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Background:Risperidone and paliperidone have been the mainstay treatment for schizophrenia and their potential role in neuroprotection could be associated with brain-derived neurotrophic factor (BDNF) and N400 (an event-related brain potential component).So far,different effects on both BDNF and N400 were reported in relation to various antipsychotic treatments.However,few studies have been conducted on the mechanism ofrisperidone and paliperidone on BDNF and N400.This study aimed to compare the effects ofrisperidone and paliperidone on BDNF and the N400 component of the event-related brain potential in patients with first-episode schizophrenia.Methods:Ninety-eight patients with first-episode schizophrenia were randomly divided into the risperidone and paliperidone groups and treated with risperidone and paliperidone,respectively,for 12 weeks.Serum BDNF level,the latency,and amplitude of the N400 event-related potential before and after the treatment and Positive and Negative Syndrome Scale (PANSS) scores were compared between the two groups.Results:A total of 94 patients were included in the final analysis (47 patients in each group).After the treatment,the serum BDNF levels in both groups increased (all P ＜ 0.01),while no significant difference in serum BDNF level was found between the groups before and after the treatment (all P ＞ 0.05).After the treatment,N400 amplitudes were increased (from 4.73 ± 2.86 μv and 4.51 ± 4.63 μv to 5.35 ± 4.18 μv and 5.52 ± 3.08 μv,respectively) under congruent condition in both risperidone and paliperidone groups (all P ＜ 0.01).Under incongruent conditions,the N400 latencies were shortened in the paliperidone group (from 424.13 ± 110.42 ms to 4.7.41 ± 154.59 ms,P ＜ 0.05),and the N400 amplitudes were increased in the risperidone group (from 5.80 ± 3.50 μv to 7.17 ± 5.51 μv,P ＜ 0.01).After treatment,the total PANSS score in both groups decreased significantly (all P ＜ 0.01),but the difference between the groups was not significant (P ＞ 0.05).A negative correlation between the reduction rate of the PANSS score and the increase in serum BDNF level after the treatment was found in the paliperidone group but not in the risperidone group.Conclusions:Both risperidone and paliperidone could increase the serum BDNF levels in patients with first-episode schizophrenia and improve their cognitive function (N400 latency and amplitude),but their antipsychotic mechanisms might differ.