- Background: The effects of creatine on brain metabolism and the potential cognitive enhancing properties of this compound raise the possibility of developing a new augmentation therapeutic strategy in schizophrenia especially in patients demonstrating negative and cognitive symptomatology. Methods: Seven inpatients with chronic schizophrenia presenting with treatment resistant negative symptoms were enrolled into exploratory treatment study with creatine monohydrate augmentation at a daily high-dose of 10 grams, administered for 6 months. Several clinical rating scales and a computerized cognitive assessment battery were applied. Results: Creatine treatment mildly improved the schizophrenia symptomatology but there were no significant changes in cognitive functions. Several ward behaviors were also improved. Tardive parkinsonism improved numerically by above 40% in 4 out of 6 patients. Conclusion: This small, open design study of high dose creatine add-on for 6 months in chronic inpatients with schizophrenia demonstrated only mild positive effects on the patients' symptomatology and behavior and might have beneficial effect on tardive parkinsonism.