Cognitive Dysfunction
Conditions
Keywords
NMDA, glutamate, N-acetylcysteine, P3
Brief summary
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.
Interventions
DRUGN-acetylcysteine and ketamine
Active drug (N-acetylcysteine)
placebo N-acetylcysteine
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Target P300 | daily | 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 | daily | 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
| Measure | Time frame | Description |
|---|---|---|
| Mismatch Negativity (MMN) Intensity | daily | 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 | daily | 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 | daily | 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) |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Overall Sample This is the group of healthy volunteers that consented to participate in the study. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Overall Sample |
|---|---|
| Age, Continuous | 27.0 years STANDARD_DEVIATION 5.6 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
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.
Time frame: daily
Population: Per protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+Saline | Novel P300 | Fz | 5.6 microvolts | Standard Error 0.8 |
| Placebo+Saline | Novel P300 | Pz | 10.7 microvolts | Standard Error 1.2 |
| Placebo+Saline | Novel P300 | Cz | 10.5 microvolts | Standard Error 1 |
| Placebo+Ketamine | Novel P300 | Cz | 7.0 microvolts | Standard Error 1 |
| Placebo+Ketamine | Novel P300 | Pz | 5.7 microvolts | Standard Error 1.2 |
| Placebo+Ketamine | Novel P300 | Fz | 5.2 microvolts | Standard Error 0.8 |
| NAC+Saline | Novel P300 | Pz | 10.8 microvolts | Standard Error 1.2 |
| NAC+Saline | Novel P300 | Cz | 11.5 microvolts | Standard Error 1 |
| NAC+Saline | Novel P300 | Fz | 7.6 microvolts | Standard Error 0.8 |
| NAC+Ketamine | Novel P300 | Fz | 5.3 microvolts | Standard Error 0.8 |
| NAC+Ketamine | Novel P300 | Pz | 6.1 microvolts | Standard Error 1.2 |
| NAC+Ketamine | Novel P300 | Cz | 7.4 microvolts | Standard Error 1 |
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.
Time frame: daily
Population: Per protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+Saline | Target P300 | Fz | 2.5 microvolts | Standard Error 0.8 |
| Placebo+Saline | Target P300 | Pz | 11.8 microvolts | Standard Error 1.1 |
| Placebo+Saline | Target P300 | Cz | 7.7 microvolts | Standard Error 1 |
| Placebo+Ketamine | Target P300 | Fz | 3.2 microvolts | Standard Error 0.8 |
| Placebo+Ketamine | Target P300 | Pz | 8.1 microvolts | Standard Error 1.1 |
| Placebo+Ketamine | Target P300 | Cz | 5.5 microvolts | Standard Error 1 |
| NAC+Saline | Target P300 | Cz | 9.9 microvolts | Standard Error 1 |
| NAC+Saline | Target P300 | Fz | 5.2 microvolts | Standard Error 0.8 |
| NAC+Saline | Target P300 | Pz | 12.6 microvolts | Standard Error 1.1 |
| NAC+Ketamine | Target P300 | Fz | 3.4 microvolts | Standard Error 0.8 |
| NAC+Ketamine | Target P300 | Pz | 8.2 microvolts | Standard Error 1.1 |
| NAC+Ketamine | Target P300 | Cz | 5.4 microvolts | Standard Error 1 |
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)
Time frame: daily
Population: Per protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+Saline | Mismatch Negativity (MMN) Duration | Pz | -2.4 microvolts | Standard Error 0.2 |
| Placebo+Saline | Mismatch Negativity (MMN) Duration | Fz | -3.2 microvolts | Standard Error 0.3 |
| Placebo+Saline | Mismatch Negativity (MMN) Duration | Cz | -3.1 microvolts | Standard Error 0.3 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Duration | Cz | -3.1 microvolts | Standard Error 0.3 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Duration | Fz | -3.1 microvolts | Standard Error 0.3 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Duration | Pz | -2.3 microvolts | Standard Error 0.2 |
| NAC+Saline | Mismatch Negativity (MMN) Duration | Cz | -3.3 microvolts | Standard Error 0.3 |
| NAC+Saline | Mismatch Negativity (MMN) Duration | Fz | -3.2 microvolts | Standard Error 0.3 |
| NAC+Saline | Mismatch Negativity (MMN) Duration | Pz | -2.4 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Duration | Fz | -2.8 microvolts | Standard Error 0.3 |
| NAC+Ketamine | Mismatch Negativity (MMN) Duration | Pz | -2.1 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Duration | Cz | -2.8 microvolts | Standard Error 0.3 |
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)
Time frame: daily
Population: Per protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+Saline | Mismatch Negativity (MMN) Frequency | Fz | -3.3 microvolts | Standard Error 0.3 |
| Placebo+Saline | Mismatch Negativity (MMN) Frequency | Pz | -2.3 microvolts | Standard Error 0.2 |
| Placebo+Saline | Mismatch Negativity (MMN) Frequency | Cz | -3.3 microvolts | Standard Error 0.3 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Frequency | Fz | -2.7 microvolts | Standard Error 0.3 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Frequency | Pz | -1.7 microvolts | Standard Error 0.2 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Frequency | Cz | -2.7 microvolts | Standard Error 0.3 |
| NAC+Saline | Mismatch Negativity (MMN) Frequency | Cz | -3.1 microvolts | Standard Error 0.2 |
| NAC+Saline | Mismatch Negativity (MMN) Frequency | Fz | -3.1 microvolts | Standard Error 0.2 |
| NAC+Saline | Mismatch Negativity (MMN) Frequency | Pz | -1.8 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Frequency | Fz | -2.9 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Frequency | Pz | -1.9 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Frequency | Cz | -2.9 microvolts | Standard Error 0.2 |
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)
Time frame: daily
Population: Per protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+Saline | Mismatch Negativity (MMN) Intensity | Fz | -3.5 microvolts | Standard Error 0.2 |
| Placebo+Saline | Mismatch Negativity (MMN) Intensity | Pz | -2.1 microvolts | Standard Error 0.2 |
| Placebo+Saline | Mismatch Negativity (MMN) Intensity | Cz | -3.2 microvolts | Standard Error 0.2 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Intensity | Fz | -2.7 microvolts | Standard Error 0.2 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Intensity | Pz | -2.0 microvolts | Standard Error 0.2 |
| Placebo+Ketamine | Mismatch Negativity (MMN) Intensity | Cz | -2.5 microvolts | Standard Error 0.2 |
| NAC+Saline | Mismatch Negativity (MMN) Intensity | Cz | -3.4 microvolts | Standard Error 0.2 |
| NAC+Saline | Mismatch Negativity (MMN) Intensity | Fz | -3.4 microvolts | Standard Error 0.2 |
| NAC+Saline | Mismatch Negativity (MMN) Intensity | Pz | -2.4 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Intensity | Fz | -2.6 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Intensity | Pz | -2.1 microvolts | Standard Error 0.2 |
| NAC+Ketamine | Mismatch Negativity (MMN) Intensity | Cz | -2.6 microvolts | Standard Error 0.2 |