Ketamine is a dissociative anesthetic — a hallucinogenic compound that gives users the feeling of detachment from their surroundings — developed by Parke Davis Laboratories (now part of Pfizer) in 1963. It has been used in both humans and animals.

In low doses, ketamine functions as an antidepressant by binding to and activating so-called N-methyl D-aspartate receptors (NMDAR). This results in a reduction in the activity of glutamate, an excitatory neurotransmitter or cell signaling molecule.

The U.S. Food and Drug Administration (FDA) approved the use of ketamine as an anesthetic in 1970. A ketamine-like medicine, esketamine, is currently endorsed as a therapy by the FDA to combat depression. The benefits of using ketamine as a therapy for Rett syndrome is the subject of ongoing preclinical and clinical research.

Ketamine and Rett syndrome

Rett syndrome is an X-linked neurodevelopmental disorder that results in impaired brain development primarily caused by mutations in the MECP2 gene that encodes for the MeCP2 protein. Rett syndrome affects 1 in 10,000 female births and symptoms include motor dysfunction, anxiety, repetitive (stereotypic) hand movements, and seizures.

Research is ongoing to better understand how Rett syndrome affects the brain cortex (part of the brain involved in sensory information processing) and how ketamine can help correct the functioning of nerve cells in the cortex.

While NMDAR antagonists or molecules that block NMDAR have been traditionally associated with less excitatory activity, a study published in Nature Molecular Psychiatry seemed to offer a contrary view. The study showed that the administration of ketamine resulted in increased brain activity to a mouse model of Rett syndrome after genetically knocking off an NMDAR component in certain neurons called parvalbumin interneurons. The parvalbumin interneurons are a group of inhibitory nerve cells in the cortex that synchronize other nerve cells.

It has been found that parvalbumin interneurons were in excess in mouse models of Rett syndrome, which resulted in much higher inhibitory effects and lowered brain activity. This could explain why brain function slows down in Rett syndrome patients. Daily administration of low doses of ketamine was found to slow down symptom progression and restore brain activity in these mouse models.

Ketamine in clinical trials

Further studies are underway in mouse models of Rett syndrome to find out exactly how ketamine works and to determine appropriate dosing for clinical trials.

A Phase 2 randomized clinical trial (NCT03633058) to assess the safety and efficacy of oral ketamine administration in Rett syndrome patients, 6 to 12 years old, is ongoing and expected to be completed by December 2019.

The Rett Syndrome Research Trust is also funding an exploratory clinical trial at the Cleveland Clinic and Case Western Reserve University to determine the efficacy of ketamine in rescuing neurological function in Rett syndrome patients. The study aims to enroll 30 patients, each of whom will receive varying doses of ketamine via intravenous administration. Depending on the results, the study could be followed by a Phase 2 multicenter trial.

Other information

Ketamine is a hallucinogenic compound with the potential to cause addiction and cravings. High doses of ketamine can result in an out-of-body or near death experience. Hence, proper dosing needs to be determined before it can become a viable therapy for Rett syndrome.

Ketamine efficacy has been shown to be dependent on the stage of the female menstrual cycle with the treatment being least effective in the initial phase of the menstrual cycle. Clinical trials should take this factor into account if ketamine is evaluated in adult females.


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