A pilot study examining the impact of lithium treatment and responsiveness on mnemonic discrimination in bipolar disorder

Introduction: Mnemonic discrimination (MD), the ability to discriminate new stimuli from similar memories, putatively involves dentate gyrus pattern separation. Since lithium may normalize dentate gyrus functioning in lithium-responsive bipolar disorder (BD), we hypothesized that lithium treatment would be associated with better MD in lithium-responsive BD patients. Methods: BD patients (N = 69; N_Responders = 16 [23 %]) performed the Continuous Visual Memory Test (CVMT), which requires discriminating between novel and previously seen images. Before testing, all patients had prophylactic lithium responsiveness assessed over ≥1 year of therapy (with the Alda Score), although only thirty-eight patients were actively prescribed lithium at time of testing (55 %; 12/16 responders, 26/53 nonresponders). We then used computational modelling to extract patient-specific MD indices. Linear models were used to test how (A) lithium treatment, (B) lithium responsiveness via the continuous Alda score, and (C) their interaction, affected MD. Results: Superior MD performance was associated with lithium treatment exclusively in lithium-responsive patients (Lithium x AldaScore β = 0.257 [SE 0.078], p = 0.002). Consistent with prior literature, increased age was associated with worse MD (β = −0.03 [SE 0.01], p = 0.005). Limitations: Secondary pilot analysis of retrospectively collected data in a cross-sectional design limits generalizability. Conclusion: Our study is the first to examine MD performance in BD. Lithium is associated with better MD performance only in lithium responders, potentially due to lithium's effects on dentate gyrus granule cell excitability. Our results may influence the development of behavioural probes for dentate gyrus neuronal hyperexcitability in BD.