The most common pitch for esketamine has been speed: a nasal spray that can ease treatment-resistant depression within days, not weeks. But a new systematic review and meta-analysis in the Journal of Affective Disorders suggests the more useful clinical lesson may be the opposite. When the authors pooled nine observational studies of intranasal esketamine used in routine practice, they found that patients were about five times more likely to be in remission at three months than at the end of the four-week induction phase. For clinicians and patients who judge the drug a failure after the first month, that finding argues for patience.
The analysis was built to answer a question that randomized trials cannot fully settle: Does esketamine work outside the tightly selected populations of registration studies? The real-world patients included people with comorbid anxiety, personality, and substance use disorders, groups often excluded from trials. Overall symptom reduction was large (Hedges’ g of -1.98), and effectiveness did not differ by sex or by psychiatric comorbidities. That matters, because the patients who end up in esketamine clinics are rarely the “clean” cases seen in trial protocols. Individual real-world cohorts have reported a similar pattern, with remission continuing to build well past induction.
The safety picture deserves equally plain talk. Among studies that reported safety data, 82 percent of patients had at least one adverse event, and nearly half had dissociation. These effects are usually short-lived and are the reason esketamine is given under supervision, with blood pressure checks and observation after each dose. But they are real, and patients should hear about them before starting, not after. The authors are also open about the study’s main weakness: None of the included studies had a control group, so the large effect sizes almost certainly overstate the true benefit. By comparison, pooled randomized trials show a more modest short-term advantage over placebo, along with roughly halved relapse risk when responders keep taking the drug.
So what should a practicing clinician take from this? First, a disappointing first month is not necessarily the verdict, and continuing through optimization deserves consideration before giving up on the drug. Second, comorbidity alone should not rule patients out. Third, the field badly needs controlled comparative studies of long-term strategies: how long to continue, how to taper, and how esketamine compares with alternatives such as electroconvulsive therapy or IV ketamine. Until those answers arrive, the real-world message is simple: In treatment-resistant depression, the patients who recover are often the ones whose clinicians gave the treatment time to work.
Ravi Singareddy is the founder and medical director of Empower Psychiatry & Sleep in north metro Atlanta, where he leads an interventional psychiatry practice offering transcranial magnetic stimulation (TMS) and Spravato (esketamine) for treatment-resistant depression. Double board-certified in psychiatry and sleep medicine, he brings more than two decades of clinical and academic experience to patients who haven’t found relief with medications alone. He is affiliated with Emory Healthcare.
His interest in neuromodulation dates back to his years as associate professor of psychiatry at Penn State College of Medicine. There, he taught annually on vagus nerve stimulation and novel depression therapies, and he published on long-term combined electroconvulsive therapy and vagus nerve stimulation in the American Journal of Psychiatry. He has authored numerous peer-reviewed papers on sleep disorders, insomnia, anxiety, and depression, with work appearing in Sleep, the Journal of Clinical Sleep Medicine, and Psychiatry Research.
Singareddy is a Fellow of the American Psychiatric Association and the American Academy of Sleep Medicine and practices measurement-based care, tracking outcomes to guide every treatment decision. He shares updates on Instagram.
