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 schizophrenia 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 suggest 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 diagnosis and for quantitatively rating symptom severity for patients prodromal for psychosis.

INTRODUCTION Individuals who develop psychotic disorders, such as schizophrenia, 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 0033-2720/99/1200-0273$16.00/0 1999 Human Sciences Press, Inc.

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deterioration in quality of life (1). Although current treatments, such as antipsychotic medication, family support, psychoeducation, 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 associated 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). Accordingly, 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 neuroleptic treatment, the better their short and long term prognosis (4-11). A few clinical research studies have explored whether intervention 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 prodromal patients, they operationally defined three states of the prodrome that appear to have predictive validity and power (1618). Group 1 patients report nonspecific anxiety and/or depressive symptoms, a recent loss of at least 30 Global Assessment of Func-

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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 behavior or appearance. Group 3 patients demonstrate transient psychotic symptoms including hallucination, delusion, or disorganized speech for less than one week before spontaneous resolution. The Australian investigators followed this operational definition, of prodromal patients at high risk for onset, with a clinical trial of antipsychotic and psychosocial treatment versus no treatment 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 preliminary, these data highlight a new potential for prevention in psychosis. 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 prodromal 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 treatments for schizophrenia have provided enough scientifically compelling and therapeutically promising evidence to support a clinical 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 Australian 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-psychotic 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 psychotic 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 directed toward extending the progress made by the Australian researchers who have provided a beginning prodromal nosology predictive of schizophrenia. SCALE DEVELOPMENT AND DESCRIPTION In developing these instruments, available descriptions were reviewed 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 definitions and rating anchors for the prodromal stages and psychosis. The current instrument is modeled after the Positive and Negative Syndrome Scale (PANSS) (25) with modifications of the positive 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 prodromal 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

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FIGURE 1. Scale of Prodromal Symptoms (SOPS).

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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.)

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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/Extremeand 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 severity ratings for the overall scale, each domain of pathology, as well as individual items. The SIPS (available by request from the authors) includes 29 major probes organized according to each positive 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 categories is based on the development of positive symptoms. Positive Symptom scores on the SOPS in the 1 to 2 range are considered 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 individuals to date who are judged to be at risk for psychosis; of

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those, 10 have been randomized into the clinical trial. The available 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 developed Bipolar Disorder. Of the other two individuals who converted, one woman, who converted to Schizophrenia, was admitted into the study with a total SOPS score of 44 and had an elevated total SOPS score of 56 upon conversion. The other subject 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 prodromal, after turning down participation in the study, went on to convert to a frank schizophrenic psychosis. Although, very preliminary, our experience of rate of conversion appears to be consistent 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. REFERENCES
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