Download At Issue: Assessment of Schizophrenia: Getting Closer to the Cause

At Issue: Assessment of Schizophrenia:
Getting Closer to the Cause
by Heather M. Conklin and William Q. lacono
ability can be said to have improved with the introduction
of explicit diagnostic criteria and structured interviews.
However, the jury is still out when it comes to validity. It
is still not known how best to define schizophrenia—that
is, how to define schizophrenia so that properly studying
identified individuals will uncover the disorder's etiology.
It may be that the focus of assessment on behavioral
observation and patient symptomatic report, although
essential, is too far removed from the cause of the symptoms to enable precise diagnosis. Uncertainty about what
constitutes accurate diagnosis greatly complicates etiologic research and likely contributes to the lack of discovery of a specific causal factor for schizophrenia, despite
decades of intensive investigation. This predicament may
be remedied by developing an assessment approach that
supplements typical symptom-based diagnosis with laboratory measures likely to be more direct manifestations of
the genetic pathophysiology of schizophrenia (e.g., psychophysiological deviations, cognitive deficits). These
measures are less susceptible to problems that commonly
plague clinical assessment, namely the characterization of
a syndrome based on consensus expertise, which provides
a valuable but imperfect prototype, and the subjective
evaluation of symptoms using information gained from
often unreliable patient sources.
We are arguing not that conventional diagnostic measures be replaced but rather that they be supplemented
with laboratory measures that have been identified as tapping the genetic diathesis for one or more schizophrenia
variants. There is now ample evidence from multiple
sources that the relatives of schizophrenia patients are
deviant on various laboratory measures. It is time to use
this information to fuller advantage to assist in the assessment of schizophrenia. As a first step, we recommend
more routine inclusion of these measures in schizophrenia
The At Issue section of the Schizophrenia Bulletin contains viewpoints and arguments on controversial issues.
Articles published in this section may not meet the strict
editorial and scientific standards that are applied to major
articles in the Bulletin. In addition, the viewpoints
expressed in the following article do not necessarily represent those of the staff or the Editorial Advisory Board of
the Bulletin.—The Editors.
Abstract
Traditionally, the diagnosis of schizophrenia has
depended on the presence of specific behavioral phenomena assessed by way of behavioral observation
and patient symptomatic report. Even though the
introduction of explicit diagnostic criteria and structured interviews has improved the reliability of schizophrenia diagnosis, it is still unclear how best to define
schizophrenia in order to further etiologic research.
This situation persists despite ample evidence that
schizophrenia is a heritable brain disorder and the
existence of laboratory measures that tap into this
neurobiological genetic diathesis. We contend that
such laboratory measures can be used to supplement
traditional clinical assessment in order to improve the
definition of schizophrenia, thereby enhancing
research into schizophrenia's origins. Ultimately, this
increased understanding of the disorder's etiology
should facilitate the development of targeted therapeutic interventions.
Keywords: Assessment, reliability, validity, etiology, diathesis, endophenotype.
Schizophrenia Bulletin, 29(3):405-^ll, 2003.
The face of schizophrenia has changed many times since
the days of Kraeplin's "dementia praecox." Change is positive and progressive, isn't it? If the outcome of these
changes is evaluated by the principal standards of clinical
judgment, reliability, and validity, one might wonder. Reli-
Send reprint requests to Dr. W.G. lacono. Department of Psychology,
University of Minnesota, 75 East River Road, Minneapolis, MN 55455;
e-mail: [email protected].
405
Schizophrenia Bulletin, Vol. 29, No. 3, 2003
Conldin and Iacono
research protocols. Just as structured interviews are used
regularly to assess DSM symptoms of schizophrenia,
promising genetically informative laboratory measures
should be used whenever possible. And just as specific
behavioral symptoms are often related to dependent variables of interest, laboratory measures can be examined for
their association with relevant dependent variables. Taking
these steps will enhance the understanding of schizophrenia and the associated laboratory measures, ultimately
leading to refinements in their application as assessment
aids. While future research is warranted, there is considerable emerging evidence supporting the construct validity
of many such laboratory measures. This includes demonstrations of moderate to high levels of familial specificity,
specificity to underlying central nervous system (CNS)
processes shared by different disorders, enhanced sensitivity and reliability, and indications of etiologic relevance.
Just as is the case for traditional symptoms of schizophrenia (e.g., auditory hallucinations and delusions), the
specificity of many candidate laboratory measures is low
or unknown. However, there is emerging evidence that
some laboratory measures demonstrate familial specificity
such that deviant performance aggregates in the family
members of only patients with a particular diagnosis.
While it is true that patients with different diagnoses
sometimes show deficits on the same measure, these
deficits may represent "phenocopies" that result from
acute episodic features or treatment effects (e.g., antipsychotic drugs). However, demonstration of deficits in the
well relatives of only one diagnostic group suggests specificity of disorder vulnerability, such as underlying neuropathology. The relatives of schizophrenia patients have
been shown to demonstrate impairment on multiple laboratory measures for which the relatives of affective
patients, with or without psychosis, demonstrate normal
performance (e.g., eye-tracking dysfunction, as reviewed
in Levy et al. 1993 and Iacono 1998; and selective cognitive deficits, including impaired memory, Kremen et al.
1998, and attention, Squires-Wheeler et al. 1997 and Kremen et al. 1998). Although the well relatives of schizophrenia patients have been found to be deviant on many
laboratory measures, familial specificity has been investigated for only a few measures. Many more empirical
investigations comparing the relatives of schizophrenia
and nonschizophrenia patients are needed, given that this
is a relatively unexplored research area with great potential for informative findings.
In addition to familial specificity, laboratory measures
may demonstrate specificity for a biological process or
mechanism that is shared by different disorders, thus
reducing diagnostic specificity. However, measures that
tap a physiological process shared by multiple disorders
still provide useful information about disorder vulnerability. For example, prefrontal dysfunction is a well-docu-
mented feature of schizophrenia. Consequently, schizophrenia patients have been shown to be impaired on a
range of putative frontal lobe cognitive tasks and to
demonstrate accompanying abnormalities in cerebral
blood flow. New evidence suggests that a functional polymorphism in the catechol-O-methyltransferase gene, a
coding region for an enzyme that metabolizes released
dopamine, may partially contribute to group differences in
frontally mediated cognition and frontal lobe efficiency
(Egan et al. 2001). Furthermore, there is evidence that this
genetic variation is associated with increased liability for
schizophrenia. Even though this liability is unlikely to be
specific to schizophrenia, these findings reveal an important mechanism by which genetic differences can be translated into differences in neurochemical regulation and
cognitive performance that may, in rum, increase risk for
psychopathology. In general, it may be impractical to think
that current diagnostic categories are in one-to-one correspondence with nature. The discovery of biological mechanisms underlying psychopathology is more likely to revolutionize psychiatric diagnosis than reveal hundreds of
types of unique neuropathological variants, each mapping
onto a specific DSM diagnosis.
The sensitivity of laboratory measures equals or
exceeds that of many traditional schizophrenia symptoms.
For instance, according to a summary derived by
Andreasen and Flaum (1991) from six samples of schizophrenia patients, the sensitivity of first rank symptoms
ranges from 0.04 to 0.42, with an overall average of 0.21.
This is considerably lower than the sensitivity of smooth
pursuit eye-tracking deficits (0.45-0.80; Holzman 2000),
high antisaccade error rate (0.70; McDowell et al. 1999),
and spatial working memory deficits as measured by
delayed response tasks (0.71; Snitz et al. 1998).
In addition to having a higher sensitivity, these laboratory measures have the advantage of being more reliably
assessed than many traditional schizophrenia symptoms.
For instance, Andreasen and Flaum (1991) reported moderate to low median interrater reliabilities for key symptoms such as incoherence (0.57), loose associations (0.57),
thought broadcasting (0.48), and bizarre delusions (0.44).
Eye-tracking measures typically have interrater reliabilities over 0.90 and have also been shown to have high 9month to 2-year test-retest reliabilities (Iacono and Lykken
1981; Gooding et al. 1994). There is also evidence for
moderate test-retest reliability for some cognitive measures in schizophrenia patients (Park et al. 1999) and their
unaffected relatives (Faroane et al. 1999).
Finally, many laboratory measures appear to have etiologic relevance because they are trait characteristics (e.g.,
remitted patients demonstrate deviant smooth pursuit eye
tracking, Iacono et al. 1982; high antisaccade error rates,
Curtis et al. 2001; and impaired spatial working memory,
Park et al. 1999) that can be measured in well relatives
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(e.g., 25-40% of relatives demonstrate deviant smooth
pursuit eye tracking, Holzman 2000; 25-50% high antisaccade error rates, McDowell et al. 1999; and 40-50%
impaired spatial working memory, Park et al. 1995).
Rather than merely indexing events occurring during an
acute psychotic episode (e.g., active psychotic symptoms)
or factors associated with chronic mental illness (e.g.,
medication status, frequent hospitalization), these measures appear to be tapping stable disorder vulnerability.
Therefore, they have distinct advantages over traditional
symptoms that vary with clinical state and episode. By
ignoring measures with demonstrated construct validity,
researchers fail to take advantage of valuable tools for
refining the definition of schizophrenia, improving diagnostic accuracy, increasing the understanding of the disorder's etiology through research, and ultimately developing
targeted therapeutic interventions.
Defining Schizophrenia: Making Waves
or Treading Water?
In the past 3 decades, schizophrenia researchers have used
over a dozen diagnostic approaches to define schizophrenia, including four editions of DSM, three World Health
Organization ICD systems, and multiple research diagnostic approaches (e.g., CATEGO, Wing et al. 1974; criteria
of Feighner et al. 1972; flexible system, Carpenter et al.
1973; RDC, Spitzer et al. 1978). These various diagnostic
approaches do not simply provide different ways of identifying the same individuals; they identify different individuals. For instance, in an epidemiologic study of 175
patients succumbing to their first lifetime episode of psychosis, Iacono and Beiser (1992) found that the least
restrictive of five diagnostic approaches identified almost
three times as many psychotic patients as having schizophrenia as the most restrictive approach. However, all
those identified as satisfying the criteria for schizophrenia
using the narrowest definition also satisfied the criteria for
the broadest definition. This latter finding is important
because it indicates that although various diagnostic
approaches identify different individuals, narrowly diagnosed schizophrenia identifies a core group of individuals
who would be regarded as having the disorder under most
diagnostic formulas.
Over this 3-decade span, the criteria that have come to
be favored for diagnosing schizophrenia have clearly narrowed. For instance, the once popular schizoaffective subtype of schizophrenia as included in DSM—II (American
Psychiatric Association 1968) has been eliminated, as has
the notion of "acute" schizophrenia. These changes, most
evident in the evolution of the DSM system and now
embraced by DSM-IV (American Psychiatric Association
1994), have reduced the likelihood that a psychotic person
407
will receive a schizophrenia diagnosis and have effectively
redefined schizophrenia as a chronic disorder. There has
also been greater emphasis on the diagnostic significance
of bizarre delusions (i.e., beliefs that the person's culture
would regard as totally implausible), negative symptoms
(i.e., avolition, affective flattening, and alogia), and compromised social-occupational adjustment. In addition,
since the introduction of DSM-III (American Psychiatric
Association 1980), the diagnosis of schizophrenia has
hinged on ruling out other disorders, most notably affective psychosis.
Although the community of schizophrenia researchers
has broadly embraced these changes, demonstrating how
the validity of the diagnosis has improved would be difficult. In fact, such a demonstration would necessitate a preconceived notion (or theory) of schizophrenia. For
instance, if one believes that schizophrenia is essentially a
chronic illness, with a heavy genetic loading and poor outcome, evidence for the validity of narrowly diagnosed
schizophrenia can be found (e.g., Cardno et al. 1999; Harrow et al. 2000). However, if one believes that schizophrenia is an episodic disorder that is strongly influenced by
psychosocial factors and may include a prominent affective component, acute forms, or variable outcome, the
same research findings reduce confidence in modem definitions.
Despite the narrowness of the DSM-IV definition,
schizophrenia remains phenotypically heterogeneous. For
instance, this diagnosis can be made if the only psychotic
symptom is a bizarre delusion, if nonbizarre delusions cooccur with hallucinations, or if in the absence of any delusions or hallucinations only disorganized speech and negative symptoms are present. We know of no research that
shows that these phenotypically distinct forms of schizophrenia are likely to be alternate manifestations of the
same underlying etiologic process or that schizophrenia is
defined as well by one of these phenotypes as it is by the
other two. With the possible exception of the paranoid
subtype, even the traditional Kraepelinian subtypes of
schizophrenia, which further point to its phenotypic diversity, have negligible construct validity.
Many schizophrenia researchers believe that individuals diagnosed with schizophrenia, even under DSM-lYs
narrow criteria, are not only phenotypically heterogeneous
but also etiologically heterogeneous. In the worst-case
scenario, the situation could be similar to that revealed by
research into mental retardation. What was once viewed as
a unified syndrome is now known to arise from a range of
etiologic causes that vary substantially in the degree to
which they are heritable or environmentally determined.
Needless to say, the treatment of an etiologically heterogeneous group as a single syndrome has dire consequences
for the understanding of what schizophrenia is and how it
is best treated. No matter how feverishly scientists search
Conklin and Iacono
Schizophrenia Bulletin, Vol. 29, No. 3, 2003
for the cause(s) of schizophrenia, findings will be confounded by a study sample consisting of members for
whom the underlying cause is not the same. In the clinical
realm, there is no reason to suppose that two syndromes
with similar presentation but different causes would
respond to the same treatment or follow the same prognostic course. While it would be premature to treat a person
based on the results of a laboratory test alone, ultimately,
combining test results with traditional diagnostic signs
should enhance the selection of treatment methods. Thus,
having the assessment tools needed to identify an etiologically homogeneous schizophrenia group would be highly
advantageous.
by first selecting individuals who meet standard criteria
for narrowly diagnosed schizophrenia and subsequently
focusing on patients who exhibit a given endophenotype.
This strategy increases the probability that identified individuals will share the same genetic variant predisposing to
schizophrenia.
Endophenotypes offer distinct advantages over the
behavioral phenomena upon which traditional psychological assessment depends. Reliance on endophenotypes
enhances assessment objectivity and provides a diagnostic sign that tends to be closer to the suspected etiologic
cause (e.g., genes, neuropathology) than behavioral displays do. Unlike positive and negative symptoms, which
show little evidence of heritability (Cardno et al. 2001),
many candidate endophenotypes have been shown to be
heritable (e.g., Cannon et al. 2000fc; Katsanis et al. 2000;
Malone and Iacono 2002). Because endophenotypes
reflect the byproduct of genetically influenced CNS
processes, finding genes for endophenotypes is likely to
provide insights into the etiology of associated disorders.
There are already published reports of association
between particular endophenotypes and genetic loci,
including eye-tracking dysfunction and chromosome 6p
(Arolt et al. 1996) as well as the P50 cerebral electrophysiological measure and chromosome 15q (Freedman
et al. 1997). Thus, using endophenotypes cuts out some
of the factors mediating between cause and outcome, so
fewer intervening variables need to be considered and
accuracy of classification improves. The following
example demonstrates this critical point.
It is likely that brain abnormalities represent an
intermediate step between the underlying genetic predisposition to schizophrenia and symptomatic presentation
(see, e.g., Meehl 1989). Therefore, cognitive testing may
be useful for identifying neuropathological correlates of
genetic risk for schizophrenia. Profiles of cognitive
deficits may be used to develop an endophenotypic
marker that identifies a homogeneous group of individuals with schizophrenia. Over the past 20 years, there has
been a proliferation of research indicating neuropsychological deficits in schizophrenia patients and their first
degree relatives. Most consistently, these deficits have
been in abstraction, auditory attention, and verbal memory (e.g., Faroane et al. 1995). Specific cognitive deficits
also provide useful information about the pathophysiology of schizophrenia. For example, spatial working
memory is impaired in schizophrenia, perhaps reflecting
dysfunction involving the dorsolateral prefrontal cortex
(e.g., Park et al. 1995). While standard clinical assessment may detect working memory deficits in schizophrenia patients as they are manifested in disorganized
speech or behavior, it is clear that structured neuropsychological examination would more directly and reliably
assess this deficit.
Resolving Diagnostic Ambiguity: Use of
Laboratory Measures as
Endophenotypes
The best lead regarding the etiology of schizophrenia
stems from well-replicated family, twin, and adoption
studies that support a significant genetic predisposition
for the development of this disorder (Gottesman 1991).
One way to improve homogeneity is to assess traits
derived from laboratory measures that are likely manifestations of this predisposition. These traits are
endophenotypes—stable, heritable, quantifiable, endogenous characteristics that identify genetic risk. Unlike
classic phenotypes, which have been developed by
observing and interviewing patients, endophenotypes
must be developed using laboratory measurement of
traits in the healthy biological relatives of affected individuals. These family members can be expected to share
endophenotypic traits that reflect the expression of their
shared genes, provided the genes are "switched on"
before manifest symptoms develop.
Schizophrenia research has provided ample evidence
that predisposing genes are in fact switched on (Cannon et
al. 2000a; Erlenmeyer-Kimling 2001). Accordingly, there
are deviant characteristics in schizophrenia relatives that
serve as candidate endophenotypes, including smooth pursuit eye tracking (Holzman 2000), antisaccade task performance (McDowell et al. 1999), working memory (Park
et al. 1995), information processing (Green et al. 1997),
and conventional neuropsychological (Cannon et al. 1994,
2000) and cerebral electrophysiological (Freedman et al.
2000) measures. The ideal endophenotype would be
highly specific to schizophrenia, thus obviating the need
for an interview-based assessment. However, because no
single putative endophenotype has this degree of specificity, endophenotypes must be used in conjunction with
each other and existing diagnostic criteria to improve classification accuracy and resolve diagnostic ambiguity. The
problem of etiologic heterogeneity is in effect sidestepped
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Schizophrenia Bulletin, Vol. 29, No. 3, 2003
demonstration of deficient sensory gating as indicated by
failure to modulate response amplitude to paired stimuli in
startle and event-related potential paradigms (e.g., Yee et
al. 1998). Similar deficits are now being identified in well
relatives of schizophrenia patients, and meaningful interrelations between these variables are being explored. As
the second century of schizophrenia research begins,
researchers are armed with new technology, such as highresolution structural and functional neuroimaging, and the
recent mapping of the human genome. The pace of schizophrenia research will likely accelerate.
Over 20 years ago Pope and Lipinski (1978, p. 826)
wisely said, "The chronically confused state of research of
schizophrenia may partially be owed to an illusory faith in
the significance of the symptoms and consequent delay in
finding more adequate definitions for its own subject matter." Are researchers still functioning under the same
guise? Has having a reliable diagnostic system encouraged
complacency, even though the system may fail to convey
meaningful information or capitalize on recent discoveries? For many decades, medical researchers have incorporated empirically substantiated laboratory measures into
their disease definitions. Is it not time that psychopathology researchers follow suit?
Conquering Complacency: Future
Directions in Schizophrenia Assessment
Because most researchers agree that schizophrenia is a
brain disorder that may be neurodevelopmental in origin,
it makes sense to take cues from neurology in designing an
assessment plan. For example, in assessing Parkinson's
disorder, multiple levels of information are combined to
arrive at a diagnosis. Neurologists gather a history of presenting symptoms such as tremors, rigidity, and bradykinesia; observe behavior such as motoric difficulties and
personality changes; may consult with a neuropsychologist to evaluate cognitive changes such as reduced attention span and confusion; and may review imaging results
to rule out other neurodegenerative disorders. This should
be how psychosis is assessed in the future. It will be
imperative that differential diagnoses critical to the accurate assessment of schizophrenia involve the traditional
approach, including patient report, behavioral observation,
family history of mental illness, and prior medication
response, as well as more innovative approaches based on
cognitive ability, neuroimaging results, and psychophysiological measures. The results will not only continue to
improve diagnostic reliability but also offer a more valid
approach to identifying an etiologically homogeneous subgroup of patients. These advances in turn will facilitate
research, diagnostic definition refinement, and targeted
therapeutic intervention development (e.g., through medications that ameliorate identified physiological dysfunctions or cognitive rehabilitation to combat identified cognitive deficits).
When we talk of the changing face of schizophrenia
we are referring to its packaging rather than its core, which
has changed little over the past century. By focusing on the
core instead of continually rearranging the packaging,
researchers have the best chance to make real headway in
unraveling schizophrenia's etiology. When research findings are used to refine the core, one or more neurobiologically homogeneous subsets of individuals with the greatest
promise of yielding etiologic insight may be identified.
Toward this end, there are many reasons to be optimistic. Over the past century, important discoveries have
been made with regard to crucial pieces of the etiologic
puzzle of schizophrenia. Prominent among these findings
are the establishment of a genetic basis for schizophrenia,
support for dysfunctional eye tracking as an indicator of
this genetic diathesis (e.g., Iacono and Clementz 1993),
indications that schizophrenia is a neurodevelopmental
disorder (e.g., Weinberger 1987), evidence for frontal lobe
dysfunction in disorder pathophysiology (e.g., Katsanis
and Iacono 1991; Snitz et al. 1998; Conklin et al. 2000),
elucidation of attentional disturbances on continuous performance tasks (e.g., Nuechterlein and Dawson 1984), and
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Heather M. Conklin, M.A., is a graduate student in clinical
psychology, Department of Psychology, and William G.
Iacono, Ph.D., is Distinguished McKnight University Professor and Professor of Psychology and Neuroscience,
University of Minnesota, Minneapolis, MN.
411
Minority Research Training in Psychiatry
Through a five-year, $2.5 million grant from the National Institute of Mental Health, the
American Psychiatric Institute for Research and Education (APIRE) is seeking through the Program
for Minority Research Training in Psychiatry (PMRTP) to increase the number of minority psychiatrists entering the field of psychiatric research.
The program provides medical students with funding for stipends, travel expenses, and tuition
for an elective or summer experience in a research environment, with special attention paid to
trainees' career development in research. In addition, stipends are available for a limited number of
one- or two-year postresidency fellowships for minority psychiatrists. Residents may engage in fullyear research training during the last year of psychiatric residency or in "year off' research training.
Training takes place at research-oriented departments of psychiatry in major U.S. medical
schools and other appropriate sites throughout the country. An individual at the site (the research
"mentor") is responsible for overseeing the research training experience.
Administered by the American Psychiatric Institute for Research and Education, the program
includes outreach efforts to identify minority medical students and residents who are potential
researchers and to put them in touch with advisors who counsel them about careers in psychiatric
research. Additional activities assist fellows and alumni in their research career development.
The director of the PMRTP is James Thompson, M.D., M.P.H.; the project manager is Ernesto
Guerra. An advisory committee of senior researchers and minority psychiatrists developed guidelines for applicants and criteria for selection. The members of this committee evaluate and select
trainees, oversee the research training experiences, and play a role in evaluating the effectiveness of
the program.
December 1 is the deadline for applications for residents seeking a year or more of training and
for postresidency fellows. For medical students, applications are due three months before training is
to begin. Summer medical students who will start their training by June 30 should submit their
applications by April 1.
For more information about the PMRTP, call the toll-free number for the PMRTP, 1-800-8521390, or 202-682-6225, e-mail [email protected], or write to PMRTP at the American Psychiatric
Institute for Research and Education, 1400 K Street, NW, Washington, DC 20005.