Perceived antidepressant efficacy associated with reduced negative and enhanced neutral mnemonic discrimination

Background: Depression is associated with general memory impairment as well as a negativity bias, where negative experiences are better remembered. One potential mechanism underlying the negativity bias in depression could be pattern separation, a hippocampal computation that processes similar experiences as unique using non-overlapping representations, enabling individuals to remember the negative details of an experience. Mnemonic discrimination tasks, which provide a behavioral correlate of hippocampal pattern separation, have found that individuals with depressive symptoms show impaired general memory but enhanced negative mnemonic discrimination accompanied by a shift in amygdala-hippocampal dynamics (e.g. increased amygdala and reduced hippocampal activity). Antidepressants are one of the first-line treatments for depression, which have been shown to reverse hippocampal volume reduction, increase neurogenesis, and impact both memory and mood in rodent models. However, the impact of antidepressants on hippocampal pattern separation has not yet been examined in humans. Furthermore, antidepressants have limited efficacy toward successfully reducing depressive symptoms. Methods: We investigated the impact of antidepressants on memory using an emotional mnemonic discrimination task, where we previously reported a negativity bias in depression selective to mnemonic discrimination. Results: We found that individuals who reported a greater improvement in their depressive symptoms after taking antidepressants (responders) showed a reduction in the negativity bias and an enhancement in neutral mnemonic discrimination compared to those with no improvement (non-responders). Discussion: These effects were specific to mnemonic discrimination and not standard memorymeasures, suggesting that effective antidepressants can selectively enhance mnemonic discrimination and reduce the negativity bias observed in depression.