SYMPTOM ASSESSMENT IN SCHIZOPHRENIC PRODROMAL STATES

SYMPTOM ASSESSMENT IN SCHIZOPHRENIC
                   PRODROMAL STATES
          Tandy J. Miller, Ph.D., Thomas H. McGlashan, M.D.,
Scott W. Woods, M.D., Kelly Stein, Ph.D., Naomi Driesen, Ph.D.,
          Cheryl M. Corcoran, M.D., Ralph Hoffman, M.D., and
                                          Larry Davidson, Ph.D.

Individuals who develop schizophrenia often suffer long standing deficits. All too
often available treatments remain palliative and do not improve the long-term
course of illness. The neurobiological deficits associated with the onset of schizo-
phrenia may be most active and damaging in the early stages of this life long
illness, a fact which has shifted the focus of research and clinical work toward
the early or prodromal stages of this disorder. Results from limited studies sug-
gest that early intervention may lead to a better prognosis. Early interventions
that could delay or prevent the onset of psychotic illnesses have obvious public
health implications and rely on being able to identify true prodromal patients.
The Structured Interview for Prodromal Symptoms and the Scale of Prodromal
Symptoms are assessment instruments developed for operationally defining di-
agnosis and for quantitatively rating symptom severity for patients prodromal
for psychosis.

                                       INTRODUCTION

Individuals who develop psychotic disorders, such as schizophre-
nia, often suffer severe losses in neurobiological functioning and

  All authors are affiliated with Yale Medical School.
  Address correspondence to Tandy J. Miller, Ph.D., Yale Psychiatric Institute,
P.O. Box 208038, New Haven, CT 06520-8038.
PSYCHIATRIC QUARTERLY, Vol. 70, No. 4, Winter 1999
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deterioration in quality of life (1). Although current treatments,
such as antipsychotic medication, family support, psychoeduca-
tion, and continuity of care have proven to be effective in outcome
studies, these treatments remain palliative and usually do not
improve the long-term course of the disease (2). Once individuals
develop a psychotic illness, they struggle with chronic deficits and
remain vulnerable to relapse throughout their lifespan. Unknown,
but often irreversible, neurobiological deficit processes are associ-
ated with the development of this disorder, are often responsible
for major losses of functioning, and are understood to be most
active in the earliest stages of these life long illnesses (3). Accord-
ingly, research very recently has shifted focus to the early course
of disorder.
   One of the most consistent correlations from this perspective
has been that the earlier post-onset individuals receive neurolep-
tic treatment, the better their short and long term prognosis
(4-11). A few clinical research studies have explored whether in-
tervention prior to onset, in the prodromal stage of the illness,
may alter the natural course of the disorder. One study applied
family psychoeducation, long-term monitoring, and conservatively
prescribed antipsychotic treatments to patients who were judged
to be in a prodromal phase of a psychotic illness in an English
County (12,13). The initiative was associated with a dramatic
drop in the rate of schizophrenia from 7.4 to 0.75 per 100,000
people per year during the four years of the study, suggesting that
early intervention at a prodromal or pre-psychotic stage of illness
could prevent or delay the onset of full-blown psychosis.
   Researchers from Australia have organized programs in the
last 5 years that focus on the early course of psychosis (14,15).
Most recently this group has developed a program for assessing
and treating young people believed to be at imminent risk for the
development of psychosis. In fact when they followed these young
people whom they had diagnosed as prodromal for psychosis, 40%
of their sample became psychotic within one year of evaluation
(16).
   To accomplish this highly successful rate of identification of pro-
dromal patients, they operationally defined three states of the
prodrome that appear to have predictive validity and power (16-
18). Group 1 patients report nonspecific anxiety and/or depressive
symptoms, a recent loss of at least 30 Global Assessment of Func-

TANDY J. MILLER ET AL.                                           275

tioning (19) points, and a first degree relative diagnosed with a
DSM IV (20) schizophrenia spectrum disorder. Group 2 patients
report recent onset of at least one attenuated psychotic symptom
from the DSM IV Schizotypal Personality Disorder criteria of
ideas of reference, odd beliefs or magical thinking, perceptual
disturbance, odd thinking and speech, paranoid ideation, and be-
havior or appearance. Group 3 patients demonstrate transient
psychotic symptoms including hallucination, delusion, or disorga-
nized speech for less than one week before spontaneous reso-
lution.
   The Australian investigators followed this operational defini-
tion, of prodromal patients at high risk for onset, with a clinical
trial of antipsychotic and psychosocial treatment versus no treat-
ment in the same type of sample. By July of 1998, approximately
20 patients had been randomized to each cell and twice as many
patients from the no treatment group had converted to psychosis
(McGorry, Personal Communication, July, 1998). Though prelimi-
nary, these data highlight a new potential for prevention in psy-
chosis. The foundation of this pivotal development has been the
ability to operationally define a truly high risk prodromal patient.
This work represents a paradigmatic shift to research focused on
the pre-psychotic phase of schizophrenia. Prior to this, pre-onset
treatment was not considered feasible or ethical because the pro-
dromal phase was too nonspecific and the risk/benefit ratio of
treatment was tilted too much toward risk.
   These efforts at the very early application of existing treat-
ments for schizophrenia have provided enough scientifically com-
pelling and therapeutically promising evidence to support a clini-
cal trial that is currently being conducted at Yale University's
PRIME Research Clinic (Prevention through Risk Identification,
Management, and Education). The aim of the research is to test
active medication (one of the new, atypical antipsychotics) versus
placebo in delaying or averting the transition from a prodromal
state to a full blown, psychotic episode. Modeled after the Austra-
lian description of prodromal types, a diagnostic semi-structured
interview, the Structured Interview for Prodromal Symptoms
(SIPS), and a severity scale, the scale of Prodromal Symptoms
(SOPS), have been designed to define, diagnose, and measure
change systematically in individuals who may be in a pre-psy-
chotic state (21).

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   The double blind placebo structure of The PRIME prevention
clinical trial provides an opportunity to study a population that,
with the exception of the current Australian research, has never
been studied prospectively. The symptom scores from the SOPS
can be tested for their value in predicting the individuals who go
on to convert to a frank psychotic disorder. The examination of
these illnesses while they are developing is particularly important
because the participants, their families and others around these
individuals are likely to be frightened and to distort retrospective
accounts of the pre-onset stage of the illness. In addition, the
growing acknowledgement of clinicians and researchers regarding
the importance of this stage of the illness, has fuelled the need to
operationalize the description of these patients.
   Early interventions that may delay or prevent the onset of psy-
chotic illnesses and their devastating effects have obvious public
health implications. These strategies rely on being able to identify
true positive prodromal patients. The SIPS and the SOPS are di-
rected toward extending the progress made by the Australian re-
searchers who have provided a beginning prodromal nosology pre-
dictive of schizophrenia.

       SCALE DEVELOPMENT AND DESCRIPTION

In developing these instruments, available descriptions were re-
viewed that used retrospective and prospective assessments to
characterize or identify the prodromal state. (17, 18, 22-24). The
scales were organized thematically to develop operational defini-
tions and rating anchors for the prodromal stages and psychosis.
The current instrument is modeled after the Positive and Nega-
tive Syndrome Scale (PANSS) (25) with modifications of the posi-
tive symptom scales to provide more breadth and detail of scoring
within the lower, pre-psychotic, ranges of severity. The first goal
of the SIPS and the SOPS is to provide a systematic measure of
the presence/absence of prodromal states as outlined above by the
Australians. The second goal is to measure the severity of prodro-
mal symptoms cross-sectionally and longitudinally, and the third
goal is to define the threshold of psychosis operationally.
   The SOPS (Figure 1) consists of five Positive Symptom items,
six Negative Symptom items, four Disorganization Symptom

TANDY J. MILLER ET AL.                                   277

         FIGURE 1. Scale of Prodromal Symptoms (SOPS).

278                        PSYCHIATRIC QUARTERLY

      FIGURE 1. (Continued.)

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                         FIGURE 1. (Continued.)

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      FIGURE 1. (Continued.)

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                         FIGURE 1. (Continued.)

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      FIGURE 1. (Continued.)

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                         FIGURE 1. (Continued.)

items, and four General Symptom items. Each item has a severity
scale rating from 0 (Never, Absent) to 6 (Severe/Extreme—and
Psychotic, for the positive items). The severity of the prodromal
state is judged according to the sum of the ratings from each of
the SOPS items and ranges from 0 to 114. Thus, there are sever-
ity ratings for the overall scale, each domain of pathology, as well
as individual items. The SIPS (available by request from the au-
thors) includes 29 major probes organized according to each posi-
tive symptom item in the SOPS. In the SIPS, patients are also
rated according to their Global Assessment of Functioning (19)
(GAF), a DSM IV Schizotypal Personality Disorder criterion
checklist (20), and family history of mental illness. Diagnosis is
accomplished using the Criteria for Prodromal States (COPS,
modeled after the criteria used by the Australians and outlined
above). The SIPS is used to determine the presence or absence of
the prodromal state, the type of prodromal state, and the presence
or absence of a psychotic state, and it includes the SOPS and the
COPS. The SOPS is used independently to determine the severity
of the prodromal state once such a state has been diagnosed.
   The diagnosis of a prodromal state in two of the Australian cat-
egories is based on the development of positive symptoms. Posi-
tive Symptom scores on the SOPS in the 1 to 2 range are consid-
ered non-prodromal. Scores of 6 are considered psychotic. Scores
in the 3 to 5 range are considered at a prodromal level and would
then be evaluated according to the frequency criteria outlined in
the COPS to determine a diagnosis.

                         PRELIMINARY DATA

The PRIME Research Clinic has interviewed and identified 15 in-
dividuals to date who are judged to be at risk for psychosis; of

284   PSYCHIATRIC QUARTERLY

TANDY J. MILLER ET AL.                                                       285

those, 10 have been randomized into the clinical trial. The avail-
able means and standard deviations for all SOPS items of those
 13 meeting criteria an attenuated prodromal positive state are
depicted in Figure 2. Of the 10 randomized individuals, 3 have
converted to psychosis. One male patient left the study prior to
his conversion, but allowed us to collect follow-along data. He de-
veloped Bipolar Disorder. Of the other two individuals who con-
verted, one woman, who converted to Schizophrenia, was admit-
ted into the study with a total SOPS score of 44 and had an
elevated total SOPS score of 56 upon conversion. The other sub-
ject who converted had a total SOPS score of 58 upon admission
and a total SOPS score of 68 at the time of his conversion to
Schizophrenia. In addition, one woman who was diagnosed as pro-
dromal, after turning down participation in the study, went on to
convert to a frank schizophrenic psychosis. Although, very prelim-
inary, our experience of rate of conversion appears to be consis-
tent with that of the Australian investigators.

                        FUTURE DIRECTIONS

The SIPS and SOPS are recently developed instruments to serve
the study and treatment of a new clinical population, the high
risk or pre-psychotic patient. Initial experience supports their
utility and validity. Future efforts are underway to refine anchor
points for the Negative, Disorganized, and General domains of
psychopathology and to demonstrate that inter-rater reliability
can be established.

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