Prefrontal GABA,glutamate And Development Of Schizophrenia

Background and Objectives:Schizophrenia(Sz)is a severe psychosis disorder.Onset of this disease is usually at late adolescent or early adult.However,the underlying pathogenesis of this disorder is still not clarified.Mounting studies observed abnormal prefrontal GABA and glutamate levels in populations with schizophrenia,which involved in pathogenesis of this disorder.However,some confounding factors such as illness duration and drug use have not been well controlled in previous studies.Additionally,whether prefrontal abnormal GABA and glutamate levels occurred before full-blown of psychosis has been scarcely investigated.In this study,subjects of first-episode schizophrenia(FEP)and clinic high risk for psychosis(CHR)were enrolled,as well as prospective follow-up was performed for CHR,to explore the role of prefrontal GABA and Glutamate in the development and progression of schizophrenia.For subjects at CHR,We also analyzed EEG measures of auditory steady state response(ASSR)and mismatch negativity(MMN)reflecting GABAergic and glutamatergic neurotransmission in brain.Methods:1.The recruited participants were divided into two phases,and the first phase only enrolled cross-sectional data.Sixteen drug-na?ve patients with FEP,twenty-one subjects at CHR and matched twenty-three healthy control subjects(HC)were included.In the second phase,300 CHR and 138 HC subjects were recruited and followed-up for one year.CHR subjects were further divided into CHR-Remit group(CHR-Remit)whose prodromal psychosis symptoms remitted at one-year follow-up and CHR-Non Remit group(CHR-Non Remit)whose prodromal psychosis symptoms did not remit at one-year follow-up.SIPS and MCCB was applied to assess clinical symptom and cognitive function in CHR population,respectively.2.With proton magnetic resonance spectroscopy and advanced edited pulse sequence MEGA-PRESS,GABA and Glx(glutamate+glutamine,glutamate compound)levels of ROI located in medial prefrontal cortex(m PFC)were examined in vivo.LCModel software was used to calculate concentration of these metabolites.Brain issue of ROI was segmented to acquire proportion of grey matter,white matter and CSF composition,which was further used to correct concentration of the metabolites.3.For the first phase study,ANOVA with grey matter proportion and white matter proportion as covariates was conducted to compare GABA and Glx levels amongst three groups(FEP vs.CHR vs.HC).For the second phase study,ANOVA with grey matter proportion and white matter proportion as covariates was conducted to compare GABA and Glx levels between two groups(CHR vs.HC);baseline GABA and Glx levels were also compared amongst three groups(CHR-Non Remit vs.CHR-Remit vs.HC)using ANOVA with grey matter proportion and white matter proportion as covariates.4.For subjects of CHR and HC included in the second phase study,auditory steady state response(ASSR)and mismatch negativity(MMN)measures were also analyzed.Results:Results of the first phase study displayed significantly lower m PFC GABA and Glx levels for FEP group(GABA:2.27±0.17,Glx:6.37±1.33)than that for HC group(GABA:3.04±0.14,p =0.003;Glx:8.28±1.58,p <0.001)and CHR group(GABA:2.96±0.15,p =0.01;Glx:8.18±1.28,p =0.001),while no significant difference between CHR and HC groups was observed(GABA:p =1.00,Glx:p =1.00).In the second phase study,compared to HC group,CHR group showed significantly lower m PFC Glx level(CHR vs.HC,8.23±0.11 vs.8.64±0.15,p=0.032),and lower GABA level with trend significance(CHR vs.HC,2.35±0.009 vs.2.45±0.10,p =0.087).Further analysis of subgroups divided by clinical outcome at one-year follow-up found significantly lower baseline m PFC GABA and Glx levels for the CHR-Non Remit group than that for the HC group(CHR-Non Remit vs.HC,GABA:2.25±0.039 vs.2.46±0.049,p =0.022;Glx:7.97±0.27 vs.8.64±0.15,p=0.025),however no significant difference in both metabolites between CHR-Remit group and HC group was shown(CHR-Remit vs.HC,GABA:p =0.10;Glx:p =0.59).In addition,baseline m PFC GABA level was positively correlated to speed of processing performance(rho =0.384,p =0.023),and Glx level was positively correlated to verbal learning performance(rho =0.378,p =0.025)within CHR-Non Remit group.Meanwhile,some subjects at CHR presented aberrant ASSR and MMN.Conclusions:Prefrontal GABA and Glx levels,both reduced in patients with first-episode schizophrenia and CHR suggested deficit pfrefrontal GABAergic and glutamatergic transmission involved in pathogenesis of schizophrenia.Degree of reduction of prefrontal GABA and Glx levels for CHR subjects were linked to the clinical prognosis indicating potential power of predicting clinical outcome.