Guest Editorial
Diagnostic Concepts and the Prevention of Schizophrenia
Ming T Tsuang, MD, PhD, DSc1,
Stephen V Faraone, PhD2
Click here for Research Funding and Support and Author Affiliations
Schizophrenia has long been recognized as a devastating disorder
for patients and their families. Although substantial progress has
been achieved in both its diagnosis and treatment, and in understanding
the disorder’s neurobiological substrates, a full understanding
of its origins and pathogenic mechanisms remains elusive. One obstacle
to better understanding the causes of schizophrenia may be its diagnostic
criteria (1). The DSM-IV and other nosologies provide a foundation
for clinical diagnosis, but there is little basis for regarding
the DSM’s operational definition as the “true” construct
of schizophrenia.
In the 1970s and 1980s, narrow diagnostic criteria for disorders
like schizophrenia were needed to improve the reliability of clinical
diagnoses. Research has also benefited from the reliability of recent
DSMs, in that clinical characteristics of samples are more standardized
across studies and thus more easily replicated. Moreover, the use
of stringent diagnostic criteria laid the groundwork for studies
to assess and demonstrate the validity of schizophrenia. For example,
schizophrenia can be delineated from other disorders, it shows familial
loading, and it demonstrates predictable measures of outcome.
Yet, despite the many benefits of classification systems such as
the DSM, could the classification of schizophrenia be improved by
integrating current knowledge with existing conceptual and classificatory
schemes? In other words, can the reliability of the DSM-IV diagnosis
of schizophrenia be retained while its validity is increased? In
this context, at least 3 limitations of the current DSM diagnosis
can be addressed: its view that schizophrenia is a discrete category,
its use of descriptive criteria that ignore information about the
etiology and pathophysiology of the disorder, and its emphasis on
psychosis (1).
As it does with other disorders, the DSM-IV places schizophrenia
in a discrete category, not in a quantitative dimension. This definition
holds that schizophrenia begins with the onset of its symptoms as
listed in the DSM-IV; before then, the disorder cannot be validly
recognized. The failure to meet diagnostic criteria has potential
consequences: it can influence what type of treatment or services
patients receive, whether individuals are accepted into a research
study of schizophrenia, and how they are classified in a genetic
investigation. In addition, the use of discrete categories raises
potential problems for patients with symptoms shared by multiple
disorders, because these symptoms may result in artificial boundary
categories and elevated rates of comorbidity (2).
Several factors indicate the value of examining whether a dimensional
model more accurately describes the biological nature of schizophrenia.
One of the most compelling factors is that a dimensional view of
schizophrenia is consistent with multigene models of inheritance,
and these provide the best account of the familial transmission
of schizophrenia (3,4). Multigene models assume that multiple genes
combine with one another and with environmental factors to cause
schizophrenia. Thus, it is possible for people to have low, moderate,
or high levels of risk factors that predispose to schizophrenia.
People with very high levels are at high risk for developing schizophrenia,
while those with moderate levels may have related conditions, such
as schizotypal personality disorder, negative symptoms, neuropsychological
impairment, or other neurobiologic manifestations of the predisposition
to schizophrenia (5).
A second feature of the DSM system is the explicit separation of
diagnostic criteria from speculation about etiology. This was essential
when the DSM-III was published, because theories of etiology had
not yet been subjected to empirical tests. By holding fast to this
approach, however, perhaps the DSM-IV limited its ability to create
more valid diagnoses. The DSM rejection of theoretical speculation
about etiology should not lead us to reject empirical facts as irrelevant
to diagnosis. If empirically validated knowledge about schizophrenia
is not incorporated into diagnostic criteria, there exists a significant
risk of maintaining a stagnant nomenclature—one that will not
provide a solid foundation for further research.
There is also a risk of continuing the disconnection of treatment
and etiology. Since antipsychotic medications were introduced, pharmacologic
treatments have focused on alleviating the most acute and florid
symptoms of schizophrenia; that is, those related to psychosis.
Current treatment is not aimed at correcting specific causes of
the disorder, nor is it aimed at preventing onset. Presumably, knowledge
of schizophrenia’s etiology would facilitate the development
of more targeted treatment strategies and, possibly, safer treatments.
In fact, in the parade of DSMs, psychosis has been the sine qua
non for schizophrenia (psychotic symptoms include delusions, hallucinations,
and gross disorganization of behaviour or thought). But is that
appropriate for a symptom that research and clinical experience
show to be a nonspecific indicator of severe mental illness? If,
in fact, psychosis has an etiology apart from other core symptoms
of schizophrenia, then the DSM diagnostic focus on psychosis in
schizophrenia could be a mistake. In the hunt for the causes of
schizophrenia, psychosis could be a red herring (1).
The evidence sustains this view. It is clear that psychosis is
not specific to schizophrenia or even to psychiatric disorders.
It occurs in neurological disease (for example, Alzheimer’s
disease, Huntington disease, schizophrenia-like psychosis of epilepsy,
vascular dementia, and traumatic brain injury), and it can be caused
by a range of toxic substances. Beyond the prima facie evidence
that apparently similar psychoses occur in diverse conditions, Schneidarian
first-rank symptoms appear commonly in psychotic conditions other
than schizophrenia (6). Moreover, several recent factor-analytic
studies showed that measures of psychosis in schizophrenia did not
differentiate it from other forms of psychopathology (7–9).
However, similarities between psychotic states do not necessarily
imply that the underlying disorders lie on the same continuum. An
alternative formulation is that, since psychotic states may impair
functioning in a relatively global manner, their net effect may
be to emphasize superficial similarities between psychotic disorders
while obscuring more subtle, but defining, differences between them.
Moreover, psychosis is an end-state condition that, compared with
other indicators, is more distal from schizophrenia’s causes
and pathophysiology. In fact, evidence suggests that schizophrenia’s
pathophysiology is put into place long before the first psychotic
episode (4). For example, higher-than-expected frequencies of obstetrical
complications and prenatal exposure to viruses have been reported
in individuals who later develop schizophrenia (10). Similarly,
post mortem studies have found brain abnormalities indicative of
developmental problems in the second or third trimester of pregnancy,
such as altered cell migration in the hippocampus, cingulate gyrus,
and prefrontal cortex (11).
A partial foundation for conceptualizing the biological and clinical
manifestations of vulnerability to schizophrenia already exists
in the body of research about “schizotaxia.” The notion
of schizotaxia was originally introduced by Meehl to describe the
unexpressed genetic predisposition to schizophrenia (12). Given
current data showing that genetic predisposition may also interact
with environmental events (especially those occurring early in development)
and augment susceptibility to schizophrenia, Faraone and others
proposed using the term to indicate the premorbid, neurological
substrate of schizophrenia (13). Indeed, studies of the nonschizotypal
and nonpsychotic relatives of schizophrenia patients show that schizotaxia
is not merely a theoretical construct. It has distinctive psychiatric
and neurobiological features, including negative symptoms, neuropsychological
impairment, deviant eye tracking, and structural brain abnormalities
(13). For reasons that are still unknown, this syndrome sometimes
expresses psychosis, and sometimes it does not. As these neurodevelopmental
indicators of the syndrome are more proximal to schizophrenia’s
initial causes than is psychosis, they could be useful as diagnostic
criteria. Schizotaxia thus represents both a clinically meaningful
condition in its own right and a potential risk factor for subsequent
psychosis.
As the prior discussion indicates, 2 aspects of diagnostic criteria
for schizophrenia should perhaps be reconsidered: their emphasis
on psychosis and their reliance on signs and symptoms that are distal
to the disorder’s etiology and pathophysiology. The concept
of schizotaxia is especially useful for this purpose, as it may
be a more specific expression of the predisposition to schizophrenia
than is the DSM-IV diagnosis. Unlike schizophrenia, schizotaxia
is not masked by the florid clinical symptoms and neurotoxic consequences
of psychosis that are seen in so many other conditions.
Incorporating schizotaxia into the diagnosis of schizophrenia would
be a radical departure from tradition, and such changes will require
a strong empirical foundation. It has, in fact, been the lack of
such a foundation that has heretofore prevented the inclusion of
such measures (for example, biological or neuropsychological abnormalities)
in previous versions of the DSM. Foremost, criteria for schizotaxia
must be developed and validated by demonstrating predictive and
concurrent validity through field trials. The criteria would presumably
reflect the biological and clinical alterations that occur before
the advent of psychosis. This would broaden the diagnosis of schizophrenia
into 2 categories: schizotaxia and schizotaxia with psychosis (schizophrenia).
Whether the term schizotaxia or some other expression is used,
nosologists will need to address both the nonspecificity of psychosis
and the existence of a syndrome that has a biological connection
with schizophrenia. The success of efforts to treat and prevent
schizophrenia will depend to an important extent on accurate understanding
of its causes. It may be time to consider research stratagies to
assess the value of a developmentally sensitive, biologically informed
approach to classification—one that would consider schizotaxia
and schizotaxia with psychosis (schizophrenia) as distinct diagnostic
conditions.
Funding and Support
Preparation of this paper was supported in part by the National
Institute of Mental Health Grants T32-MH17119, U01-MH46318, 2R01-MH43518,
R01-MH50647, and R25-MH60485 to Dr Ming T Tsuang and the Veterans
Administration’s Medical Research Health Services Research
and Development and Cooperative Studies Programs; by a NARSAD Distinguished
Investigator Award to Dr Tsuang.
References
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1 Stanley Cobb Professor of Psychiatry and Head, Department of
Psychiatry, Harvard Medical School, 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 Service, Brockton-West
Roxbury Veterans Affairs Medical Center, Brockton, Massachusetts;
Professor, Department of Epidemiology, Harvard School of Public
Health, Boston, Massachusetts; Clinical Associate, Harvard Medical
School, Department of Psychiatry, Massachusetts General Hospital,
Boston, Massachusetts.
2 Associate Professor, Department of Psychiatry, Harvard Medical
School, Massachusetts Mental Health Center, Boston, Massachusetts;
Chief, Psychiatric Genetics, Harvard Institute of Psychiatric Epidemiology
and Genetics, Boston, Massachusetts; Director, Pediatric Psychopharmacology
Research, Department of Psychiatry, Massachusetts General Hospital,
Boston, Massachusetts.
Address for correspondence: Dr MT Tsuang, Massachusetts Mental
Health Center, 74 Fenwood Road, Boston, MA 02115.
E-mail: ming_tsuang@hms.harvard.edu
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