Study data published in the Journal of the American Academy of Child & Adolescent Psychiatry indicate that acute medication treatment may resolve functional connectivity abnormalities in youth with bipolar disorder.

Compared with healthy individuals, patients with bipolar disorder displayed reduced connectivity in regions of the brain associated with cognitive processing. Following combination treatment with quetiapine or lithium, however, the patient group experienced normalization of brain connectivity. These findings suggest that functional connectivity may be an early biomarker of treatment response in patients with bipolar disorder.

This clinical trial was conducted at the University of Cincinnati Medical Center between 2009 and 2016. Adolescents aged 12 to 17 years with bipolar disorder type I in the mixed-manic phases were matched by age and sex to healthy youth from the surrounding community. Participants underwent functional magnetic resonance imaging (fMRI) while completing a working memory task with both active and control phases.

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Weighted seed-based connectivity (wSBC) was used to assess regional brain interactions during the attention task compared with the control condition. Following baseline evaluation, patients with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium for 6 weeks. Treatment response was assessed using the Young Mania Rating Scale (YMRS). Both patients and control participants underwent follow-up imaging at 1 and 6 weeks postbaseline.

Normalization of functional connectivity in patients was defined using the connectivity observed in the control group. Longitudinal within-group connectivity changes were modeled with linear regression.

The study cohort comprised 71 patients with bipolar disorder and 55 healthy youth. Demographic characteristics were comparable between patient and control groups and between the quetiapine and lithium treatment arms.

At baseline, patients with bipolar disorder displayed the following connectivity differences compared with controls: (1) significantly increased connectivity between the left ventrolateral prefrontal cortex (VLPFC) and left temporal pole (P =.037), left orbitofrontal cortex and right postcentral gyrus (P =.010), and right amygdala and right occipital pole (P =.005); and (2) decreased connectivity between the left VLPFC and left insula (P =.024) and the left insula and anterior cingulate cortex (ACC) (P =.007).

At week 1 of follow-up, quetiapine but not lithium treatment was associated with significant shifts in connectivity towards patterns observed in healthy participants. At week 6, both treatment groups displayed normalization of functional connectivity. In the pooled patient cohort, the group-by-time interaction effect was significant for functional connectivity between the left insula and bilateral ACC (P =.003) and between the right amygdala and right occipital pole (P =.025).

Per correlation analyses, changes in connectivity between the left VLPFC and left temporal pole were significantly associated with reductions in YMRS scores (P =.029). Further, baseline connectivity between the left insula and bilateral ACC was positively correlated with treatment-related reduction in YMRS score at 6 weeks (P =.047).

These data underline the role of functional connectivity in bipolar disorder and treatment response. As study limitations, investigators noted the short follow-up period. Further research is necessary to clarify the long-term effects of bipolar disorder treatment on functional connectivity.

“[T]he present study is one of few fMRI studies focusing on the changes in functional connectivity during cognitive task performance related to effective pharmacological treatment in youth with mixed/manic [bipolar disorder],” investigators wrote.

“Significant normalization of some alterations of functional brain connectivity were observed as early as the first week of treatment with quetiapine, suggesting that imaging approaches as used in our study may provide a useful approach for establishing target engagement for standard as well as promising novel treatments for [bipolar disorder].”

Disclosure: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Li W, Lei D, Tallman MJ, et al. Pretreatment alterations and acute medication treatment effects on brain task-related functional connectivity in youth with bipolar disorder: a neuroimaging randomized clinical trial. J Am Acad Child Adolesc Psychiatry. Published online January 25, 2022. doi:10.1016/j.jaac.2021.12.015