Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue5.2000:

Towards the Prevention of Schizophrenia
Ming T. Tsuang, William S. Stone, and Stephen V. Faraone
There is a growing emphasis on attempts to identify the
early signs and symptoms of schizophrenia, largely because early detection and treatment of psychosis (i.e.,
secondary prevention) are associated with relatively favorable clinical outcomes. This raises the issue of whether
prevention of psychosis itself is possible. The achievement
of this goal will require the identification of a premorbid
state that could serve as the foundation for treatment
strategies aimed ultimately at the prevention of schizophrenia. Fortunately, evidence for such a state is emerging, in part because schizophrenia may result from a
neurodevelopmental disorder that is associated with a
variety of clinical, neurobiological, and neuropsychologic
features occurring well before the onset of psychosis.
These features may serve as both indicators of risk for
subsequent deterioration and the foundation of treatment
efforts. We reformulated Meehl’s term schizotaxia to
describe this liability and discuss here how its study could
form the basis for future strategies of prevention. We also
include a description of our initial attempts to devise
treatment protocols for schizotaxia. It is concluded that
schizotaxia is a feasible concept on which to base prevention efforts, and that treatment of adult schizotaxia may be
among the next steps in the process. Biol Psychiatry

2000;48:349 –356 © 2000 Society of Biological
Psychiatry
Key Words: Schizotaxia, genetics, negative symptoms,
neuropsychology, risperidone

Introduction

D

uring the past decade, researchers have focused schizophrenia treatment studies on the early treatment of
psychosis. Wyatt’s (1995) review of 21 controlled studies
found that patients who had been treated with antipsychotic
medicine during their first or second hospitalization had a
better outcome than patients who had not been treated early

From the Harvard Medical School Department of Psychiatry at Brockton/West
Roxbury VA Medical Center and Massachusetts Mental Health Center (MTT,
WSS, SVF), Psychiatry Service, Massachusetts General Hospital (MTT, SVF),
Harvard Institute of Psychiatric Epidemiology and Genetics (MTT, WSS,
SVF), and the Department of Epidemiology, Harvard School of Public Health

(MTT), Boston, Massachusetts.
Address reprint requests to Ming T. Tsuang, M.D., Ph.D., Stanley Cobb Professor
of Psychiatry and Head, Harvard Department of Psychiatry, Massachusetts
Mental Health Center, 74 Fenwood Road, Boston MA 02115.
Received October 6, 1999; revised May 2, 2000; accepted May 9, 2000.

© 2000 Society of Biological Psychiatry

in the course of illness. Others have suggested that early
treatment, especially with newer agents, might preserve brain
plasticity and reduce the clinical deterioration of chronic
schizophrenia (Green and Schildkraut 1995; Lieberman
1996; McGlashan and Johannessen 1996). It is also possible
that, rather than having a neuroprotective effect, early treatment mitigates the social consequences of schizophrenic
psychopathology, which may result in better outcome by
allowing for the easier reintegration of patients into their
social networks. In fact, it may help prevent patients from
losing these networks in the first place. These lines of
reasoning have motivated the creation of early detection and
intervention projects seeking to treat schizophrenic patients

during their prodrome or first episode (Falloon et al 1996;
Green and Schildkraut 1995; McGlashan 1996; McGlashan
and Johannessen 1996; McGorry et al 1996; Olin and
Mednick 1996; Vaglum 1996; Yung et al 1996).
The treatment of incipient psychosis is an outstanding
secondary prevention strategy. But will it be enough? The
compelling reasons for pursuing secondary prevention also
provide compelling reasons for developing primary prevention protocols. There are, however, two reasons why the
progress toward the primary prevention of schizophrenia
remains in its infancy. First, we cannot implement a primary
prevention protocol unless we can accurately define the
population at risk for schizophrenia. Second, we must have a
solid rationale for any proposed preventive treatment.
In this review, we outline an approach to these issues by
focusing on “schizotaxia,” a term that Meehl (1962, 1989)
introduced to describe the predisposition to schizophrenia
and Faraone et al (in press) modified to fit with data collected
since Meehl’s formulation. We begin with a brief discussion
of the role of prevention in schizophrenia, and then outline
the concept of schizotaxia. This leads to a consideration of

how research into schizotaxia could facilitate the development of strategies for the primary prevention of schizophrenia, followed by a description of our initial steps towards this
goal, which include the establishment of research protocols
for the treatment of schizotaxia in adults.

Early Identification and Treatment of
Schizophrenia
Although 100 years of research have not produced a cure
for schizophrenia, we have made significant progress in its
diagnosis and treatment, and in our understanding of its
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PII S0006-3223(00)00934-3

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underlying neurobiology. A substantial portion of this
credit goes to the development of antipsychotic drugs.
Successive generations of these agents have had an enormous beneficial effect on the lives of patients and their

families. Despite progress in treatment, there is clearly a
long way to go before the symptoms of schizophrenia are
fully “controlled” in most patients, in the sense that normal
clinical and cognitive functions are restored (or attained).
Thus, researchers have been testing secondary prevention
strategies, which focus on the early detection and treatment of the disorder. In 1938 Cameron (cited in McGorry
et al 1996) first described the need to treat schizophrenia
early to prevent subsequent deterioration. Since then,
evidence has accumulated to support the view that the
longer treatment is delayed, the poorer is the subsequent
prognosis (Green and Schildkraut 1995; Wyatt 1995;
Wyatt et al 1996).
Several benefits of early treatment are likely, including
the prevention of the social, interpersonal, cognitive, and
affective disruptions that accompany and follow the initial
psychotic episode. One potential consequence of secondary prevention is simply the delay of onset. This may be
especially valuable for early-onset cases, as these patients
would then have more time to mature before having to
cope with a serious and chronic illness. Moreover, untreated schizophrenia may become more resistant to treatment, in part because psychosis itself may create widespread neurobiological abnormalities (Knoll et al 1998)
that, at best, complicate current treatment strategies. If the

early treatment of psychosis mitigates the course of
schizophrenia, implementing early identification and treatment programs should be valuable because psychotic
symptoms are present for an average of about 2 years
before treatment is sought (e.g., Loebel et al 1992).
Research and theory about the early treatment of psychosis naturally lead to the question, can psychosis be
avoided? Most researchers have approached the issue by
focusing on prodromal symptoms as indicators of an
impending psychotic disorder, but the issue is far from
straightforward. McGorry et al (1995) showed, for example, that DSM-III-R prodromal symptoms for schizophrenia occurred in 15–50% of high school students. This
raises obvious questions about the validity of intervening
on the basis of such symptoms. Are prodromal symptoms
like social withdrawal, or subtle changes in thinking or
affect, valid enough indicators of early schizophrenia to
warrant intervention, possibly with antipsychotic medications and their associated side effects? Do such nonspecific symptoms warrant the potential anxiety and stigmatization (for both “patients” and their families) that might
attend the classification of an individual as likely to
develop schizophrenia, probably in the near future? Unfortunately, these questions cannot yet be answered in the

M.T. Tsuang et al

affirmative. There is little clear evidence that prodromal

symptoms are specific for schizophrenia or for other
psychotic illness (Larsen and Opjordsmoen 1996). Given
this state of affairs, the risks of primary prevention
programs are magnified even further if high-risk status is
assigned and interventions are proposed before clinical
symptoms emerge.
Our current state of knowledge, then, appears to preclude the application of preventative treatments for people
without clinical symptoms of psychosis, or at least the
prodrome. If this is so, how might prevention strategies
proceed?

Schizotaxia: Toward a Definition of
“Preschizophrenia”
The concept of schizotaxia was first introduced by Meehl
to describe a “neural integrative defect” that was the
neurobiological consequence of the schizophrenia’s genetic origins (Meehl 1962). In other words, schizotaxia
was intended to describe the genetic vulnerability to
schizophrenia. Meehl suggested that all individuals with
schizotaxia would, through the normal processes of social
learning, develop schizotypal personality structures. Depending on the protection or liability afforded by environmental circumstances, a minority of these individuals

would decompensate and develop schizophrenia. Over the
next 25 years, Meehl revised the concept to allow for the
possibility that some people with schizotaxia would develop neither schizophrenia nor schizotypal personality
disorder (Meehl 1989). Although the term schizotaxia
achieved popularity in the research literature as a broad
description of clinical or biological features thought to
reflect the genetic liability for schizophrenia, it did not
enter the clinical psychiatric nomenclature.
Now, over 30 years later, the accumulated evidence
shows that the liability for schizophrenia can be characterized clinically by deficits in psychiatric, neuropsychologic, neurobiological, and psychosocial domains, in nonpsychotic, first-degree relatives of people with
schizophrenia. Clinical psychiatric features in such relatives frequently include negative symptoms that are similar qualitatively, but milder quantitatively, than those
observed frequently in schizophrenia (Tsuang et al 1991).
Positive symptoms, however, are usually less evident in
these relatives than they are in schizophrenia or in schizotypal personality disorder. We stress that the symptoms of
schizotaxia are distinct from the symptoms of the prodrome, and typically appear well before the onset of
prodromal symptoms. Neuropsychologic impairments in
biological relatives of people with schizophrenia are also
similar to, but milder than, those that occur in schizophrenia (Faraone et al 1995b, in press; Kremen et al 1994; Park

Prevention of Schizophrenia

et al 1995). Particular areas of deficit frequently include
attention/working memory, long-term verbal memory, and
executive functions.
Recently we suggested modifications to the concept of
schizotaxia that focused on negative symptoms and neuropsychologic deficits (Faraone et al, in press; also see
Table 1 for a summary of our tentative research criteria for
the assessment of schizotaxia). Our empirical analyses
showed that the percentage of adult relatives who demonstrated these features among first-degree biological relatives of schizophrenic patients is substantial. Unlike
schizotypal personality disorder, which occurs in less than
10% of the adult relatives of patients diagnosed with
schizophrenia (Battaglia and Torgersen 1996), and schizophrenia, which occurs in about 10% of first-degree relatives (Gottesman 1991), these basic symptoms of schizotaxia occur in 20 –50% of adult relatives (Faraone et al
1995a, 1995b, in press). These findings indicate that the
genetic liability to schizophrenia does not lead inevitably
to either schizophrenia or schizotypal personality disorder.
Our concept of schizotaxia has several advantages. One
is its usefulness for genetic studies (Faraone et al 1999). If
the proportion of first-degree relatives with schizotaxia is
larger than the proportions of relatives with other related
conditions (like schizotypal personality disorder or schizophrenia), then the classification of schizotaxia may allow

for a more accurate differentiation of individuals who are
genetically “affected” from those who are not (for a
review of the technical aspects of this issue, see Faraone et
al 1995a). Second, the utilization of neuropsychologic
symptoms in our reformulation emphasizes “endophenotypic” measures (Gottesman 1991) that are more proximal
to their underlying genetic/biological etiologies than are
the relatively end-state clinical symptoms that define
schizophrenia and schizotypal personality disorder. Third,
and most relevant for this discussion, schizotaxia extends
the spectrum of liability to schizophrenia to a clinically
meaningful but premorbid state. This makes it ideal for
identifying preschizophrenic persons and for designing
primary prevention strategies for schizophrenia.
Although our initial characterizations of schizotaxia are
encouraging, it is an evolving concept rather than a strictly
defined diagnostic condition. As noted above, the concept
needs to be validated empirically, and criteria sets need to
be established to differentiate it reliably from potentially
comorbid conditions like schizotypal personality disorder.
It is also likely that schizotaxia will come to incorporate

biological measures of dysfunction caused by combinations of schizophrenia genes and adverse environmental
events.
Our view of schizotaxia is consistent with neurodevelopmental models of schizophrenia. Consistent with other
neurodevelopmental hypotheses (Goldman-Rakic 1995;

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2000;48:349 –356

351

Table 1. Preliminary Research Criteria for the Assessment of
Schizotaxia
Inclusion criteria
Pre-evaluation

Clinical

Neuropsychologic

Exclusion criteria

First-degree relative of patient with
schizophrenia
Adult aged 19 –50
Native speaker of English
IQ $ 70
Provide informed consent
Six or more items rated 3 or higher on the
Scale for the Assessment of Negative
Symptoms (Andreasen 1983)
Deficits in one of three specified cognitive
domains $ 2 SDs below normal
(see text)
Deficits in a second cognitive domain $ 1
SD below normal
Any lifetime history of psychotic disorders
A substance abuse diagnosis within 6
months of the study
A head injury with loss of consciousness
$ 5 min or subsequent cognitive
deficits
A history of neurologic disease or damage
A medical condition with significant
cognitive sequelae
A history of electroconvulsive treatment

Seidman 1990; Weinberger 1995a, 1995b), we hypothesize that a combination of genes and environmental events
leads to altered development of the brain, perhaps as early
as the second trimester of life. This combination results in
schizotaxia, which is a neurodevelopmental syndrome that
is characterized by neuropsychologic and neurobiological
dysfunctions, the latter of which may include reduced
volumes in several brain areas, and/or altered patterns of
brain activation in response to external challenges or
stimuli (Seidman 1997).
Evidence in favor of neurodevelopmental hypotheses in
schizophrenia is extensive (e.g., Beauregard and Bachevalier 1996; Faraone et al, in press; Tsuang and Faraone
1995; Tsuang et al 1991; Weinberger 1995a, 1995b;
Woods 1998). Briefly, it includes 1) studies showing
elevated rates of pregnancy and/or delivery problems, and
exposure to viruses; 2) postmortem studies showing brain
abnormalities indicative of second or third trimester problems of development; 3) animal models demonstrating that
neonatal hippocampal lesions produce effects that are not
fully apparent until adulthood; 4) neuropsychologic deficits in nonpsychotic, first-degree relatives of patients with
schizophrenia; 5) elevated rates of negative, but not
positive, symptoms in schizophrenia families; and 6)
evidence of brain volume loss before the onset of psychotic symptoms in some schizophrenic patients. Most of
this evidence is consistent with the view that at least some
significant aspects of the premorbid substrate of schizo-

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phrenia are formed before the onset of the illness. Negative symptoms and neuropsychologic deficits in family
members, for example, are significant because they occur
in schizophrenia, and in some family members who later
develop schizophrenia or a related disorder. The extent to
which factors like pregnancy and delivery complications
increase the liability for schizophrenia remains to be
established, as does their specificity, although a variety of
studies have shown them to be elevated in schizophrenic
patients (Zornberg et al 2000). Evidence for prenatal
viruses is less clear, but remains suggestive (Tsuang and
Faraone 1995).
Our view of schizotaxia fits in with another feature of
the neurodevelopmental models noted above. For reasons
that remain unknown, the syndrome sometimes results in
psychosis (i.e., schizophrenia) and sometimes does not.
Moreover, the notion of schizotaxia as a neurodevelopmental disorder with genetic and environmental etiologic
components, and variable outcomes, also parallels diathesis/stress conceptualizations of the origins of schizophrenia (Gottesman 1991). Each of these views emphasizes the
importance of genetic/biological risk factors for schizophrenia. If, as suggested above, these factors constitute the
premorbid substrate of the disorder, then it may be
possible to intervene therapeutically before schizophrenia
emerges. Because early treatment is associated with better
outcomes, these views are thus consistent with the hypothesis that successful treatments of schizotaxia will modify
or even prevent its subsequent progression to a more
severe disorder, such as schizophrenia.

The Schizotaxia Treatment Protocol: A
Prelude to Prevention
One key to the prevention of schizophrenia will be the
identification of abnormalities that reflect the etiologic
processes that lead to the onset of psychosis. This means
that, in addition to assessing clinical symptoms, there is a
need for assessing areas of dysfunction that are closer than
clinical symptoms to the etiologic process that ultimately
causes schizophrenia. Indeed, a significant weakness of
the reliance on prodromal symptoms, and one that is
related to their lack of prognostic specificity, is that they
often reflect relatively distal effects of etiologic processes.
Fortunately, we are at a point where we are not limited to
the use of clinical symptoms alone to identify the vulnerability for schizophrenia.
Given the hypothesis that features of schizotaxia reflect
the predisposition to schizophrenia, what steps must be
taken to design a strategy aimed at preventing schizophrenia? Clearly, the validity of schizotaxia as a predictor of
subsequent schizophrenia must be firmly established. As
Robins and Guze (1970) pointed out, it is crucial to

M.T. Tsuang et al

establish both the concurrent and predictive validities of
putative syndromes. Does the classification of schizotaxia
predict neuropsychologic, neuroimaging, or psychophysiologic findings that are consistent with what is known
about the neurobiology of schizophrenia? As we have
reviewed elsewhere, a growing body of literature suggests
that the answer is yes (Faraone et al, in press). Abnormalities found among relatives of schizophrenic patients
include eye-tracking dysfunction (Levy et al 1994), allusive thinking (Catts et al 1993), neurologic signs (Erlenmeyer-Kimling et al 1982), characteristic auditory-evoked
potentials (Friedman and Squires-Wheeler 1994), neuroimaging-assessed brain abnormalities (Seidman et al
1997), and neuropsychologic impairment (Kremen et al
1994).
More importantly, does schizotaxia predict the subsequent emergence of psychotic symptoms or other forms of
psychopathology? Studies of children at risk for schizophrenia show that schizotaxic features do predict subsequent schizophrenia and related disorders (Auerbach et al
1993; Dworkin et al 1994; Erlenmeyer-Kimling 2000;
Ingraham et al 1995; Olin and Mednick 1996; L. Erlenmeyer-Kimling, personal communication, 1997). But
more work is needed to create measures of schizotaxia that
will accurately classify children who do and do not go on
to become schizophrenic. It should be noted that the issue
of risk factors in schizotaxia also raises the issue of
“protective” factors to mitigate them. Like risk factors,
protective factors may be genetic/biological and/or environmental (Tsuang 2000). We use the term here to
describe independent factors that reduce risk, rather than
using it to describe the absence of factors that confer risk.
This is an intriguing notion that has been difficult to
pursue (deficits have been more amenable to detection),
but that will hopefully “come of age” with advances in
technology.
Although schizotaxic features cannot yet be used to
select preschizophrenic children for primary prevention
protocols, our current knowledge about schizotaxia suggests a method for evaluating medications that may
someday be useful for the prevention of schizophrenia.
This method, which we call the “schizotaxia treatment
protocol,” is straightforward: select a sample of schizotaxic first-degree relatives of schizophrenic patients and,
using standard randomized clinical trial methodology,
determine if a putative preventative treatment modifies the
features of schizotaxia in an acute trial. Presumably, any
medicine that mitigates the features of schizotaxia will be
a reasonable candidate for a primary prevention trial when
such trials are possible.
The use of the schizotaxia treatment protocol assumes
that the syndrome of schizotaxia observed among firstdegree relatives of schizophrenic patients shares etiologic

Prevention of Schizophrenia

and pathophysiologic pathways with preschizophrenic
people. If this assumption is true, then any medication that
targets these pathways to mitigate schizotaxic features
may also work to reduce the likelihood of the onset of
psychosis. This assumption is reasonable because 1) firstdegree relatives of schizophrenic patients are at high risk
for carrying schizophrenia susceptibility genes (Gottesman 1991) and 2) the features of schizotaxia observed
among these relatives are similar to the features of
schizotaxia seen in children who eventually become
schizophrenic (Faraone et al, in press).
A major advantage of the schizotaxia treatment protocol
is that it can avoid some of the ethical issues raised by
primary prevention studies of schizophrenia. Prevention
studies will label children and adolescents as potential
future schizophrenic persons. This opens up the possibility
of stigmatization and psychologic harm to the subject and
their families. It is also possible that medications chosen
for prevention trials may pose greater risks to children and
adolescents than adults. That would preclude their use in
the absence of a solid rationale for efficacy. But because
schizotaxia can be defined in the adult relatives of schizophrenic patients, using an acute schizotaxia trial for
putative preventative medicines will not require studies of
children or adolescents.
We view the schizotaxia treatment protocol as a model
system for testing hypotheses about primary prevention. It
is a model because only some elements of the risk for
schizophrenia are present. This is analogous to the use of
animal models of disorders that attempt to define and
manipulate specified components of the system. Such
models are useful in that they facilitate focused analyses of
the behavior of simpler systems. Moreover, models are
often necessary because the ultimate goal of the research is
not yet amenable to study for other reasons. In the case of
prevention research for schizophrenia, the ethical and
safety concerns about identifying and treating “high-risk”
children still outweigh the benefits of proceeding with
such studies. Eventually, however, as elements are incorporated into the models, the comprehensiveness of the
system, and its approximation to the condition of interest,
increases. In this case, our model of the prevention of
schizophrenia starts out as the treatment of clinically
meaningful symptoms in schizotaxia, in adults.
If successful treatments are developed and tested, and
the syndrome of schizotaxia is validated, then treatments
at earlier ages may be considered. For example, if an acute
schizotaxia treatment trial in adults is successful, one
might consider an acute trial for adolescents. If an adolescent trial were to be successful, then we might consider a
trial to prevent psychosis (assuming that the target, preschizophrenic population could be accurately defined).
One of the difficulties with implementing the schizo-

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353

taxia treatment protocol is the lack of a consensual
definition of schizotaxia. Although we can make many
measurements of schizotaxic features (e.g., neuropsychologic symptoms, negative symptoms, social functioning),
the field has yet to agree on how these measures should be
combined to create a schizotaxic category.
Tsuang et al (1999) recently described a working
definition of schizotaxia based on a set of specific criteria,
for the purpose of developing a treatment protocol. Table
1 shows our initial research criteria for the diagnosis of
schizotaxia.
The cognitive domains included vigilance/working
memory, long-term verbal memory, and executive functions. Specific tests and measures on tests were used to
meet the neuropsychologic criteria (Tsuang et al 1999).
Our decision to require moderate deficits in different
domains ensured that our initial treatment attempts would
include only adults with demonstrable clinical and neuropsychologic difficulties. This was important both to demonstrate the clinically meaningful nature of schizotaxia
and to make the risk/benefit assessment of treatment more
favorable. Although we wanted to start with a restrictive
set of criteria, it is likely that modifications will be
necessary in order to conduct large-scale studies. Some of
the exclusion criteria in particular, like that involving
substance abuse diagnoses, may need to be altered if
requisite numbers of subjects are to be enrolled in research
protocols. Nevertheless, the stringent nature of the criteria
underscores the clinical meaningfulness of schizotaxia and
the potential importance of developing treatment protocols
to attenuate it, independent of its value as a strategy to
prevent schizophrenia.
Our first application of the schizotaxia treatment protocol
(Tsuang et al 1999) used risperidone, a novel antipsychotic
medication. As we noted above, trials of these medications
would appear reasonable on the basis of our assumption that
individuals with schizotaxia share etiologic and psychopathologic elements with schizophrenia. Trials with the older,
typical antipsychotics, however, were limited by reluctance
to use these medications in nonpsychotic populations, mainly
because of their side effects and subsequently high rates of
noncompliance (Hymowitz et al 1986), but also because of
their essential inability to alleviate negative symptoms
(Marder and Meibach 1994) or neuropsychologic deficits
(Cassens et al 1990).
Another reason we chose risperidone was that, compared with other novel antipsychotics medications, it had
(at the inception of the study) been shown to reduce
positive and some negative symptoms in schizophrenia
(Marder and Meibach 1994; Rossi et al 1997; Tamminga
1997). It was clearly safer than typical neuroleptics, in that
it produced fewer extrapyramidal side effects (at least at
lower doses; e.g., Marder and Meibach 1994; Tamminga

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1997). Notably, it also improved cognitive functions in
schizophrenia, especially in attention or working memory
(Green et al 1997; Rossi et al 1997; Stip 1996), but
possibly in verbal long-term memory (Stip 1996) and
executive functions (Rossi et al 1997) as well. This latter
feature was especially important given that neuropsychologic impairment is a hallmark of schizotaxia.
Based on these issues, we began an open trial of
risperidone with people who met our criteria for schizotaxia (Tsuang et al 1999). After all entrance criteria were
met, subjects received low doses (starting at 0.25 mg and
reaching maximum doses of 2.0 mg) of risperidone for 6
weeks. During that period they were evaluated weekly for
side effects and for clinical and neuropsychologic effects
of treatment. After 6 weeks most clinical and neuropsychologic tests were repeated. We reported on the effects of
treatment in our first four cases (Tsuang et al 1999) and
have since completed two additional cases. Five out of six
cases showed marked improvements in a demanding test
of auditory attention (improvements were 1.5–2.0 SDs in
magnitude, which placed subjects in the normal range of
performance), and all subjects showed reduced negative
symptoms after 6 weeks. In three cases, reductions in
negative symptoms were marked (approximately 50%
reductions in total Scale for the Assessment of Negative
Symptoms scores), whereas in two they were modest (25%
reductions). One individual did not improve in either
cognition or negative symptoms. Interestingly, this subject
had lower overall cognitive abilities (an IQ of 75) than did
the other cases (IQs ranged from 92 to 111). Her low test
scores may thus represent the effect of two interrelated but
distinct problems: schizotaxia and low cognitive abilities.
In this view, the treatment may have been effective against
symptoms of schizotaxia, but ineffective against the more
general problem of limited intellectual abilities. Consequently, this subject did not improve with treatment.
Side effects, when they occurred, were mild to modest
in severity. No one requested the discontinuation of
treatment, but in some cases the doses were lowered to
reduce discomfort. Side effects tended to differ between
cases, but included symptoms such as dry mouth, sedation,
and weight gain.

Future Directions
Our initial application of the schizotaxia treatment protocol is encouraging, as five out of six cases showed
reductions in negative symptoms and neuropsychologic
deficits. We stress the preliminary nature of these findings,
however, and do not yet recommend the use of risperidone
or other medications to treat schizotaxia. Larger, controlled studies are needed to determine if the treatment
implications of these pilot findings are correct.

Despite this caveat, our findings suggest the feasibility of developing treatment strategies for adult schizotaxia. It is clear that we are only starting this process.
Perhaps the most important task for the near future, in
addition to the need for more methodologically rigorous
replications, is the validation of schizotaxia as a syndrome. This process will likely include the eventual
incorporation of additional clinical, neurobiological,
neuropsychologic, and neurodevelopmental measures.
At some point it will also include molecular biological
data, as the genes that cause schizotaxia are located. As
the validity of schizotaxia becomes established, the risk
(for subsequent psychosis) provided by its component
features will become measurable. That knowledge base
will provide the foundation for strategies aimed at the
prevention of schizophrenia, hopefully in the not too
distant future.

Preparation of this chapter was supported in part by the National Institute
of Mental Health Grants Nos. 1 R01MH4187901, 5 UO1 MH4631802,
and 1R37MH4351801 (MTT); the Veterans Administration’s Medical
Research, Health Services Research, and Development and Cooperative
Studies Programs; and a National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award (MTT).

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