Ketamine and esketamine should be reserved for patients who have not responded to two to four adequate antidepressant trials. For mild depression, these treatments may not be appropriate. Esketamine may be considered for acute suicidality in treatment-resistant depression, even though clinical trials did not show a clear benefit; placebo groups receiving excellent inpatient care improved substantially, which masked the drug's effect. These drugs should be avoided in people with active substance use disorder and used with caution even in early recovery, reconsidering only after years of sustained remission.
For patients who relapse after tapering off ketamine or esketamine, restarting an index course—twice weekly for a few weeks then spreading out doses—is recommended. Dysphoric reactions occur in about 1 in 200 to 300 treatments; most resolve with supportive care, while some need a short-acting benzodiazepine like lorazepam. Patients should fast for two hours before esketamine sessions. Nausea can be managed with low-dose ondansetron, and post-treatment headache with over-the-counter ibuprofen or acetaminophen.