A Phase 1/2 interventional study of N-acetylcysteine and ketamine and placebo and ketamine in Cognitive Dysfunction, sponsored by Yale University. Completed at 1 site in United States. Open to participants aged 21 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2015-05-08.
Sponsored by Yale University · Phase 1/2 and Interventional
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.
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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
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
Drug pages: Acetylcysteine · Ketamine
Active drug (N-acetylcysteine)
Also known as: NAC
placebo N-acetylcysteine
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.
Time frame: 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.
Time frame: daily
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)
Time frame: 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)
Time frame: 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)
Time frame: daily
The study was approved by the institutional review boards of Yale Medical School and the Veterans Administration Connecticut Healthcare System. Healthy volunteers were recruited by advertisements. as determined by Structured Clinical Interview for DSM-IV, Non-Patient Edition.
| Milestone | Day 1: Active NAC; Day 2: Placebo NAC | Day 1: Placebo NAC; Day 2: Active NAC |
|---|---|---|
| Started | 8 | 8 |
| Completed | 8 | 8 |
| Not completed | 0 | 0 |
| Milestone | Day 1: Active NAC; Day 2: Placebo NAC | Day 1: Placebo NAC; Day 2: Active NAC |
|---|---|---|
| Started | 8 | 8 |
| Completed | 8 | 8 |
| Not completed | 0 | 0 |
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.
| microvolts | Placebo+Saline | Placebo+Ketamine | NAC+Saline | NAC+Ketamine |
|---|---|---|---|---|
| Fz | 2.5 ± 0.8 | 3.2 ± 0.8 | 5.2 ± 0.8 | 3.4 ± 0.8 |
| Cz | 7.7 ± 1.0 | 5.5 ± 1.0 | 9.9 ± 1.0 | 5.4 ± 1.0 |
| Pz | 11.8 ± 1.1 | 8.1 ± 1.1 | 12.6 ± 1.1 | 8.2 ± 1.1 |
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)
| microvolts | Placebo+Saline | Placebo+Ketamine | NAC+Saline | NAC+Ketamine |
|---|---|---|---|---|
| Fz | -3.5 ± 0.2 | -2.7 ± 0.2 | -3.4 ± 0.2 | -2.6 ± 0.2 |
| Cz | -3.2 ± 0.2 | -2.5 ± 0.2 | -3.4 ± 0.2 | -2.6 ± 0.2 |
| Pz | -2.1 ± 0.2 | -2.0 ± 0.2 | -2.4 ± 0.2 | -2.1 ± 0.2 |
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.
| microvolts | Placebo+Saline | Placebo+Ketamine | NAC+Saline | NAC+Ketamine |
|---|---|---|---|---|
| Fz | 5.6 ± 0.8 | 5.2 ± 0.8 | 7.6 ± 0.8 | 5.3 ± 0.8 |
| Cz | 10.5 ± 1.0 | 7.0 ± 1.0 | 11.5 ± 1.0 | 7.4 ± 1.0 |
| Pz | 10.7 ± 1.2 | 5.7 ± 1.2 | 10.8 ± 1.2 | 6.1 ± 1.2 |
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)
| microvolts | Placebo+Saline | Placebo+Ketamine | NAC+Saline | NAC+Ketamine |
|---|---|---|---|---|
| Fz | -3.3 ± 0.3 | -2.7 ± 0.3 | -3.1 ± 0.2 | -2.9 ± 0.2 |
| Cz | -3.3 ± 0.3 | -2.7 ± 0.3 | -3.1 ± 0.2 | -2.9 ± 0.2 |
| Pz | -2.3 ± 0.2 | -1.7 ± 0.2 | -1.8 ± 0.2 | -1.9 ± 0.2 |
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)
| microvolts | Placebo+Saline | Placebo+Ketamine | NAC+Saline | NAC+Ketamine |
|---|---|---|---|---|
| Fz | -3.2 ± 0.3 | -3.1 ± 0.3 | -3.2 ± 0.3 | -2.8 ± 0.3 |
| Cz | -3.1 ± 0.3 | -3.1 ± 0.3 | -3.3 ± 0.3 | -2.8 ± 0.3 |
| Pz | -2.4 ± 0.2 | -2.3 ± 0.2 | -2.4 ± 0.2 | -2.1 ± 0.2 |
Collected over Adverse events were collected across the duration of the intervention in both arms. These data were not collected at the specific intervals in either arm.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Day 1: Placebo NAC; Day 2: Active NAC | — | 0/8 (0%) | 4/8 (50%) |
| Day 1: Active NAC; Day 2: Placebo NAC | — | 0/8 (0%) | 0/8 (0%) |
| Event | Day 1: Placebo NAC; Day 2: Active NAC | Day 1: Active NAC; Day 2: Placebo NAC |
|---|---|---|
| NauseaGastrointestinal disorders | 4/8 | 0/8 |
| Age, Continuous(years) | Overall Sample |
|---|---|
| Mean | 27.0 ± 5.6 |
| Sex: Female, Male(Participants) | Overall Sample |
|---|---|
| Female | 3 |
| Male | 13 |
The record gives a start of Jan 2006, a primary completion of Feb 2011 and a completion of Feb 2011. It does not say whether these dates are actual or estimated.
Results were first posted in May 2015, 4 years 3 months after primary completion.
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Studies of the drugs tested here: Acetylcysteine · Ketamine