A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome.
Kathleen Campbell, Jeffrey L Neul, David N Lieberman, Elizabeth Berry-Kravis, Tim A Benke, Cary Fu, Alan Percy, Bernhard Suter, David Morris, Randall L Carpenter, Eric D Marsh, Jana von Hehn
Journal of neurodevelopmental disorders January 24, 2025 DOI: 10.1186/s11689-025-09591-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial, crossover Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 23 |
| Population | 6-12-year-old girls with Rett syndrome |
| Intervention | oral ketamine |
| Dose | 0.75 mg/kg/dose twice daily (Cohort 1) or 1.5 mg/kg/dose twice daily (Cohort 2) |
| Duration | 5 days treatment, 9-day wash-out period |
| Topics | Ketamine Esketamine |
| Keywords | Electroencephalography Rett syndrome Clinical trials Neurological disorders Pediatric medicine Experimental treatments Ketamine therapy |
| Citations | 5 |
| Registration | NCT03633058 |
| Key findings | Short-term low-dose oral ketamine was safe and tolerated in girls with Rett syndrome but showed no clinical efficacy over placebo after five days of treatment. |
Abstract
Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy. This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy. Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity. Twenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019-11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine. Short-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT. Registered at clinicaltrials.gov NCT03633058.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cited by 2
- Ketamine alters the aperiodic EEG exponent in major depression: implications for cortical E/I balance and treatment prediction. Therapeutic Advances in Psychopharmacology 2026
- Therapeutic potential of classic and non-classic psychedelics in neurodevelopmental disorders: Opportunities and challenges Pharmacological Research August 26, 2026
Cites 7
- Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action PLoS One September 24, 2012
- Oral ketamine for the treatment of pain and treatment-resistant depression The British Journal of Psychiatry February 1, 2016
- Neural complexity EEG biomarkers of rapid and post-rapid ketamine effects in late-life treatment-resistant depression: a randomized control trial Neuropsychopharmacology April 19, 2023
- Identification of an Optimal Dose of Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Bayesian Adaptive Randomization Trial Neuropsychopharmacology November 27, 2021
- Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety. The International Journal of Neuropsychopharmacology August 1, 2018
and 2 more in the library