This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clozapine remains the only antipsychotic that has been FDA approved for treatment-resistant schizophrenia. Unfortunately, partial response to clozapine is common. In most controlled trials, forty to seventy per cent of treatment-resistant patients fail to adequately respond to clozapine treatment, and there are no proven viable treatment alternatives. The emerging clinical practice is to treat clozapine non-responders by adding a second antipsychotic to clozapine. In the State of Maryland, 15% of all clozapine-treated patients are treated with a second new generation antipsychotic and an additional 5-10% treated with an adjunctive conventional antipsychotic. There are a number of small case series reports but, to date, there is little empirical evidence to support the efficacy or safety of this practice. The proposed 16-week randomized double-blind comparison of adjunctive risperidone and placebo-risperidone in clozapine-treated patients with schizophrenia will address the following primary and secondary specific aims: Primary Study Objectives 1. To determine if adjunctive risperidone is superior to placebo for the treatment of persistent positive symptoms in clozapine-treated patients with schizophrenia. 2. To determine if adjunctive risperidone is superior to placebo for the treatment of cognitive impairments in clozapine-treated patients with schizophrenia. Secondary Study Objectives 1. To determine if adjunctive risperidone is superior to placebo for the treatment of persistent negative symptoms in clozapine-treated patients with schizophrenia. 2. To determine if adjunctive risperidone is associated with increased incidence of side effects as compared to placebo in clozapine-treated patients with schizophrenia. 3. To determine if adjunctive risperidone is superior to placebo for the treatment of anxiety/depression and hostility symptoms, clinical global improvement, quality of life, and patient satisfaction with treatment in clozapine-treated patients with schizophrenia. The proposed study is a randomized, double-blind comparison of adjunctive risperidone or placebo to clozapine. The sample will consist of 90 clinically stable inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder. There will be a 4-week evaluation phase and a 16-week treatment phase. In the 4-week evaluation phase, patients will undergo baseline symptom, medical, safety, clozapine and prolactin levels, and neurocognitive assessments. In the 16-week treatment phase, patients will receive biweekly symptom, side effect, and vital sign assessments. At the end of the study (16 weeks), ripseridone, clozapine and prolactin levels will be obtained and neurocognitive assessments will be repeated.