The purpose of this research study is to compare the "real-world" effectiveness of two FDA-approved and widely used long-acting injectable antipsychotic medications (paliperidone palmitate and haloperidol decanoate) in patients with schizophrenia or schizoaffective disorder who are expected to benefit from the improved medication compliance associated with injectable medications. The goal is to evaluate the effects of the medications on outcomes of importance to patients (relapse, symptoms, adverse effects, functioning) as well as policy makers (all of the above plus costs).

The purpose of this comparative effectiveness research study is to learn more about different medications called antipsychotics that are used to treat schizophrenia or schizoaffective disorder. Specifically, we are looking at long-acting medications that are given by injection every month, instead of being taken by mouth every day. In this multi-site study, we are comparing the risk and benefits of two FDA-approved long-acting injectable medications (paliperidone palmitate and haloperidol decanoate). Study participants with schizophrenia or schizoaffective disorder are expected to benefit from the improved medication schedule.

This study aims to enroll 360 individuals with schizophrenia or schizoaffective disorder for whom treatment with a long-acting injectable antipsychotic medication is likely to be helpful. Study participants will be randomly assigned to treatment with either paliperidone palmitate and haloperidol decanoate for up to 24 months. Participants will have an equal chance of being assigned to each medication, however participants will not know which medication they are taking.

Inclusion Criteria:

• Diagnosis of schizophrenia or schizoaffective disorder as defined by DSM-IV-TR criteria
• Age 18-65 years
• Capacity to provide informed consent
• Patients who are likely to benefit from treatment with long-acting injectable paliperidone palmitate or haloperidol decanoate
• Women of child bearing potential must have a negative serum pregnancy test at the Screening Visit.

Exclusion Criteria:

• Patients who are currently stable and doing well on an antipsychotic regimen
• Patients not expected to benefit from the study medications due to past experience with risperidone, paliperidone or haloperidol
• Patients with tardive dyskinesia that is moderate or severe
• Patients with any medical condition that, in the judgment of the investigator, might preclude safe completion of the study
• Women who are pregnant or breastfeeding
• Patients with mental retardation