Schizophrenia Research Forum - A Catalyst for Creative Thinking

In Pursuit of Positive ID for Schizophrenia Prodrome—A Research Roundup

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

Comments on News and Primary Papers

Primary Papers: Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America.

Comment by:  Patricia Estani
Submitted 30 May 2008
Posted 31 May 2008
  I recommend this paperComment by:  Patricia Estani
Submitted 31 May 2008
Posted 31 May 2008
  I recommend the Primary Papers
Comments on Related News

Related News: Attempts to Address Schizophrenia Prodrome Show Promise, Pitfalls

Comment by:  Thomas McGlashan
Submitted 18 May 2006
Posted 19 May 2006

I appreciate Dr. Yung's comments on our pharmacotherapeutic treatment trial in a sample of young persons with "prodromal" symptoms and high risk for becoming psychotic within a short period of time. It was her work with Pat McGorry that first demonstrated this population could be identified, thus opening up the potential for prospective study of the mechanisms of onset and the study of treatment as preventive as opposed to merely ameliorative. We were concerned about the high dropout rate for obvious reasons, but in retrospect we should not have been surprised. Our sample was young and perhaps more resistant for that reason, as Dr. Yung implies, but the fact is that 2 years is a very long clinical trail no matter what the age! In part we wanted to allow sufficient time to elapse to capture higher numbers of converting subjects, and that still seems to be a reasonable strategy insofar as the conversion rate in the placebo group had not clearly plateaued by 1 year. Nevertheless, in retrospect, a trial of 2 years was unrealistic.

The optimal design, clearly, would be larger samples treated for a shorter period, but recruiting larger samples proved to be very difficult, even with four sites, which gets to Dr. Yung's final point. The true positive prodromal person/patient emerges in the population at the incidence rate of schizophrenia which is not robust (one in 10,000 per year). Furthermore, the earliest symptoms are often negative in nature and hard to identify, especially if the person is no longer living at home with family, that is, with people who might be sensitive to nuance changes. The bottom line is that research in this field is an uphill battle vis-à-vis sampling and recruitment. Yet I feel strongly that such samples are extraordinarily valuable for studies of the pathophysiology and preventive treatment of schizophrenia because, unlike retrospective studies, predictions that are prospectively falsifiable can be made and tested.

Therefore, like Dr. Yung, I endorse current efforts to consolidate samples across sites and to plan studies that are multisite so that sufficient numbers of such potentially informative patients can be gathered and pooled. In North America, for example, eight sites have used a common prodromal assessment battery (the same assessment instruments used in the Lilly clinical trial) and have pooled their data with the help of supplemental funds from NIMH. This group, called the North American Prodromal Longitudinal Study (NAPLS), includes three of the sites from the Lilly trial (Yale, UNC, and Toronto) and five additional sites (Harvard, Hillside, Emory, UCLA, and UCSD). Together, the group has a consolidated sample of over 400 prodromal patients, thus demonstrating that the "prodromal recruitment problem" is not insurmountable.

View all comments by Thomas McGlashan

Related News: Attempts to Address Schizophrenia Prodrome Show Promise, Pitfalls

Comment by:  Patricia Estani
Submitted 28 September 2006
Posted 28 September 2006
  I recommend the Primary Papers

Related News: ICOSR 2007—NAPLS Targets the Schizophrenia Prodrome

Comment by:  Tara Niendam
Submitted 11 May 2007
Posted 11 May 2007

I just wanted to clarify a mistake in the article above. The new social and role functioning measures discussed by Barbara Cornblatt were incorrectly identified. The correct titles are Global Functioning Scale: Social (Auther et al., 2006) and Global Functioning Scale: Role (Niendam et al., 2006). Data on these new measures were recently published as part of a collaboration between LIJ and UCLA (Cornblatt et al., 2007). The references for these measures are listed below. Researchers interested in using these measures can contact either author (A. Auther or T. Niendam) for copies of the measures.


Auther, A.M., Smith, C.W. & Cornblatt, B.A. (2006). Global Functioning: Social Scale (GF: Social). Glen Oaks, NY: Zucker Hillside Hospital.

Niendam, T.A., Bearden, C.E., Johnson, J.K. & Cannon, T.D. (2006). Global Functioning: Role Scale (GF: Role). Los Angeles: University of California, Los Angeles.

View all comments by Tara Niendam

Related News: ICOSR 2007—NAPLS Targets the Schizophrenia Prodrome

Comment by:  Patrick McGorry, SRF AdvisorAlison Yung (Disclosure)
Submitted 17 May 2007
Posted 18 May 2007

The key issue of the confounding of the transition process and the related predictive analyses by uncontrolled treatment, especially with antipsychotic medications, has not been highlighted in the report. It would be illuminating to ask the collaborators to comment on this issue in the Forum. The randomized controlled trial conducted by Dr. McGlashan and colleagues (many of whom are now NAPLS investigators) was a stronger design since it contained a placebo arm which allows purer study of the prediction issue ( McGlashan et al., 2006). This should be supported in the future by NIMH and other funders in our opinion.

View all comments by Patrick McGorry
View all comments by Alison Yung

Related News: ICOSR 2007—NAPLS Targets the Schizophrenia Prodrome

Comment by:  Tyrone Cannon
Submitted 5 September 2008
Posted 6 September 2008

The case for testing antipsychotic drugs as prophylactic measures rests entirely on their empirically proven efficacy in decreasing the severity of positive psychotic symptoms among patients with established illness. Initial applications of these agents in studies of prodromal patients have produced discouraging results on the primary question of preventive effects. Among patients with established illness whose positive symptoms respond to antipsychotics, such treatment must be continuous in order to maintain treatment gains; it is therefore not surprising that trials of antipsychotics in prodromal patients would show effects of drug on positive symptom reduction only during the active treatment phase. With no demonstrable prophylactic effects, and with little or no effect on motivational symptoms or functional disability, antipsychotic drug treatment in the prodromal phase is clearly not the “silver bullet” of psychosis prevention.

Some have suggested that randomized controlled studies of antipsychotics provide the most coherent platform from which to monitor natural progression of the prodromal phase, since there is no confounding of progressive processes and treatment effects among individuals assigned to placebo. However, the ability to identify predictors and mechanisms of psychosis depends critically on the enrollment of large samples of prodromal subjects who are representative of the at-risk population. In the antipsychotic drug trials with prodromal patients, only a small fraction (on the order of 25 percent to 40 percent) of the potential subjects who screened as eligible for inclusion in the studies consented for participation and enrolled in the trials. Further, a relatively large fraction (on the order of 30 to 50 percent) of the initially enrolled subjects withdrew from these studies during the active treatment phase or follow-up period. Low rates of consent for participation combined with high attrition rates (likely due at least partially to side effects of drug treatments) have been reported in all prodromal randomized clinical trials and can thus be expected to severely constrain the generalizability of findings related to prediction and mechanisms of onset in such studies.

Therefore, ideally the next wave of studies into the natural progression of neurobiological factors in prodromal patients will employ a treatment algorithm by which antipsychotics are not prescribed until a patient displays positive symptoms at a fully psychotic level of intensity. This design will result in standardization of treatment across the participating sites and avoid confounding antipsychotic drug treatment with measurements of the biological processes hypothesized to underlie progression to psychosis.

View all comments by Tyrone Cannon