Could Low-Dose Ketamine Be a Treatment for ADNP Syndrome in Children?

Treatment with low-dose ketamine is safe, well-tolerated, and effective among children with ADNP syndrome.

Low-dose ketamine may be safe and improve clinical symptoms of activity-dependent neuroprotective protein (ADNP) syndrome among children, according to study findings published in Human Genetics and Genomics Advances.

The leading genetic cause of intellectual disability and autism spectrum disorder (ASD) is ADNP syndrome. Patients often present with aberrant behavior, delayed language development, anxiety, and sleep disturbance. Preclinical evidence found ADNP could be induced by ketamine and may be a potential treatment target.

For this small open-label study ( Identifier: NCT04388774), researchers recruited 10 children at the Icahn School of Medicine at Mount Sinai in the United States between 2020 and 2021. Patients received an open-label infusion of 0.5 mg/kg ketamine and were evaluated from baseline through week 4 for safety and efficacy.

The study population comprised 7 boys and 3 girls, aged mean 9.50 (standard deviation [SD], 2.30) years, 8 were White, 2 were Hispanic, 6 had a frameshift mutation, 4 had a nonsense mutation, 7 children had attention-deficit/hyperactivity disorder (ADHD), and 4 had autism spectrum disorder (ASD). The patients had mean verbal developmental quotient (VDQ) scores of 26.71 (range, 5.65-52.48), nonverbal developmental quotient (NVDQ) scores of 31.28 (range, 8.87-58.42), and full-scale developmental quotient (FSDQ) scores of 28.81 (range, 7.26-54.5).

Findings are intended to be hypothesis generating and provide preliminary support for the safety and efficacy of ketamine in ADNP syndrome in addition to identifying useful endpoints for a ketamine clinical development program.

The researchers found ketamine was associated with improvements in ADHD symptoms, restricted and repetitive behaviors, and sensory reactivity.

Common adverse reactions to ketamine included:

  • Elation or silliness (50%)
  • Aggression (40%)
  • Fatigue (40%)
  • Decreased appetite (30%)
  • Anxiety (30%)
  • Increased appetite (20%)
  • Restless (20%)
  • Increased fluid intake (20%)
  • Nausea or vomiting (20%)
  • Moodiness or irritability (20%)
  • Dry mouth (20%)

At week 1, significant changes were observed in the caregiver assessment at week 1 compared with baseline in the following:

  • Children’s Sleep Habits Questionnaire (CSHQ) total score (P =.02);
  • Short Sensory Profile (SSP) total score (P =.022);
  • Conners instrument subdomains of inattention, hyperactivity or impulsivity (both P ≤.028);
  • Aberrant Behavior Checklist (ABC) subdomains of irritability, social withdrawal, motor stereotypes, and hyperactivity (all P ≤.041); 
  • Anxiety, Depression, And Mood Scales (ADAMS) subdomains of hyperactivity, social avoidance, and obsessive or compulsive (all P ≤.041); 
  • Repetitive Behavior Scale-Revised (RBS-R) compulsive subdomain (P =.041); and
  • Caregiver Strain Questionnaire (CSQ) subdomain of subjective externalized strain (P =.046)

At week 1, clinician evaluation differed significantly compared with baseline in the following:

  • Clinical Global Impression Scale (CGI) improvement subdomain (P =.009)
  • Clinician visual analog scale (VAS) scores for:
  • Thinking and learning (P =.007)
  • Speech (P =.011)
  • Activities of daily living (P =.011)
  • Restricted and repetitive behaviors (P =.027)
  • Social communication (P =.027)
  • Attention, impulsivity, and hyperactivity (P =.028)
  • Sensory Assessment for Neurodevelopmental Disorders (SAND) total score (P =.025)

During the electroencephalogram assessment, gamma wave intertrial phase coherence (ITC) increased from baseline to week 1 (P =.05) while beta wave ITC decreased (P =.05).

Based on the results of the joint attention eye-tracking exam, the researchers did not find any significant effects following ketamine infusion.

They acknowledged that their “Findings are intended to be hypothesis generating and provide preliminary support for the safety and efficacy of ketamine in ADNP syndrome in addition to identifying useful endpoints for a ketamine clinical development program.”

“Future studies will employ a randomized, placebocontrolled design and study the effects of repeated ketamine dosing over a longer duration of time and in a larger cohort of participants,” the researchers concluded.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Kolevzon A, Levy T, Barkley S, et al. An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome. HGG Adv. 2022;3(4):100138. doi:10.1016/j.xhgg.2022.100138