitive factors associated with symptoms of schizophrenia by electronic search (using Medline and Psycinfo). This paper integrates experimental findings and clinical treatment. RESULTS: Recent studies focusing on the psychological aspects of schizophrenia demonstrate the importance of common cognitive biases and distortions that are functionally related to the maintenance of symptoms. Understanding the disorder in cognitive terms provides a framework for psychotherapeutic intervention. Adapting cognitive strategies successfully used in cognitive therapy of depression and anxiety provides an important adjunct to standard treatment of schizophrenia. CONCLUSION: Given that the outcome of current treatment for schizophrenia remains poor, attention to therapist training in psychological approaches is essential.     

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.     

Early diagnosis of schizophrenic psychosis

Schizophrenia is an illness characterized by its syndromic polimorphism and a global impairment of personality traits, that means a lot of suffering for patients and their families. Lately, under the framework of the "neurodevelopmental theory of schizophrenia", the scientific community has paid attention to the need of detecting the illness before onset or as soon as possible. The study of premorbid personality traits, as "schizotaxia" or schizoid or schyzotypal personality, altogether with the study of the so called "basic symptoms" an premorbid states are designed to detect at risk subjects. The need of not waiting until acute onset syndromes in an attempt to more early interventions, due to the fact that there is strong evidence about the existence of early symptoms which proper identification will allow, in the future, to identify subjects at risk an earlier interventions. In this paper we will review only some of the great number of papers recently published on the subject.     

The prevention of schizophrenia

Preventive strategies can be divided into universal, selective and indicated prevention and early intervention. Universal interventions are directed to the general population. Selective approaches are targeted at people who have risk factors for an illness, but who do not show any current signs. Indicated approaches target high risk individuals with minimal signs or symptoms foreshadowing mental disorder, but who do not meet diagnostic levels at the current time. Early intervention involves treating those with already diagnosable disorder in a timely and optimal manner aiming to decrease the severity of the illness, and reduce secondary morbidity. Although universal and selective interventions are not yet viable strategies, indicated prevention and early intervention are now realistic possibilities in schizophrenia. Development of methods to identify those at risk of psychosis continues to evolve. Promising results in the prevention and delay of transition to psychotic disorder from high risk state have been found. Early intervention in schizophrenia, including promotion of early help-seeking, has been shown to reduce the duration of untreated psychosis, which is known to be associated with poor outcome in schizophrenia. Early intervention programmes which optimise the care of the first episode have been shown to produce better outcomes than routine management.     

The prevention of schizophrenia

Preventive strategies can be divided into universal, selective and indicated prevention and early intervention. Universal interventions are directed to the general population. Selective approaches are targeted at people who have risk factors for an illness, but who do not show any current signs. Indicated approaches target high risk individuals with minimal signs or symptoms foreshadowing mental disorder, but who do not meet diagnostic levels at the current time. Early intervention involves treating those with already diagnosable disorder in a timely and optimal manner aiming to decrease the severity of the illness, and reduce secondary morbidity. Although universal and selective interventions are not yet viable strategies, indicated prevention and early intervention are now realistic possibilities in schizophrenia. Development of methods to identify those at risk of psychosis continues to evolve. Promising results in the prevention and delay of transition to psychotic disorder from high risk state have been found. Early intervention in schizophrenia, including promotion of early help-seeking, has been shown to reduce the duration of untreated psychosis, which is known to be associated with poor outcome in schizophrenia. Early intervention programmes which optimise the care of the first episode have been shown to produce better outcomes than routine management.     

The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches.

Schizophrenia is commonly considered a neurodevelopmental disorder that is associated with significant morbidity; however, unlike other neurodevelopmental disorders, the symptoms of schizophrenia often do not manifest for decades. In most patients, the formal onset of schizophrenia is preceded by prodromal symptoms, including positive symptoms, mood symptoms, cognitive symptoms, and social withdrawal. The proximal events that trigger the formal onset of schizophrenia are not clear but may include developmental biological events and environmental interactions or stressors. Treatment with antipsychotic drugs clearly ameliorates psychotic symptoms, and maintenance therapy may prevent the occurrence of relapse. The use of atypical antipsychotic agents may additionally ameliorate the pathophysiology of schizophrenia and prevent disease progression. Moreover, if treated properly early in the course of illness, many patients can experience a significant remission of their symptoms and are capable of a high level of recovery following the initial episode. Because the clinical deterioration that occurs in schizophrenia may actually begin in the prepsychotic phase, early identification and intervention may favorably alter the course and outcome of schizophrenia.     

首发精神分裂症的早期症状调查

目的探讨精神分裂症早期症状的特异性。方法采用自编调查表,通过对42例首发精神分裂症与32例首发情感性精神障碍患者的回顾性调查,比较分析两者早期症状的发生率。结果精神分裂症患者早期多见有轻度阳性症状、某些阴性症状及个性的改变,比情感性精神障碍患者的发生率高且有显著性差异(P<0.05)。神经症性症状、情感性症状、社会功能障碍等发生率高但与情感性精神障碍没有显著性差异(P>0.05)。结论精神分裂症早期症状多种多样,某些轻微阳性和阴性症状发生率高,具有一定的特异性,应针对这些症状应进行早期干预。