Combined Use Of High Frequency RTMS And Family Intervention To Improve Psychiatric Symptoms And Cognitive Function In First-episode Schizophrenia And Its Mechanism

Objectives1.To observe the improvement of psychiatric symptoms and cognitive function of patients with first-episode schizophrenia by combining high-frequency repetitive transcranial magnetic stimulation(rTMS)and family intervention on the basis of antipsychotic medication.2.To observe the changes of adjunctive high-frequency rTMS and family intervention on serum brain-derived neurotrophic factor(BDNF)and glial cell line-derived neurotrophic factor(GDNF)in patients with first-episode schizophrenia on the basis of antipsychotic medication.3.On this basis,studying the relationship between psychiatric symptoms,cognitive function improvement and changes in the serum levels of BDNF and GDNF in schizophrenia patients before and after treatment,and exploring the possible mechanism of r TMS in the treatment of schizophrenia.Material and methods1.From January 2016 to September 2017,150 untreated first-episode patients with schizophrenia(case group)were recruited from the Department of Psychiatry at the First Affiliated Hospital of Zhengzhou University,and 50 healthy volunteers were recruited(normal control group).Case group enrolled that day were obtained detailed history,physical examination and psychiatric examination,clinical data were collected.Psychiatric symptoms were evaluated by Positive and Negative Symptoms Scale(PANSS).The patients were randomly divided into three groups for a 12-week randomized controlled study.All patients were treated with risperidone only.One group was treated with risperidone alone(case control group)(n=50),one group was given risperidone with 10Hz rTMS treatment(r TMS group)(n=50),and one group was treated with risperidone combined with 10Hz rTMS treatment and famliy intervention therapy(combination group)(n=50).Patients treated with rTMS were enrolled 10 times for 2 weeks after enrollment,and patients who had family intervention therapy were initiated immediately after enrollment.2.All patients were collected venous blood sample on the second day and the 6th and 12th weekends.Serum BDNF and GDNF levels were measured by enzyme-linked immunosorbent assay(ELISA),and fasting blood glucose was measured by glucose oxidasemethod.Theleveloffastinginsulinwasmeasuredby electrochemiluminescenc.At the same time,psychiatric symptoms were assessed by PANSS scale and cognitive function were assessed by MCCB.The TESS scale was used to assess side effects during treatment.The general data of the normal control group were collected,fasting blood glucose,insulin and serum BDNF,GDNF levels were measured,and cognitive function was assessed.3.SPSS22.0 statistical software was used for experimental data analysis.Measured data are expressed as the mean plus/minus standard deviation(?x±s),and the percentage of count data use cases(example(%)).ANOVA was used to compare multiple groups.The q-tests were used to compare the data between groups.The overall curative effect before and after treatment was compared by repeated measures analysis of variance.The treatment protocol was intergroup factors.The time before and after the treatment was the intragroup factor.Chi-square test or chi-square test with continuous correction was used to analyze the count data.The correlation test was in accordance with the normal distribution using the Pearson correlation analysis,and the Spearman correlation analysis was used for the abnormal distribution.All statistical analyses were statistically significant with a bilateral P<0.05.Results1.142 patients completed the 12-week of follow-up.48 patients in the combined group,47 patients in the rTMS group and 47 patients in the case control group.Into the normal control group,there were 50 cases.The age,education,gender,smoking history,body weight,BMI,blood glucose,insulin and insulin resistance index were no significant differences between the case group and the normal control group(all P>0.05).There were no significant difference in PANSS scale scores,cognitive function scores,and serum levels of BDNF and GDNF among the combination group,the rTMS group,and the case control group(all P>0.05).2.On the PANSS scale.The PANSS total scores,positive symptom scores,negative symptom scores,and general pathology scores of the 6th and 12th weekend,groups were all significantly lower than that in baseline period(all P<0.05).In the negative symptom scores,there was statistically significant difference among the three groups at the 6th and the 12th week(all P<0.05);at the 6th week,the negative scores of the combined group(16.8±3.8)were lower than the case control group(18.4±3.1)(P<0.05),there was no significant difference in the negative symptom score between the combined group and the rTMS group(16.5±3.5)(P>0.05);at the12th week,the negative symptom scores of the combination group(14.7±4.5)were significantly lower than the case control group(17.6±2.5)(P<0.05).There was no significant difference between the combined group and the rTMS group(15.9±2.4)in the negative symptom score(P>0.05).In terms of PANSS total scores,there was statistically significant difference among the three groups at the 12th week(P<0.05).The combined group(53.4±5.7)was significantly lower than the rTMS group(56.8±5.5)and the case control group(59.5±5.1)(P<0.05).The difference between the rTMS group and the case control group was statistically significant(P<0.05).There was no significant difference in the improvement of positive symptoms and general pathology scores between the three groups(all P>0.05).3.In terms of cognitive function,at the the 6th week,there were statistically differences in attention/alertness T scores(39.5±5.6,39.1±5.7,34.1±7.8),work-learning T scores(45.7±6.1,44.6±7.0,41.6±7.7),visual memory T scores(48.6±5.9,47.4±8.3,42.0±6.8)among three groups(all P<0.05).There was no significant difference between the combined group and the rTMS group(all P>0.05),both were higher than the case control group.At the 12th week,there were statistically significant difference in scores in all areas of cognitive function between the three groups(all P<0.05);it was higher in combined group at information processing speed T scores(49.9±7.3),attention/alertnessTscores(48.9±5.8),wordlearningT scores(49.9±8.5),reasoning and problem solving T scores(42.9±9.2)and social cognitiveTscores(50.3±9.2)thanthatincasecontrol group(43.9±7.4,37.6±8.2,45.5±8.7,38.1±6.5,46.1±7.6)(all P<0.05).There was no significant difference between the combined group and the rTMS group(all P>0.05).In working memory T scores(53.1±10.3,45.8±8.0)and visual learning T scores(49.9±8.5,45.5±8.7),the scores were higher at the combined group than that in case control group(all P<0.05),there was no significant difference between the rTMS group and the case control group(all P>0.05).4.Changes of serum BDNF and GDNF levels.At the 6th week,the serum levels of BDNF and GDNF in combined group[(7.8±1.9)ng/ml,(450.9±80.8)pg/ml]and rTMS group[(7.6±1.4)ng/ml,(452.1±78.2)pg]were increased compared with baseline levels(all P<0.05).There was no significant difference in serum BDNF and GDNF levels between combined group and rTMS group(all P>0.05).Serum levels of BDNF and GDNF[(7.1±1.8)ng/ml,(432.7±78.5)pg/ml]in the case-control group were not significantly different from baseline(all P>0.05).At the 12th week,the levels of serum BDNF and GDNF in the three groups were significantly higher than those at baseline(all P<0.05);in the serum BDNF levels,the combined group[(9.3±2.3)ng/ml]was higher than rTMS group[(8.3±1.6)ng/ml](P<0.05),the rTMS group was higher than the case control group[(7.5±1.6)ng/ml](P<0.05),in the serum GDNF levels,the combined group[(486.1±78.2)pg/ml]was higher than the case control group[(448.7±75.1)pg/ml](P<0.05),there was no significant difference between the combined group and the rTMS group[(470.9±102.2)pg/ml](P>0.05).5.Changes in metabolic indicators.At the 6th week,there were no statistically significant among combination group,rTMS group,case control group in the metabolic indicators compared with pre-treatment metabolic indicators(all P>0.05).At the 12th week,there was no significant difference in metabolic indicators of the combined group compared with that before treatment(all P>0.05);the fasting insulin and insulin resistance index[(6.6±0.7)μU/mL,1.6±0.3]in rTMS group were increased than that of baseline levels[(6.2±1.1)μU/mL,1.4±0.4](P<0.05);in the case control group,BMI,fastingbloodglucose,fastinginsulin,andinsulinresistance index[(21.8±1.8)kg/m~2,(5.7±0.6)mmol/L,(6.7±0.8)μU/mL,1.7±0.2]were higher than that of baseline[(20.6±1.6)kg/m~2,(5.2±0.7)mmol/L,(6.1±0.8)μU/mL,1.4±0.3](all P<0.05);there were no significant difference in insulin resistance and insulin resistance index between the rTMS group and the case control group(all P>0.05),both were higher than the combined group(all P<0.05).6.Correlation analysis.(1)Before treatment,serum BDNF levels in combination group,rTMS group,and case control group were negatively correlated with the negative symptom scores(r=-0.316,-0.304,-0.278,P<0.05),there were no correlation with the rest of the PANSS scores.At the the 6th and 12th week,serum BDNF levels in combined group,rTMS group,and case control group were not correlated with any of the PANSS scores.Before and after treatment,there were no correlation between serum GDNF levels and PANSS scores in combination group,rTMS group,and case control group.(2)Before treatment,the serum BDNF levels in combined group and rTMS group were positively correlated with attentional/alert T scores(r=0.339,0.389,all P<0.05),and working memory T scores(r=0.346,0.363,all P<0.05)and visual learning T scores(r=0.289,0.334,all P<0.05).The serum BDNF levels in the case-control group was positively related to the attention/alert T scores and working memory T scores(r=0.475,0.436,all P<0.05).Before treatment,serum GDNF levels in combined group and rTMS group were positively associated with attention/alerting T scores(r=0.203,0.397,all P<0.05)and visual learning T scores(r=0.443,0.491,all P<0.05).At the 6th week,serum GDNF levels in combined group was positively correlated with attentional/alertness T scores,working memory T scores,and visual learning T scores(r=0.307,0.314,0.398,all P<0.05).There was a positive correlation between serum GDNF levels and working memory T scores and visual learning T scores(r=0.388,0.309,all P<0.05)in rTMS group.At the 12th week,the serum GDNF levels of rTMS group was positively related to visual learning T scores(r=0.294,P<0.05).6.Safety measures.There was no significant differences in the incidence of transient head discomfort,tinnitus,tachycardia,extrapyramidalreactions and drug-related adverse reactions during the treatment(all P>0.05).Conclusions1.10Hz rTMS combined with family interventional therapy can better relieve the psychiatric symptoms of schizophrenia patients,improve the patient’s attention,memory and executive function,thereby improving the patient’s cognitive function.2.Serum levels of BDNF and GDNF are abnormal in patients with schizophrenia.10Hz rTMS combined with family interventional therapy can improve serum BDNF and GDNF abnormalities in patients with schizophrenia.3.10Hz rTMS combined with family intervention adjuvant therapy may improve neuronal function by improving serum neurotrophic factors in patients with schizophrenia,and relieve negative symptoms and cognitive impairment in patients.