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
Intervention: Ketamine; Dexmedetomidine
Intervention description: Ketamine without dexmedetomidine; Ketamine plus dexmedetomidine
Intervention MeSH terms: Dexmedetomidine; Ketamine
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 40.0
Sex: All
Minimum age: 7 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: NMDA antagonist-induced psychosis; Children; Memory Impairment; Decreased cognitive function; Increased memory impairment

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).
    

Eligibility criteria:

        Inclusion Criteria:

        Patients presenting to St. Louis Children's Hospital's Emergency Department who require
        reduction of an acute forearm fracture will be recruited for enrollment if they satisfy the
        following:

          1. Age 7-17 years, inclusive;

          2. Are psychiatrically healthy (i.e. have never been under the care of a psychiatrist or
             taken psychiatrically active medications);

          3. Meet American Society of Anesthesiologist (ASA) Class I and II criteria (I=healthy,
             II=chronic disease under good control);

          4. Have had no prior fracture reduction or ketamine administration;

          5. Present for care when research assistants are present (Monday-Friday, 09:00-23:00);
             and

          6. Have a home telephone or ready means of establishing telephone contact.

        All subjects and their parent/guardian will give Washington University Human Studies
        Committee approved written informed assent and consent prior to participation.

        Exclusion Criteria:

          1. Solid food intake 2 hours or less before procedure;

          2. Compromised cardiorespiratory function; central nervous system, hepatic, or renal
             abnormality;

          3. History of psychosis in patient or first degree relative;

          4. Currently taking medications that stimulate or depress mental function, e.g.
             methylphenidate for attention deficit hyperactivity disorder or drugs of abuse;

          5. History of allergy or adverse reaction to alpha-2 adrenoreceptor agonist drugs, e.g.
             clonidine.

        These exclusion criteria relate to contraindications for use of the agents employed in the
        study. Criteria 1, 2, 3 and 4 are current routine practice for ketamine sedations.