The Value Of Clinical And Magnetic Resonance Imaging Features Of Depressive Episodes In The Identification Of Translation To Bipolar Disorder: A 5-year Follow-up Study

Objective:Bipolar disorder(BD)is a recurrent severe mental disease with high disability.Most patients with BD often suffer from depression for the first onset.It is difficult to identify clinically,which leads to delayed diagnosis and improper treatment,and makes patients face worse prognosis and more substantial economic burden.In this study,patients with major depressive disorder(MDD)were followed up longitudinally for five years to explore the incidence of conversion to BD and related risk factors.After a 5-year follow-up,the patients were divided into two groups:unipolar depression(UD)group and bipolar depression before manic episode(BDbME)group.Resting-state functional MRI(rsfMRI)was applied to explore the characteristics of brain structure and spontaneous nerve activity during the depressive episode.Then we investigated whether the indicators can be used as biomarkers to identify the disease diagnosis.Finally,the early discriminant model of MDD to BD was established through the clinical and imaging features.Methods:The 18-50-year-old MDD patients who met the diagnostic criteria of DSM-IV(Diagnostic and Statistical Manual of mental disorders)in Brain Hospital Affiliated to Nanjing Medical University and the healthy controls matched with general demographic characteristics were recruited.3.0T MRI scanning performed after demographic and clinical data collection.All subjects were followed up every six months for five years to analyze conversational incidence and risk factors of MDD transforming to BD.After MRIcron software processed the imaging data of all subjects,Dparsf 2.0 was used for time correction,head movement correction,space normalization and mapping to Monte Carlo standard template.We regrouped BDbME,UD and healthy control(HC)based on the modified diagnosis.The data of clinical characteristics,volume-based morphometry(VBM)and resting function were analyzed between the three groups.In addition,the receiver operating characteristic curve(ROC)analysis was used to determine clinical features and imaging parameters.SPSS 19.0 was used to analyze the social demographic data and clinical data.The two-sided Pearson chi-square test conducted the gender comparison of three groups.Single-factor analysis of variance was utilized to compare the age and education years of three groups.The age of onset,the total course and the numbers of disease episode,the duration of the current episode,and the HAMD₁₇scores were tested by two-sample t-test between the BDbME and UD.Also,the family history of mood disorders,the course of chronic disease,treatment resistance,attempted suicide,and the circadian rhythm of mood change were detected by Pearson chi-square.The imaging discrepancy among the three groups was estimated by one-way Analysis of variance(ANOVA).This study included three parts:a clinical follow-up study,structural MRI study and rsfMRI study.Result:1.Clinical follow-up studyTwo hundred and eighty-one MDD patients and 122 HC were enrolled in this study.Twenty-five patients were out of followed,and 37 cases converted to BD in the MDD group.The conversion did not occur at last available assessment in 219 MDD patients,and 92 of them didn't convert in 5 years.Seven healthy controls were excluded because of mental disorder or physical disease in the follow-up.Finally,a total of 138 patients(37 BDbME,92 UD)and 115 HC were included in the statistical analysis.At the end of the 5-year follow-up,the conversion rate of MDD to BD was14.45%.There was no significant difference in age and gender among the three groups(p>0.05).There was significant difference in education years(F=12.759,p<0.001).There was no significant difference in education years,HAMD₁₇total score,HAMA total score,YMRS total score,age of onset,number of episode,chronicity and refractory(p>0.05),and,significant difference in the family history of mood disorders(?2=4.768,P=0.029))and attempted suicide(?2=10.080,p=0.001)were founded between two patient groups.ROC analysis was performed on the age of onset,numbers of episode,the total score of HAMD₁₇,family history of mood disorder,chronicity,refractory and attempted suicide in BDbME and UD groups.AUC=0.693(95%confidence interval(CI)0.586-0.799,p<0.001).2.Structural MRI studyA total of 66 patients(33 BDbME,33 UD)and 36 HC were included in this study.There was no significant difference in age,gender and years of education among the three groups.There was no significant difference between BDbME and UD in age of onset,number of episode,total course of disease,total score of HAMD₁₇,family history of mood disorders,chronicity,refractory,attempted suicide and circadian rhythm of emotional change(p>0.05).The different areas of grey matter volume among the three groups were the left precuneus,left superior parietal lobule and left postcentral gyrus.Compared with the HC group,the volume of the left superior parietal lobule in BDbME group increased,the volume of the left superior parietal lobule,the left precuneus and the left postcentral gyrus in UD group increased.The volume of the left precuneus and the left postcentral gyrus in BDbME group decreased compared with the UD group.ROC analysis was performed between the patients with the left precuneus and left postcentral grey matter volume.AUC=0.757(95%CI:0.640-0.874,p<0.001).3.rsfMRI studyThe amplitude of low frequency vibration(ALFF)values of the right superior frontal gyrus and right precentral gyrus were significantly different among three groups(GRF correction,p<0.05).Compared with HC,ALFF value of the right superior frontal gyrus decreased in BDbME group,and ALFF value of the right superior frontal gyrus and right precentral gyrus decreased in UD group.Compared with UD,ALFF value of right superior frontal gyrus in BDbME group increased(GRF correction,p<0.05).In BDbME group,the correlation between ALFF value of the right superior frontal gyrus and family history of mood disorder was statistically significant(p<0.05,uncorrected).ROC analysis was performed with ALFF value of right superior frontal gyrus between patients,AUC=0.654(95%CI:0.521-0.787,p=0.032).The difference of fALFF between three groups was the left calcarine gyrus and right lingual gyrus(GRF correction,p<0.05).Compared with HC,the value of fALFF in the left calcarine gyrus decreased in the patient groups and increased in the right lingual gyrus in BDbME group compared with UD group(GRF correction,p<0.05).In BDbME group,there was no significant correlation between the value of fALFF and clinical features(p>0.05).ROC analysis was used to distinguish BDbME and UD by the value of fALFF in the right lingual gyrus.The results showed that AUC=0.778(95%CI:0.668-0.887,p<0.001).There were significant differences in the regional homogeneity(Re Ho)values among the three groups in the right fusiform,right parahippocampal gyrus,left inferior temporal gyrus,left middle temporal gyrus,left rectal gyrus and bilateral cuneus lobe(p<0.05).In the BDbME group,the Re Ho value of the left inferior temporal gyrus was higher than that of the right parahippocampal gyrus and the left direct gyrus.Compared with the HC group,the Re Ho values of the right fusiform gyrus and left inferior temporal gyrus in BDbME group increased,while the left cuneus lobe decreased.Compared with HC,the Re Ho values of right inferior temporal gyrus,right fusiform gyrus and left middle temporal gyrus in the UD group increased.In contrast,the Re Ho values of right cuneus lobe decreased(GRF correction,p<0.05).In BDbME group,there was no significant correlation between Re Ho value and clinical characteristics(p>0.05).ROC analysis was used to distinguish BDbME and UD.The results showed that AUC=0.889(95%CI0.811-0.967,p<0.001).In the functional connectivity(FC)analysis based on the region of interest,only the FC values between the ventral tegmental area(VTA)and the ventral striatum(VS)were significantly different between BDbME and UD(FDR correction,p<0.05).ROC analysis of FC value of left VTA and left VS was used to distinguish BDbME and UD.The results showed that AUC=0.70.ROC analysis,combined with clinical data and imaging features,was used to distinguish BDbME and UD groups.The results showed that AUC=0.972(95%CI0.938-1,p<0.001).Conclusion:Inpatients with MDD have a higher risk of conversion to BD.Patients with family history of mood disorder,attempted suicide,and other risk factors might be the key indicators to evaluate and follow up.BD has different clinical,structural and resting-state functional imaging characteristic from UD before the manic episode,and these clinical and imaging features can be used as predictors of future diagnosis.