Could Low-Dose Ketamine Help Patients with Rett Syndrome?

Collaborative clinical trial to provide first assessment

By Thomas W. Frazier, PhD; Sumit Parikh, MD; and the Rett Ketamine Study Investigative Team

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Researchers from Cleveland Clinic and Case Western Reserve University are conducting an exploratory human study of low-dose ketamine for use in the treatment of the complex neurodevelopmental disorder known as Rett syndrome. The investigation — the first of its kind — is being funded by a grant from the Rett Syndrome Research Trust. If the study is successful, a multicenter phase 2 trial will follow.

Rett syndrome essentials

Rett syndrome results from loss-of-function mutations in MECP2, the gene encoding methyl-CpG binding protein 2, a transcriptional regulatory protein. After a period of apparently normal early development, affected individuals develop a spectrum of symptoms that generally includes the following:

  • Loss of acquired speech
  • Head growth deceleration
  • Motor, respiratory and autonomic dysfunction
  • Stereotypic hand movements
  • Anxiety
  • Increased risk of seizures

Patients with Rett syndrome also experience behavioral symptoms similar to those of autism spectrum disorder, including difficulties with social interaction and repetitive behaviors. As a result, Rett syndrome is one of the most debilitating genetic neurodevelopmental syndromes associated with autism-like features.

Rett syndrome is diagnosed in 1 of 10,000 female births. Treatment focuses on improving the physical and behavioral manifestations. Common treatment modalities are physical, occupational, speech and behavior therapy, along with feeding assistance. Medications can be used to provide some symptomatic relief and to control seizures in some patients, but there is no cure. Treatments that directly influence the pathology of Rett syndrome are desperately needed.

Why ketamine?

The use of ketamine as a treatment strategy is modeled on the recent success of low-dose ketamine for treating major depressive disorder and obsessive-compulsive disorder. In these studies, IV infusion of ketamine has been shown to acutely reverse symptoms, with relief lasting up to a week or more in some cases.

Ketamine has a long history of safe use as an anesthetic, mostly for dental procedures, and more recently for pain management. It is also known as a drug with potential for abuse at higher doses. However, human studies in psychiatric disorders have focused on low, subanesthetic doses that have shown modest side effects relative to substantial benefit. These subanesthetic doses are the focus of our current Rett syndrome trial.

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Potential for acute rescue of neurological function in Rett syndrome

The therapeutic potential of ketamine for treatment of Rett syndrome was first demonstrated by Katz and colleagues, who found that treatment of MECP2-mutant mice with a subanesthetic dose of ketamine acutely reverses or improves several disease symptoms, including abnormalities in brain activity, cognitive function, breathing and locomotion.1,2 Even more recently, chronic administration of ketamine was also found to improve symptoms and extend life span in MECP2-mutant mice.3

In other disease models, ketamine treatment has been shown to rapidly stimulate dendritic growth, brain-derived neurotrophic factor (BDNF) translation and expression of key synaptic proteins through activation of mTOR signaling, which is deficient in MECP2-mutant mice.

Taken together, these findings suggest that, in addition to acute rescue of neurological function, ketamine has the potential to induce long-term synaptic repair by enhancing structural and functional brain connectivity in Rett syndrome.

Trial design and next steps

Approximately 30 patients with Rett syndrome will be enrolled in our exploratory trial (co-principal investigators are David M. Katz, PhD, and Daniel Sessler, MD — see Acknowledgment below). Each participant will be randomized to receive three of five possible doses of ketamine plus a placebo dose. Each dose will be administered intravenously at one of four consecutive monthly visits while safety and efficacy outcome measures are carefully tracked.

The primary aim of the study is to determine the safety and tolerability of single-dose subanesthetic ketamine. Secondary aims are to evaluate potential efficacy, including improvements in breathing, behavioral symptoms, brain function (assessed by EEG and auditory evoked potentials) and overall clinical severity. The study’s within-subjects design allows each patient to be his or her own control and may enable determination of potential dose-safety and dose-efficacy relationships.

If the trial is successful, the next step will be to plan for a large-scale, multisite phase 2 trial of ketamine in patients with Rett syndrome. We may also explore the efficacy of an oral ketamine formulation as an alternative to the IV infusion used in the current trial.

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  1. Kron M, Howell CJ, Adams IT, Ransbottom M, Christian D, Ogier M, Katz DM. Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. J Neurosci. 2012;32:13860-13872.
  2. Mather RJ, Adams I, Lang M, Dunlop J, Aberg E, Quirk MC, Katz DM. Remacemide eliminates apneic breathing in a mouse model of Rett syndrome. Presented at: 2014 Society for Neuroscience Annual Meeting; Nov. 18, 2014; Washington, D.C. Poster 515.06.
  3. Patrizi A, Picard N, Simon AJ, et al. Chronic administration of the N-methyl-D- aspartate receptor antagonist ketamine improves Rett syndrome phenotype. Biol Psychiatry. 2015 Aug 24 [Epub ahead of print].


Dr. Frazier is Director of Cleveland Clinic Children’s Center for Autism.

Dr. Parikh is a pediatric neurologist in Cleveland Clinic’s Center for Pediatric Neurology.

In addition to Drs. Frazier and Parikh, the Rett Ketamine Study Investigative Team includes David M. Katz, PhD, Professor of Neurosciences and Psychiatry, Case Western Reserve University (co-principal investigator), and Daniel Sessler, MD, Chair of Outcomes Research at Cleveland Clinic (co-principal investigator).