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Dr. McGlashan and the rest of the PRIME team are to be congratulated on their study. Having worked on similar studies myself, with the Ultra High Risk (or “prodromal”) population, I can attest to the difficulties of conducting such a trial. The high dropout rate from both the active medication group and the placebo group is of note. My experience working with young people in the UHR group, as well as young people with psychotic and non-psychotic disorders, is that they tend to be reluctant to take any medication for 12 months. So this finding from the PRIME study is not surprising. The high dropout rate does, however, have implications for the effectiveness (as opposed to efficacy) of using medication for the prodromal population. Additionally, the finding that cognitive therapy may significantly reduce the transition to psychosis rate in UHR individuals (Morrison et al., 2004) points to the need for the ongoing evaluation of which UHR patients should be medicated and when.

One area that needs ongoing investigation is the refinement of the UHR criteria, so that those who are at most risk can be targeted for preventive treatment. Demographic, psychopathological, neurocognitive, neurophysiological, and neurobiological variables could all be evaluated. Ideally, those at highest risk of transition could be detected and treated. Other targets for medication could be ongoing functional decline and suicidal and homicidal risk. I agree with the PRIME researchers’ recommendations that future trials are needed. An alternative strategy to a simple medication trial could be to have a medication-free period during which cognitive therapy versus supportive therapy could be assessed, followed by a medication trial in those who fail to respond to initial psychological treatment. The problems of low numbers and long recruitment phases continue to dog the area of UHR research. As the PRIME authors note, multisite trails and pooling of subjects would aid the endeavor.

View all comments by Alison Yung

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

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