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N-acetylcysteine and NMDA Antagonist Interactions

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Yale University
ClinicalTrials.gov Identifier:
NCT00611897
First received: January 29, 2008
Last updated: May 7, 2015
Last verified: May 2015
  Purpose
This study tests the hypothesis that extrasynaptic mechanisms are critically linked with cognitive effects of NMDA antagonism as evidenced by event-related potentials (ERPs) in healthy humans.

Condition Intervention Phase
Cognitive Dysfunction
Drug: N-acetylcysteine and ketamine
Drug: placebo and ketamine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Official Title: N-acetylcysteine and NMDA Antagonist Interactions

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • Target P300 [ Time Frame: daily ] [ Designated as safety issue: No ]

    The Target P300 measures were obtained from the Fz, Cz and Pz electrodes.

    Target stimuli were 1000 Hz tones (500 ms) and novel stimuli (~250 ms) were unique environmental sounds (e.g., dog bark) used in prior studies of the novelty P300. Subjects were instructed to respond to the target sounds by pressing a button using their dominant hand index finger. The standard stimuli were 20, 30 or 40 Hz click trains (500 ms) in the first, second, and third runs, respectively. The auditory steady state EEG driving data obtained from these standard stimuli will be presented in a separate report. All stimuli were presented at 80 dB SPL.


  • Novel P300 [ Time Frame: daily ] [ Designated as safety issue: No ]

    The Novel P300 measures were obtained from the Fz, Cz and Pz electrodes.

    Target stimuli were 1000 Hz tones (500 ms) and novel stimuli (~250 ms) were unique environmental sounds (e.g., dog bark) used in prior studies of the novelty P300. Subjects were instructed to respond to the target sounds by pressing a button using their dominant hand index finger. The standard stimuli were 20, 30 or 40 Hz click trains (500 ms) in the first, second, and third runs, respectively. The auditory steady state EEG driving data obtained from these standard stimuli will be presented in a separate report. All stimuli were presented at 80 dB SPL.



Secondary Outcome Measures:
  • Mismatch Negativity (MMN) Intensity [ Time Frame: daily ] [ Designated as safety issue: No ]

    Mismatch Negativity (MMN) Intensity difference waves at midline electrodes (Fz, Cz and Pz).

    The frequent standard tones were of 75 ms duration with 5 ms rise and fall time, and were composed of 500, 1000, and 1500 Hz sinusoidal partials (harmonics) that resulted in a single high pitched beep sound.

    All tones were presented at 76 dB sound pressure level (SPL) with the exception of intensity deviants. The three deviants were distinguishable from standard tones in either intensity, frequency, or duration.

    Subjects performed a visual discrimination distractor task during the MMN runs and were instructed to ignore the tones.

    The mismatch negativity (MMN) measure included 3 types of deviant tones (stimuli) that the subjects heard: 1. Frequency deviant, 2. Intensity deviant, 3. Duration deviant. The response to these 3 types of deviants were recorded in the EEG. Therefore each deviant was associated with different waves which we measured in amplitude (microvolts)


  • Mismatch Negativity (MMN) Frequency [ Time Frame: daily ] [ Designated as safety issue: No ]

    Mismatch Negativity (MMN) Frequency difference waves at midline electrodes (Fx, Cz and Pz).

    The frequent standard tones were of 75 ms duration with 5 ms rise and fall time, and were composed of 500, 1000, and 1500 Hz sinusoidal partials (harmonics) that resulted in a single high pitched beep sound.

    All tones were presented at 76 dB sound pressure level (SPL) with the exception of intensity deviants. The three deviants were distinguishable from standard tones in either intensity, frequency, or duration.

    Subjects performed a visual discrimination distractor task during the MMN runs and were instructed to ignore the tones.

    The mismatch negativity (MMN) measure included 3 types of deviant tones (stimuli) that the subjects heard: 1. Frequency deviant, 2. Intensity deviant, 3. Duration deviant. The response to these 3 types of deviants were recorded in the EEG. Therefore each deviant was associated with different waves which we measured in amplitude (microvolts)


  • Mismatch Negativity (MMN) Duration [ Time Frame: daily ] [ Designated as safety issue: No ]

    Mismatch Negativity (MMN) Duration difference waves at midline electrodes (Fz, Cz and Pz).

    The frequent standard tones were of 75 ms duration with 5 ms rise and fall time, and were composed of 500, 1000, and 1500 Hz sinusoidal partials (harmonics) that resulted in a single high pitched beep sound.

    All tones were presented at 76 dB sound pressure level (SPL) with the exception of intensity deviants. The three deviants were distinguishable from standard tones in either intensity, frequency, or duration.

    Subjects performed a visual discrimination distractor task during the MMN runs and were instructed to ignore the tones.

    The mismatch negativity (MMN) measure included 3 types of deviant tones (stimuli) that the subjects heard: 1. Frequency deviant, 2. Intensity deviant, 3. Duration deviant. The response to these 3 types of deviants were recorded in the EEG. Therefore each deviant was associated with different waves which we measured in amplitude (microvolts)



Enrollment: 16
Study Start Date: January 2006
Study Completion Date: February 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I
The NAC capsules were administered orally in divided doses: 2000 mg followed by 1000 mg 2 hours later. Each morning, 165 min after NAC administration, subjects received a 1-min bolus of normal saline, followed by a 70-minlong saline infusion during which behavioral, cognitive, and ERP data were collected. Ketamine was administered intravenously as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min (SPM and RVP), and then .29 mg/kg for 40 min (P300 and MMN).
Drug: N-acetylcysteine and ketamine
Active drug (N-acetylcysteine)
Other Name: NAC
Placebo Comparator: Arm II
The placebo capsules were administered orally in divided doses: 2000 mg followed by 1000 mg 2 hours later. Each morning, 165 min after placebo administration, subjects received a 1-min bolus of normal saline, followed by a 70-minlong saline infusion during which behavioral, cognitive, and ERP data were collected. Ketamine was administered intravenously as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min (SPM and RVP), and then .29 mg/kg for 40 min (P300 and MMN).
Drug: placebo and ketamine
placebo N-acetylcysteine

  Eligibility

Ages Eligible for Study:   21 Years to 45 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Ages of 21-45 years from all ethnic backgrounds.
  • Male or female.
  • Written informed consent.

Exclusion criteria

  • DSM-IV diagnosis for a psychotic, depressive or anxiety disorder.
  • A history of significant medical/neurological disease such as cardiac, thyroid, renal, hepatic abnormality, seizure disorder. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, LFTs, TFTs, UA, Utox, Urine pregnancy test) .
  • History of severe allergies or multiple adverse drug reactions.
  • Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures.
  • Any other conditions which in the opinion of the investigator would preclude participation in the study.
  • History of major psychiatric disorder in first degree relatives.
  • Current substance abuse/dependency determined by urine toxicology.
  • Current treatment with medications with psychotropic effects.
  • Treatment with benzodiazepines within one week prior to testing.
  • Current pregnancy, unsatisfactory birth control method report for females.
  • Education < 10th grade.
  • IQ < 70, MR as determined by Wechsler Abbreviated Scale of Intelligence.
  • Non-English speaking.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00611897

Locations
United States, Connecticut
VHA Connecticut
West Haven, Connecticut, United States, 06516
Sponsors and Collaborators
Yale University
Investigators
Principal Investigator: Handan Gunduz-Bruce, M.D. Yale School of Medicine
  More Information

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT00611897     History of Changes
Other Study ID Numbers: 0508000518 
Study First Received: January 29, 2008
Results First Received: January 10, 2013
Last Updated: May 7, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by Yale University:
NMDA
glutamate
N-acetylcysteine
P3

Additional relevant MeSH terms:
Ketamine
Acetylcysteine
N-monoacetylcystine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Antidotes

ClinicalTrials.gov processed this record on September 26, 2016