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Carbonyl stress in patients with schizophrenia has been reported to be reflected by an increase in peripheral pentosidine levels. This cohort study tested whether the accumulation of pentosidine was related to the disease severity or the treatment (routine administration of high antipsychotic doses).We followed up our original investigation using a new group of 137 patients with acute schizophrenia and 45 healthy subjects, and then pooled the two cohorts to conduct the following analysis on a total of 274 patients. The associations of serum pentosidine and pyridoxal levels with duration of education, estimated duration of medication, the severity of symptoms, and daily doses of antipsychotics, antiparkinsonian drugs, and anxiolytics were evaluated by multiple linear regression analysis.The combined cohort of 274 patients exhibited abnormally high serum levels of pentosidine, were associated with a higher daily dose of antipsychotic drugs and a longer estimated duration of medication without statistical significance of diagnosis. This was also observed in the patients treated with antipsychotic polypharmacy, but the serum pentosidine levels of patients treated with first- or second-generation antipsychotic monotherapy showed no relationship with these two variables.High levels of serum pentosidine were associated with high daily doses of antipsychotic drugs and a longer estimated duration of medication in patients treated with antipsychotic polypharmacy.A large cohort of 274 schizophrenia cases exhibited high pentosidine serum levels.Pentosidine levels were associated with the daily dose of antipsychotic polypharmacy.Pentosidine levels were associated with the duration of medication of polypharmacy.Antipsychotic monotherapy at an optimal dose may be better for patients' health.