Modulation of early non-rapid eye movement slow wave activity by ketamine in treatment-resistant depression.
Nadia Hejazi, Mina Kheirkhah, Brady Riedner, Qiaoping Yuan, Robin Chholak, Reza Momenan, Gregory Jones, David Goldman, Carlos A Zarate
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 16, 2026 Peer reviewed DOI: 10.1038/s41386-026-02465-4 via PubMed
Summary
Ketamine increases slow-wave activity (SWA) during non-rapid eye movement (NREM1) sleep in individuals with treatment-resistant depression (TRD), particularly among those who respond to the treatment. In a study of 91 unmedicated TRD patients and 42 healthy volunteers, TRD patients exhibited lower baseline NREM1 SWA compared to healthy individuals. Ketamine also improved total sleep time, sleep efficiency, and reduced sleep latency in TRD patients, while having no effect on healthy participants. The increase in SWA associated with ketamine was less pronounced in older patients.
Study at a glance
| Design | placebo-controlled study |
|---|---|
| Sample size | 133 |
| Population | unmedicated patients with treatment-resistant depression and healthy volunteers |
| Key finding | Ketamine increased NREM1 slow-wave activity in treatment-resistant depression patients but had no effect on healthy volunteers. |
Abstract
Slow-wave activity (SWA), a key indicator of sleep homeostasis, is often diminished in individuals with treatment-resistant depression (TRD). Ketamine, a rapid-acting antidepressant, increases SWA during the first period of non-rapid eye movement (NREM1) sleep. However, research into how ketamine affects sleep and its connection to treatment outcomes in TRD has been limited by small sample sizes and a lack of comparison with healthy volunteers (HVs). This placebo-controlled study compared the effects of ketamine on NREM1 SWA in a large sample of unmedicated TRD patients (n = 91; 51 F/40 M) and HVs (n = 42; 23 F/19 M). Linear mixed-effects models and regression analyses, with post-hoc testing (paired ttests and Wilcoxon matched-pairs signed rank tests), were used to assess condition-related effects across baseline, ketamine, and placebo in TRD and HV participants. Age-related moderation of ketamine-associated NREM1 SWA changes and condition-related changes in sleep variables were also examined. At baseline, TRD patients had lower NREM1 SWA than HVs. Ketamine, but not placebo, increased NREM1 SWA in TRD patients, particularly in responders. In contrast, ketamine had no effect on NREM1 SWA in HVs. Following ketamine, TRD patients also showed significant increases in total sleep time and sleep efficiency and a reduction in sleep latency. In TRD patients, the ketamine-related increase in NREM1 SWA diminished with increasing age. Together, the results indicate that ketamine's antidepressant effects appear closely associated with its ability to modulate early SWA. These effects may also be linked to ketamine's ability to improve sleep architecture in TRD. Clinical Trials Identifier: www.clinicaltrials.gov , NCT00088699, NCT01204918.