In Review
Understanding Predisposition to Schizophrenia: Toward Intervention
and Prevention
Ming T Tsuang, MD, PhD1,
William S Stone, PhD2,
Stephen V Faraone, PhD3
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Objective: Early intervention to prevent schizophrenia
is one of the most important goals of schizophrenia research.
However, the field is not yet ready to initiate trials to
prevent prodromal or psychotic symptoms in people who are
at risk for developing the disorder. In this paper, we consider
some of the major obstacles that must be studied before prevention
strategies become feasible.
Method and Results: One of the most important hurdles
is the identification of a syndrome or set of traits that
reflects a predisposition to schizophrenia and that might
provide potential targets for intervention. In a recent reformulation
of Paul Meehl’s concept of schizotaxia, we integrate
research findings obtained over the last 4 decades to propose
a syndrome with meaningful clinical manifestations. We review
the conceptualization of this syndrome and consider its multidimensional
clinical expression. We then describe preliminary research
diagnostic criteria for use in adult, nonpsychotic, first-degree
relatives of patients diagnosed with schizophrenia, based
on negative symptoms and neuropsychological deficits. We follow
this with evidence supporting the validity of the proposed
syndrome, which mainly includes social dysfunction and response
to a low dosage of one of the newer antipsychotic medications.
Conclusions: Continued progress toward the eventual
initiation of prevention strategies for schizophrenia will
include sustained efforts to validate the traits reflecting
a predisposition to develop the disorder (for example, schizotaxia),
follow-up studies to confirm initial findings, and the identification
of potentially useful preventive interventions.
(Can J Psychiatry 2002;47:518–526)
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Funding and Support and Author Affiliations
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Clinical Implications
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The predisposition to develop schizophrenia in
nonprodromal, nonpsychotic adult relatives of patients
with schizophrenia may be expressed as a meaningful,
diagnosable, clinical syndrome or set of traits,
called schizotaxia.
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In adults, at least some schizotaxia symptoms may
be attenuated with interventions.
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Interventions that attenuate schizotaxia symptoms
in adults may eventually be useful in strategies
aimed at preventing schizophrenia.
Limitations
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Double-blind intervention studies of schizotaxia
are needed.
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Longitudinal neuroimaging data are needed for children
at high risk for developing schizophrenia.
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Molecular-genetic studies of schizotaxia are needed
to extend and validate the syndrome.
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Key Words: schizophrenia, schizotaxia, genetics,
negative symptoms, neuropsychological deficits, schizotaxia
treatment protocol
Résumé : Comprendre
la prédisposition à la schizophrénie
: vers l’intervention et la prévention
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Schizophrenia is a neurobiologically based disorder whose etiology
is rooted in a combination of genetic and environmental risk factors
(1). At-risk individuals often manifest this liability clinically,
in the form of psychiatric symptoms and neurobiological abnormalities,
without fully developing schizophrenia. Characterizing the predisposition
for schizophrenia is important from both a clinical and a research
perspective. For example, identifying individuals who have this
liability affords us the opportunity to develop interventions aimed
at alleviating its clinical manifestations. Moreover, the study
of adult relatives of schizophrenia patients who carry the risk,
but who are without psychosis and do not develop schizophrenia,
could aid in identifying which individuals will or will not develop
the disorder. As the accuracy of prediction increases, the potential
for preventing schizophrenia onset moves closer to reality.
However, the field is not yet ready to initiate treatment strategies.
In this article, we focus on issues that may serve as preludes to
intervention; resolving them will help us to develop viable approaches
to prevention. In particular, we focus on a concept of the predisposition
for schizophrenia called “schiz- otaxia” and on the use
of a schizotaxia intervention protocol to evaluate treatments that
may be potentially useful for preventing schizophrenia. We begin
by reviewing the concept of schizotaxia and examining its clinical
expression in nonpsychotic relatives of patients with schizophrenia.
The Concept of Schizotaxia
In 2001, starting from the premise that the neurobiological basis
of schizophrenia comprises the combined effect of genes and adverse
environmental risk factors, we proposed a modified view of Paul
Meehl’s concept of schizotaxia to describe a neurodevelopmental
condition underlying the predisposition to schizophrenia (2). In
1962, Meehl used the term to characterize the genetic predisposition
to schizophrenia, which he thought was rooted in a “neural
integrative defect” (3). As a result of inherited factors (for
example, a predisposition to high or low anxiety) and environmental
influences, including the effects of social learning, vulnerable
individuals developed schizotypy. Where environmental and genetic
circumstances were favourable, the clinical symptoms were minor
(that is, “compensated schizotypy”), but less favourable
circumstances resulted in more severe conditions, including schizophrenia.
The term schizotypy (in the form of schizotypal personality disorder
[SPD]) eventually entered the diagnostic nomenclature, but schizotaxia
did not. It has been used in research to indicate the premorbid,
physiological substrate of schizophrenia, but it has not been examined
as a clinical syndrome. However, considerable research now suggests
that schizotaxia is a clinically consequential condition. Abnormalities
in affect, cognition, and social functioning among the nonschizotypal
and nonpsychotic relatives of schizophrenia patients show that schizotaxia
is not merely a theoretical construct but has psychiatric and neurobiological
features that justify further research about its nosologic validity
(2).
Although our use of the term schizotaxia is consistent with Meehl’s
view of it as the underlying defect among people genetically predisposed
to schizophrenia, we have reformulated some aspects of his theory.
First, as we describe at greater length in a subsequent section,
we have proposed an operational research definition of schizotaxia
that allows the concept to be validated or disproved experimentally
(4). Second, although Meehl viewed schizotypy as the only clinical
phenotype of schizotaxia, we have suggested that schizotaxia produces
a stable syndrome of neuropsychological deficits and negative symptoms
in most relatives of schizophrenia sufferers (5). Our empirical
studies suggest that basic symptoms of schizotaxia are evident in
20% to 50% of first-degree relatives of schizophrenia patients (6,7).
In contrast, a much smaller number of such individuals will express
schizotypy or schizophrenia. Thus, we view schizotaxia as a broader
construct than schizophrenia or SPD. Consistent with this view,
only about 10% of relatives will develop psychosis, and less than
10% will develop SPD (8,9). Despite differences with the DSM-IV
definition of SPD, we view schizotaxia as a possible form of it.
In particular, it is similar conceptually to negative schizotypy,
with the addition of neuropsychological deficits. Additional research
will be needed to confirm or disprove this view.
A second area of disagreement with Meehl’s view involves his
suggestion that the etiology of schizotaxia is exclusively genetic.
In part because the neurobiological effects of genes cannot always
be separated from the neurobiological effects of other adverse environmental
variables (for example, pregnancy or delivery complications), we
view schizotaxia as the combined effect of both factors. A third
area of disagreement involves the nature of the genetic influence
in schizophrenia. In 1962, Meehl suggested that schizophrenia resulted
from a highly penetrant, dominant gene; however, a more current,
consensual view is that most cases of schizophrenia result from
the influence of multiple genes of small or moderate effect combined
with adverse environmental factors (1,10). Thus, schizotaxia (like
schizophrenia) is a genetic disorder in the same sense that diabetes
and many other complex conditions are genetic disorders. In these
conditions, genetic factors play important, but usually not determining,
etiologic roles that interact with environmental factors to produce
illness (11). A consequence is that schizotaxia may express itself
through various clinical phenotypes, depending on which environmental
circumstances and which genes are involved. Consistent with this
possibility, studies of nonmedicated, first-degree biological relatives
without psychosis show that they differ from control subjects along
multiple clinical, biological, cognitive, and social dimensions
of function. Below, we briefly consider several of these.
Clinical Expressions of Schizotaxia
Areas of investigation that have received particular attention
in first-degree relatives include psychiatric symptoms, psychophysiological
abnormalities, neuroimaging-assessed brain abnormalities, neuropsychological
deficits, and psychosocial impairments. The following discussion
summarizes representative findings in each domain.
Psychiatric Symptoms
Compared with the general population, nonpsychotic relatives of
schizophrenia patients are at high risk for symptoms associated
with SPD (9,12,13), although relatives tend to show more negative
than positive symptoms. In the Roscommon family study, for example,
odd speech, social dysfunction, and negative symptoms strongly discriminated
relatives of schizophrenia patients from control subjects, whereas
positive symptoms, suspicious behaviour, and avoidant symptoms were
less discriminating (14). Moreover, Grove and others showed that
relatives have greater deficits on the Physical Anhedonia Scale
(which measures negative schizotypal features) than on the Perceptual
Aberration Scale (which measures positive schizotypal features)
(15), and Tsuang and others reported that negative symptoms (especially
flat affect and avolition) were elevated significantly in the schizophrenia
families, while positive symptoms were not (16).
Psychophysiological Abnormalities
Psychophysiological abnormalities observed in nonpsychotic relatives
of schizophrenia patients include difficulties in smooth-pursuit
eye tracking (17,18), prepulse inhibition (19), startle habituation
(20), and suppression of auditory-evoked potentials (for example,
P50 and P300 waves) (21,22). Although these sensorimotor gating
deficits are not specific to schizophrenia (23), they are more prevalent
in relatives with schizophrenia spectrum disorders, such as SPD,
than they are in control subjects (24–26). Deficits in sensory
gating may represent a subset of a broader class of electrophysiological
abnormalities in patients with schizophrenia and their relatives.
For example, subjects with SPD show abnormal P3 waves over the left
temporal lobe (27) and abnormal N400 waves during language-processing
tasks (28). It is of particular interest here that sensorimotor
(and other electrophysiological) deficits are similar to those observed
in schizophrenia patients (21,29–33), and the likelihood of
having such abnormalities increases with a greater degree of biological
relatedness to a schizophrenia sufferer (for example, [33]). Moreover,
these abnormalities are not restricted to relatives with SPD (34).
Interestingly, there is long-standing speculation that failures
of habituation to sensory stimuli are related both to heightened
levels of arousal and to a resultant withdrawal from that arousal
(35). These symptoms of withdrawal are consistent with the notion
of negative symptoms, which may account in part for the elevated
rates of negative symptoms and sensorimotor gating deficits in relatives
of schizophrenia patients.
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