24 individuals with schizophrenia or schizoaffective disorders, who are currently considered stable, will be recruited, screened for entry criteria into a blinded study with a 4-week randomization to either lurasidone, haloperidol, or perphenazine to examine glutamate-related outcomes with lurasidone as compared to haloperidol and perphenazine.

At study start all volunteers will be discontinued from their current antipsychotic drug (APD) and switched to haloperidol 4mg for 5 days. At the end of this discontinuation period, all baseline symptom ratings and cognition testing will be done, as well as the baseline imaging procedures. At the end of the baseline procedures, volunteers will be blindly randomized, either to lurasidone at 40mg (N=12), or to haloperidol at 4mg/d or perphenazine at 16mg/d (N=12). Doses will increase to 80mg/d lurasidone, 8 mg/d haloperidol, or 32 mg/d of perphenazine at the beginning of week two. Dose should be stable for the last 3 weeks of treatment unless side effects are prominent, then the dose can be decreased to 40 lurasidone/4 haloperidol/16 perphenazine mg/d for optimal clinical management. The randomization strategy will be designed and implemented by the research pharmacist in four blocks of six volunteers; drug will be dispensed by the research pharmacy according to the randomization schedule. The randomization will be followed by a four week treatment period at optimal dose levels. On the last two days of the 4 week stable dosing period, the specified glutamate outcome measures will be completed (neuroimaging and cognitive testing) along with all the symptom outcome measures, testing for drug plasma levels, and usual blood safety measures. Patients will be seen weekly for clinical evaluation; suicidality will be monitored weekly. All medications other than study drugs will be discontinued, as much as possible, for the 24-48 hr assessment period. After the evaluation phase, patients will be cross-titrated back to their original treatment medication and dosing.

This design will generate outcomes from 12 patients on lurasidone vs. 12 patients on haloperidol/ perphenazine.

Inclusion Criteria:

• Subject at least 18 years old
• Subject meets criteria diagnosis of schizophrenia or schizoaffective disorder.
• Subject is not pregnant and is not planning pregnancy within the projected duration of the study.
• Female subject who is of reproductive potential agrees to remain abstinent or use adequate and reliable contraception throughout the study
• Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.
• Eyesight corrected to 20-40 or better
• Able to read, speak, and understand English*

Exclusion Criteria:

• Any medications being used as mood stabilizers (i.e., anticonvulsants)
• Subject currently has a clinically significant medical condition(s) that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study.
• Subject demonstrates evidence of acute/chronic hepatitis which is clinically significant
• Subject has a history of malignancy < 5 years prior
• Subject has a history of neuroleptic malignant syndrome (NMS).
• Subject has a history of alcohol or substance abuse within 3 months prior to screening or alcohol or substance dependence within 12 months prior to screening
• Subject tests positive for drugs of abuse at screening. In the event a subject tests positive for cannabis, the investigator will evaluate the subject's ability to abstain from cannabis during the study.
• Subjects diagnosed with type 1 diabetes
• Subject has a prolactin concentration > 200 ng/mL at screening
• Subject has a history or presence of abnormal ECG which is clinically significant
• Subject has a history of hypersensitivity to more than two distinct chemical classes of drug (e.g., sulfas and penicillins).
• Subjects have received depot neuroleptics within 12 weeks prior to randomization.
• Subject has a history of treatment with clozapine for refractory psychosis and/or subject has been treated with clozapine within 4 months of randomization.
• Subject does not have a stable residence for the 3 months prior to randomization.
• Subject requires treatment with any potent CYP3A4 inhibitors or inducers during the study.
• Subject has received electroconvulsive therapy (ECT) within 90 days prior to
• Subject has been randomized in a prior clinical trial of lurasidone.
• History of serious head injury with unconsciousness for >30 minutes