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The Schizotaxia Intervention Protocol
Even with a working research definition of schizotaxia and preliminary
evidence of its validity, the field is not ready for prevention
trials. As noted above, we are not yet able to identify with acceptable
levels of certainty who will and will not develop schizophrenia.
However, our current knowledge about schizotaxia does suggest a
method for evaluating treatments that may someday be useful for
preventing schizophrenia. The method, called the “schizotaxia
intervention protocol,” is straightforward: among schizophrenia
patients, select a sample of first-degree relatives with schizotaxia.
Then, using standard clinical trial protocols, determine whether
a putative preventive intervention modifies symptoms of schizotaxia
in an acute trial. The underlying assumption is that any intervention
which attenuates a feature of schizotaxia is a reasonable candidate
for a prevention trial, when such trials become feasible.
The notion that schizotaxia symptoms or traits observed in first-degree
relatives share etiologic and pathophysiological pathways with schizophrenia
was central to our hypothesis that low dosages of risperidone would
attenuate such symptoms, as described above. In that study, we administered
the treatment to adults aged 30 to 49 years. Their risk for developing
schizophrenia was thus statistically lower than when they were younger,
although it still exceeded that of the general population. The same
reasoning that underlies treatment of schizotaxia for its own sake
(that is, to reduce symptoms in affected individuals who might not
otherwise receive treatment) underlies its utility in prevention
strategies. If adult first-degree relatives share etiologic and
pathophysiological elements with their ill relatives, it follows
that the ill relatives share such elements with subjects who may
be regarded as preschizophrenic. If this is true, then any intervention
that seeks to mitigate these elements (that is, schizotaxia symptoms
or the function of their underlying neurobiological substrates)
might also work to reduce the likelihood of psychosis. Further,
this assumption is reasonable because first-degree relatives of
patients with schizophrenia show an elevated risk for carrying schizophrenia
susceptibility genes (1), and features of schizotaxia observed among
adult relatives are similar to those seen in children who eventually
develop schizophrenia (2).
The schizotaxia intervention protocol has several major advantages.
One is that it is applicable to a wide range of potential interventions.
While the use of medications is particularly likely to receive attention,
other modalities, such as psychotherapy, psychosocial treatments
(for example, [2,75]), or combinations of treatments, may be at
least as useful. Another major advantage of the schizotaxia intervention
protocol is that it can avoid some of the ethical issues raised
by primary prevention studies in schizophrenia. In particular, prevention
studies with children and adolescents have the unintended effect
of labelling them as future schizophrenia patients. This raises
the very real possibility of stigmatization and emotional harm to
the subjects and to their families. Moreover, the type of medications
likely to be used in prevention trials may pose greater risks to
children and adolescents than to adults. The use of antipsychotic
medications to treat children, for example, has been limited in
part because of concerns about side effects (76). Both considerations
(that is, concerns about stigmatization and about medication effects)
preclude their use without solid evidence of their efficacy, but
even nonpharmacologic interventions can be psychologically harmful
if their use is not predicated on a solid rationale. Schizotaxia,
by contrast, can be defined in adult relatives of patients with
schizophrenia, and putative preventive interventions can be evaluated
without the use of children or adolescents.
Eventually, if schizotaxia is validated in adults, if successful
remediation of schizotaxic symptoms or traits is demonstrated, and
if a homogeneous target population is accurately defined, then interventions
at earlier ages may be considered. Presumably, trials with older
adolescents would precede trials with younger age groups. The end
point would involve trials with preprodromal, prepsychotic samples.
At present, the focus is likely to remain on adults. Although our
study of risperidone in relatives of patients with schizophrenia
is an encouraging initial application of the schizotaxia intervention
protocol (in addition to the evidence it provides for the validation
of the syndrome) (72), larger studies, double-blind protocols, and
additional treatments are needed to clarify the extent to which
symptoms of schizotaxia are reversible.
Present and Future Directions
While the concept of a predisposition to schizophrenia has intrigued
researchers for close to 100 years, its study is more recent. Four
decades of research, however, have established schizotaxia as a
clinically meaningful condition (2). One of the most significant
aspects of research with relatives of schizophrenia patients involves
the nature of schizotaxia symptoms. It is clear from high-risk longitudinal
studies, from family studies of cognitive function, and from studies
of neuroimaging, neurochemistry, psychophysiology, and social functioning
(22,43,48,56,63,77), that the predisposition to develop schizophrenia
involves more than the clinical symptoms required for a DSM or ICD
diagnosis of the disorder. As we proposed recently, the clinical
symptoms required for a diagnosis emphasize the role of psychosis
and may reflect a relatively nonspecific end state of the effects
of schizotaxia plus psychosis (78). In contrast, many of the features
of schizotaxia may be closer to the genetic and other adverse etiologic
factors that produce the predisposition to schizophrenia. Consequently,
symptoms of schizotaxia may come to represent particularly promising
treatment targets for prevention protocols. These points do not
detract from the major achievements and utility of the DSM and ICD
systems in advancing psychiatric diagnosis, especially in reliability
but also in validity. Rather, they suggest possible pathways for
continued progress in confirming the reliability and validity of
psychiatric classification.
At this point, a reasonable strategy is to proceed on the 2 parallel
fronts described above. First, there is a clear need to continue
to validate schizotaxia as a syndrome or set of traits. Although
we do not suggest that our conception of the predisposition to develop
schizophrenia is the only one possible, it is a promising one that
merits additional investigation. Whether our conception or another
one is used, a working model is needed to address the existence
of a syndrome that has a biological connection to schizophrenia
and to address its relation to the nonspecificity of psychosis.
To some extent, the emergence of a more unified model of schizotaxia
(that is, one that is likely to include most of the major themes
of schizotaxia research) is mainly a matter of time. For example,
if the current components of the schizotaxia syndrome are validated
(that is, negative symptoms and neuropsychological deficits), the
concept will certainly evolve to encompass additional dimensions
of schizotaxic features (for example, neuroanatomical, neurochemical,
neuroendocrine, psychophysiological, social, and other clinical
components). As it evolves, an understanding of the interrelations
among these dimensions will provide an increasingly integrated view
of the predisposition to develop schizophrenia.
The second line of research is related to the first and involves
the continued use of the schizotaxia intervention protocol to develop
methods to reduce schizotaxia symptoms. Progress in each of these
areas will spur progress in the other. As the identification and
validation of schizotaxic features progresses, clearer treatment
targets will become available. Similarly, as the field develops
interventions to reduce symptoms, the pressure to define a syndrome
of predisposition will become more acute. Hopefully, each of these
lines of research will aid the development of interventions to prevent
psychosis in people with schizotaxia.
Funding and Support
Preparation of this paper was supported in part by the National
Institute of Mental Health (NIMH)Grants T32-MH17119, U01-MH46318,
2R01-MH43518, R01-MH50647, and R25-MH60485 to Dr Ming T Tsuang and
the Veterans Administration Medical Research, Health Services Research
and Development and Cooperative Studies Programs; by a NARSAD Distinguished
Investigator Award to Dr Tsuang; and by a NARSAD Young Investigator
Award to Dr Stone.
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Manuscript received and accepted June 2002.
1 Stanley Cobb Professor of Psychiatry and Head, Harvard Medical
School Department of Psychiatry at Massachusetts Mental Health Center,
Boston, Massachusetts; Director, Harvard Institute of Psychiatric
Epidemiology and Genetics, Boston, Massachusetts; Director, VA Cooperative
Studies of Genetics of Schizophrenia, Psychiatry Services, Brockton–West
Roxbury VA Medical Center, Brockton, Massachusetts; Professor, Department
of Epidemiology, Harvard School of Public Health, Boston, Massachusetts;
Clinical Associate, Harvard Medical School, Psychiatry Service,
Massachusetts General Hospital, Boston, Massachusetts
2 Assistant Professor, Harvard Medical School Department of Psychiatry
at Massachusetts Mental Health Center, Boston, Massachusetts; Researcher,
Harvard Institute of Psychiatric Epidemiology and Genetics, Boston,
Massachusetts; Associate Director of Neuropsychology, Massachusetts
Mental Health Center, Boston, Massachusetts.
3 Associate Professor, Harvard Medical School Department of Psychiatry
at Massachusetts Mental Health Center, Boston, Massachusetts; Chief
of Psychiatric Genetics, Harvard Institute of Psychiatric Epidemiology
and Genetics, Boston, Massachusetts; Director, Pediatric Psychopharmacology
Research, Psychiatry Service, Massachusetts General Hospital, Boston,
Masssachusetts.
Address for correspondence: Dr MT Tsuang, Harvard Medical School
Department of Psychiatry, Massachusetts Mental Health Center, 74
Fenwood Rd, Boston, MA 02115
e-mail: ming_tsuang@hms.harvard.edu
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