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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm I | Active Comparator | 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). |
|
| Arm II | Placebo Comparator | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| N-acetylcysteine and ketamine | Drug | Active drug (N-acetylcysteine) |
|
| 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 |
| 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) |
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Inclusion Criteria:
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Handan Gunduz-Bruce, M.D. | Yale University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VHA Connecticut | West Haven | Connecticut | 06516 | United States |
All subjects gave written informed consent. They had no personal or family history of psychiatric or substance abuse disorders. A total of 43 subjects consented; 21 of them never initiated the study due to ineligibility or scheduling conflicts, and 6 subjects dropped out. Sixteen subjects completed the study procedures.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Day 1: Active NAC; Day 2: Placebo NAC | Subjects were randomized to receive ACTIVE NAC on day one, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Subjects then received PLACEBO NAC on day two, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. |
| FG001 | Day 1: Placebo NAC; Day 2: Active NAC | Subjects were randomized to receive PLACEBO NAC on day one, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Subjects then received ACTIVE NAC on day two, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1: Initial Treatment |
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| Day 2: Crossover Treatment |
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| ID | Title | Description |
|---|---|---|
| BG000 | Overall Sample | This is the group of healthy volunteers that consented to participate in the study. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Per protocol | Posted | Least Squares Mean | Standard Error | microvolts | daily |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Day 1: Placebo NAC; Day 2: Active NAC | Subjects were randomized to receive PLACEBO NAC on day one, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Subjects then received ACTIVE NAC on day two, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Handan Gunduz-Bruce, MD | Yale School of Medicine, Department of Psychiatry | (203) 785-2117 | handan.gunduz-bruce@yale.edu |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D000111 | Acetylcysteine |
| D007649 | Ketamine |
| ID | Term |
|---|---|
| D003545 | Cysteine |
| D000603 | Amino Acids, Sulfur |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
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| placebo and ketamine | Drug | placebo N-acetylcysteine |
|
| 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 |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | Placebo+Ketamine | NAC placebo capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min. |
| OG002 | NAC+Saline | NAC active capsule administered after receiving 1-min bolus of saline, followed by a 70-min long saline infusion during which behavioral, cognitive, and ERP data were collected. |
| OG003 | NAC+Ketamine | NAC active capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min. |
|
|
| Secondary | 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) | Per protocol | Posted | Least Squares Mean | Standard Error | microvolts | daily |
|
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| Primary | 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. | Per protocol | Posted | Least Squares Mean | Standard Error | microvolts | daily |
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| Secondary | 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) | Per protocol | Posted | Least Squares Mean | Standard Error | microvolts | daily |
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| Secondary | 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) | Per protocol | Posted | Least Squares Mean | Standard Error | microvolts | daily |
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| 8 |
| 4 |
| 8 |
| EG001 | Day 1: Active NAC; Day 2: Placebo NAC | Subjects were randomized to receive ACTIVE NAC on day one, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Subjects then received PLACEBO NAC on day two, before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. | 0 | 8 | 0 | 8 |
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| D000596 |
| Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
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