Effects of short-term quetiapine and lithium therapy for acute manic or mixed episodes on the limbic system and emotion regulation circuitry in youth with bipolar disorder

Abstract

Disruptions in the limbic system, and in emotion regulation circuitry that supports affect modulation, have been reported during acute manic episodes of bipolar disorder (BD). The impact of pharmacological treatment on these deficits, especially in youth, remains poorly characterized. 107 youths with acute manic or mixed episodes of bipolar I disorder and 60 group-matched healthy controls were recruited. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. Task-based fMRI studies were performed using an identical pairs continuous performance task (CPT-IP) at pre-treatment baseline and post-treatment weeks one and six. Region of interest analyses focused on the limbic system and ventral PFC - basal ganglia - thalamocortical loop structures known to be involved in emotion regulation. Changes in regional activation were compared between the two treatment groups, and pretreatment regional activation was used to predict treatment outcome. Mania treatment scores improved more rapidly in the quetiapine than lithium treated group, as did significant normalization of neural activation toward that of healthy individuals in left amygdala (p = 0.007), right putamen (p < 0.001), and right globus pallidus (p = 0.003). Activation changes in the right putamen were correlated with reduction of mania symptoms. The limbic and emotion regulation system activation at baseline and week one predicted treatment outcome in youth with bipolar disorder with significant accuracy (up to 87.5%). Our findings document more rapid functional brain changes associated with quetiapine than lithium treatment in youth with bipolar disorder, with most notable changes in the limbic system and emotion regulation circuitry. Pretreatment alterations in these regions predicted treatment response. These findings advance understanding of regional brain alterations in youth with bipolar disorder, and show that fMRI data can predict treatment outcome before it can be determined clinically, highlighting the potential utility of fMRI biomarkers for early prediction of treatment outcomes in bipolar disorder.Clinical Trials Registration: Name: Multimodal Neuroimaging of Treatment Effects in Adolescent Mania. URL: https://clinicaltrials.gov/ . Registration number: NCT00893581.

Fig. 1. Longitudinal changes of clinical symptoms in patients of bipolar disorder by treatment group.

Along with the treatment procedure, the clinical symptoms of patients with bipolar disorder were alleviated. A–E YMRS total, CDRS total, CGI severity mania, CGI severity depression and CGI severity overall). Cross-sectional comparison shows the group-wise differences between lithium and quetiapine treatment group in mania symptoms (YMRS and CGI-mania, A, C) in week 1 and 6 as illustrated by asterisks. The longitudinal treatment-by-time interaction effect was significant in YMRS (F = 3.54, p = 0.03). *p < 0.05; **p < 0.01. YMRS Young mania rating score, CDRS children’s depression rating scale, CGI clinical global impression.

Fig. 2. Longitudinal changes of task-related activation and its correlation with mania symptom changes.

A The treatment-by-time interaction effects were significant in the left amygdala (F = 3.56, p = 0.0074); B right putamen (F = 4.76, p < 0.001,); C right globus pallidus (F = 4.13, p = 0.0029,); D Correlation relationship between changes of mania symptoms and changes of regional activation after drug treatment. The correlation analysis showed the 0-W6 changes of activation in right putamen were positively correlated with the 0-W6 changes of YMRS (r = 0.29, p = 0.040) in the quetiapine treatment group but not the lithium treatment group (r = −0.018, p = 0.92). 0-W6 from baseline to Week six, L left, R right.

Fig. 3. Receiver operating characteristic curves for different prediction models based on regional activation within the limbic and emotion regulation system.

Left panel Performance of models based on baseline regional activation. Right panel Performance of models based on one-week change of regional activation.