Trial Outcomes & Findings for N-acetylcysteine and NMDA Antagonist Interactions (NCT NCT00611897)

NCT ID: NCT00611897

Last Updated: 2015-05-08

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 16 participants
• Primary outcome timeframe: daily
• Results posted on: 2015-05-08

Participant Flow

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.

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.

Participant milestones

Measure	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.	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.
Day 1: Initial Treatment STARTED	8	8
Day 1: Initial Treatment COMPLETED	8	8
Day 1: Initial Treatment NOT COMPLETED	0	0
Day 2: Crossover Treatment STARTED	8	8
Day 2: Crossover Treatment COMPLETED	8	8
Day 2: Crossover Treatment NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

N-acetylcysteine and NMDA Antagonist Interactions

Baseline characteristics by cohort

Measure	Overall Sample n=16 Participants This is the group of healthy volunteers that consented to participate in the study.
Age, Continuous	27.0 years STANDARD_DEVIATION 5.6 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants

PRIMARY outcome

Timeframe: daily

Population: Per protocol

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.

Outcome measures

Measure	Placebo+Saline n=16 Participants NAC placebo 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.	Placebo+Ketamine n=16 Participants NAC placebo capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.	NAC+Saline n=16 Participants 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.	NAC+Ketamine n=16 Participants NAC active capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.
Target P300 Cz	7.7 microvolts Standard Error 1.0	5.5 microvolts Standard Error 1.0	9.9 microvolts Standard Error 1.0	5.4 microvolts Standard Error 1.0
Target P300 Fz	2.5 microvolts Standard Error 0.8	3.2 microvolts Standard Error 0.8	5.2 microvolts Standard Error 0.8	3.4 microvolts Standard Error 0.8
Target P300 Pz	11.8 microvolts Standard Error 1.1	8.1 microvolts Standard Error 1.1	12.6 microvolts Standard Error 1.1	8.2 microvolts Standard Error 1.1

PRIMARY outcome

Timeframe: daily

Population: Per protocol

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.

Outcome measures

Measure	Placebo+Saline n=16 Participants NAC placebo 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.	Placebo+Ketamine n=16 Participants NAC placebo capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.	NAC+Saline n=16 Participants 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.	NAC+Ketamine n=16 Participants NAC active capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.
Novel P300 Cz	10.5 microvolts Standard Error 1.0	7.0 microvolts Standard Error 1.0	11.5 microvolts Standard Error 1.0	7.4 microvolts Standard Error 1.0
Novel P300 Fz	5.6 microvolts Standard Error 0.8	5.2 microvolts Standard Error 0.8	7.6 microvolts Standard Error 0.8	5.3 microvolts Standard Error 0.8
Novel P300 Pz	10.7 microvolts Standard Error 1.2	5.7 microvolts Standard Error 1.2	10.8 microvolts Standard Error 1.2	6.1 microvolts Standard Error 1.2

SECONDARY outcome

Timeframe: daily

Population: Per protocol

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)

Outcome measures

Measure	Placebo+Saline n=16 Participants NAC placebo 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.	Placebo+Ketamine n=16 Participants NAC placebo capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.	NAC+Saline n=16 Participants 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.	NAC+Ketamine n=16 Participants NAC active capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.
Mismatch Negativity (MMN) Intensity Fz	-3.5 microvolts Standard Error 0.2	-2.7 microvolts Standard Error 0.2	-3.4 microvolts Standard Error 0.2	-2.6 microvolts Standard Error 0.2
Mismatch Negativity (MMN) Intensity Cz	-3.2 microvolts Standard Error 0.2	-2.5 microvolts Standard Error 0.2	-3.4 microvolts Standard Error 0.2	-2.6 microvolts Standard Error 0.2
Mismatch Negativity (MMN) Intensity Pz	-2.1 microvolts Standard Error 0.2	-2.0 microvolts Standard Error 0.2	-2.4 microvolts Standard Error 0.2	-2.1 microvolts Standard Error 0.2

SECONDARY outcome

Timeframe: daily

Population: Per protocol

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)

Outcome measures

Measure	Placebo+Saline n=16 Participants NAC placebo 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.	Placebo+Ketamine n=16 Participants NAC placebo capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.	NAC+Saline n=16 Participants 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.	NAC+Ketamine n=16 Participants NAC active capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.
Mismatch Negativity (MMN) Frequency Fz	-3.3 microvolts Standard Error 0.3	-2.7 microvolts Standard Error 0.3	-3.1 microvolts Standard Error 0.2	-2.9 microvolts Standard Error 0.2
Mismatch Negativity (MMN) Frequency Cz	-3.3 microvolts Standard Error 0.3	-2.7 microvolts Standard Error 0.3	-3.1 microvolts Standard Error 0.2	-2.9 microvolts Standard Error 0.2
Mismatch Negativity (MMN) Frequency Pz	-2.3 microvolts Standard Error 0.2	-1.7 microvolts Standard Error 0.2	-1.8 microvolts Standard Error 0.2	-1.9 microvolts Standard Error 0.2

SECONDARY outcome

Timeframe: daily

Population: Per protocol

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)

Outcome measures

Measure	Placebo+Saline n=16 Participants NAC placebo 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.	Placebo+Ketamine n=16 Participants NAC placebo capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.	NAC+Saline n=16 Participants 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.	NAC+Ketamine n=16 Participants NAC active capsule, Ketamine was administered intravenously as a bolus of .29 mg/kg for 40 min.
Mismatch Negativity (MMN) Duration Fz	-3.2 microvolts Standard Error 0.3	-3.1 microvolts Standard Error 0.3	-3.2 microvolts Standard Error 0.3	-2.8 microvolts Standard Error 0.3
Mismatch Negativity (MMN) Duration Cz	-3.1 microvolts Standard Error 0.3	-3.1 microvolts Standard Error 0.3	-3.3 microvolts Standard Error 0.3	-2.8 microvolts Standard Error 0.3
Mismatch Negativity (MMN) Duration Pz	-2.4 microvolts Standard Error 0.2	-2.3 microvolts Standard Error 0.2	-2.4 microvolts Standard Error 0.2	-2.1 microvolts Standard Error 0.2

Adverse Events

Day 1: Placebo NAC; Day 2: Active NAC

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Day 1: Active NAC; Day 2: Placebo NAC

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Day 1: Placebo NAC; Day 2: Active NAC n=8 participants at risk 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.	Day 1: Active NAC; Day 2: Placebo NAC n=8 participants at risk 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.
Gastrointestinal disorders Nausea	50.0% 4/8 • Number of events 4 • 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.	0.00% 0/8 • 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.

Additional Information

Handan Gunduz-Bruce, MD

Yale School of Medicine, Department of Psychiatry

Phone: (203) 785-2117

Email: handan.gunduz-bruce@yale.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place