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There is increasing concern about the serious metabolic side effects and neurotoxicity caused by atypical (second-generation) antipsychotics. In a previous study by our group (Walss-Bass et al. Int J Neuropsychopharmacol 2008;11:1097–104), using a novel proteomic approach, we showed that clozapine treatment in SKNSH cells induces oxidation of proteins involved in energy metabolism, leading us to hypothesize that protein oxidation could be a mechanism by which atypical antipsychotics increase the risk for metabolic alterations. In this study, the same proteomic approach was used to identify specific proteins oxidized after clozapine treatment in lymphoblastoid cell lines from patients with schizophrenia and normal controls. Cells were treated with 0 and 20 μM clozapine for 24 hours and protein extracts were labeled with 6-iodoacetamide fluorescein (6–IAF). The lack of incorporation of 6-IAF into the thiol group of cysteine residues is an indicator of protein oxidation. Labeled proteins were exposed to two dimensional electrophoresis, and differential protein labeling was assessed. Increased oxidation after clozapine treatment was observed in 9 protein spots (P<0.05). The following 7 proteins were identified by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) in those 9 spots: enolase, triosephosphate isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPD), Rho GDP dissociation inhibitor (GDI), cofilin, uridine monophosphate/ cytidine monophosphate (UMP-CMP) kinase, and translation elongation factor. Several of these proteins play important roles in energy metabolism and mitochondrial function. These results further support the hypothesis that oxidative stress may be a mechanism by which antipsychotics increase the risk of metabolic syndrome and diabetes.