This study will determine the efficacy of oral risperidone (Risperdal) versus long-acting injectable paliperidone palmitate (Invega Sustenna) in treating people with first-episode schizophrenia.

Schizophrenia is a severely disabling brain disorder. People with schizophrenia often experience hallucinations, delusions, thought disorders, and movement disorders. Proper treatment of first-episode schizophrenia may increase the chances of controlling disease progression on a long-term basis. People experiencing their first episode of schizophrenia are more responsive to treatment than those with chronic schizophrenia, but are also more susceptible to adverse treatment side effects. Atypical antipsychotic medications have been shown to produce fewer extrapyramidal side effects than older "typical" antipsychotics. Oral risperidone is an atypical antipsychotic medication that is very commonly used to control the symptoms of schizophrenia. Adherence to prescribed oral medication continues to be a major clinical issue. This study will determine the effectiveness of oral risperidone versus a long-acting injectible alternative, paliperidone palmitate, in treating people with first-episode schizophrenia. Impact on clinical symptoms and cognitive functioning will be examined.

Participants in this open label study will be randomly assigned to receive either orally administered risperidone or long-acting paliperidone palmitate administered via injection. Participants assigned to oral risperidone will receive medication in doses that are determined to be optimal by the study psychiatrist. Participants assigned to long-acting risperidone will receive an injection of paliperidone palmitate once every 4 weeks. Dosages will be adjusted as necessary to achieve the optimal dosage. Following 2 to 3 months to achieve outpatient oral risperidone dosage stabilization, the randomized medication conditions will begin and participants will be monitored for 1 year. Study visits will occur once weekly throughout the study. They will include psychiatrist monitoring of medication response and side effects; group therapy meetings focused on everyday living skills; family education about schizophrenia; and individual meetings with a case manager for counseling and evaluations of schizophrenia symptoms, work recovery, and social functioning.

Inclusion Criteria:

1. A first episode of a psychotic illness is occurring or did occur within the last 2 years;
2. A diagnosis by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV)of schizophrenia, schizoaffective disorder, depressed type, or schizophreniform disorder; and
3. Between 18 and 45 years of age.

Exclusion Criteria:

1. Neurological disorder (e.g., epilepsy) or significant head injury;
2. Significant alcohol or substance use disorder within the six months prior to the first episode and evidence that substance abuse triggered the psychotic episode or makes the schizophrenia diagnosis ambiguous;
3. Mental retardation, i.e. premorbid intelligence quotient (IQ) less than 70;
4. Insufficient acculturation and fluency in the English language to avoid invalidating research measures of thought, language, and speech disorder or of verbal abilities;
5. Residence likely to be outside of commuting distance of the University of California, Los Angeles (UCLA) Aftercare Research Program; or
6. Patient has shown an inadequate response to an adequate previous trial of oral or long-acting injectable risperidone, paliperidone, or paliperidone palmitate.