N-methyl-d-aspartate receptor hypofunction (NRH) and its downstream consequences, especially excitotoxicity, may explain the progressive psychosocial deterioration and ventriculomegaly observed in at least some patients with schizophrenia. Topiramate has several properties that address downstream consequences of NRH. In this open-label investigation, the authors examined the salutary therapeutic effects of adjuvant topiramate in 12 patients with schizophrenia and schizoaffective disorder. Patients were selected on the basis of the presence of negative symptoms. An optimal dose of topiramate was determined for each patient during a slow 4-week titration process. Patients were maintained on topiramate and their stable antipsychotic medications for 8 weeks, after which topiramate was tapered and discontinued. Patients were followed for an additional 4 weeks on their stable antipsychotic medications. Clinical measures of efficacy (eg, Positive and Negative Syndrome Scale), cognitive measures (eg, verbal fluency, memory), and safety measures (eg, postural sway) were assessed throughout this study. Topiramate administration (average dose, 110.42 mg/day) decreased total scores on the Positive and Negative Syndrome Scale. Topiramate was also associated with a selective and reversible worsening of verbal fluency performance. These results encourage further testing of topiramate and kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonists in schizophrenia patients and support the heuristic model of NRH.