Prevention of N-methyl-D-aspartate (NMDA) Antagonist-induced Psychosis in Kids
Condition: Psychoses, Substance-Induced
MeSH terms: Psychoses, Substance-Induced; Psychotic Disorders; Mental Disorders; Shared Paranoid Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      Ketamine, an FDA approved anesthetic agent, is becoming the sedative/analgesic of choice for
      emergency sedation in children because it causes deep sedation with minimal respiratory
      depression in comparison to other available agents. However, emergence reactions are an
      important adverse effect of ketamine, characterized by transient changes in cognitive
      function, dissociation and mild schizophrenia-like symptoms. These cognitive and behavioral
      effects are dose-dependently induced by ketamine and other antagonists of the
      N-methyl-D-aspartate (NMDA) glutamate receptor. NMDA receptor hypofunction can disinhibit
      excitatory (cholinergic/glutamatergic) projections in key areas of the brain, and this has
      been proposed to explain key features of schizophrenia. Several treatments that block
      excessive excitatory transmitter release have also been shown to prevent cognitive and
      behavioral effects of ketamine-induced NMDA receptor hypofunction in humans. Alpha-2
      adrenergic agonists, which can presynaptically inhibit acetylcholine release, can prevent
      mild ketamine-induced behavioral and cognitive symptoms in healthy human adults. However,
      this prevention strategy has not been evaluated in children. Children currently receive
      clinically-indicated treatment with the NMDA antagonist, ketamine, and this age group is an
      important target for pharmacological strategies aimed at the prevention of schizophrenia.
      This application proposes a double-blind, placebo-controlled, randomized trial to test the
      safety and effectiveness of dexmedetomidine, an FDA approved alpha-2 adrenergic agonist, in
      preventing ketamine-induced mental symptoms in children. Planned primary analyses will
      evaluate effects of the hypothesized prevention treatment on clinical and cognitive variables
      using analysis of variance (ANOVA). The proposed experiments are relevant to future
      prevention trials for individuals at risk for schizophrenia, and to preventing adverse
      effects of NMDA antagonist anesthetic agents (ketamine, nitrous oxide).
    

Detailed description: 
      The proposed study will be conducted using existing dedicated clinical and research space in
      St. Louis Children's Hospital's Emergency Department, Pediatric Clinical Research Center
      (PCRC), and Orthopedic Clinic. This project has 3 major aims and 1 exploratory aim addressed
      by a prospective randomized blinded placebo controlled drug trial to test whether a
      pharmacological strategy can prevent NMDA receptor hypofunction-induced behavioral and
      cognitive dysfunction in pre- and post-pubertal children. Based on previous preclinical and
      clinical research on the effects and blockade of the effects of ketamine and similar
      compounds, the study investigators have carefully selected a dose of the alpha-2 adrenergic
      agonist dexmedetomidine that will permit this study to be conducted with low risk to enrolled
      subjects who are undergoing clinically-indicated ketamine sedation for forearm fracture
      reduction.

      General Experimental Design: This project will test the safety and effectiveness of
      dexmedetomidine for preventing ketamine-induced behavioral and cognitive symptoms in healthy
      human children undergoing clinically indicated ketamine sedation for forearm fracture
      reduction.

      Aims 1 and 2 will be addressed by randomized, blinded administration of dexmedetomidine or
      saline placebo to ketamine-sedated subjects to test the efficacy of dexmedetomidine in
      preventing ketamine-induced behavioral and cognitive changes during recovery from sedation.

      Aim 3 will be addressed by comparing between the subjects randomized to receive
      dexmedetomidine or saline placebo measurements of distress and frequency of adverse
      cardiopulmonary effects during sedation, fracture-reduction, and recovery.
    

Intervention name(s): Ketamine; Dexmedetomidine
Intervention type(s): Drug; Drug
Intervention description(s): Ketamine without dexmedetomidine; Ketamine plus dexmedetomidine
Other intervention name(s): Ketanest; Ketaset; Ketalar; Precedex
Intervention MeSH terms: Dexmedetomidine; Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: NMDA antagonist-induced psychosis; Children; Memory Impairment; Decreased cognitive function; Increased memory impairment