Important aims of schizophrenia research have been not only to learn about the pathogenesis of the illness but also to improve our ability to diagnose early and hence provide early treatment for psychosis. Outcome studies have found an association between the duration of untreated psychosis and poor functional outcome,1
suggesting the possible toxic effect of psychosis on the brain,2
but clear causation has not been established. With the potential of making an impact on the course of schizophrenia by intervening early and preventing many of the devastating effects of the illness, greater emphasis in schizophrenia research has been placed on the identification of individuals in the prodromal phase of schizophrenia.
In 1996 Yung, McGorry and their colleagues3
set up a clinic in Australia to monitor and care for young people considered at a high risk for developing psychosis based on demographic and symptom measures. They selected individuals in an age range that is at higher risk for schizophrenia (14–30 years) who had recently developed subsyndromal psychotic symptoms and/or had a familial risk for schizophrenia plus a recent deterioration in functioning. Using these criteria, Yung et al. reported a 40% conversion rate to psychosis at the end of 1 year.4
The Australian program inspired the development of similar programs worldwide.5–13
These programs are actively engaged in studying individuals at risk for developing psychosis in an effort to learn more about the “at risk” states and to assess the predictive power and diagnostic efficiency of the prodromal criteria for the eventual development of schizophrenia.
These prodromal research programs may have far-reaching clinical implications. In addition, ethical considerations surrounding prodromal research remain a fundamental concern of investigators worldwide.6,14–17
For example, a number of questions have been raised in terms of how to best identify who is at risk and the potential stigmatization, loss of confidentiality, and insurability problems these individuals may encounter.15,18
The base rates for conversion to schizophrenia have not been established in large samples,15
and the early clinical trials in the at-risk population have been criticized for having too many false positives (or subjects who do not convert to schizophrenia) to justify early treatment with antipsychotic agents.15,17,19
The rate of false positives in some studies has been as high as 60–90 %,4,5,9,16,20–30
leading to unfavorable risk-to-benefit ratios in studies with lower conversion rates. The rates of conversion vary across studies, depending on prodromal assessment methods, age of the subjects, sample size, and follow-up time (). This false positive group likely includes individuals who fit the “prodromal” criteria but were not really destined to convert; those who are truly at risk and are somehow protected or have not had the second “hit” necessary to convert but still may develop psychosis in the future. There are also concerns regarding the risks of treating false positive subjects with unnecessary medication16,31
and the need for an exit strategy (when or if to ever stop treatment),15,32
as well as risks of treating true positives with placebo.16
Additionally, the heterogeneity of the at-risk samples has raised the question of whether antipsychotics should be the first line of treatment.15
In a recent review Corcoran, Malaspina, and Hercher14
note that the negative impact of intervention on the patients’ lives will potentially increase in any shift toward a target population that is younger, less symptomatic, or less strictly delineated.
Comparison of Prodromal Schizophrenia Studies
Provocative and convincing arguments have been made for both initiating randomized clinical trials in the at-risk sample and withholding treatment until a more definitive diagnosis is made.11,15–17,31,33
It has been argued that we need “number needed to treat” data (NNT—the number of patients one needs to treat to prevent one additional bad outcome) from randomized clinical trials to assist patients and families in making informed decisions.17
With the brewing debate about potential treatment of prodromal subjects in the schizophrenia literature, concern has also been expressed that community clinicians may want to initiate early antipsychotic treatment in at-risk patients before we have definitive NNT data and decrease the pool of potential subjects for clinical trials in which base rates can be determined.16
Despite the controversy regarding risk/benefits of early interventions for schizophrenia, there are indications that the use of antipsychotics in children and adolescents has been increasing.34,35
Additionally, recent marketing by the pharmaceutical industry has advocated the use of atypical antipsychotics for a variety of nonpsychotic conditions such as mood or anxiety disorders.36–38
Now clinicians are more willing to use an antipsychotic agent to target a variety of mood, anxiety, or behavioral problems that do not necessarily include psychosis.
The CARE (Cognitive Assessment and Risk Evaluation) program is a National Institute of Mental Health–funded longitudinal study that is modeled after the program in Australia. One of the primary aims of the CARE program is to improve early identification of psychosis and decrease the false positive rate by also assessing brain-based vulnerability markers for schizophrenia. At-risk subjects in the CARE program receive treatment as usual (both pharmacological and psychosocial) according to presenting symptoms and are not participating in a clinical trial. The current report assesses the clinical and demographic data of 50 subjects enrolled in the CARE program at the end of 1 year. Comparisons are made between those individuals who had converted to psychosis and those who had not. Given the high false positive rate of this population in published reports, another objective was to further assess those individuals who did not convert to psychosis. The plan was to develop hypotheses as to why this population initially fit the prodromal criteria and did not convert to psychosis and to determine whether it is possible to identify factors that protected them or delayed conversion. Additionally, by examining the rate of conversion and nonconversion in this sample of individuals, we hope to contribute to the discussion of implications for clinical practice and the direction of future research in the schizophrenia prodrome. Finally, our data can serve to strengthen the evidence base available to inform the discussion of empirical ethics regarding this important area of research.