Editor's Note: A symposium on Friday, 30 March 2007, at the International Congress on Schizophrenia Research in Colorado Springs, detailed progress in prodromal research. Wendy Hasenkamp, from the Atlanta VA/Emory School of Medicine, reports here on "The North American Prodrome Longitudinal Study: a multi-site approach to prodromal schizophrenia research."
22 April 2007. Studies show that early treatment of psychosis is related to improved clinical outcome in schizophrenia (McGlashan, 1988; 1998; also see SRF related news story). The critical time period before the onset of psychosis during which functional impairments emerge and attenuated symptoms may be identified is known as the schizophrenia prodrome. The prodrome is characterized by symptoms such as cognitive impairments, marked social and/or behavioral decline, and changes in affect (emergence of anxiety and depression). In hopes of improving the possibility of early detection and intervention, as well as furthering our understanding of the developmental process underlying psychotic disorders, research has recently intensified in the once-controversial area of the schizophrenia prodrome (an SRF related news story summarizes some recent developments in this field). In 2004, principal investigators for eight research projects in the U.S. and Canada agreed to combine data on psychosis risk factors and clinical outcomes for nearly 900 subjects enrolled in prodromal schizophrenia research programs. This consortium, known as the North American Prodrome Longitudinal Study (NAPLS) is under the direction of Robert Heinssen at the NIMH (Addington et al., 2007). The 10 participating investigators are Jean Addington (University of Toronto), Kristin Cadenhead and Ming Tsuang (UCSD), Tyrone Cannon (UCLA), Barbara Cornblatt (Zucker Hillside Hospital), Thomas McGlashan and Scott Woods (Yale University), Diana Perkins (UNC Chapel Hill), Larry Seidman (Harvard University), and Elaine Walker (Emory University). The NAPLS symposium at ICOSR marked the second time that the consortium has presented its early findings, the first being in Birmingham, England, last October at the 5th International Conference on Early Psychosis.
Jean Addington served as chair, and began the symposium with an overview of the consortium’s methods and operational definitions. To ensure comparability of data across the eight sites, all NAPLS researchers use the same diagnostic criteria to identify individuals with prodromal symptoms. The Structured Interview for Prodromal Syndromes (SIPS; Miller et al., 2003), created by Thomas McGlashan, was employed to rate each subject on the degree of severity of five classes of symptoms: unusual thought content/delusional ideas, suspiciousness, grandiosity, perceptual abnormalities, and conceptual disorganization. Based on SIPS scores, the consortium has identified three prodromal syndromes: attenuated psychotic symptoms (APS), genetic risk plus deterioration (GRD), and brief intermittent psychotic symptoms (BIPS). Addington then described how the current NAPLS subjects were divided into six groups: individuals believed to be at heightened risk for psychosis (HRP); those at genetic high risk but without prodromal symptoms; those who meet criteria for schizotypal personality disorder but do not display prodromal symptoms; those who have already developed psychotic symptoms; and two comparison groups, those who failed to meet criteria for being at elevated risk (helpseekers), and non-psychiatric controls. Having explained the basic approach of the consortium, Addington turned the floor over to three NAPLS members who detailed more specific questions being asked about this interesting prodromal subject population.
Sifting through these many abbreviations adopted by NAPLS to describe syndromes and subgroups, Tyrone Cannon discussed the rate of conversion to psychosis within the sample. Conversion was defined as one or more positive symptoms reaching the psychotic level of conviction, frequency, and duration (>1 hour/day for 4 or more days within the past month) and impact (disorganizing or dangerous). Among the HRP subjects, risk for conversion was 17 percent per year, with an ultimate conversion rate of 35 percent after 30 months of follow-up. Delving deeper, Cannon explained his efforts to improve our ability to predict the likelihood of conversion for a given individual based on initial risk factors. His group identified five variables (a mixture of SIPS scores and clinical, neurocognitive, and historical variables assessed at baseline) as being the most important for successful for prediction: genetic risk with decreased functioning, unusual thought content, suspicion/paranoia, level of social functioning, and drug use of any kind. Using a single-variable model, the positive prediction power reached 50 percent; Cannon suggested that about 80 percent would be needed to justify pre-emptive intervention programs. However, when more variables were added to the model, positive predictive power improved. Models incorporating two out of five symptoms reached up to 69 percent, while three out of five symptoms yielded up to 74 percent. However, gains in predictive power were achieved with corresponding losses in sensitivity of the models. While still a work in progress, these findings suggest that NAPLS efforts are resulting in improved risk ascertainment algorithms, which may help identify individuals for early intervention.
Barbara Cornblatt continued the discussion by describing her work on relating the duration of prodromal symptoms to clinical outcome. To determine the outcome associated with earlier-appearing symptoms, she compared two similar subject groups. The first comprised 357 individuals who, based on SIPS criteria, displayed moderate to severe attenuated positive symptoms for 12 months or less (APS); the second group was 100 subjects who met the same SIPS criteria, but had a longer duration of symptoms (long duration prodromals, LDP). She found that after 30 months, the APS group had a conversion rate of 38 percent compared to only 14 percent in the LDP group. However, she noted the caveat that LDP subjects were younger and more functionally impaired than APS subjects, but had a lower degree of severity of positive symptoms. This suggests that the LDP group may be at an earlier phase of illness and conversion rates may increase with continued follow-up. Cornblatt concluded that while this study gave strong support for the predictive validity of the APS syndrome as defined by the SIPS, the results also suggest that LDP may be a risk group of its own, and perhaps a longer risk window should be incorporated into future prodromal studies.
The last NAPLS member to speak at the symposium was Diana Perkins, who focused on the development of various functional impairments throughout the prodrome. In order to compare data on functional outcomes across sites, Cannon and Cornblatt have developed two 10-point scales rating social (Global Social Functioning Scale, GSFS) and vocational (Instrumental Role Functional Scale, IRFS) functioning (Cornblatt et al., 2007). Perkins examined the 357 subjects who met SIPS criteria for APS, as well as the 11 subjects who were classified as having BIPS syndrome. Using scores from the new social and vocational functioning sales, she compared these “at-risk” subjects to 196 healthy comparison subjects. She found, as expected, that the at-risk group had lower scores on both the social and vocational functioning scales, as well as lower Global Assessment of Function (GAF) scores, than the healthy controls. Perhaps most importantly, however, the at-risk subjects had experienced a significantly greater decline in function (as measured by the change in scores on the GSFS, IRFS and GAF) than controls in the year prior to analysis. Thus, Perkins suggested that early identification and intervention may be helped by targeting the initial declines in social and vocational functioning that are seen in these at-risk states.
The NAPLS consortium has recently published its rationale, design, and some preliminary findings in Schizophrenia Bulletin (Addington et al., 2007). NAPLS is one of two large collaborative studies of populations at clinical or genetic risk for psychosis; the European Prediction of Psychosis Study (EPOS) is made up of six sites and undertakes similar research in Europe (Klosterkotter et al., 2005). It is thanks to groups like these that we may soon have improved ability to target psychosis and hopefully provide much needed intervention at the early stages of psychiatric disease.— Wendy Hasenkamp.