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

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.

Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress–Induced Damage in Patients with Bipolar Disorder

“…The antipsychotic actions of quetiapine are likely derived from its antagonistic activity against DA D 2 receptors and serotonin 5-hydroxytryptamine 2 receptors [350]. Quetiapine is an atypical antipsychotic agent that is administered orally [351,352]. On occasion, it is recommended for the treatment of BD, although some studies have suggested that it is more successful specifically in alleviating the symptoms of anxiety and depression accompanying BD [351][352][353][354].…”

“…Quetiapine is an atypical antipsychotic agent that is administered orally [351,352]. On occasion, it is recommended for the treatment of BD, although some studies have suggested that it is more successful specifically in alleviating the symptoms of anxiety and depression accompanying BD [351][352][353][354]. Five double-blind RCTs evaluated the tolerability and effectiveness of quetiapine over 8 weeks in BD patients who were undergoing a major depressive episode [350].…”

Research Status in Clinical Practice Regarding Pediatric and Adolescent Bipolar Disorders

“…The imaging mechanism of BD is still not clear, but many studies confirmed that BD might be related to neuroanatomical changes, distinct alterations in brain activity, and abnormal metabolism. Lei et al ( 20 ) studied the local anatomical traits of children with BD and found that they presented with an altered structural connector index (increasing cluster coefficient and characteristic path length), which normalized after treatment (lithium and quetiapine). Further, the authors found that the gray matter morphology index was 80% accurate in identifying the response of those children who had received treatment ( 20 ).…”

Pretreatment Alterations and Acute Medication Treatment Effects on Brain Task–Related Functional Connectivity in Youth With Bipolar Disorder: A Neuroimaging Randomized Clinical Trial

“…19 Though quetiapine and lithium exert effects via different mechanisms, there are few neuroimaging studies to understand their systems J o u r n a l P r e -p r o o f level impact on the brain connectome, their differences in location and timing of such effects, and their relation to treatment outcomes in vivo. 20,21 In adult patients with BD presenting with an acute manic episode, a resting-state fMRI study found that lithium treatment showed a more rapid normalization with respect to abnormal functional connectivity observed at baseline. 22 While pediatric connectome studies of drug effects in BD are limited, difference in regional effect of the antipsychotic risperidone and divalproex have been reported in children with BD presenting with an acute manic or mixed episode.…”