Cognitive impairment is a significant aspect of bipolar disorder, affecting both emotional and non-emotional domains, leading to ongoing challenges and poorer outcomes. Efforts to enhance cognitive functioning in these patients have intensified, yet effective treatments remain elusive. Existing bipolar disorder treatments often do not improve and can even worsen cognitive function. Recent studies have highlighted the link between the glutamatergic system and cognitive impairment, particularly through the activation of the N-methyl-d-aspartate receptor (NMDAR). This has sparked interest in NMDAR modulators as potential therapeutic agents. Currently, only a few have been approved for clinical use, and clinical studies are limited in scope. This review examines research on NMDAR modulation aimed at enhancing cognitive function in individuals with bipolar disorder, highlighting promising findings from animal studies and initial clinical trials.

A PubMed and Google Scholar search adhering to PRISMA guidelines was conducted for articles on NMDAR antagonists for the treatment of cognitive deficits in patients with bipolar disorder.

Memantine as an add-on therapy has been linked to improvements in cognitive issues, enhancing memory after traumatic brain injury (TBI), boosting cognitive functioning in treatment-resistant bipolar disorder (BD), and elevating cognitive status in patients with depression before electroconvulsive therapy (ECT) in patients with bipolar disorders. Ketamine infusions have also improved processing speed and verbal learning in bipolar disorder patients.

Evidence suggests that NMDA receptor-modulating agents play a significant role in improving cognitive function in patients with bipolar disorder. Researchers should consider recently identified NMDA receptor antagonists for potential benefits. It is also important to conduct longer and multicenter studies to address the persistent cognitive impairments, such as impairment in attention, executive function, and verbal memory, that patients with bipolar disorder experience throughout their illness, while also assessing the safety of these treatments.