Changes in the brain structural connectome after a prospective randomized clinical trial of lithium and quetiapine treatment in youth with bipolar disorder

Du Lei,Jing Yang,Yuan Ai,Wenjing Zhang,Kun Qin,L Rodrigo Patino,Qiyong Gong,Su Lui,Fabiano G Nery,Melissa P Delbello,Caleb M Adler,Robert K Mcnamara,Christina C Klein,John A Sweeney,Maxwell J Tallman,David E Fleck,Jeffrey R Strawn,Wenbin Li

doi:10.1038/s41386-021-00989-5

Abstract

The goals of the current study were to determine whether topological organization of brain structural networks is altered in youth with bipolar disorder, whether such alterations predict treatment outcomes, and whether they are normalized by treatment. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. High-resolution MRI images were collected from children and adolescents with bipolar disorder who were experiencing a mixed or manic episode (n = 100) and healthy youth (n = 63). Brain networks were constructed based on the similarity of morphological features across regions and analyzed using graph theory approaches. We tested for pretreatment anatomical differences between bipolar and healthy youth and for changes in neuroanatomic network metrics following treatment in the youth with bipolar disorder. Youth with bipolar disorder showed significantly increased clustering coefficient (Cp) (p = 0.009) and characteristic path length (Lp) (p = 0.04) at baseline, and altered nodal centralities in insula, inferior frontal gyrus, and supplementary motor area. Cp, Lp, and nodal centrality of the insula exhibited normalization in patients following treatment. Changes in these neuroanatomic parameters were correlated with improvement in manic symptoms but did not differ between the two drug therapies. Baseline structural network matrices significantly differentiated medication responders and non-responders with 80% accuracy. These findings demonstrate that both global and nodal structural network features are altered in early course bipolar disorder, and that pretreatment alterations in neuroanatomic features predicted treatment outcome and were reduced by treatment. Similar connectome normalization with lithium and quetiapine suggests that the connectome changes are a downstream effect of both therapies that is related to their clinical efficacy.

Highlights

Bipolar disorder is a common debilitating illness that often has an onset during adolescence [1,2,3]
Young Mania Rating Scale (YMRS) and Children’s Depression Rating Scale-Revised (CDRS-R) scores decreased over time from baseline to week 6 (p < 0.001) (Supplemental Information, Table S1)
Regions were considered abnormal in the bipolar disorder group if they exhibited significant between-group differences (P < 0.05, uncorrected) in at least two of the three nodal centralities

Summary

Introduction

Bipolar disorder is a common debilitating illness that often has an onset during adolescence [1,2,3]. Studying adolescents with bipolar disorder provides a window of opportunity for clarifying illness neurobiology close to the time of onset, and for identifying biological alterations that predict and track clinical change after treatment in individuals with limited prior medication exposure. While anatomy has generally been considered to be relatively static in adult life, recent evidence indicates that both behavioral training and acute treatment with psychotropic medications measurably alter gray matter structures. This includes studies of antipsychotics and lithium in patients with schizophrenia and bipolar disorder [6,7,8]. Evidence suggests that the pathophysiology of bipolar disorder involves network dysconnectivity [10,11,12], so that examining the brain connectome may be a promising strategy for advancing illness understanding and biomarker development

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Results

Conclusion