Clinical studies suggest that (
R,S)-ketamine may improve cognitive impairment in patients with mood disorders. Six repeated infusions of (
R,S)-ketamine (0.5 mg/kg) were found to ameliorate cognitive impairment (i.e., processing speed) in treatment-resistant patients with MDD or BD [
84‐
86]. A systematic review revealed that (
R,S)-ketamine infusion led to significant improvements in cognitive impairment in treatment-resistant patients with MDD, and (
R,S)-ketamine did not worsen cognitive function in depressed patients [
87]. Furthermore, the improvement in working memory may be predictive of the anti-suicidal ideation response to (
R,S)-ketamine in treatment-resistant patients with MDD [
88]. Repeated infusion of (
R,S)-ketamine (0.5 mg/kg) caused significant improvement of working memory in MDD patients with PTSD [
89]. Interestingly, depression symptom severity and processing speed performance in patients with MDD or BD partially mediated the improvements in suicidal ideation after repeated infusion of (
R,S)-ketamine [
90]. A recent systematic review indicated potential procognitive effects of subanesthetic doses of (
R,S)-ketamine among patients with depression, although there is evidence for immediate altered cognitive dysfunction in healthy subjects [
91]. In addition, precognitive effects of (
R,S)-ketamine were pronounced in cognitive domains of executive function. A short course of repeated infusion of (
R,S)-ketamine (0.5 mg/kg) produced significant improvements in several cognitive domains, including attention, working memory, verbal memory, and visuospatial memory in treatment-resistant patients with MDD [
92]. Taken together, these findings suggest that (
R,S)-ketamine has beneficial effects on cognitive impairment in depressed patients, although further studies with larger sample sizes are needed.
Patients with MDD or BD typically exhibit a range of negative beliefs, such as worthlessness, hopelessness, and pessimism, and these conditions are considered to be a major public mental health concern [
93,
94]. A recent study demonstrated that infusion of (
R,S)-ketamine (0.5 mg/kg) improved depressive symptoms in treatment-resistant patients with MDD, and that the improvement was associated with changes in belief-updating processes [
95]. These recent data provide new insights into the cognitive mechanisms of action of (
R,S)-ketamine in mood disorders.