26 February 2008. The push for early detection and treatment of schizophrenia has led to definition of the schizophrenia prodrome, a set of risk factors and symptoms that foreshadows the onset of psychosis. People in this stage show diminished functioning and signs of disease that are readily apparent, but not severe enough to trigger a diagnosis of schizophrenia. As a group, people with prodromal symptoms have much higher risk of developing schizophrenia, and about 35 percent will progress to psychosis in a year (McGorry et al., 2002; McGlashan et al., 2006). The challenge, for both treatment and prevention, is to figure out who falls in that one-third, and who are at lower or no risk of disease. Several recent studies have addressed this question from different angles, coming up with some new insights into the outward manifestations of an inward pathology that commences long before a first psychotic episode.
NAPLS reports data
The results of the latest and largest study of prodromal progression appear in the January 2008 issue of the Archives of General Psychiatry. By following 291 patients for two and a half years, the investigators of the North America Prodrome Longitudinal Study (NAPLS, see SRF meeting report) by Wendy Hasenkamp) identified five additional symptoms that, if present at baseline, increase the chances that a person will develop schizophrenia. Including two or three of these variables with the current prodromal criteria improved predictive power to as high as 80 percent, the researchers report.
“These findings demonstrate that prospective ascertainment of individuals at risk for psychosis is feasible, with a level of predictive accuracy comparable to that in other areas of preventive medicine,” writes corresponding author Tyrone Cannon of the University of California in Los Angeles for the group. In addition, the authors say, the findings provide a benchmark against which standardized preventive interventions can be compared.
In the study, which was carried out at eight clinical research centers in the United States, investigators tallied 77 individual potential predictor variables at baseline in the study group. The variables covered 10 domains, including demographics, genetics, social and role functioning, substance abuse, and a range of symptoms. Criteria for entry was based on the Structured Interview for Prodromal Syndromes (SIPS), which emphasized onset or worsening of mild positive symptoms that do not reach the severity of full psychosis, or the presence of brief intermittent psychosis. Participants were reassessed every 6 months for an average of 30 months.
Over the course of the study, 35 percent of the group converted to full psychosis. This translates to a relative risk of 405 compared to the general population, showing that the SIPS criteria are already highly predictive of impending disease. In addition, though, the investigators identified five features that, if present at baseline, contributed to the prediction of psychosis: genetic risk with a recent deterioration in function; higher levels of unusual thoughts; higher levels of suspicion or paranoia; greater social impairment; and history of substance abuse, though no specific substance was implicated. Including two or three of these variables with the current prodromal criteria improved predictive power to 80 percent, but reduced the sensitivity.
The degree of prodromal symptoms was important, too. The findings suggest that the poorer the social function and the more severe the unusual thought content and suspiciousness, the closer the person was to the onset of psychosis.
The idea that the prodrome predicted imminent psychosis was supported by an observation that in this group, onset declined over time. The rate of conversion declined from 13 percent in the first 6 months to 2.7 percent in the last 6 months. “This finding indicates that the prodromal criteria are sensitive to risk for imminent onset and provide an empirical basis on which to time the application of preventive interventions,” the authors write.
In an accompanying commentary, Patrick McGorry of the University of Melbourne in Australia and colleagues, who originally described the schizophrenia prodrome they call the ultra-high-risk (UHR) state, write that the NAPLS confirms the findings of their own “first generation of research.”
McGorry and colleagues go on to take issue with the study, however, because treatment during the study period was not adequately tracked or taken into account. The investigators did note whether patients received treatment or not during the study period, finding that 35 percent of the study participants received antipsychotic medications, and that such treatment was not associated with conversion. Treatment for prodromal symptoms is not standardized, however, and dosing and duration information were not available.
According to McGorry and colleagues, the treatment question is a “key weakness that has been minimized by Cannon and colleagues.” A major limitation of the study, they write, is its naturalistic design. To move the field ahead requires large, international, multi-center trials testing various interventions in the early stages, of the type pioneered on a smaller scale by McGorry's group and by Thomas McGlashan's group at Yale University, New Haven, Connecticut (see SRF related news story). In the meantime, researchers await data from the ongoing European Prediction of Psychosis Study (EPOS) another large collaborative study of at-risk subjects (Klosterkotter et al., 2005).
Searching for markers
The search for new markers of the schizophrenia prodrome continues apace, with a report in the February Archives of General Psychiatry from Vijay Mittal and Elaine Walker at Emory University, Atlanta, Georgia, that zeroes in on abnormal bodily movements as a potential tip-off to impending disease. Their rationale is neurological—the striatal dopamine circuit hyperactivity that has been implicated in psychotic symptoms is also involved in dyskinesias. In the study, the researchers videotaped participants and tallied unusual facial gestures or limb movements in a group of 121 adolescents, 42 of whom had been diagnosed with schizotypal personality disorder.
The main findings of the study were that movement abnormalities correlated with prodromal symptoms, but in a way that varied with body region. Facial movements correlated with prodromal symptoms at baseline, but not at either of two follow-ups. Upper or lower body movements showed an increased correlation with prodromal symptoms over the course of the study. The authors found minor differences when they separately analyzed medication-free subjects, who made up 71 percent of the group. “The results are consistent with the hypothesis of shared neuronal circuitry for movement abnormalities and psychotic symptoms and suggest the potential value of including an assessment of motor signs in screening for psychosis risk,” the authors write. The next step in the ongoing study will be to analyze conversion data to assess the predictive value of longitudinal measure of movement abnormalities.
Another recent report highlights a tendency to interpret nonsensical babbling as words and phrases as a marker of impending psychosis in prodromal patients. Study authors Ralph Hoffman, Thomas McGlashan, and colleagues at Yale and collaborators at Eli Lilly and Co., Indianapolis, Indiana, hypothesized that the tendency to read meaning into meaningless sensory information may produce a “matrix of unreality” that prompts the initial psychotic phase of disease. They studied 43 prodromal subjects who listened to recorded babble produced by mixing normal speech from multiple speakers to give an unintelligible audio stream. The investigators found that among untreated participants, those who reported hearing the longer word phrases in the phonetic noise were significantly more likely to convert to schizophrenia-spectrum disorder over the next year. Interestingly, subjects in the study who were taking olanzapine (sold by Lilly in the United States as Zyprexa®) showed no correlation between phrase length and conversion, suggesting that the medication reduced the risk of conversion associated with this perceptual marker. The study was small, but if confirmed could open the possibility of using serial assessments of the tendency to extract meaning from meaningless noise as an inexpensive way to identify those patients with early warning symptoms who are most likely to benefit from pre-emptive drug treatment. The work appeared in the October issue of the British Journal of Psychiatry.
Searching for treatment
Treatment for prodromal symptoms varies depending on both patient and doctor, and often involves antidepressants, antipsychotics, or a combination of both. Barbara Cornblatt and colleagues at Zucker Hillside Hospital in Glen Oaks, New York, have examined the use of antidepressants in a small naturalistic study of pre-psychotic adolescents enrolled in an early detection and prevention program. The work, published last year in the April issue of the Journal of Clinical Psychiatry, found that of 20 study participants treated with antidepressants, none converted to psychosis over the follow-up period, which averaged 30 months. That compares with 12 conversions among 28 subjects who were prescribed antipsychotic drugs, although 11 turned out to be noncompliant with the medication. The authors caution that they cannot compare the two treatments, because the assignment was non-random. Thus, baseline characteristic of the patients undoubtedly influenced the choice of medication, and they cannot rule out that a substantial number of the antidepressant-treated group were prodromal false-positives, since patients with more severe symptoms might be more likely to start on antipsychotic medication. Nonetheless, they conclude with a prescription that tries to balance the uncertainty around prognosis with the unpleasant side effects of antipsychotic drugs, writing, “The findings suggest that, in some cases, it might be preferable to begin treatment with antidepressants and progress to antipsychotics once symptoms intensify, since adherence to the latter is difficult to maintain.”—Pat McCaffrey.
Cannon TD, Cadenhead K, Cornblatt B, Woods SW, Addington J, Walker E, Seidman LJ, Perkins D, Tsuang M, McGlashan T, Heinssen R. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America.
Arch Gen Psychiatry. 2008 Jan;65(1):28-37. Abstract
McGorry PD, Yung AR, Bechdolf A, Amminger P. Back to the future: predicting and reshaping the course of psychotic disorder. Arch Gen Psychiatry. 2008 Jan;65(1):25-7. Abstract
Mittal VA, Neumann C, Saczawa M, Walker EF. Longitudinal progression of movement abnormalities in relation to psychotic symptoms in adolescents at high risk of schizophrenia. Arch Gen Psychiatry. 2008 Feb;65(2):165-71. Abstract
Hoffman RE, Woods SW, Hawkins KA, Pittman B, Tohen M, Preda A, Breier A, Glist J, Addington J, Perkins DO, McGlashan TH. Extracting spurious messages from noise and risk of schizophrenia-spectrum disorders in a prodromal population.Br J Psychiatry. 2007 Oct;191:355-6. Abstract
Cornblatt BA, Lencz T, Smith CW, Olsen R, Auther AM, Nakayama E, Lesser ML, Tai JY, Shah MR, Foley CA, Kane JM, Correll CU. Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents. J Clin Psychiatry. 2007 Apr;68(4):546-57. Abstract