Schizophrenia in adolescents is an understudied area and data on its psychopharmacological treatment are scarce. The goal of this First Independent Research Support and Transition (FIRST) Award proposal is to contribute to the development of a rational foundation for the pharmacological treatment of schizophrenia in adolescents. A program for the evaluation of risperidone will be used as a model. Over a 42 month period a minimum of 70 adolescents who meet DSM IV criteria and who need inpatient hospitalization are expected to complete the study. The primary aims of the study in this population are (1) to assess the short efficacy of risperidone (2) to assess critically the short-term safety of risperidone. Secondary aims are to examine the relationship of risperidone plasma levels to clinical response and side effects, the relationship of serotonin-2 (5-HT2) binding in blood platelets to risperidone treatment response and the effect of risperidone on cognitive functioning. The importance of this research arises from the pressing need for data about the safety and efficacy of neuroleptics in adolescents with schizophrenia; current treatment of this disorder in adolescents is based largely on extrapolation from research on adults even though research with other medications suggests that the response of adolescents to psychotropics may differ from adults. A double blind, placebo controlled parallel groups design will be used. An initial one week washout will be followed by a one week placebo baseline during which placebo will be administered under single-blind conditions. Patients who meet clinical criteria will be randomly assigned to two independent treatment groups, risperidone or placebo, for a period of four weeks. Treatment response will be measured with the Positive and Negative Syndrome Scale for Schizophrenia as well as other widely used measures sensitive to medication effects. Side effects will be carefully monitored with standard instruments. Plasma levels of risperidone plus 9-OH-risperidone will be monitored throughout the treatment period and related to treatment response and side effects. Pre- and post-treatment serotonin platelet will be assessed and related to treatment response. The study will advance knowledge about the pharmacological treatment of schizophrenia in adolescents (1) it will replace clinical anecdote and case reports about this now widely used medication with systematic data regarding efficacy and safety relative to placebo (2) it will provide needed information about the relationship between plasma levels, treatment response and side-effects and serve as guide for minimal effective therapeutic dose in the future (3) it will explore 5-HT2 platelet binding as a predictor of treatment response to risperidone, which may permit the selection of patients most likely to respond (4) it will examine the effects of risperidone on cognitive function. The study will also provide the basis for other innovative grant proposals by the Principal Investigator to study questions relevant to the treatment of schizophrenia in adolescents.
