Ketamine rapidly reduces depressive symptoms in treatment-resistant depression but does not improve working memory, attention, or concentration. In a crossover trial, 21 individuals with treatment-resistant depression (14 with bipolar disorder, 7 with major depressive disorder) received ketamine or placebo infusions. Brain activity measured by magnetoencephalography during a working memory task showed increased gamma power in the parieto-occipital junction and decreased gamma power in the posterior superior temporal sulcus and inferior frontal gyrus after ketamine compared to placebo. These distinct gamma power changes in brain regions linked to attention and working memory suggest that ketamine alters neural activity without improving cognitive performance, highlighting the need for further research into its neurobiological mechanisms.
In a double-blind randomized controlled trial, 25 adults with bipolar I or II disorder and treatment-resistant depression received either nitrous oxide (25% concentration for 20 minutes) plus intravenous saline or medical air plus intravenous midazolam (2 mg total). No significant between-group differences emerged in depression severity change or treatment response 24 hours after treatment. However, the nitrous oxide group showed significantly greater same-day reductions in depression severity. Lower baseline regional cerebral blood flow predicted greater 24-hour improvement with nitrous oxide but not midazolam. Midazolam was associated with regional cerebral blood flow reductions compared to nitrous oxide. These secondary findings suggest differential associations of the two agents with depression severity and brain hemodynamics, warranting larger studies.