N-acetylcysteine and NMDA Antagonist Interactions

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.

Study Overview

• Status: Completed
• Conditions: Cognitive Dysfunction
• Intervention / Treatment: Drug: N-acetylcysteine and ketamine; Drug: placebo and ketamine

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VHA Connecticut

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Target P300	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.	daily
Novel P300	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.	daily

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mismatch Negativity (MMN) Intensity	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)	daily
Mismatch Negativity (MMN) Frequency	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)	daily
Mismatch Negativity (MMN) Duration	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)	daily

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Handan Gunduz-Bruce, M.D., Yale School of Medicine

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: January 29, 2008
• First Submitted That Met QC Criteria: January 29, 2008
• First Posted (Estimate): February 11, 2008

Study Record Updates

• Last Update Posted (Estimate): May 8, 2015
• Last Update Submitted That Met QC Criteria: May 7, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: N-acetylcysteine; glutamate; NMDA; P3
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Ketamine; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 0508000518