Previous reports have described accelerated loss of cerebral white matter in schizophrenia. Others have reported changes of ventricle volumes in schizophrenic patients, with greatest increases following remission of psychotic symptoms. In this study changes in cerebral white matter volumes and psychotic symptoms were measured in 16 recently decompensated schizophrenic patients from neuroleptic-free baseline to 4 weeks later during treatment with antipsychotics. Serial white matter assessments were also performed in eight controls at similar intervals. Thirteen of 16 patients showed reduction of psychotic symptoms (reduction of SAPS scores by 24.4+/-12.6) during treatment. Three patients failed to respond (increase of SAPS scores by 15.7+/-13.8). Serial volumetric studies of cerebral white matter during the 4-week period showed a decrease of white matter volume in the responders by 8.2+/-8.2 cm(3) (P=0.003). Patients who failed to respond showed a non-significant increase in white matter during the same period by 11.4+/-11.7 cm(3). Absolute and percentage changes change in white matter volumes during the 4-week period were positively correlated with changes in SAPS scores (both P<0.01). Cerebral white matter, composed of myelin-containing oligodendrocytes, is highly sensitive to excitotoxicity. Swelling of myelin and of white matter, associated interference with the speed of neurotransmission through myelinated axons, and dyssynchrony of information processing by subcortical and cortical networks may be associated with psychosis exacerbation. Partial remission of symptoms may mark temporary reduction of an active, toxic process that interferes with information processing.