Healthy, Schizoaffective Disorder, Schizo Affective Disorder, Schizophrenia
Conditions
Brief summary
This application seeks to determine if neurophysiological metrics of memantine (MEM)-enhanced early auditory information processing (EAIP) in schizophrenia (SZ) mediate gains in auditory processing fidelity (APF) and auditory learning.
Interventions
DRUGMemantine
To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS.
DRUGPlacebos
To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS.
Sponsors
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* diagnosis of schizophrenia OR schizoaffective-depressed OR healthy subjects * ages 18-50 for all subjects * double barrier contraception for all subjects * not pregnant for all subjects
Exclusion criteria
* DSM-IV Axis I or II Diagnosis for for healthy subjects * MEM or amantadine for patients * current substance abuse for all subjects * current recreational drug use for all subjects * history of other significant medical illness (e.g. cancer, diabetes, heart disease, HIV, seizures) for all subjects * open head injury or closed head injury with loss of consciousness \> 1 min for all subjects * hearing or visual impairment for all subjects * pregnancy for all subjects * dementia for all subjects * mental retardation for all subjects
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prepulse Inhibition (PPI) | 7 and 14 days post baseline | PPI of the startle reflex is the automatic reduction in startle magnitude (assessed by EMG of orbicularis oculi) when a startling stimulus (40 ms 118 dB(A) noise burst; PULSE) is preceded (10-120 msec) by a weak stimulus (here a 20 msec burst 16 dB over background PREPULSE). A %PPI metric is calculated based on the relative startle magnitude on (PREPULSE + PULSE) trials vs. PULSE alone trials. Possible maximal inhibition is 100%; there is no maximal negative value of inhibition. There is no clear advantage or disadvantage for lower or higher %PPI values, though on average, schizophrenia patients demonstrate lower % values compared to matched healthy subjects. Day 1 was baseline testing: testing occurred, data was collected, but no intervention was given. There were two possible interventions: active (MEM 20 mg po) and placebo. One intervention was given on day 7 post baseline, the other intervention was given on day 14 post baseline, with order of intervention balanced. |
| Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | 7 and 14 days post baseline | 85 dB SPL stimuli were presented via Etymotic ER3-A insert earphones. A 4-tone auditory oddball paradigm with 82% standards & 18% deviant stimuli, differed from standard in pitch, duration, or both. A pseudorandomized sequence produced a minimum of 3 standard tones between each deviant stimulus. All tones had 5-ms rise/fall times presented with a fixed 500-ms stimulus onset asynchrony. Subjects viewed a silent movie & instructed to ignore auditory stimuli. EEG were continuously recorded at a sampling rate of 2048-Hz from 64 channels, using BioSemi ActiveTwo system & downsampled to 512-Hz. Deviant-minus-standard difference waves were generated for each deviant type & low-pass filtered (20-Hz zerophase shift, 24 dB/octave rolloff). MMN was computed as mean amplitude across 135-205 ms range for each deviant type in difference waveforms at electrode Fz. Data were analyzed by RM-ANOVA, with diagnosis as a between-subject factor, & drug condition (placebo vs MEM) as a within-subject factor. |
| Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | 7 and 14 days post baseline | 1 ms, 85 dB clicks were presented in 500 ms trains at a frequency of 40 Hz; 250 click trains were played (inter-train interval=0.5 s). EEG was continuously recorded with 64-channel BioSemi ActiveTwo system (sampling rate=2048 Hz). Data processed offline via Matlab, EEGlab, & BrainVision Analyzer. Continuous data were segmented relative to stimulus onset (-100 ms to 500 ms) & each epoch was baseline-corrected relative to 100 ms pre-stimulus interval. γEP was assessed based on first 100 artifact-free epochs at Fz. Averaged epochs across click trains were transformed into power spectrum via fast Fourier transform using a bin width of 2 Hz. 40 Hz power spectrum was averaged across 4 Hz band from 38-42 Hz. Data were analyzed by RM-ANOVA, with diagnosis as a between- & drug condition (placebo vs MEM) as a within-subject factor. Analyses revealed robust & time bin-independent effects of diagnosis & drug across 200-500 ms window & thus this interval was the focus of all subsequent analyses. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine Memantine: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS.
Placebos: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS. | 11 |
| Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo Memantine: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS.
Placebos: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS. | 11 |
| Healthy Subjects: Placebo 1st, Then 20 mg Memantine Memantine: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS.
Placebos: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS. | 10 |
| Healthy Subjects: 20 mg Memantine 1st, Then Placebo Memantine: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS.
Placebos: To assess the acute effects of MEM (0 vs. 20 mg) on measures of auditory processing fidelity, auditory learning and EAIP, in AP-medicated adult SZ patients and HS. | 10 |
| Total | 42 |
Baseline characteristics
| Characteristic | Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine | Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo | Healthy Subjects: Placebo 1st, Then 20 mg Memantine | Healthy Subjects: 20 mg Memantine 1st, Then Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 10 Participants | 10 Participants | 42 Participants |
| Age, Continuous | 40.1 years | 41.0 years | 29.6 years | 29.3 years | 35.3 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 4 Participants | 4 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 4 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 3 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 23 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 4 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 11 | 0 / 11 | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared.
1 ms, 85 dB clicks were presented in 500 ms trains at a frequency of 40 Hz; 250 click trains were played (inter-train interval=0.5 s). EEG was continuously recorded with 64-channel BioSemi ActiveTwo system (sampling rate=2048 Hz). Data processed offline via Matlab, EEGlab, & BrainVision Analyzer. Continuous data were segmented relative to stimulus onset (-100 ms to 500 ms) & each epoch was baseline-corrected relative to 100 ms pre-stimulus interval. γEP was assessed based on first 100 artifact-free epochs at Fz. Averaged epochs across click trains were transformed into power spectrum via fast Fourier transform using a bin width of 2 Hz. 40 Hz power spectrum was averaged across 4 Hz band from 38-42 Hz. Data were analyzed by RM-ANOVA, with diagnosis as a between- & drug condition (placebo vs MEM) as a within-subject factor. Analyses revealed robust & time bin-independent effects of diagnosis & drug across 200-500 ms window & thus this interval was the focus of all subsequent analyses.
Time frame: 7 and 14 days post baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Placebo | 0.08 Microvolts-squared | Standard Error 0.02 |
| Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Memantine | 0.09 Microvolts-squared | Standard Error 0.04 |
| Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Memantine | 0.06 Microvolts-squared | Standard Error 0.02 |
| Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Placebo | 0.07 Microvolts-squared | Standard Error 0.02 |
| Healthy Subjects: Placebo 1st, Then 20 mg Memantine | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Placebo | 0.14 Microvolts-squared | Standard Error 0.03 |
| Healthy Subjects: Placebo 1st, Then 20 mg Memantine | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Memantine | 0.23 Microvolts-squared | Standard Error 0.06 |
| Healthy Subjects: 20 mg Memantine 1st, Then Placebo | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Placebo | 0.14 Microvolts-squared | Standard Error 0.03 |
| Healthy Subjects: 20 mg Memantine 1st, Then Placebo | Gamma Auditory Steady-state Response (ASSR). The Primary Unit of Measure of Auditory Steady State Response (ASSR) is Gamma Evoked Power (γEP), Expressed as Microvolts-squared. | Memantine | 0.23 Microvolts-squared | Standard Error 0.06 |
Primary
Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts.
85 dB SPL stimuli were presented via Etymotic ER3-A insert earphones. A 4-tone auditory oddball paradigm with 82% standards & 18% deviant stimuli, differed from standard in pitch, duration, or both. A pseudorandomized sequence produced a minimum of 3 standard tones between each deviant stimulus. All tones had 5-ms rise/fall times presented with a fixed 500-ms stimulus onset asynchrony. Subjects viewed a silent movie & instructed to ignore auditory stimuli. EEG were continuously recorded at a sampling rate of 2048-Hz from 64 channels, using BioSemi ActiveTwo system & downsampled to 512-Hz. Deviant-minus-standard difference waves were generated for each deviant type & low-pass filtered (20-Hz zerophase shift, 24 dB/octave rolloff). MMN was computed as mean amplitude across 135-205 ms range for each deviant type in difference waveforms at electrode Fz. Data were analyzed by RM-ANOVA, with diagnosis as a between-subject factor, & drug condition (placebo vs MEM) as a within-subject factor.
Time frame: 7 and 14 days post baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Placebo | -3.15 microvolts | Standard Error 0.45 |
| Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Memantine | -2.44 microvolts | Standard Error 0.54 |
| Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Memantine | -1.70 microvolts | Standard Error 0.28 |
| Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Placebo | -1.60 microvolts | Standard Error 0.31 |
| Healthy Subjects: Placebo 1st, Then 20 mg Memantine | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Memantine | -3.28 microvolts | Standard Error 0.5 |
| Healthy Subjects: Placebo 1st, Then 20 mg Memantine | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Placebo | -3.52 microvolts | Standard Error 0.5 |
| Healthy Subjects: 20 mg Memantine 1st, Then Placebo | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Memantine | -3.28 microvolts | Standard Error 0.5 |
| Healthy Subjects: 20 mg Memantine 1st, Then Placebo | Mismatch Negativity (MMN); Unit of Measure of MMN is Microvolts. | Placebo | -3.52 microvolts | Standard Error 0.5 |
Primary
Prepulse Inhibition (PPI)
PPI of the startle reflex is the automatic reduction in startle magnitude (assessed by EMG of orbicularis oculi) when a startling stimulus (40 ms 118 dB(A) noise burst; PULSE) is preceded (10-120 msec) by a weak stimulus (here a 20 msec burst 16 dB over background PREPULSE). A %PPI metric is calculated based on the relative startle magnitude on (PREPULSE + PULSE) trials vs. PULSE alone trials. Possible maximal inhibition is 100%; there is no maximal negative value of inhibition. There is no clear advantage or disadvantage for lower or higher %PPI values, though on average, schizophrenia patients demonstrate lower % values compared to matched healthy subjects. Day 1 was baseline testing: testing occurred, data was collected, but no intervention was given. There were two possible interventions: active (MEM 20 mg po) and placebo. One intervention was given on day 7 post baseline, the other intervention was given on day 14 post baseline, with order of intervention balanced.
Time frame: 7 and 14 days post baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine | Prepulse Inhibition (PPI) | Placebo | 32.45 % inhibition of startle | Standard Error 5.11 |
| Subjects With Schizophrenia: Placebo 1st, Then 20 mg Memantine | Prepulse Inhibition (PPI) | Memantine | 10.11 % inhibition of startle | Standard Error 12.88 |
| Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo | Prepulse Inhibition (PPI) | Memantine | 20.55 % inhibition of startle | Standard Error 4.07 |
| Subjects With Schizophrenia: 20 mg Memantine 1st, Then Placebo | Prepulse Inhibition (PPI) | Placebo | 26.85 % inhibition of startle | Standard Error 6.77 |
| Healthy Subjects: Placebo 1st, Then 20 mg Memantine | Prepulse Inhibition (PPI) | Placebo | 14.11 % inhibition of startle | Standard Error 8.97 |
| Healthy Subjects: Placebo 1st, Then 20 mg Memantine | Prepulse Inhibition (PPI) | Memantine | 21.36 % inhibition of startle | Standard Error 4.56 |
| Healthy Subjects: 20 mg Memantine 1st, Then Placebo | Prepulse Inhibition (PPI) | Placebo | 11.78 % inhibition of startle | Standard Error 8.73 |
| Healthy Subjects: 20 mg Memantine 1st, Then Placebo | Prepulse Inhibition (PPI) | Memantine | 25.55 % inhibition of startle | Standard Error 6.37 |