Participants were 130 patients with schizophrenia and 130 healthy controls (75 men and 55 women in each group) from the Schizophrenia Center of the University of Pennsylvania, Philadelphia. Controls were selected from a larger sample to match patients sociodemographically. All were right-handed. Patients had a DSM-IV21 diagnosis of schizophrenia established by medical, neurological, and psychiatric evaluations22 using the Structured Clinical Interview for DSM-IV–Patient Version.23 Those with schizophreniform disorder at study entry met the criteria for schizophrenia at the 6-month follow-up. The healthy controls, recruited by newspaper advertisement, underwent medical, neurological, and psychiatric evaluations24 using the Structured Clinical Interview for DSM-IV–Nonpatient Version.25 Subjects had no history of a disorder or event that might affect brain function, including hypertension (blood pressure >140/90 mm Hg), cardiac disease, diabetes mellitus, endocrine disorders, renal disease, chronic obstructive pulmonary disease, cerebrovascular disease, head trauma with loss of consciousness, seizure disorder, migraines, or any other neurological condition. The groups did not differ (mean±SD) in age (patients, 29.2±7.5 years; controls, 27.7±6.0 years) or parental education (patients, 12.9±2.5 years; controls, 12.4±2.8 years), but as expected, patients had a lower educational level than controls (12.9±2.3 vs 14.9±2.0 years [t258=7.34, P<.001]). There were 51 neuroleptic-naive and 79 previously treated patients. The neuroleptic-naive patients were younger (men: 23.4±5.2 years; women: 27.2±7.2 years) than the previously treated patients (men: 31.5±6.6 years; women: 32.2±7.7 years [t73=5.64, P<.001 for men vs t53=2.40, P=.02 for women]), but did not differ in education or parental education. The previously treated patients received typical neuroleptics only (n=48), typical followed by atypical neuroleptics (n=22), or atypical neuroleptics only (n=9). Mean duration of treatment for the typical neuroleptics was 1094.7±1431.3 days (range, 2-5739 days), and the mean dosage was 546.4±501.8 chlorpromazine-equivalent units per day (range, 25-1916 chlorpromazine-equivalent units per day). Atypical neuroleptics included clozapine (n=15) and risperidone (n=18). Mean duration of treatment for the atypical neuroleptics was 714.0±712.7 days (range, 2-2765 days), and the mean dosage was 463.3±336.4 chlorpromazine-equivalent units per day (range, 4-1295.1 chlorpromazine-equivalent units per day). For patients treated only with atypical neuroleptics, the mean duration of treatment was 435.28±516.1 days (range, 2-1232 days), and the mean dosage was 223.6±117.6 chlorpromazine-equivalent units per day (range, 100-428.5 chlorpromazine-equivalent units per day). Age of onset of psychotic symptoms in the context of functional decline was 22.4±5.9 years and duration of illness was 6.8±6.2 years. Clinical assessments, neurocognitive testing, and MRI studies were conducted within a week after enrollment. All neuroleptic-naive patients were studied before therapeutic intervention. Of the previously treated patients, 51 presented to the center and were studied while off medication, and 28 were studied while on medication. After complete description of the study, written informed consent was obtained prior to participation.