Pharmacologic Augmentation of Neurocognition and Cognitive Training in Psychosis
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: University of California, San Diego

Study Protocol 
Biomarker Strategies for Medication-Enhanced Cognitive Training in Schizophrenia 
NCT02634684 
5R01MH059803-15 
Latest IRB approval date: July 9, 2020 
IRB expiration date: July 8, 2021 

 
200993 
 
 
 
UNIVERSITY OF CALIFORNIA, SAN DIEGO  
HUMAN RESEARCH PROTECTIONS PROGRAM 
 
 
 
 
TO: 
 
Dr. Neal Swerdlow 
 
RE: 
 
Project #200993 
 
 
Human Psychophysiological Correlates of Sensorimotor Functioning 
 
Dear Dr. Swerdlow: 
 
The above-referenced project was reviewed and approved by one of this institution's Institutional Review 
Boards in accordance with the requirements of the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR 46 and 21 CFR 50 and 56), including its relevant Subparts. This approval, 
based on the degree of risk, is for 365 days from the date of IRB review and approval unless otherwise 
stated in this letter. The regulations require that continuing review be conducted on or before the 1-year 
anniversary date of the IRB approval, even though the research activity may not begin until some time 
after the IRB has given approval. 
 
The IRB determined that this project presents more than minimal risk to human subjects in that the 
probability and magnitude of harm or discomfort anticipated in the research are greater in and of 
themselves than those ordinarily encountered in daily life or during the performance of routine physical or 
psychological examinations or tests. 
 
Date of IRB review and approval: 07/09/2020 
 
On behalf of the UCSD Institutional Review Boards,  
 
 
 
 
 
 
 
/js 
Kip Kantelo  
Director 
UCSD Human Research Protections Program 
858-246-HRPP (858-246-4777); hrpp@ucsd.edu 
 
 
Note: IRB approval does not constitute funding or other institutional required approvals. Should your 
studies involve other review committees such as Office of Clinical Trials Administration (OCTA), Office 
of Coverage Analysis Administration (OCAA), Conflict of Interest (COI), Protocol Review Monitoring 
Committee (PRMC), and committees under Environmental Health & Safety (EH&S) such as Institutional 
Biosafety Committee (IBC), Human Exposure Committee (HERC), and RSSC (Radiation Safety and 
Surveillance Committee), it is the researchers responsibility to ensure that all approvals are in place prior 
to conducting research involving human subjects or their related specimens. 
 
 

 
If you have questions regarding this correspondence, please contact the “B” analyst who drafted 
this letter, Joel Stinson, at jstinson@ucsd.edu. 
 
Approval release date: 7/9/2020 

Biomedical IRB Application Instructions 
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UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
1. 
PROJECT TITLE 
Human Psychophysiological Correlates of Sensorimotor Functioning 
2. 
PRINCIPAL INVESTIGATOR 
Neal R. Swerdlow, M.D., Ph.D., Professor, Psychiatry 
3. 
FACILITIES 
Clinical Teaching Facility, UCSD Medical Center, Hillcrest 
General Clinical Research Center, UCSD Medical Center, Hillcrest 
4. 
ESTIMATED DURATION OF THE STUDY 
7 years from original date of approval 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS 
These studies assess information processing and neurocognition in clinically normal individuals and in 
individuals with specific brain disorders. In some cases, studies assess the effects of medications on 
information processing and neurocognition, either as a means to understand the biological mechanisms that 
control these processes, or as a way to test the potential clinical value of medications for improving these 
processes in patients with brain disorders. 
6. 
SPECIFIC AIMS 
Certain neuropsychiatric disorders are characterized by a brain-based deficit in the ability to effectively 
inhibit, or “gate” sensory, cognitive or motor information. To study the physiological basis of this inhibitory 
deficit, we use prepulse inhibition of the acoustic startle reflex as an operational measure of sensorimotor 
gating. We study the acoustic startle reflex, including prepulse inhibition (PPI) and prepulse facilitation of 
startle in neuropsychiatric patients and appropriate control comparison populations. 
A substantial literature of preclinical studies demonstrates that prepulse modification of the startle reflex, 
including PPI, is regulated by specific neurochemical substrates. Among these, brain dopamine (DA) 
activity is known to regulate PPI via D2-family receptors in portions of the striatum. PPI is disrupted or 
eliminated in rats by systemic or intracerebral treatment with DA agonists. These and related animal 
studies have allowed us to identify a specific neural circuitry, connecting limbic cortical structures, through 
their basal ganglia efferents, to pontine structures, that regulates the amount of sensorimotor gating, as 
measured by PPI. It would be critically important to determine whether these same substrates regulating 
PPI in rats, could be extrapolated to humans, and thus allow us to interpret the neural basis for abnormal 
patterns of PPI in neurologic and psychiatric patients. 
In a series of studies, we investigated the neurochemistry of PPI in humans, by documenting changes in 
PPI in response to specific pharmacologic probes, using adequate sample sizes, agonist-antagonist 
interactions and informative dose-response profiles where possible. The similarities and differences 
between the responses to pharmacological manipulations in humans and rats provide important evidence 
for understanding the neural circuit substrates of PPI in humans. 
Differences in sensorimotor gating also distinguish certain groups of normal subjects. For example, lower 
levels of PPI are found in clinically normal individuals who carry the Val/Val vs. Met/Met alleles for the 
Val158Met polymorphism of the gene for catechol-O-methyltransferase. In other cases, differences in PPI 
drug sensitivity distinguish certain groups of normal subjects. For example, amphetamine differentially 
changes PPI among individuals characterized as having low vs. high novelty seeking personalities. For 
these reasons, some of our studies interrogate specific genetic and personality characteristics of our test 
subjects: genotyping is conducted using blood samples, and specific questionnaires are used to evaluate 
personality and behavioral characteristics of the study populations. 
Differences in sensorimotor inhibition will be detected by some, but not other laboratory-based measures, 
reflecting differences in the particular psychophysical demands of the measure. To add to our 

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understanding of patterns of sensorimotor inhibition across normal and patient populations, and of 
changes in sensorimotor inhibition in response to specific manipulations of brain circuitry thought to 
regulate one form of sensorimotor inhibition (PPI), we also assess Latent Inhibition, Negative Priming, 
Mismatch Negativity and Gamma Band Synchronization in some of our study groups. 
Importantly, measures of sensorimotor gating are associated with higher brain functions, including 
neurocognitive processes. Thus, in some cases, our subjects complete measures of neurocognition, 
designed specifically to assess drug effects on processes such as working memory. In this way, we can 
test the hypothesis that drug-induced increases in sensorimotor gating can contribute to neurocognitive 
improvements in patients populations. 
Our current studies are designed to achieve 3 Specific Aims (see Figure 1): 
1. To assess the effects of the indirect dopamine agonist, d-amphetamine, on PPI and neurocognition in 
healthy subjects, and the moderating roles of personality and genotype in these effects. 120 healthy 
subjects will complete a within-subject study of placebo vs. 20 mg amphetamine (p.o.) on two separate 
days, completing measures of sensorimotor gating and neurocognition on each test day. All subjects will 
be characterized in terms of specific genetic and personality characteristics. 
2. To assess the effects of the NMDA antagonist, memantine, on PPI and neurocognition in healthy 
subjects, and the moderating roles of personality and genotype in these effects. 30 healthy subjects will 
complete a within-subject study of placebo vs. 20 mg memantine (p.o.) on two separate days, completing 
measures of sensorimotor gating and neurocognition on each test day. All subjects will be characterized 
in terms of specific genetic and personality characteristics. 
3. To assess the effects of the NMDA antagonist, memantine, on PPI and neurocognition in schizophrenia 
patients, and the moderating roles of genotype in these effects. 60 well-characterized and clinically stable 
individuals with schizophrenia will complete a within-subject study of placebo vs. 10 mg memantine (p.o.) 
(n=30) or placebo vs. 20 mg memantine (n=30) on two separate days, completing measures of 
sensorimotor gating and neurocognition on each test day. All subjects will be characterized in terms of 
specific genetic characteristics. 

Biomedical IRB Application Instructions 
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Figure 1. Schematic "flow chart" of current studies 
Healthy Subjects 
Schizophrenia Subjects 
Amphetamine Study 
Memantine Study 
Memantine Study 
(n=120) 
 
(n=30) 
 
(n=60) 
Within-subject 
 Within-subject 
 
Within-subject 
placebo vs. 20 mg 
placebo vs. 20 mg 
placebo vs. 10 mg (n=30) or 
administration 
administration 
placebo vs. 20 mg (n=30) 
administration 
Psychophysiological and neurophysiological measures 
 
Neurocognitive measures 
 
Genotyping 
7. 
BACKGROUND AND SIGNIFICANCE 
The startle reflex is a constellation of responses to sudden, relatively intense stimuli that is usually 
classified as a defensive response. One major advantage of startle response paradigms is that the same 
phenomena can be studied across species. In humans, the blink reflex component of the startle response 
is measured using electromyography of the orbicularis oculi muscle. Despite its simplicity, startle 
demonstrates several forms of plasticity - including habituation and fear-potentiation - that are regulated 
by forebrain circuitry. Even these more complex processes exhibit striking similarities across species, 
from rodents to humans. One form of startle plasticity is "prepulse inhibition" (PPI), which is the normal 
suppression of the startle reflex, which occurs when the intense startling stimulus is preceded by a weak 
prestimulus. 
In PPI, a weak prepulse inhibits a reflex response to a powerful sensory stimulus. PPI occurs when the 
prepulse and startling stimuli are in the same or different sensory modalities. PPI also occurs in virtually 
all mammals and primates, including humans. It is not a form of conditioning, since it occurs on the first 
exposure to the prepulse and pulse stimuli, and it does not exhibit habituation or extinction over multiple 
trials. PPI thus appears to reflect the activation of a ubiquitous "hard-wired" centrally mediated behavioral 
"gating" process. The PPI paradigm has been widely applied in studies of information processing in 
normal animals and humans. The inhibitory processes activated by the weak "prepulse" and the resulting 
decrement in startle amplitude are used in an operational definition of sensorimotor gating: the degree to 
which startle amplitude is inhibited by a prepulse is a measure of the amount of sensorimotor gating. 
Our interest in PPI as a measure of sensorimotor gating grew from the observation that human disorders 
characterized by dysfunction in brain substrates that regulate  PPI are accompanied by evidence of 
 

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impaired cognitive or sensorimotor inhibition. Thus, our laboratory and others have reported impaired PPI 
in patients with Schizophrenia, Obsessive Compulsive Disorder (OCD), Huntington’s Disease, nocturnal 
enuresis and Attention Deficit Hyperactivity Disorder or Tourette’s Syndrome. These disorders are all 
characterized by a loss of gating in sensory, motor or cognitive domains, and are characterized 
neurologically by abnormalities in cortico-striato-pallido-pontine circuitry that modulates PPI. 
Over the past 20+ years, the PI and colleagues have systematically studied the neural substrates of PPI 
in rats. These studies have revealed that PPI is regulated by sequential neural connections between 
limbic cortex (temporal and medial prefrontal cortex), the ventral striatum, the ventral pallidum and the 
pontine tegmentum. This limbic cortico-striato-pallido-pontine circuitry then interfaces with the primary 
startle circuit at the level of the nucleus reticularis pontis caudalis. The neurotransmitters active at each 
level of this circuitry have been studied as well: the cortico-striatal interface involves interactions between 
glutamate and D2 dopamine receptors; the striato-pallidal input is GABAergic, as is the pallido-pontine 
input. Thus, by identifying patterns of PPI deficits in neuropsychiatric populations, we are able to use this 
information to understand the pathophysiology of these disorders, as well as to develop strategies for 
designing optimal drug treatments. We have already made significant steps towards these ends. 
Some evidence already suggests that findings from preclinical studies of the neural substrates regulating 
PPI can “cross species” and be applied to humans. For example, PPI is disrupted in patients with 
Huntington’s Disease (HD), and in rats with cytotoxic lesions of striatal regions that model features of the 
pathophysiology of HD. Preliminary studies suggest that the “cross-species” parallels of this measure can 
also be demonstrated with pharmacologic probes: PPI is disrupted in both rats and humans by indirect DA 
agonists (e.g. amphetamine) and by direct DA agonists (e.g. bromocriptine and apomorphine). These 
pharmacologic studies of PPI in humans are not fully compelling at this time, since they were either 
performed only in small samples, or in patients with neurologic disorders (e.g.. Parkinson’s Disease) that 
might complicate interpretation of the findings as they relate to the normal neural regulation of PPI. 
More recent studies have clarified that the sensitivity of PPI to drug effects in normal humans is 
moderated by several factors, including the presence of specific genes, and personality dimensions 
associated with those genes. For example, several groups have reported that PPI and its sensitivity to 
drug challenge differs significantly between normal men who carry different alleles for the COMT 
Val158Met polymorphism. In these studies, the Val/Val allele is associated with high COMT activity, rapid 
DA catabolism, high novelty seeking scores, low basal PPI and PPI-enhancing effects of the COMT 
inhibitor, tolcapone. In contrast, the Met/Met allele is associated with low COMT activity, low DA 
catabolism, low novelty seeking scores, high basal PPI, and PPI-reducing effects of tolcapone. We 
previously reported that rats expressing high levels of COMT within the ventral striatum exhibit PPI- 
enhancing effects in response to DA agonists, like amphetamine, while rats expressing low levels of 
COMT in this region exhibit PPI-reducing effects in response to amphetamine. More recently, we 
confirmed that normal women with high novelty seeking scores (who as a group predominantly express 
the Val/Val high activity COMT allele) respond to amphetamine with elevations of PPI, while those with 
low novelty seeking (associated with the Met/Met low activity COMT allele) respond to amphetamine with 
reduced PPI. We also detected PPI-enhancing effects of the NMDA antagonist and weak DA agonist, 
memantine, among men exhibiting low baseline PPI and/or high novelty seeking, both of which are 
associated with the Val/Val COMT genotype. Thus, across species, genetically determined levels of 
COMT activity appear to moderate the impact of specific drugs on sensorimotor gating. These findings 
suggest a biological explanation for a genetically based "vulnerability" to the gating-disrupted effects of 
increased dopamine activity and/or reduced NMDA activity, thought to be core features of brain disorders 
such as schizophrenia and Tourette Syndrome. We now plan to extend this work to further clarify the role 
of COMT polymorphisms and other genetic substrates on the sensitivity of PPI to drug effects in humans. 
The most recent development in our studies has emerged as other groups, as well as our own, have 
reported that levels of PPI are significantly associated (correlated) with specific neurocognitive processes, 
including measures of executive functioning and working memory. In the process of our pharmacological 

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studies of PPI, we identified specific agents (e.g. memantine) that increased PPI, particularly among 
individuals with specific physiological (e.g. low baseline PPI) and psychological (e.g. high novelty seeking) 
"biomarkers" associated with the Val/Val COMT polymorphism. These two lines of findings led us to test 
whether such drug-induced increases in PPI predicted increases in neurocognitive functions in biomarker- 
identified subgroups. If so, we might be able to develop laboratory-based measures for predicting 
procognitive drug effects in patient populations - particularly among disorders associated with impaired 
PPI and working memory, such as schizophrenia. 
In total, we expect to accomplish three goals by extending a new line of research, investigating the effects 
of specific pharmacologic agents on PPI and other psychophysiological measures in humans: 
1) Extension of the preclinical findings into humans, to allow interpretation of anatomical and genetic 
correlates of observed behavioral deficits in psychiatric patients. 
2) Replicate and extend findings in humans with specific pharmacologic probes. 
3) Determine the relationship between specific drug effects on PPI and neurocognitive functions, in 
healthy and patient populations, as a function of specific physiological, psychological and genetic 
biomarkers. 
8. 
PRELIMINARY STUDIES/PROGRESS REPORT 
Psychophysiological measures and some other aspects of the protocol described in this application have 
been used for the past thirteen years in the PI's laboratory.   No untoward effects have been observed. 
The success of the protocol in evaluating sensorimotor gating encouraged us to expand this protocol to 
include the use of pharmacologic agents. Results from our control population led to modifications in 
experimental designs that facilitate the detection of subtle drug effects and differences in control vs. 
patient populations. 
Previous work of this type has been completed successfully at this institution and elsewhere. Specifically, 
Dr. David Braff undertook studies of the effects of d-amphetamine on PPI in humans, and the present PI 
was a co-investigator on that protocol (91-516), which has now expired. The PI pursued studies of the 
effects on PPI in humans of the NMDA antagonist ketamine, in collaboration with Dr. Mark Wallace (96- 
0003); ketamine and other NMDA antagonists disrupt PPI in rats. Studies at other institutions have 
examined the effects of caffeine, ketamine, apomorphine, amphetamine, nicotine or bromocriptine on PPI 
(the latter given alone, and in combination with haloperidol); as in rats, these studies report that PPI can 
be disrupted (apomorphine, amphetamine, bromocriptine, ketamine) or enhanced (nicotine) in humans, 
and that the PPI-disruptive effects of DA agonists can be prevented by the D2 antagonist haloperidol. In 
some cases, a lack of consistent drug effects on PPI in humans demonstrated parallel “negative” effects 
of pharmacological probes on PPI across species. While PPI measures had already been completed in 
humans using some of the drugs in this proposal, other proposed drugs had not been tested (e.g.. 
amantadine, pergolide, and quetiapine). The PI under this protocol has now completed studies with these 
drugs, in addition to caffeine, bromocriptine and amphetamine, and proposed studies will include 
memantine (see below). Thus, the proposed studies are designed to both replicate and extend the 
literature of the pharmacology of PPI in humans. 
As described in our past progress reports, we continue to actively test subjects using our proposed 
measures. They include bilateral measures of eyeblink acoustic startle, prepulse inhibition and 
habituation of acoustic startle, visuospatial priming and latent inhibition. Additional variations of these 
measures are developed on a regular basis to enhance their sensitivity. 
After completing a series of studies using the non-DA stimulant caffeine, we undertook a systematic 
series of studies to examine the effects of DA agonists on startle and related measures in normal humans. 
We assessed the time course of action of several DA agonists - pergolide (0.025 and 0.1 mg), 
amphetamine (20 mg), amantadine (200 mg) and bromocriptine (1.25 and 2.5 mg) - on startle measures, 

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autonomic changes, and self-ratings of somatic and physiological symptoms. We then completed 
detailed, within-subject studies of the effects of amphetamine, amantadine, bromocriptine and 
pramipexole on PPI and related measures. Findings from these studies were described in published 
reports, cited in Section 22, and many have already been replicated and extended by other groups. 
Most recently, we have begun to assess the broader neurocognitive correlates of drug-induced changes 
in sensorimotor gating. Our group and others have reported that levels of PPI correlate significantly with 
global neurocognitive measures, and specifically, with working memory (WM); in schizophrenia patients, 
we reported that levels of PPI correlate significantly with global levels of functioning. We also reported that 
the Alzhemier's Disease medication and NMDA antagonist, memantine, significantly increases PPI, 
particularly      among      individuals      with   Effects of memantine (MEM) vs. placebo 
* 
phenotypes - low baseline PPI and high (PBO) on WM (%ile score from MCCB, see 
novelty seeking - associated with the Val/Val 
text). WM was increased by MEM in 7 out 
COMT genotype. As a result, we have 
of 8 subjects, and unchanged in the 8th. In 
WM 
initiated studies in normal subjects to test the 
these subjects (F=10.68, p<0.015), MEM 
hypothesis that memantine will increase WM, 
also significantly increased PPI. This 
particularly among subjects exhibiting high 
ongoing study is conducted with a double- 
memantine PPI sensitivity. Our initial findings   blind, balanced order design. 
PBO MEM 
in a double-blind, within-subject, balanced 
order, placebo-controlled study, are quite promising: memantine (20 mg po) significantly increased WM in 
normal subjects, despite the fact that most of these subjects are UCSD undergraduate students with high 
baseline levels of WM (see figure, right). PPI was also significantly increased in these subjects, 
particularly among the predicted "sensitive" subgroups. 
The implications of these preliminary findings are potentially quite significant, as they suggest that MEM 
might enhance PPI and WM, particularly among subgroups of individuals carrying "biomarkers" that 
include low baseline PPI, high novelty seeking, and/or the Val/Val COMT genotype. If this same pattern of 
results is detected in clinical populations, it will suggest a means to prospectively identify patients in whom 
memantine (or other putative pro-cognitive agents) can enhance specific neurocognitive abilities (e.g. 
WM) to synergize with therapeutic interventions (e.g. cognitive training) that rely on these abilities.   We 
are currently planning to test this prediction in clinical populations, including patients with schizophrenia, 
who are enrolled in IRB-approved clinical trials of cognitive training. 
Summary of Progress to Date 
A. Drug Effects on Prepulse Inhibition of Startle: 
1. We carefully examined the effects of 4 dopamine agonists (amphetamine, 20 mg), bromocriptine, 1.25 
mg), pramipexole (0.125 and 0.175 mg) and amantadine, 200 mg) and one NMDA antagonist 
(memantine, 20 and 30 mg) on prepulse inhibition (PPI) and related measures, and reported on these 
effects in five papers (below). Paradigms were modified to increase the sensitivity to drug effects (e.g. via 
use of within-subject designs or optimal stimulus parameters), and new paradigms were developed to 
provide new insights into these drug effects (e.g. via the development of a novel sensory gating 
paradigm). Our findings identified quite distinct effects of these drugs in our behavioral paradigms; for 
example, amphetamine on the one hand, and amantadine and memantine on the other, produced 
opposite effects on PPI, with amphetamine significantly disrupting and amantadine and memantine 
significantly increasing PPI. These effects were not predicted based on our preclinical findings in rats, and 
have led to new hypotheses and insights related to cross-species differences in the regulation of 
sensorimotor gating. 
2. We studied the effects of an atypical antipsychotic (Seroquel) on PPI and related measures in normal 
male subjects, the first of its kind in the literature. Seroquel (12.5 mg) was used without any adverse 
effects on normal males. This initial study helped us design our current, ongoing experiments, examining 
 

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interactions between Seroquel and amphetamine and between Seroquel and amantadine, using the dose 
of the DA agonist as a within-subject variable and Seroquel dose as a between-subject variable. 
Furthermore, our experience with Seroquel led to a contract for a specific study with AstraZeneca 
Pharmaceuticals, which has been completed. The contract with AstraZeneca expired at study completion. 
During this research period, all of our human drug studies have been relocated to the GCRC at the UCSD 
Medical Center with the option to test at the UCSD Clinical Teaching Facilities. 
3. We have recently detected pro-cognitive (WM) effects of memantine (20 mg) among normal controls 
who also exhibit PPI-enhancing effects of this drug (see above). 
B. Paradigm development 
Studies led to the development and optimization of two paradigms: a) a within-subject latent inhibition (LI) 
paradigm that was studied both in normal controls treated with DA agonists, and in normal control vs. 
schizophrenia subjects. Developing a within-subject LI paradigm suitable for human use has been a 
longstanding goal of our psychophysiology program. 
C. Relationship of physiological and personality measures to startle gating in normal subjects 
As part of our ongoing process of screening normal control subjects for drug studies, we have collected 
data from large samples (current n > 400), adequate for examining relationships between sensorimotor 
gating and normal physiological and personality markers, as well as factors such as ethnicity, that may 
ultimately be relevant to genetic studies with PPI. These studies have led to several interesting findings, 
including an inverse relationship between resting blink rate (a physiological variable related to central DA 
function) and PPI, as well as robust ethnic differences in startle magnitude (but not sensorimotor gating) 
between Caucasian and Asian American populations. 
We have had no adverse reactions associated with drug ingestion in any of our testing, including tests 
completed with DA agonists, Seroquel, or drug combinations. Nausea previously experienced by a small 
number of test subjects after pergolide was reported in a previous IRB update; we have not since used 
pergolide in any studies. One brief syncopal episode during venopunture was recently reported, but had 
no long-term sequellae. The DA agonists used for the majority of the studies during this period were 
amphetamine and amantadine, which are very well tolerated. Seroquel results in mild sedation, but 
subjects remain quite comfortable. All other drugs, experimental measures, testing procedures, etc. 
proposed for studies in this application have already received UCSD IRB approval in Project #031317. 
Several modifications to the protocol have been approved and incorporated into the protocol. 
*REFERENCES ARE LISTED IN SECTION 22 
9. 
RESEARCH DESIGN AND METHODS 
GENERAL METHODS: 
a) Study populations: Study subjects, ages 18-45, are recruited from the community. Two subject 
populations are recruited: clinically normal control subjects, and patients with schizophrenia. The patient 
populations and upper age limit of 45 are used only for studies with memantine, which is prescribed 
clinically in geriatric populations for the treatment of Alzheimer's Disease. For all other studies, the sample 
is limited to clinically normal controls and the upper age limit is 35. 
b) We ask new participants whether they would allow us to contact them regarding future studies. If they 
agree, our plan is to contact them at a future date for appropriate IRB approved studies. 
c) For all drug evaluation studies, normal control subjects are recruited and screened for evidence of 
physical or psychological impairment; schizophrenia patients are recruited and screened only for 

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participation in drug evaluation studies with memantine. Each recruited subject is given a complete 
physical and psychiatric examination including medical, psychiatric, social and drug histories, an EKG and 
a urine test. For most studies, only male subjects, ages 18-35, are recruited. For a subset of studies, 
female subjects, and subjects up to age 45 will be recruited, as discussed below.   All subjects are asked 
to arrange for transportation to and from any test session due to possible adverse effects for up to 12 
hours after drug administration. During some or all of the tests the subject’s performance may be 
monitored by the use of a non-recording camera. This is to ensure that the subject is awake and 
performing the task as instructed. Only the investigator running the test session will be able to see the 
subject, and this allows quantification of blink rate. 
d) Subject payment (also see below, section 18): For subjects participating in the “Within-Subject” test 
sessions, payment will be divided in the following schedule: on completion of screening day: $30; on 
completion of first TEST SESSION day: $100; On completion of second TEST SESSION day: $130. This 
payment schedule provides appropriate incentive for the subjects to return for the second test day. This is 
to ensure that subjects return for the second and third test days. If subjects fail screening criteria for 
recreational drug use prior to any TEST SESSION day, they will not be tested further and will not be paid 
for that test day. We will recommend that subjects remain in our laboratory for monitoring until six and one 
half hours after pill ingestion. Should they choose to leave our facility for any reason prior to that time, it 
will be at their own risk. Their involvement in the study will be completed and payment on the Test 
Session day will be prorated to $16 per hour. 
e) Venopuncture: Venopuncture for COMT allelic testing in some subjects will occur during the initial visit, 
before or after what normally is titled the SCREENING SESSION in the studies listed below. A single 
venopuncture performed by certified individuals within the UCSD Medical Center GCRC/CTRI or Blood 
Drawing Station will be used to 10 cc of blood for COMT allelic testing. Based on specific needs of the 
experimental design (e.g. equal number of Met/Met, Val/Met and Val/Val allelic carriers, or subgroups of 
"high" vs. "low" PPI levels, based on the upper vs. lower quartile of a normal population distribution), 
subjects may be asked to come back for further testing, if they indicate they would like to do so. If 
participants continue to the remainder of the study, there will be 2 test days, one of which will involve 
placebo, and the other day involving an active dose of amphetamine (20 mg), memantine (20 mg) or other 
approved test drug/dose. The TEST SESSIONS will mimic those in the WITHIN-SUBJECT model below; 
however, venopuncture occurs only during the first visit. 
f) Clinical assessment: Specific clinical assessment tools used in control and schizophrenia subjects are 
described in Section 10. 
g) Test schedules: 
1. The "WITHIN-SUBJECT" study involves a single drug. There will be 2 test days – on the additional test 
day, subjects will receive either placebo or an active dose of one of the following: amphetamine (20 mg), 
memantine (10 mg) and memantine (20 mg). Some studies may require a venopuncture for genetic 
analysis as discussed above. A "model" example of a WITHIN-SUBJECT test schedule is shown below: 
Test Day 1 
0815-0845 
Subject signs required forms, provides urine sample, eats standardized breakfast, 
venopuncture (if required) 
0845-0900 
Vital signs (VS) check, hearing and vision test, symptom rating scale. 
0900-0915 
drug or placebo administration. 
0915-0930 
VS check; symptom rating scales. 
0930-0945 
EMG electrodes applied. 
0945-1000 
VS check; symptom rating scales. 

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1000-1125 
Startle response measurement, including PPI, habituation and intensity assessment. 
1125-1140 
VS check; symptom rating scales. 
1140-1155 
Visual LI or Visuospatial priming or MCCB 
1155-1210 
VS check; symptom rating scales. 
1210-1300 
Subject offered lunch from cafeteria. 
1300-1600 
VS check hourly; subject dismissed if VS within established parameters at 1600. 
Test Day 2: 7-30 days after Test Day 1 
0815-0845 
Subject signs required forms, provides urine sample, eats standardized breakfast, 
venopuncture (if required) 
0845-0900 
Vital signs (VS) check, hearing and vision test, symptom rating scale. 
0900-0915 
drug mg or placebo administration: WHICHEVER DOSE WAS NOT RECEIVED ON 
TEST DAY 1 
0915-0930 
VS check; symptom rating scales. 
0930-0945 
EMG electrodes applied. 
0945-1000 
VS check; symptom rating scales. 
1000-1125 
Startle response measurement, including PPI, habituation and intensity assessment. 
1125-1140 
VS check; symptom rating scales. 
1140-1155 
Visual LI or Visuospatial priming or MCCB 
1155-1210 
VS check; symptom rating scales. 
1210-1300 
Subject offered lunch from cafeteria. 
1300-1600 
VS check hourly; subject dismissed if VS within established parameters at 1600. 
Subjects will be instructed to not eat on the morning of the test, and instead will be served a standardized 
meal 30 min prior to drug administration, so as to maintain a controlled and consistent impact on drug 
absorption. 
Vital sign assessment during and after testing will be performed in lying, sitting and standing positions, by 
a trained researcher or health professional. Sessions will be discontinued for 55>HR>110, 90> SBP>160, 
45>DBP>95, emesis, severe discomfort or other unanticipated medical or psychological consequence. At 
the end of testing, at the times described above, subjects will be dismissed if their heart rate is between 
55 - 90, their SBP is between 90 -150, their DBP is between 45 - 90, and there is no evidence of dizziness 
or significant heart rate increase or blood pressure reduction on postural changes, from lying to sitting to 
standing. 
2. The "ONE-DAY" test session: When developing new test sessions, we often examine correlations 
between response characteristics elicited by different stimulus parameters. The subjects participating 
these types of studies will be tested with air puff and all acoustic stimuli. Acoustic stimuli will be no louder 
than 118 dB(A), a level already approved in previous protocols (most recently 071154). No drugs are 
administered during these studies. 
These studies will include up to 50 normal control subjects per year. Some subjects may be screened on 
the phone and in person, as done in previous studies. The consent form used will have the different 
possible tests listed. The options are: 
1. A urine test will be required to test for the presence of illicit drug use. Your study participation will be terminated if 
the urine test is positive for any drugs, and you will be paid for your time, which will be prorated as stated below. 
Only the researcher will know the results of the test. This procedure takes approximately 10 minutes. 
2. You will be asked to fill out several personality questionnaires. You can skip any questions you do not 
want to answer. This procedure takes approximately 30 minutes. 
3. You will be a given a psychiatric examination that includes medical, psychiatric, social and drug 
histories. This procedure takes approximately 20 minutes. 

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4. Eyeblink startle: two electrodes with adhesive backing will be placed next to both eyes so that your 
blink reflex can be measured, and one will be placed behind the left ear as a reference measure. This 
procedure takes approximately 10 minutes. The procedures listed below may occur concurrently. 
5. You will be asked to complete one or more computer task(s), each approximately 15 to 20 minutes. 
6. You will be asked to listen to a series of brief tones, experience a series of air puffs under your chin, 
and/or experience a series of brief vibrations delivered via speaker to your hand for approximately 25 
minutes. Some of the tones will be so loud that you might find them annoying or uncomfortable. Some 
puffs and vibrations might be so strong that you might be surprised. 
7. You will be asked to make marks on a piece of paper in response to the tones. 
8. You will be asked to evaluate your present mood state in a questionnaire. 
9. You will be asked to make a mark on a line to indicate how loud a sound seems to you with a pencil, or 
by using a computerized rating scale called the "slider" that has a knob on its surface. Movement of the 
knob corresponds to movement on a computer screen, which will sit in front of you. 
The participant will be informed over the phone that some or all or the options may not be used, and will 
not be a part of the procedure. 
h. Information pertaining to specific pharmacologic agents to be used in these studies: 
Proposed list of pharmacologic agents and doses (doses based on previous human studies with these 
agents, or the lowest dose initiated in standard treatment algorithms, as described by the Physician’s 
Desk Reference): 
Drug 
Route     Doses 
“Common” side effects (single dose)* 
Amphetamine 
Oral       20 mg 
Increased HR, BP, restlessness, dizziness, euphoria
Memantine 
Oral       10, 20 mg 
Dizziness, restlessness, nausea, headache 
• 
most reports define “common” to either mean >5% incidence or >10% incidence; most side effects 
reported only with continued use or repeated dosing, rather than single dose use, and typically 
occur with doses substantially higher than those to be used in this study, or in vulnerable clinical 
populations (e.g. elderly patients with dementia); in several cases, these effects were observed at 
rates that were not statistically different from placebo. 
The dose of amphetamine used in this study (20 mg po) is one that is used commonly in healthy adult 
subjects. References are provided below for examples of studies in which this dose has been used, 
without untoward effects; two papers from our studies are included among these. Subjects in our studies 
are 18 - 35 years old, and are carefully screened by a physician, or a nurse under supervision of a 
physician, who takes a medical history and performs a physical examination. Screening also includes an 
EKG and urine toxicology tests. 
Medications are administered in the UCSD Clinical Teaching Facility, rooms A-304A and A305, which are 
staffed by a physician or registered nurse. To date, amphetamine as a single 20 mg oral dose has been 
administered to 65 subjects in our studies, 49 in a within-subject double-blind placebo-controlled study, 
and 16 in a between-subject double blind study. No subjects reported adverse effects of this dose of 
amphetamine. Measures of autonomic function indicated the expected increases in heart rate and blood 
pressure after amphetamine, as indicated below. However, in each case, these increases were 
numerically small (see Table 1) and did not approach levels that would normally be of medical 
consequence in a healthy young adult population. Only one subject exhibited a heart rate with 
amphetamine in excess of 100; several placebo subjects exhibited heart rates in the 90's. 
Table 1. Autonomic effects of 20 mg d-amphetamine po in 65 subjects tested to date 
Placebo 
Amphetamine 
Ave. Heart Rate during test session (mean (SEM)) 66.55 (1.24) 
68.92 (1.14) 

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Maximum HR (mean (SEM)) 
73.27 (1.40) 
75.94 (1.49) 
SBP (mean (SEM)) 
113.15 (1.74) 
116.65 (1.54) 
DBP (mean (SEM)) 
67.23 (1.01) 
70.02 (0.86) 
Subjective ratings also demonstrated no adverse effects of this drug dose, based on visual analog scale 
(VAS) self-assessments (Table 2). In these scales, 0 = no effect, 100 = extreme effect. Other scales 
indicated that this dose of d-amphetamine reduced drowsiness, and was associated with a trend towards 
an increased sense of being "happy". 
Table 2. VAS scores for subjective effects of 20 mg d-amphetamine po in 65 subjects tested to date 
Placebo 
Amphetamine 
Dizzy (mean (SEM) 
2.73 (0.68) 
3.04 (0.76) 
Queasy (mean (SEM)) 
2.10 (0.52) 
1.78 (0.30) 
Summary: A 20 mg po dose of amphetamine is used commonly in the published literature in studies of 
normal, healthy adults, without common adverse reactions. This experience is validated in our own 
studies of 65 normal adult subjects. 
References are included at the end of this section. 
Memantine is the only drug in this application that is being proposed for testing in schizophrenia patients. 
It is FDA-approved for the treatment of dementia, but has been widely used in a number of different 
clinical conditions (see below). 
Memantine, Basic Information: The NMDA receptor is a ligand-gated ion channel, permeable to 
monovalent and divalent ions. Activation of NMDA receptors leads to Ca++ influx, which is blocked by 
NMDA channel blockers. High affinity channel blockers, like PCP, are not easily studied in man, due to 
side effects such as psychosis and neurotoxicity. However, low affinity channel blockers are used 
clinically, and are well tolerated, with potential neuroprotective properties. Several lower affinity NMDA 
antagonists reduce long-interval PPI, though this effect is generally weaker than that caused by high 
affinity antagonists. Wiley et al. reported PPI-disruptive effects of dextromethorphan and memantine; the 
effects of memantine were dose-related, reaching significance at 10 mg/kg (an effect that we have 
replicated), while those of dextromethorphan were evident only at the highest dose (100 mg/kg). At these 
doses, neither drug altered startle magnitude, while a lower affinity NMDA antagonist, ibogaine, reduced 
PPI only at doses that significantly depressed startle. In this report, amantadine did not alter PPI at a dose 
(56 mg/kg) lower than the one we have found to reduce long interval PPI, and to increase short interval 
PPI (100 mg/kg). 
Memantine, Clinical Information: Memantine has been prescribed in Europe for > 15 years for dementia, 
with formal EU marketing approval. Published studies document safety and high tolerability in >1000 
elderly patients with dementia, and tolerability of doses 2-4X above typical therapeutic ranges in normal, 
younger adults, who reported no adverse effects at a dose of 40 mg po. The active dose in the present 
proposal (20 mg po) is one-half the dose found to be well-tolerated in studies in these younger male 
subjects. Studies have reported no neuropsychological changes or mood changes after administration of 
20-40 mg memantine po in healthy young men, and only a short-lasting sensation of restlessness and 
dizziness in 4 out of 7 healthy young adults, 2 hours after administration of 30 mg memantine po. Other 
studies using intravenous loading of memantine in healthy young adults reported no side effects. 
Memantine was developed for many clinical indications (e.g. dementia, neuropathic pain and diabetic 
neuropathy). Full FDA approval was received 10/17/03. Since its approval, memantine has been 
prescribed widely, both for its FDA indication of mild-to-moderate dementia, and off-label, for more severe 
dementia, and for other conditions, including diabetic neuropathy. Data continue to support its excellent 
safety profile; a recent study reported in JAMA with > 200 subjects treated daily with 20 mg memantine 

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resulted in fewer treatment discontinuations due to adverse events for memantine (7.4%) than for placebo 
(12.4%). Memantine is prescribed routinely for patients at the UCSD Medical Center Senior Behavioral 
Health Unit; these patients are studied in the PI's protocol before and after initiation of memantine 
therapy. Thus, in essence, the current request for an amended protocol will extend our existing studies in 
elderly, medically complex patients to include healthy, younger, normal control subjects. 
Based on our published and unpublished findings to date, we have studied memantine in a full placebo- 
controlled double-blind cross-over design in 45 clinically normal individuals. Data from 37 subjects was 
reported in a published paper (20 mg, n = 19; 30 mg, n = 18), and data from 8 addition subjects (20 mg) 
was recently submitted as an abstract for the upcoming 2010 meeting of the Society for Neuroscience. No 
AEs were detected with any subjects in these studies. 
The present protocol proposes the use of 10 and 20 mg memantine; our experience to date is limited to 
the higher of these two doses (20 mg); based on the published literature, we expect any potential AEs to 
be dose-dependent, and thus the 20 mg dose (vs. the 10 mg dose) represents the one with the highest 
likelihood of AEs, should any occur. In our published data (n=19), the only detectable impact of 20 mg 
memantine (other than those in our neurophysiological measures) were: 1) an increase in self-reported 
level of happiness 30–230 min after pill administration; and 2) a small decrease in spontaneous blink rate, 
an effect generally suggestive of reduced fatigue or somnolence. No significant changes in self-rated 
dizziness, queasiness or drowsiness were detected at any time after 20 mg memantine. Autonomic 
measures (heart rate, systolic or diastolic blood pressure) were also not significantly changed by 
memantine. Our unpublished data (n=8) with 20 mg memantine (see above), confirms all of these 
findings, including no significant change in autonomic measures or self-rated dizziness, queasiness or 
drowsiness, a trend towards increased self-rated happiness and decreased blink rate. In addition, as 
described above, we noted a significant increase in working memory after memantine, as measured by 
the MCCB. 
Memantine has been studied in schizophrenia patients. It is important to note that these studies involved 
daily dosing for many weeks or longer, while the present protocol proposes only a single active dose of 
memantine. Nonetheless, the findings are informative: 
Memantine use in schizophrenia patients: A recent double-blind study reported large reductions in positive 
and negative symptoms (d=1.38-3.33) and improved Mini-Mental State Exam scores after 12 weeks of 
memantine (20 mg/d; n=10) vs. placebo (PBO; n=11) added to clozapine; so significant adverse events 
were reported. An earlier 8-week double-blind, study of memantine (20 mg/d; n=70) vs. PBO (n=68) 
added to atypical APs detected no change in positive or negative symptoms or Brief Assessment of 
Cognition in Schizophrenia scores, but found that memantine was associated with more adverse events 
(AEs; memantine vs. PBO = 8.7% vs. 6.0%) and treatment discontinuation due to AEs (11.6% vs. 3.0%). 
Importantly, the most frequent serious AE in memantine group patients was an exacerbation of 
schizophrenia symptoms, but this AE actually occurred LESS OFTEN in the memantine group (2.9%) 
than in the placebo group (6.0%). Overall, the incidence of ANY adverse events over the 8 week trial was 
92.4% in the placebo group vs. 88.3% in the memantine group; no changes in autonomic measures, EKG, 
laboratory measures or extrapyramidal functions were detected with memantine. A smaller, 6-week, open 
label study of memantine (5 - 20 mg/d) in symptomatic schizophrenia inpatients reported a significant 
improvement in positive and negative symptoms but not cognitive performance, with no AEs. Three case 
reports described beneficial effects of memantine (5 - 10 mg/d) in schizophrenia patients, with reductions 
in negative symptoms and functional impairment and no AEs; in two reports, symptoms returned on 
memantine discontinuation and resolved again after restarting memantine. 
All drugs/doses proposed in this application (for amphetamine and memantine) are equal to or lower than 
those already approved by this IRB and studied in the PI's laboratory for several years in > 170 total 
normal adult subjects, with no adverse reactions. These doses are at or near the lowest recommended 
starting dose of a given medication when it is used in a clinical setting, and well below the typical 

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maintenance dose of these medications. 
Drugs will be dispensed by a licensed physician, and a licensed physician will be present on the premises 
at all times during testing. 
No drugs will be used in studies with subjects < 18 years of age. Nonetheless, it is reasonable to ask 
whether these drugs have been used safely in 18-35 year old subjects (or, in the case of memantine, 18- 
45 year old subjects). Although dopamine agonists have primarily been used and tested in Parkinsonian 
patients, some of these dopamine agonists are used in children. Amphetamine is used safely and 
effectively in children with Attention Deficit Disorder. The only drug in this proposal that does not have a 
specific indications or common use in adolescents is memantine. We have published findings of 
memantine's safe use in 18-35 year old study subjects, as described above. The fact that memantine is 
most often used in patients with multi-system medical illness (Alzheimer's Disease) accounts for some of 
its rare but more significant side effects (e.g. hallucinosis). 
i. Laboratory Measures: 
1. Startle Reflex: The startle reflex will be measured in control populations in men and women to examine 
sex differences in the startle-facilitating and inhibiting effects of weak and strong prepulses presented at 
short and long prepulse intervals. Sex differences in prepulse modulation of startle also will be measured 
using cross-modal stimuli (acoustic prepulse and tactile pulse). Sensorimotor inhibition and facilitation will 
be measured in women during different phases of the menstrual cycle. 
Testing occurs during the light circadian phase (0900-1700). The testing room is maintained at 68-70° F. 
Subjects are screened for hearing impairment with a Saico Audiometer at .5, 1 and 6K Hz; impairment at 
40 dB(A) leads to exclusion. Startle is measured with an SR-LAB IBM PC computer monitoring system 
and a custom EMG amplifier with a 1K Hz band pass filter. Subjects sit in a quiet room, with 2 Beckman 
miniature Ag-AgCl electrodes placed 1 cm lateral and inferior to the right and/or left external canthus, over 
the orbicularis oculi (R< 5K Ohm). A ground electrode is placed behind the left ear, over the mastoid. 
Subjects wear Telephonics headphones (TDH-39-P) and look forward to a point that allows them to be 
comfortable with their eyes open. A 5-min 70 dB (A) background white noise is followed by acoustic or air 
puff startle trials. The startle pulse is either a 118 dB(A) 40 msec noise burst (P-ALONE) or a comparably 
startling air puff stimulus presented alone or during prepulse trials, preceded at a 100 msec interval by a 
prepulse (20 msec noise burst a few dBs above background). Background white noise is continuous until 
the session ends. The session lasts about 25 minutes with repeated trials and an intertrial interval of 30 
seconds. 
Digitized blink responses are displayed graphically on the PC monitor; voluntary and spontaneous blinks 
are excluded based on published criteria. Startle reactivity is defined by P-ALONE amplitude. A small 
number of subjects are startle "non-responders": following criteria previously established, subjects whose 
startle amplitude does not exceed set levels are excluded from analysis of PPI (non-responder mean 
amplitude <10 units on P-ALONE, compared to typical "responder" mean of 75 units). 
Tactile stimuli: In some studies, the subject rests their hand on a sound speaker that delivers a vibration to 
the thenar eminence of the dominant hand, followed 60-240 ms later either by 40 psi 40 ms air puff 
presented to the sternal notch or an acoustic 118 dB(A) or 105 dB(A) 40 msec noise burst. 
2. Electroencephalographic (EEG) recordings and processing: EEG measures will be acquired using 
methods identical to those approved by this UCSD IRB for an existing protocol (#071128, PI: Dr. Greg 
Light), using a Neuroscan NuAmps system (Neuroscan Labs, El Paso, Tx). The EEG will be recorded 
from the scalp through 34 sintered Ag/AgCl electrodes using an electrode cap (EasyCap, Falk Minow 
Services). Electrodes placed at the tip of the nose and at Fpz will serve as the reference and ground, 
respectively. Four additional electrodes placed above and below the left eye and at the outer canthi of 

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both eyes will be used for monitoring blinks and eye movements. All impedances are kept below 4 kΩ. 
Signals will be digitized at a rate of 1 kHz with system acquisition filter settings at 0.5-100 Hz. Auditory 
stimuli will be presented to subjects using foam insert earphones (Model 3A, Aearo Auditory Systems). 
EEG and stimulus markers will be recorded continuously. Subjects will not smoke for at least 60 minutes 
prior to EEG recording and will be instructed to minimize eye movements and muscle artifact during the 
recording. During testing, subjects will be observed through a one-way mirror. In addition, signal quality 
and the number of sweeps free of gross artifacts (defined as ±100 μV across the 0 to 512 msec following 
stimuli) will be closely monitored. Data processing will be performed offline and blind to group 
membership using automated procedures. First, continuous recordings will be mathematically corrected 
for eye movement artifacts using established methods. Continuous data will be epoched relative to the 
onset of stimuli and centered at the mean of the prestimulus baseline. Following blink correction, epochs 
containing > ±50 μV will be automatically rejected. Epochs will also be manually reviewed to reject EEG 
segments with other artifacts (e.g., muscle activity). EEG testing, including electrode setup and running 
the two paradigms (MMN and gamma band entrainment) takes approximately 60 minutes. 
Mismatch Negativity (MMN): Stimulation, recording, and analysis techniques for calculating MMN 
amplitude will follow our previously established methods. Briefly, Subjects will be presented with binaural 
stimulation (1 kHz computer-generated square wave stimuli, 85 dB[A] SPL, 1 msec rise/fall) with a fixed 
stimulus onset-to-onset asynchrony of 500 milliseconds. Standard (P=0.90; 50 msec duration) and 
deviant (P=0.10; 100 msec duration) stimuli will be presented to subjects in pseudorandom order while 
they watch a silent video. Signals will be digitized at a rate of 1 kHz with system acquisition filter settings 
at 0.5-100 Hz. MMN waveforms will be generated by subtracting ERP waveforms in response to standard 
tones from the ERPs generated in response to the deviant tones. The MMN amplitude will be measured 
as the mean voltage from 135 to 205 milliseconds. Primary dependent measure: MMN amplitude at 
electrode Fz. 
Gamma Band Entrainment (neural network synchronization to sensory stimuli): Evoked EEG power and 
inter-trial coherence analyses will be assessed in response to 20, 30, and 40-Hz stimulation at Fz 
following our published methods, as this is the electrode with maximal responses. The stimuli will be 1- 
millisecond duration, 93 dB clicks presented in 500 msec trains varying in rate of presentation (20, 30, and 
40 Hz) in each of 3 blocks (order fixed). Blocks contain 200 trains of clicks with 500-millisecond intertrain 
intervals. For evoked power analyses, averages will be computed on 120 artifact-free epochs in each 
block and digitally filtered using a zero-phase shift, 10-60 Hz bandpass filter (24 dB/octave). The 
averaged epochs across the click trains (0-512 msec) will then be transformed into power spectra by 
means of fast Fourier transform (FFT) using a bin width of 1.95 Hz for the assessment of evoked power 
analyses. The 20, 30, and 40-Hz power spectra will be averaged across 10 Hz bands from 15-25 Hz, 26- 
35 Hz, and 36-45 Hz, respectively. Time/frequency ITC analyses will be performed using EEGLab in 
order to assess ITC of the stimulus-driven EEG signals. ITC provides an estimation of the strength of 
phase locking of the EEG signals across individual trials independent of the signal amplitude. In this 
analysis, a parameter is obtained that ranges from 0 (for non-phase locked, random activity) to 1 (for 
activity that is fully locked in phase across individual trials at a given latency). Considered together, the 
evoked power and ITC provide a conceptual framework for observing the event-related brain dynamics 
that occur consistently across both blocks of time and individual trials.   Primary dependent measure: 40 
Hz evoked power at electrode Fz. 
3. Neurocognitive testing will consist of the MATRICS Consensus Cognitive Battery (MCCB), which 
includes ten tests that assess seven cognitive domains. The MATRICS battery was developed by an NIH 
Task Force for the purpose of testing drug effects on cognitive measures of relevance to schizophrenia. 
We are already using the MCCB for this purpose as approved in this protocol for control subjects, and will 
now also administer it to psychiatric patients. We previously used the MCCB for this purpose in another 
UCSD IRB-approved protocol (#071824). The battery takes about 1 hour to complete. 
4. Visuospatial priming: The subject's task is to press one of four computer keys, which correspond 
spatially to four loci on a PC screen. Each trial includes two successive displays, each consisting of a brief 

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presentation of an 'X' and an 'O' in two of the four locations. On each presentation, subjects press the key 
corresponding to the location of the target letter 'O' while ignoring the distractor letter 'X'. The 'X' and 'O' 
within each display are visible for 150 msec; the time between displays is 350 msec. The task consists of 
50 display pairs. There is a baseline condition in which the positions of the target ('O') and non-target ('X') 
in the probe display are unrelated to their positions in the prime display. In "repetition priming" (the 
facilitation condition) the position of the target remains the same on the successive displays. In "negative 
priming" (the inhibition condition) the target in the probe display appears in the location where the non- 
target had previously been. 
5. Latent Inhibition: A computerized visual latent inhibition task is used. Subjects are pre-exposed or non-
preexposed to a visual stimulus (pattern on a computer screen) that will, in the subsequent phase of the 
testing, have predictive value. Using the computer keyboard for responding the subjects will predict 
computer screen changes, being influenced by the earlier exposure parameter. Each phase requires 5 
minutes time to run. Preexposed control subjects require more trials prior to reaching a criterion score on 
their predictive response. 
Pregnancy test: The pregnancy test is able to detect tiny amounts of the pregnancy hormone hCG 
(Human Chorionic Gonadotropin) in urine. This hormone is produced in increasing amounts during the 
first part of pregnancy. HCG will be measured by a urine “dip-stick” (“Surecheck Early Pregnancy Test”). 
This test is a midstream format test for the detection of the pregnancy hormone in urine. 
j. Statistics: Tests for homogeneity of variance are performed, and if appropriate, analyses of variance 
(ANOVA) used. Statview/Superanova software is used on the Macintosh. For startle data, P-Alone 
amplitude, PPI and startle latency are analyzed by ANOVAs; for drug studies, drug dose is used as a 
within-subject factor. Habituation is detected by a significant effect of trial block. Visuospatial priming is 
analyzed separately for baseline, facilitation, and inhibition conditions using ANOVAs. Baseline is a 
measure of visuospatial response time, while facilitation and inhibition scores are measures of 
sensorimotor modulation. Nonparametric statistics are used for the Latent Inhibition analyses because 
data from this test tend toward a bimodal distribution. A rank sum factorial analysis is used for the data. 
Other dependent measures will be analyzed with parametric or non-parametric analyses, generally 
consisting of mixed design ANOVAs, as appropriate. Following a significant ANOVA, specific comparisons 
are made using Tukey's tests. Alpha is 0.05. 
Power considerations: Sample sizes vary across the different studies, based on issues ranging from the 
study design and goals to empirical evidence for effect sizes with the proposed drug or measure. For 
example, "ONE-DAY" studies are designed to identify and "pilot" optimal stimulus parameters for testing 
specific hypotheses, and these studies may not be powered to achieve traditional levels of statistical 
significance. On the other hand, designing studies of drug effects on PPI and related measures in control 
or patient populations requires detailed power information. 
For example, to assess the effects of memantine on "gating" measures in schizophrenia patients, the 
primary measure will be evaluated by 2-way repeated-measure ANOVA of PPI with memantine dose and 
prepulse interval as within-subject factors. The hypothesis that memantine will increase PPI in 
schizophrenia patients will be confirmed by a significant effect of dose (active > PBO) or significant dose x 
interval (int) interaction and post-hoc comparisons at one or more prepulse intervals. Existing data (see 
above) provide a strong a priori prediction that the 120 ms prepulse interval will be most sensitive to PPI- 
enhancing effects of MEM. The effect size (d) for PPI-enhancement by 20 mg memantine in HCS was 
0.91; with a similar “d” in patients, 30 patients/dose yields power of 0.92 to detect the predicted 
memantine effects; with maximum expected attrition (n=24), power is 0.85. Past findings also lead to the 
prediction that these MEM effects would be most robust in subjects exhibiting the lowest basal PPI levels 
(d=1.80). Using a median split of mean basal (screening) PPI levels, ANOVA as above will detect a 
significant interaction of memantine dose x basal PPI level, or dose x basal level x int, and significant 
post-hoc comparisons at one or more prepulse intervals (again, 120 ms being the strongest a priori 
candidate). Given the published “d” in control subjects, a comparable “d” in the proposed 12-15 “low PPI” 
patients/dose group would yield power >0.95 to detect the predicted memantine effects. 

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Lastly, based on the impact of basal PPI level and personality measures in controls, we hypothesize that 
a critical moderating factor underlying PPI memantine sensitivity is COMT Val158Met genotype; 
specifically, we predict that “Val/Val” individuals will be most sensitive to memantine-enhanced PPI. This 
will be tested in two ways: first, by ANOVA as above, with COMT status as a between-subject factor, and 
memantine dose and prepulse interval as within-subject factors. Significant genotype x dose or genotype 
x dose x int interactions, with appropriate post-hoc comparisons, would confirm the hypothesis. Estimating 
d=1.53, based on the mean “d” of two “COMT phenotypes” in controls – low basal PPI (d=1.80) and high 
“novelty seeking” personality (d=1.27) - the proposed 11 Val/Val and 7 Met/Met patients/dose group would 
yield power of 0.90 to detect genotype-sensitive memantine effects. It is possible that various factors 
(including a skewed distribution of allele frequencies, or substantial genotype effects on basal PPI levels) 
might preclude detection of a significant 2- or 3-way interaction. A secondary (albeit weaker) test of the 
hypothesis will utilize separate ANOVAs in Val/Val vs. Met/Met subgroups, with predicted PPI-enhancing 
effects of memantine in the Val/Val but not Met/Met subgroups. Previous reports also predict a significant 
main effect of genotype, with PPI levels following the Met/Met>Val/Met>Val/Val gradient. Logistic 
regressions might be used, with genotype coded to reflect “dose” of the Met allele (Val/Val=0, Val/Met=1, 
and Met/Met=2), to assess the distribution of the neurophysiological and neurocognitive measures. All 
analyses will be conducted independently for each dose group. If comparable effects are evident with 10 
and 20 mg doses, dose groups may be pooled to increase power for exploratory analyses (e.g. to detect 
genotype x drug effects). 
Main effects of memantine on WM will be tested by one-way ANOVA with memantine dose as a within- 
factor. Based on d=0.73 for increased WM after 20 mg MEM in controls (see above), the proposed 30 
patients/dose group would yield power of 0.79 to detect significant WM-enhancing effects. While 
preliminary data yield less robust predictions for COMT subgroup sensitivities in memantine effects on 
WM performance, given the significant correlation of WM and PPI, and known impact of COMT genotype 
on PPI levels, we predict some differential (Val/Val > Met/Met) memantine sensitivity in this measure. If 
we estimate effects of COMT status on WM memantine-sensitivity to be comparable to those for PPI 
(65% increase in effect size), then the estimated d for Val/Val vs. Met/Met sensitivity should be 1.20, and 
the proposed genotype subgroup sizes would yield power of 0.65 to detect genotype-sensitive memantine 
effects on WM. 
Secondary “biomarkers” are MMN and GBS. For MMN, positive memantine effects will be detected by 
increased MMN amplitude at electrode Fz. For GBS, positive memantine effects would be detected by 
increased 40 Hz evoked power at electrode Fz. Unlike those for PPI, predictions of positive memantine 
effects on MMN and GBS are not based directly on previous findings from our laboratory, using measures 
identical to those proposed herein. However, based on reports in healthy subjects from other laboratories 
of memantine effects on MMN (d=0.87) and ketamine effects on GBS (d=0.69), the proposed 30 
patients/dose group would yield power of 0.90 and 0.75, respectively, to detect positive memantine effects 
on these measures. 
10. 
HUMAN SUBJECTS 
The subject population will include normal controls and individuals with existing diagnoses of 
schizophrenia. Men and women will be represented and ethnic representation in the sample groups will 
be determined by recruitment responses. Exclusion criteria for control subjects are psychiatric disorders in 
self or first degree relative, organic brain dysfunction, pregnancy or history of substance abuse. 
Psychiatric subject exclusion criteria are serious medical or neurologic illness, history of seizures, 
sustained loss of consciousness, substance abuse/dependence or pregnancy. 
The drug evaluation studies will include normal subjects and individuals with existing diagnoses of 
schizophrenia. They will range in age from 18-35 years for all studies except those involving memantine, 
in which case they will range from 18-45 years. Males and females will be included in future studies. 
Subjects will be given a complete screening physical exam and will be excluded if showing any evidence 
of cardiovascular disease (e.g., hypertension, arrhythmia). Control subjects will also be screened for 
evidence of psychopathology or history of substance abuse using a modified SCID-N interview. If either is 
evident, the subject will be excluded from the study.   All subjects will be informed of the nature of the 
study by a research assistant who will obtain consent if the subject wishes to participate. All subjects will 
be mentally competent and capable of giving informed consent. 

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Table 3. Proposed samples for ongoing / planned studies: 
Study 
 Population 
Total Sample 
Rate 
  Status 
"ONE-DAY" parametric studies 
Normal Controls 
up to 50/yr 
50/yr 
 as needed 
"WITHIN-SUBJECT" amphetamine/COMT Normal Controls 
120 
60/yr 
 ongoing 
"WITHIN-SUBJECT" memantine 
Normal Controls 
30 
30/yr 
ongoing 
"WITHIN-SUBJECT" memantine 
schizophrenia 
 60 
 24/yr 
planned 
The proposed study samples (Table 3) reflect both logistical and power consideration (see above, section 
"8. j. Statistics.") that differ across the several different studies covered by this application. Testing in the 
"ONE-DAY" session is designed for parametric "mini-studies", and the proposed sample of "up to 50 
subjects" per year will allow us to study up to 5 different sets of stimulus parameters, with n's of 10 
subjects per study. To study drug effects on PPI in normal control subjects, our target samples have 
historically been 20-30 subjects per dose; however, with the addition of COMT subgroup analyses, we 
currently plan to test 120 subjects in the within-subject amphetamine study, over a 2 year period 
(n=60/year). To study the effects of memantine on PPI and related measures in schizophrenia patients, 
we are proposing to study a total of 60 subjects: 30 per dose (10 and 20 mg). As this testing will be 
conducted over 2 - 3 years, we estimate recruitment needs of approximately 2 subjects per month, which 
will be easily accommodated by our recruitment capacity at the UCSD Medical Center, based on 
experience over the past 25 years. 
Records and data will be rigorously protected, as described below. Aside from historical and questionnaire 
data, startle response, negative priming, MCCB, mismatch negativity and gamma band synchronization 
data will be obtained. Urine will be obtained for toxicological analysis as part of the subject exclusion 
process. Blood samples will be collected to identify genes that may be associated with PPI or its 
sensitivity to drugs. 
The ethnic population in our male studies from the last 5 years (as we’ve only studied males exclusively 
based on drug study exclusion criteria) and is expected in the following years are: 
Asian/Pacific Islander 
29% 
Black (not Hispanic) 
3% 
Hispanic 
10% 
White (not Hispanic) 
56% 
Other/unknown 
2% 
The ethnic population in our non-drug female studies from the last 5 years and is expected in the following 
years are: 
Asian/Pacific Islander 
12.5% 
Black (not Hispanic) 
2.5% 
Hispanic 
8.75% 
White (not Hispanic) 
72.5% 
Other/unknown 
3.75% 
These numbers reflect the location of where we typically recruit subjects. 
11. 
RECRUITMENT 
1) Control subjects: Recruitment of clinically normal control subjects will follow our established and 
successful methods, using public announcements (e.g., newspapers and bulletin boards, online 
advertisements). Fliers that are posted and faxes that are sent to the UCSD Guardian (on-campus 
newspaper) are enclosed. Phone screening excludes subjects with a history of serious medical or 
neurologic illness or trauma, mental illness (including substance abuse), psychotropic medication use, 
known or suspected pregnancy or hearing problems. Screening is repeated at the time of testing, and a 
urine sample is collected for toxicological analysis (exclusion for illicit substances). The SCID is used with 
our published criteria to exclude theoretically   “psychosis-prone” control subjects,   important for 
 

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comparisons with schizophrenia patients. A handedness questionnaire is used to distinguish right and left 
handed subjects and a questionnaire for evaluating sexual preference is used to identify gender 
orientation, an important control in studies of sexual dimorphism of sensorimotor gating. Subjects also fill 
out cognitive and personality questionnaires: the Eysenck Personality Questionnaire (EPQ), 
Tridimensional Personality Questionnaire (TPQ), the Sensation Seeking Scale - Form V (SSS-V). 
2) Schizophrenia patients: Recruitment of schizophrenia subjects will follow our established and 
successful methods. Patients will be recruited from the UCSD Outpatient Clinic, the UCSD VAMC clinics 
or community hospitals, and board and care facilities. Clinical assessment of schizophrenia patients 
follows our established procedures approved by the UCSD IRB for existing protocols (e.g. #071128, Dr. 
Greg Light, PI; #071306, Dr. Elizabeth Twamley, PI). Specifically, after giving informed consent, some 
schizophrenia patients will be interviewed using the SCID-I/P to ensure that they meet the DSM-IV criteria 
for schizophrenia. Demographic information, including age, age of onset, duration of illness, number and 
duration of hospitalizations, socioeconomic status, education, a detailed medication history, medical and 
psychiatric history, and family history of schizophrenia disorders will be obtained. Positive and negative 
symptoms of schizophrenia will be assessed during the Schedule for the Assessment of Positive 
Symptoms (SAPS) and Schedule for the Assessment of Negative Symptoms (SANS). Inclusion criteria 
include: 1) DSM-IV diagnosis of schizophrenia; 2) Written informed consent to participate in the study; 3) 
Age > 18; 4) Absence of dementia or mental retardation; 5) Urine toxicology negative for recreational 
drugs; 6) Fluent and literate in English (needed for completion of MCCB). Exclusion criteria include: a) 
meets DSM-IV criteria for current substance abuse or dependence and has been substance abstinent for 
less than 30 days; b) a history of traumatic brain injury; c) auditory or visual impairments severe enough to 
prevent study participation. 
Recruitment of female subjects: As per NIH guidelines, it is important to establish whether observed drug 
effects on these psychophysiological measures are sex-specific. Our current NIMH application thus 
proposes the use of female subjects in within-subject studies of drug effects on PPI, LI and related 
measures. At present, approval for studies in females is sought only for studies with amphetamine and 
memantine. Methods for these studies will be identical to those described above for male subjects, with the 
following exceptions: 1) urine pregnancy tests (“Surecheck Early Pregnancy Test”) will be completed at the 
time of initial screening and test day 2 (exclusion: positive test); 2) testing will occur only during post-menses 
days 1-10; 3) blood will be drawn on the morning of testing and stored for possible later hormonal analyses 
using the GCRC/CTRI laboratory services; a total of 5 cc will be collected by venopuncture using 
GCRC/CTRI or hospital phlebotomy services. 
12. 
INFORMED CONSENT 
Recruitment of subjects and informed consent procedures will follow Dr. Swerdlow's established methods. 
For all subjects we will have a consent form indicating any or all of the following procedures to be used: 
startle gating, mismatch negativity, gamma band synchronization, MCCB, negative priming and latent 
inhibition. Subjects included in drug studies will be told of any potential side effects they may expect from 
the drug to be used during testing. Specifically, all subjects will be asked to read a description of the test 
drug, modified from the Physician’s Desk Reference, which includes the following information: 1) the 
typical indications for this drug; 2) the recommended starting dose for this drug, and details regarding 
typical maintenance doses and schedules; 3) common side effects experienced by individuals taking this 
drug, based on trials with the indicated clinical population; and 4) an assessment of the likelihood that 
they will experience significant side effects from this drug, in the doses to be used in this study. In all 
cases, fully informed consent will be obtained and Dr. Swerdlow will be directly available to clarify any 
questions raised by a subject. Signed and witnessed consents will be kept on file with other patient data. 
The UCSD IRB has authorized no waivers or modifications of normal procedures. 
Subjects will be carefully screened to ensure their ability to comprehend study procedures, risks, and 
benefits. Potential participants will be fully informed of all risks and benefits prior to giving their written 
informed consent and prior to enrollment in the study. Participants will be asked to repeat back 
understanding of this material, and if there is any question as to whether a person is able to provide 
informed consent then they will not be permitted to participate. A copy of the signed consent form will be 
stored in a separate locked filing cabinet from other de-identified coded materials, and a copy will be given 
to the study participant. 

Biomedical IRB Application Instructions 
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All study personnel involved in obtaining written informed consent will have completed a web-based course 
with post-test on Human Subject Research Protections and Good Clinical Practice, in addition to being 
trained by the Principal Investigator (PI) on obtaining informed consent. These study personnel will also be 
authorized to obtain informed consent by the IRB and Human Studies Subcommittee. Informed consent will 
be documented using standardized IRB-approved forms. The forms will be presented to all potential 
participants at the initial visit. Briefly, the informed consent form will describe the purpose of the study, 
procedures and participant involvement, nature of assessments and treatments, potential risks, alternatives 
to participation, costs and compensation, confidentiality, right to withdraw, potential benefits, relevant 
contact personnel, and information regarding the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996. Because participation in the proposed study is entirely voluntary, patients can choose to 
discontinue the study at any point for any reason and this will in no way affect future medical treatment 
decisions or practices. 
Genetic Testing, Material & Storage: One goal of this proposal is to identify single nucleotide polymorphisms 
associated with differential sensitivity to drug effects on sensorimotor gating and neurocognition in clinically 
normal and schizophrenia subjects. To accomplish this, blood samples will be sought from all subjects by 
venopuncture at the UCSD Medical Center. Five ml (less than half of a tablespoon) of blood will be 
collected. DNA will be extracted by the Genomics Core Laboratory at UCSD. Tubes will be stored in a -80 
degree freezer located at the CTF room A-310. All samples will be identified only by their subject ID to 
ensure confidentiality. 
Subjects will be fully informed of the risks involved in providing a sample for DNA testing. Subjects will be 
told that Dr. Swerdlow will be responsible for how the blood specimen is used and that the specimens 
collected from the subjects and the DNA that they contain may also be used in additional research by Dr. 
Swerdlow. However, neither the blood, DNA nor information that identifies the subject will be shared with 
any other entity or collaborator or other party outside of our immediate research lab at UCSD. It will not 
be shared with any member of their family. Subjects will also be told that none of the results of their 
genetic tests could provide meaningful information related to their likelihood of developing or transmitting 
any specific disorder or medical condition. Results of the research that are specific to the subject will not 
be shared with anyone whether they have authorized it or not. If any publication results, the subject’s 
name will not be used. 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
As stated in the current consent form, the alternative to study participation is to withdraw from the study. 
14. 
POTENTIAL RISKS 
Potential risks are minimal. The rating scales and questionnaires are innocuous. Startle testing exposes 
subjects to the application of skin tape electrodes and to brief loud sounds, which in >30 years of testing 
in the Braff and Swerdlow laboratories has caused no side effects. All other measures require only 
computer keyboard use and involve no risk. The cumulative risks of this proposal are judged as small. 
Below is a summary of the language in the consents. 
1. An alcohol swab is used to clean the skin before electrodes are applied and some minor skin irritation 
and redness may occur. 
2. Some participants might experience fatigue, boredom or irritation during the test session. 
3. Some participants may be embarrassed or feel uncomfortable by some of the questions asked in the 
questionnaires. 
4. Eyeblink startle exposes subjects to the application of skin tape electrodes and to brief loud sounds, 
which in our experience has caused no side effects. 
5. During the study, your blood pressure and pulse will be regularly monitored. 
6. Blood drawing may cause a small amount of pain. In addition, a temporary bruise or “black and blue 
mark” may develop. Rarely, people faint after having their blood drawn. Very rarely, the vein in which 
the needle has been inserted may become inflamed or infected, which can be treated. 

Biomedical IRB Application Instructions 
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For the drug evaluation study, the proposed drugs carry a very small risk of toxicity or adverse side effects in 
the doses to be used in this study. The most common side effects associated with each drug are listed in 
Section 8 above, and typically include nausea, somnolence and dizziness. We do not plan to administer 
these drugs to subjects in whom it is contraindicated, such as subjects with known cardiovascular or 
neurological disorders. The doses selected for use in these studies are in the low- or below-therapeutic 
range for these drugs when they are used clinically, and in most cases, the selected dose is equal to or less 
than the lowest recommended starting clinical dose for the drug. To address the potential for some of these 
drugs to produce changes in blood pressure, we will carefully monitor subjects’ vital signs, and will not 
release subjects from the hospital until their vital signs are within normal limits. To address the possible side 
effect of somnolence, we will instruct subjects to arrange for their transportation from the hospital on test 
days. For studies that include women of childbearing potential, there is the possibility of unforeseen harm to 
an unborn child due to the administration of drugs. To address this risk, all female subjects will be asked to 
provide a urine sample to test for pregnancy and we will exclude participants who test positive. Additionally, 
all female subjects in these studies will be required to use a non-drug birth control method, such as 
abstinence, diaphragm, non-hormone intrauterine device to prevent pregnancy during the study. Subjects 
will be told to report if their menstrual cycle is inconsistent or if suspect that they are pregnant. Drugs will be 
dispensed by a licensed physician, and a licensed physician will be present on the premises at all times 
during testing. The consent forms include the related risks specific to the drug it refers to. 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
The overall risks of this proposal are small. Protection of subject confidentiality and privacy will be 
rigorously guarded by the assignment of coded numbers to each file in the computer analysis and 
database. Resulting data will not be released to any subject, and released only to a patient’s primary 
physician when an appropriate release form is signed by the patient. The UCSD psychophysiology 
research laboratory of Dr. Swerdlow has studied over 1000 control subjects and patients without any 
problems with confidentiality. 
For the drug evaluation study, risk management procedures include: 1) Subjects will be asked to refrain 
from alcohol or other drug use while on the study. 2) Each subject will receive a complete history and 
physical examination prior to acceptance into the study. 3) A battery of psychological tests will be 
administered, as will an EKG and urine toxicology screen (which will also be used to test for pregnancy in 
drug studies including women of childbearing potential). 4) Subjects involved in studies with drugs will 
arrange for their transportation from the hospital, and any subject reporting any sedation upon completion 
of the study will be instructed to not operate a motor vehicle until the sedation is resolved. Subjects known 
or determined to have cardiovascular disease by EKG or patient history will be excluded. All subject 
information will be kept in a secure and locked area of the laboratory, CTF Building, UCSD Medical 
Center. Confidentiality will be protected to the extent provided by law. 
If a participant has any questions regarding the study, they may contact the PI, Neal Swerdlow, M.D., 
Ph.D., Monday-Friday, 8 a.m. – 4:30 p.m. at (619) 543-6270. He may be reached after hours by 
contacting the UCSD operator at (619) 543-6222 and having them page Dr. Swerdlow. If any 
emergencies arise related to participating in these studies, the participant may proceed to the nearest 
emergency room or call 9-1-1. 
Subjects will be told that they can terminate the experiment at any time if an aspect of the procedure causes 
them discomfort. 
Risks associated with specific study populations: Because the proposed studies include schizophrenia 
patients, it is important to consider any risks that might be specifically elevated in this study population. As 
noted above, clinical trials with schizophrenia patients in which daily dosing of 10 - 20 mg memantine was 
added to ongoing medications have generally reported no or minimal evidence of either clinical 
improvement or adverse events. Thus, the likelihood that a single pill of 10 - 20 mg memantine would be 
associated with clinical changes is low. The population of schizophrenia patients to be enrolled in these 
studies will come primarily or exclusively from subjects who are seeking enrollment in an existing protocol 

Biomedical IRB Application Instructions 
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for supported employment (#071306, Dr. Elizabeth Twamley, PI); based on this, they will most likely be high 
functioning, clinically stable, and (by definition) seeking employment. Nonetheless, should the subjects voice 
any thoughts of self-harm or suicidality, all testing staff are instructed to immediately contact the licensed 
physician who is on-site and covering each test session. The physician will then immediately evaluate the 
subject, and based on their clinical condition, might escort them across the street to the Emergency Room 
at the UCSD Medical Center for further evaluation and, if necessary, treatment. It is important to note that, in 
over 30 years of testing schizophrenia patients at the CTF in the laboratories of Drs. Swerdlow and Braff, 
including several thousand schizophrenia patients and several drug challenge studies, only 1 subject has 
ever required an escort to the UCSDMC Emergency Room. 
16. PRIVACY 
AND 
CONFIDENTIALITY 
CONSIDERATIONS 
INCLUDING 
DATA 
ACCESS 
AND 
MANAGEMENT 
All data and specimens are de-identified, and coded numbers are assigned to each file in the computer 
analysis and database. Research records are kept in a room separate from the data and specimens. Both 
the separate room and the filing cabinet containing the records are locked. Only the study coordinator has 
the key to access the files. Subject unique identifiers (name, DOB, SS#, etc.) will never be connected with 
the de-identified data. When published, data will remain de-identified, though subjects' non-unique 
demographic information (age, sex, ethnicity, handedness, diagnosis) may be reported together with the de- 
identified data. No other information will be provided to entities beyond the PI and key personnel noted in 
this application. The PI’s UCSD research laboratory has studied over 1000 subjects and patients without 
any problems with confidentiality. 
Positive drug screen results, if they became known outside the research, could reasonably place the subject 
at risk of criminal civil liability or be damaging to the subject’s financial standing or employability. There is 
also the possibility of loss of confidentiality. Research records will be kept confidential to the extent allowed 
by the law. A study number will be used to identify information from participants. The database that relates 
the participants to a specific study number will be maintained using initials. Any database file will be 
encrypted on a password-protected computer. 
All recruitment, interviewing, consenting, physical examinations and testing will take place in a private 
setting, specifically a dedicated interview room at the UCSD Medical Center, occupied only by the 
interviewing staff, physician and test subject, with the door closed, and a "DO NOT DISTURB" sign posted 
on the door. 
It is NOT reasonably foreseeable that the study will collect information that Federal, State, and/or local 
laws/regulations requires to be reported to other officials (e.g., child or elder abuse; positive results from 
lab tests). However, as is true of any clinical population, and particularly in patients with brain disorders, it 
is possible that subjects may exhibit severe psychiatric symptoms including the description of suicidal 
ideation. An on-call licensed physician is covering all studies; should any such clinical issues arise, the 
covering physician will be contacted and will assess the situation for the most appropriate clinical 
intervention. 
17. POTENTIAL BENEFITS 
The information gained in these studies is expected to lead directly to a greater understanding of the 
pathophysiology of serious illnesses, and will facilitate the development of novel treatment strategies. 
For the drug evaluation study, those likely to benefit most from the proposed project are severely ill 
psychiatric patients, as enhanced understanding of their cognitive and neurochemical abnormalities will 
allow for more accurate assessment and treatment of their symptoms. Individual subjects will benefit from a 
medical and psychological evaluation. Control subjects are unlikely to receive any other direct benefits from 
the proposed study other than the opportunity to contribute to efforts designed to relieve human suffering; 
there is evidence that participation in generative activities that improve self-esteem can have a positive 
impact on an individual’s quality of life. Individuals with schizophrenia may or may not benefit from the long 
term goal of their study: to identify medications that will enhance the clinical impact of cognitive interventions 
in psychiatric patients. 

Biomedical IRB Application Instructions 
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18. RISK/BENEFIT RATIO 
For the drug evaluation study, the risks from study participation include mild discomfort from drug effects, 
and the benefits include careful medical evaluation and potential gains in self-esteem among study 
participants, and significant benefit to patients in terms of knowledge gained related to the nature and 
optimal treatments of psychiatric disorders. The risk-benefit ratio of this study is very low. 
19. EXPENSE TO PARTICIPANT 
N/A 
20. COMPENSATION FOR PARTICIPATION 
The subjects will be paid $30 for the SCREENING SESSION and $130 for completion of the TEST 
SESSION. These payments have been accepted by the Human Subjects Committee as reasonable 
amounts for the length of subject participation. Subjects that participate in the “WITHIN-SUBJECT” study 
will be paid $30 for the SCREENING SESSION, $100 after the first test day and $130 for the completion 
of the second test day. This is a total of $260. Subjects will be reimbursed for parking costs on the 
SCREENING and TEST days and given breakfast and lunch on the TEST day. 
Participants in the ONE-DAY study will be paid a total of $30. Compensation will be prorated to $10 per hour 
if the following happens: participants do not pass the tests; participants voluntarily withdraw from the study; 
or study personnel withdraw participants from the study. 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
The PI, Neal Swerdlow, M.D., Ph.D., is a licensed physician and Board Certified Psychiatrist. Co- 
investigators, Drs. Greg Light and Elizabeth Twamley, are licensed Clinical Psychologists. The Human 
Subjects Coordinator, Jo Talledo, has a BA in psychology and along with the PI analyze data collected from 
psychiatric and control subjects. Dr. Swerdlow and Ms. Talledo are trained to test psychiatric and control 
subjects with the described psychophysiological procedures, Reza Farokhpay, M.D. is a licensed physician. 
Susrutha Thanam, M.D., Samantha Hines (student) and Sarah Lamb (BA in psychology) are short term 
volunteers and employees who will be trained by Dr. Swerdlow and Ms. Talledo to become Laboratory 
Technicians. Maria Bongiovanni will assist in administrative issues. 
22. BIBLIOGRAPHY 
• 
Alessi SM, Greenwald M, Johanson CE. The prediction of individual differences in response to D- 
amphetamine in healthy adults. Behav Pharmacol. 2003 Feb;14(1):19-32. 
• 
Bitsios et al. Increased prepulse inhibition of the acoustic startle response is associated with better 
strategy formation and execution times in healthy males. Neuropsychologia 44:2494-9, 2006. 
• 
Giakoumaki et al. Improvement of prepulse inhibition and executive function by the COMT inhibitor 
tolcapone depends on COMT Val158Met polymorphism. Neuropsychopharmacol 33:3058-68, 2008. 
• 
Giakoumaki et al. The level of prepulse inhibition in healthy individuals may index cortical modulation 
of early information processing. Brain Res 1078:168-70, 2006. 
• 
Hutchison KE, Wood MD, Swift R. Personality factors moderate subjective and psychophysiological 
responses to d-amphetamine in humans. Exp Clin Psychopharmacol. 1999 Nov;7(4):493-501. 
• 
Light et al. Prepulse inhibition of startle is positively associated with higher order cognition in women. 
Abstr, Soc Neuroscience 806.17, 2007. 
• 
Mattay et al. Catechol 0-methyltransferase val158-Met genotype and individual variations in the brain 
response to amphetamine. PNAS 100: 6186-6191, 2003. 
• 
Roussos et al. Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase 
Val158Met gene polymorphism. Psychol Med 38:1651-8, 2008. 
• 
Swerdlow et al. The effects of memantine on prepulse inhibition. Neuropsychopharmacol 34:1854-64, 
2009. 
• 
Swerdlow NR et al. Antipsychotic effects on prepulse inhibition in normal 'low gating' humans and 
rats. Neuropsychopharmacology. 2006 Sep;31(9):2011-21. 
• 
Swerdlow NR et al. Amphetamine effects on prepulse inhibition across-species: replication and 
parametric extension. 
• 
Swerdlow NR et al. Effects of amantadine and bromocriptine on startle and sensorimotor gating: 
parametric studies and cross-species comparisons. Psychopharmacology (Berl). 2002 Oct;164(1):82- 
92. 

Biomedical IRB Application Instructions 
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• 
Swerdlow NR et al. Effects of amantadine and bromocriptine on startle and sensorimotor gating: 
parametric studies and cross-species comparisons. Psychopharmacology (Berl). 2002 Oct;164(1):82- 
92. 
• 
Swerdlow NR et al. Pramipexole effects on startle gating in rats and normal men. 
Psychopharmacology (Berl). 2009 Sep;205(4):689-98. 
• 
Talledo et al. Amphetamine effects on startle gating in normal women and female rats. Psychopharm 
204:165-75, 2009. 
• 
White TL, Lejuez CW, de Wit H. Personality and gender differences in effects of d-amphetamine on 
risk taking. Exp Clin Psychopharmacol. 2007 Dec;15(6):599-609. 
23. FUNDING SUPPORT FOR THIS STUDY 
The following are UCSD grants. Yvette Obando is the Fiscal Contact: 
• 
NIDA 5R03 DA027483-02 (PI) 9/1/09 – 8/31/11 
• 
NIMH R01 MH059803 (PI) 12/7/2010 – 11/30/2013 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
NA 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
NA 
26. IMPACT ON STAFF 
NA 
27. CONFLICT OF INTEREST 
NA 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
NA 
29. OTHER APPROVALS/REGULATED MATERIALS 
NA 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
Schizphrenia patients who have been identified for participation in our studies will also be enrolled in IRB- 
approved clinical trials of cognitive training with Dr. Twamley. Dr. Twamley has approval to screen and 
administer surrogate identification process. Any patients that have been identified as having impairment in 
their decision-making ability will be determined by Dr. Twamley and will not be referred to our studies. 
 
Revision date: October 29, 2010