BackgroundAtypical antipsychotics as first-line drugs have been used in patients with schizophrenia in China and abroad. However, its safety still needs to be evaluated in a large population, especially in Chinese patients.ObjectiveThe main objective of this study is to evaluate the safety and related factors of long-term atypical antipsychotic use in patients with schizophrenia in China. The secondary objective includes the long-term efficacy of atypical antipsychotics in these patients, as well as pharmacoeconomic evaluation, population pharmacokinetic studies and pharmacogenomics studies.MethodsThis study has an observational design. The atypical antipsychotics include quetiapine, olanzapine, risperidone, aripiprazole, ziprasidone, paliperidone, amisulpride, perospirone and clozapine. Visits occur at 0, 4, 8, 13, 26, 52, 78, 104, 130 and 156 weeks. The efficacy evaluations include symptoms, social function, recurrence rate and hospitalisation. The safety measures include physical examination, vital signs, abdominal circumference, laboratory tests (such as blood cell analysis, blood biochemical tests and serum prolactin/thyroxine levels), 12-lead ECG, extrapyramidal syndrome assessment, sexual function evaluation, medication and other adverse events. The secondary measures include the Positive and Negative Syndrome Scale, Clinical Global Impression-Severity of Illness Scale, Calgary Depression Scale for Schizophrenia, Personal and Social Performance Scale, relapse rate, drug consolidation, medical-related expenses, income, drug plasma concentration and genetic information.ResultsThis is a large sample, non-interventional and long-term prospective clinical study designed to truly reflect the specific details of clinical practice, fully respect patients’ needs, and understand patients’ treatment intentions and actual treatment details.ConclusionsThis research method details the aims, methods, study design, strengths and limitations of the study.
Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling.
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