Neural Signatures of Bipolar Disorder and Psychotropic Medication Effects: A Multimodal Positron Emission...

Synaptic loss and altered network function in frontolimbic brain regions have been implicated in the neurobiology of bipolar disorder (BD), but in vivo evidence remains limited. Synaptic vesicle glycoprotein 2A (SV2A), a biomarker of synaptic density, can be quantified using [¹¹C]UCB-J positron emission tomography (PET).

Nineteen individuals with BD, including BDI (n = 13) and BDII (n = 6), and healthy control (HC) participants (n = 26) completed SV2A PET imaging in parallel with structural and functional magnetic resonance imaging to assess frontolimbic synaptic density, gray matter volume (GMV), and intrinsic connectivity, respectively.

Individuals with BD showed lower frontolimbic SV2A density, which exploratory analyses revealed to be seemingly driven by individuals taking psychotropic medications (BD-med). Conversely, group differences in GMV were observed only when accounting for medication status, with higher GMV in BD-med individuals relative to unmedicated individuals with BD (BD-none). Connectivity was higher in the BD group overall, but lower in the BD-med group relative to the BD-none group. SV2A and GMV were positively correlated in HC participants. However, this relationship was absent in individuals with BD, with lower SV2A/GMV ratios being associated with greater impulsivity in BD.

These findings provide the first in vivo evidence of synaptic deficits in BD and offer preliminary evidence suggesting that psychotropic medications may differentially influence brain structure and function. These results underscore the importance of accounting for medication effects when interpreting neuroimaging findings in BD and the need to disentangle illness-related changes from medication effects on brain and behavior in BD.