Memantine Augmentation of Targeted Cognitive Training in Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: University of California, San Diego

NCT04857983: Memantine Augmentation of Targeted Cognitive Training in Schizophrenia  
Study Protocol and Statistical Analysis Plan 
2/14/2020 

7. Project Summary/Abstract:  
In response to RFA-MH-18-705, this application develops and tests a novel treatment strategy for improving 
cognition in patients with schizophrenia (SZ), via Pharmacologic Augmentation of Cognitive Therapies 
(PACTs), and directly addresses a critical need for more effective treatments for these disabling impairments. 
Cognitive benefits in SZ patients can be achieved via bottom-up sensory-based targeted cognitive training 
(TCT) therapies, but such treatments are time- and resource-intensive, and responses are incomplete and 
variable. This application tests a rational and empirically supported platform for augmenting the benefits of TCT 
in antipsychotic medicated SZ patients by adjunctive daily treatment of 20 mg memantine (MEM), an FDA 
approved medication for the treatment of cognitive dysfunction in Alzheimers Disease.  Recent meta-analyses 
of MEM augmentation in antipsychotic-medicated SZ patients have demonstrated its safety, tolerability, and 
effectiveness at improving scores on brief cognitive screening tests. We hypothesize that MEM will augment 
TCT learning and hence the clinical gains from TCT, and that this PACT approach will be most effective 
in biomarker-defined subgroups of patients. Preliminary support for these hypotheses comes from our 
proof-of-concept, randomized, controlled studies of single-dose exposure to MEM relative to placebo.  In these 
studies, we found that MEM significantly enhanced learning in auditory discrimination, the key component of 
the TCT program which is known to drive the cognitive gains in SZ patients following 30-50h of TCT. We also 
found that a single dose of MEM significantly enhanced several biomarkers of early sensory information 
processing in antipsychotic medicated SZ patients.  Dose-response and time course studies identified the 
optimal MEM dose (20 mg) for maximal pro-learning effects. This application conducts a careful assessment of 
this PACT strategy for SZ: Aim 1) Confirmation of target engagement: 54 SZ patients will be tested to 
confirm that MEM (20 mg) enhances measures of TCT learning; Aim 2) Efficient pilot testing: Subjects from 
Aim 1 will be randomized into 2 treatment arms (n=27/arm) for a double-blind placebo-controlled 30-session 
clinical trial of MEM+TCT vs. placebo+TCT, to determine whether daily dosing of MEM augments the 
magnitude, rate and/or durability of TCT gains, and whether these gains are associated with target 
engagement, using specific Go/No-Go criteria and outcome measures of symptoms, cognition and real-life 
function; Aim 3) Predictive biomarker identification of the PACT response, based on cognitive, 
electrophysiological, and performance-based measures assessed pre- and post-TCT. This is a highly novel, 
high-risk high-reward application to develop a PACT-based treatment paradigm that will enhance cognition, 
improve recovery and enhance outcomes for patients with schizophrenia, and will determine whether a future, 
fully-powered Confirmatory Efficacy trial of this approach is warranted.  
 
 
 
 
 
 
Contact PD/PI: LIGHT, GREGORY A 
Project Summary/Abstract
Page 6

8. Project Narrative 
 
Treatment of schizophrenia currently includes antipsychotic medications and cognitive therapies which improve 
some symptoms, but do not sufficiently restore cognitive functioning or reduce psychosocial disability. We 
hypothesize that medications that specifically target sensory information processing deficits, rather than 
psychotic symptoms per se, will significantly enhance the benefits of a sensory-based targeted cognitive 
training (TCT) intervention in patients with schizophrenia. We will complete a randomized, double-blind clinical 
trial to: 1) confirm that the drug memantine augments TCT learning; 2) determine whether memantine 
enhances the clinical benefits from a full 30 session course of TCT vs. TCT plus placebo in antipsychotic-
medicated schizophrenia patients, and 3) determine if memantines enhancement of TCT is most effective in 
biomarker-defined subgroups of patients. 
 
Contact PD/PI: LIGHT, GREGORY A 
Project Narrative
Page 7

SPECIFIC AIMS: Memantine Augmentation of Targeted Cognitive Training in Schizophrenia 
Cognitive impairment affects the majority of patients with schizophrenia (SZ) and directly contributes to their 
psychosocial disability. Unfortunately, treatment approaches designed to improve cognition in SZ have been 
limited. Recent findings demonstrate that cognitive functioning in SZ can be improved by interventions that 
leverage neuroplasticity-based perceptual learning mechanisms. Targeted Cognitive Training (TCT) is a 
computerized intervention designed to sharpen the acuity and fidelity of sensory information processing 
through specific exercises that systematically increase demands on early perceptual and attentive processes. 
For many participants, TCT leads to bottom-up gains in perceptual functioning that lead to improvements in 
verbal learning and memory after 20-30h. While these benefits of TCT are evident at the group level, nearly 
half of all patients fail to show cognitive gains, even after extended 40-100h courses of TCT. For patients, their 
families, clinicians and health systems, the costs and logistical complexities associated with these time- and 
resource-intensive interventions, even under optimized conditions, can be prohibitive.  
 
A novel approach to bridge this divide between the therapeutic promise of TCT and its mixed effectiveness is 
to combine TCT with an intervention that augments the clinical gains of TCT. This application responds to 
RFA-MH-18-705 by conducting efficient pilot testing of a novel intervention strategy for chronic psychotic 
disorders - Pharmacologic Augmentation of Cognitive Therapy (PACT) - via an experimental medicine 
approach. We propose to test a novel augmentation strategy of daily dosing of 20 mg of memantine to 
enhance the benefits of TCT in stable, antipsychotic medicated SZ patients. 
 
Memantine is a non-competitive NMDA receptor modulator which is currently FDA-approved for the treatment 
of moderate-to-severe Alzheimers disease, and is often used adjunctively in a variety of neuropsychiatric 
illnesses, including SZ. Recent meta-analyses of memantine augmentation in antipsychotic-medicated SZ 
patients have demonstrated its safety, tolerability and modest effectiveness at improving cognition. We 
hypothesize that memantine will augment TCT learning (Aim 1) and hence the clinical gains from TCT 
(Aim 2), and that this PACT approach will be particularly effective in biomarker-defined subgroups of 
patients (Aim 3).  
 
 
Preliminary support for these hypotheses and the proposed design comes from both laboratory- and clinic-
based studies conducted over the past decade. In our laboratory, we have tested both dose-effects of a 
single pill of memantine on neurophysiological measures of early auditory information processing (EAIP) and 
TCT learning in antipsychotic-medicated SZ patients. In these studies, memantine (20 mg > 10 mg = 0 mg) 
significantly enhanced several EEG-based measures of EAIP, as well as learning in an auditory discrimination 
task -- a key component of the TCT suite of exercises with established efficacy in SZ patients.  Although 
memantine-enhanced TCT learning during a 1h Sound Sweeps test provides a valuable assay of target 
engagement, we do not yet have evidence that it predicts greater, faster or more lasting clinical, 
neurocognitive or functional gains with a full course of memantine+TCT.  
 
Our clinic-based studies yielded key findings related to biomarkers, Sound Sweeps performance, and 
predictors of therapeutic sensitivity to a full course of TCT. First, baseline levels of EAIP predicted TCT 
learning during 1h of Sound Sweeps. Second, SZ patients exhibited clinical, neurocognitive and functional 
gains after 30h of TCT, and changes in EAIP during the first hour of Sound Sweeps testing predicted 
neurocognitive and clinical gains after a full 30h course of TCT. In total, these findings with memantine, EAIP, 
TCT learning, and clinical outcomes provide a strong empirical and conceptual framework for a 
mechanistically-based hypothesis to be tested via the proposed randomized, placebo-controlled 30h pilot trial 
of (memantine+TCT) vs. (placebo+TCT). Via the below Aims, this application provides efficient pilot testing of 
this PACT strategy in antipsychotic-medicated SZ patients, using Go/No-Go criteria to inform a future, fully-
powered Confirmatory Efficacy trial:   
 AIM 1  Replicate previous findings of memantine target engagement on TCT learning: In two, 1h tests, 
determine if memantine increases Sound Sweeps TCT learning in SZ patients (n=54) vs. placebo.   
 AIM 2  Test clinical, neurocognitive and functional impact of memantine on TCT, and its relationship 
to target engagement: In a 30-session course of TCT over 10 weeks, determine if memantine augments the 
magnitude, rate and/or durability of TCT-induced gains, and whether these gains are associated with target 
engagement. 
 Aim 3  Explore biomarkers of memantine-induced gains: Determine whether higher basal levels of EAIP 
(and related functional and neurophysiological measures) or changes in these measures across the first hour 
of Sound Sweeps predict greater sensitivity to memantine-enhanced clinical, neurocognitive or functional gains 
among SZ patients receiving combined memantine+TCT. 
Contact PD/PI: LIGHT, GREGORY A 
Specific Aims
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Pharmacologic Augmentation of Cognitive Therapy (PACT): In Pharmacologically Augmented Cognitive 
Therapies (“PACTs”) for SZ40-42, as first described by our group42, drugs with pro-cognitive effects are used 
specifically, and perhaps synergistically, to augment the clinical benefits of a range of cognitive therapies. These 
drugs do not replace APs, which remain essential for limiting active psychotic symptoms that impede a patient’s 
ability to participate in cognitive therapy. While suppressing active psychosis with APs can benefit a cognitive 
intervention, we are trying to identify drugs that more specifically, and perhaps synergistically, enhance the 
clinical benefits of cognitive therapies. PACT works when a medication engages brain substrates regulating 
neurocognitive resources that are engaged by the form of learning being applied in cognitive therapy. With 
enhanced resources, greater learning is possible. With greater learning, the learning-based therapy is presumed 
to produce an enhanced clinical impact.  
Pharmacologic Augmentation of TCT Learning: Towards this end, we reported that in AP-medicated SZ patients, 
the pro-attention drug, amphetamine, enhances learning of an auditory frequency discrimination task 
(henceforth, “auditory learning”) that is a key component of TCT43. This finding provided a crucial PACT “proof 
of concept”: even in severely ill, AP-medicated SZ patients, one pill acutely enhanced learning in a manner that 
would be predicted to accelerate or increase the clinical benefits of TCT. Clearly, substantial plasticity is retained 
in TCT learning-relevant neural substrates in SZ patients; leveraging this plasticity is a rational and novel clinical 
strategy that is the ultimate goal of our work. Towards this end, we are pursuing separate R33 support to extend 
studies of amphetamine-enhanced TCT in SZ patients (see Budget Justification). Importantly, however, there 
are theoretical and practical reasons that stimulants might not be optimal for use in some SZ patients, even in 
the setting of stable antipsychotic medications; thus, while we explore the viability of stimulants for PACT 
approaches, we are also motivated to pursue alternative classes of drugs for their PACT potential in SZ patients.  
Memantine is a strong PACT candidate: Memantine (MEM) is a non-competitive NMDA receptor modulator that 
is currently FDA-approved for the treatment of moderate-to-severe Alzheimer’s disease44,45, and is often used 
adjunctively in a variety of neuropsychiatric illnesses, including SZ46. A recent meta-analysis of 15 randomized 
controlled trials (n=512 SZ patients; see also Table 2), showed that daily adjunctive MEM treatment is well-
tolerated and modestly effective at reducing negative symptoms and improving mini-mental state exam (MMSE) 
cognition scores in antipsychotic medicated SZ patients without adverse drug reactions or discontinuation due 
to any reason relative to comparator conditions46. Importantly, none of these studies utilized MEM in concert with 
a systematic cognitive intervention, nor were any specific biomarkers used to predict sensitive patient subgroups. 
For the past decade, we have studied the acute neurophysiological effects of MEM, first in laboratory rats47 and 
then in healthy human subjects (HS) and schizophrenia (SZ) patients48-51, with the goal of using MEM or related 
drugs as pro-cognitive interventions in SZ. [Note: no investigators in this application have financial relationships 
with the commercialization of MEM.] In the past 5 years, supported by NIMH, these studies assessed the effects 
of acute MEM challenge (placebo, 10, 20 or 30 mg, po) on measures of early auditory information processing 
(EAIP) and neurocognition in SZ patients and HS. Prepulse inhibition (PPI), mismatch negativity (MMN) and 
gamma band auditory steady-state response (ASSR) were used as dependent measures because they: 1) are 
neurophysiological measures of EAIP, i.e. of the brain’s automatic response to a simple sensory event proximal 
to, or independent of, a point at which it engages conscious or volitional processing; 2) consistently detect deficits 
in SZ patients; 3) are reliable, objective and quantitative52,53; 4) reflect “automatic” vs. volitional processes and 
are relatively insensitive to motivational or effort-based artifact; 5) are suited to repeated testing in a cross-over 
design without significant order or carry-over effects 6) are associated with important domains of clinical, 
cognitive, and psychosocial functioning in SZ54-60; 7) are each regulated by NMDA activity, 8) have been 
previously reported to be increased by MEM47,61,62, including MEM-enhanced PPI47 and MMN62 in HS. 
Memantine acutely “moves” cognitively and functionally-relevant neurophysiologic biomarkers: The findings from 
our previous studies were striking. We detected statistically significant effects of MEM (20 mg po) on PPI, MMN, 
ASSR, and related measures49,50,63. In each case, one pill of MEM significantly “moved” these measures in SZ 
patients towards “normal” values. These changes could not be explained on the basis of AP medication 
interactions, or other artifacts related to illness treatment or chronicity, as qualitatively similar changes were also 
detected in HS. For PPI, these MEM-induced changes were somewhat less robust in HS; for MMN, they were 
somewhat more robust in HS; and for ASSR, they were roughly comparable in HS and patients (Fig. 2). 
To our knowledge, these studies served as a critical first demonstration that deficient PPI, MMN and ASSR in 
SZ patients – widely viewed to reflect fixed, heritable abnormalities in brain mechanisms regulating auditory 
information processing – can be significantly enhanced (i.e. brought significantly closer to normal values) via an 
acute intervention in chronically ill SZ patients. These findings are novel and important, as they demonstrate 
significant plasticity in brain mechanisms that are thought to contribute to “core” neurocognitive deficits in SZ. 
Contact PD/PI: LIGHT, GREGORY A 
Research Strategy
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neurobiology of these disorders, it is not surprising that a drug acting through one mechanism to enhance one 
domain of functioning might not generate significant improvement in a non-stratified patient cohort.  
The PACT approach in general, and in this application specifically, diverges from past “negative” pro-cognitive 
trials in these two critical ways. First, PACTs pair a putative pro-cognitive agent with a cognitive “load” that puts 
demand on cognitive resources that are augmented by that drug. For example, as described below, this 
application proposes to combine a drug that enhances early auditory information processing with a TCT task 
that specifically targets auditory information processing. By pharmacologically enhancing low-level sensory 
information processing, we found (Fig. 3) that we can enhance TCT learning in an optimized laboratory setting; 
if this finding is replicated in Aim 1, we will test the hypothesis that enhanced learning generates greater clinical 
gains from a full course of TCT (Aim 2). Second, PACTs incorporate biomarkers to identify individuals who are 
most likely to benefit from the pairing of drug and cognitive therapy. In the PACT design described herein, 
potential biomarkers range from neurophysiological measures of forebrain mechanisms that regulate early 
auditory information processing, to performance markers of sensitivity to a “test dose” of a drug+TCT pairing.  
The proposed use of EEG and objective behavioral biomarkers will produce system-level mechanistic insights, 
e.g. regarding the relationship of early sensory processing, auditory discrimination, and target engagement to 
clinical and neurocognitive benefits of pharmacologically augmented TCT. This approach is consistent with the 
NIMH goal to “identify reliable and stable biomarkers that… are correlated with individual treatment response, or 
identify subjects that would most benefit from the intervention” (NOT-MH-14-007). In a future, larger trial, these 
biomarkers may be implicated as mediators of PACT clinical gains60.   
“Does this application challenge... current research/clinical practice?” As noted above, the PACT strategy in this 
application fundamentally challenges current treatment models for SZ. In a successful use of PACT, there is a 
specific pairing of drug and cognitive “load”: a drug that enhances specific neurocognitive domains is paired with 
a cognitive therapy that utilizes/places demands on those domains. Ultimately, treatment choice will be guided 
by biomarkers that might include laboratory-based measures, e.g. a patient's neurophysiological and TCT 
performance response to a challenge-dose of a pro-cognitive agent. A "deliverable" innovation of this application 
will be a novel PACT “prototype”: a validated paradigm through which MEM will enhance the therapeutic benefits 
of TCT in biomarker-identified SZ patients.  
Another innovative feature in this application fundamentally challenges existing paradigms by suggesting that 
treatment should be aimed at spared, healthy circuitry in SZ patients - identified in laboratory studies - rather 
than at pathological circuitry per se (which is both widely distributed and highly variable among SZ patients  41,88). 
The goal of enhancing "spared" function departs from a prevailing failed strategy of trying to use drugs to "undo" 
decades of miswired neuropathology of SZ41; a focus on intact physiological mechanisms (e.g. auditory 
processing) and normal brain circuit function rather than disorder-specific pathology and symptoms is also 
consistent with an RDoC framework. We propose that evidence for the requisite “spared” neural circuitry in 
patients, and hence a target for MEM action, is provided by gains in auditory processing in response to a MEM 
“challenge”. This approach parallels the use of a test-dose to predict clinical benefits from treatments ranging 
from hormones89 to anti-Parkinsonian drugs90 to bronchodilators91. Evidence for enhanced EAIP in response to 
MEM challenge suggests that neural circuits relevant to auditory processing are spared, plastic and hence viable 
targets for pharmacotherapy. Ultimately, gains in EAIP and/or higher auditory processing after a “test-dose” of 
MEM could be used as a predictive biomarker for clinical MEM sensitivity. This “personalized medicine” approach 
has been used in other fields92-94, and attempted for some psychotherapeutics61, but not yet for SZ. 
C. Approach: This application uses an experimental therapeutics approach in an “efficient pilot test” of the 
hypothesis that MEM will augment TCT-induced learning, and thereby clinical, neurocognitive and functional 
gains, in antipsychotic-medicated SZ patients. In so doing, this application will advance a PACT model for TCT 
in two specific ways: 1) building on strong preliminary findings, this application will confirm target engagement 
and identify biomarkers that predict the effectiveness of MEM-enhanced TCT learning, and 2) this application 
will provide the first randomized controlled trial to assess the ability of medication-enhanced TCT learning (target 
engagement) to produce significant and lasting clinical, neurocognitive and functional gains in biomarker-
characterized SZ patients. In this way, this application responds to RFA-MH-18-705, “Development of 
Psychosocial Therapeutic and Preventive Interventions for Mental Disorders”, which supports “efficient pilot 
testing of novel psychosocial therapeutic and preventive interventions for mental disorders… using an 
experimental therapeutics approach.” Moreover, in this application, “results, whether positive or negative, will 
provide information of high scientific utility and… support ‘go/no-go’ decisions about further development or 
testing of the intervention.” The application uses a “novel intervention strategy” - the PACT model - in a design 
that will “replicate target engagement and relate change in the… target/mechanism to clinical benefit.” Findings 
from this pilot study will inform a future, fully-powered Confirmatory Efficacy trial. 
 
Contact PD/PI: LIGHT, GREGORY A 
Research Strategy
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General Clinical Monitoring: In addition to their established ongoing care, patients are carefully monitored at 
each session as per our well-established procedures, and through to the week-22 follow-up, for any clinical 
changes. Each week, a member of our research staff checks vital signs and weight, does a detailed assessment 
of symptom changes, focusing on psychosis, depression, suicidality and abnormal movements, and tests UTox 
and pregnancy. A designated unblinded staff member processes UTox results.  In the event that a subject tests 
positive for recreational drugs or a positive pregnancy test, it is promptly reviewed with the on-site Psychiatrist; 
any “yes” on the Columbia Suicide Severity Rating Scale98 (C-SSRS) “Since Last Visit”, or an exacerbation of 
psychotic symptoms, prompts detailed review, with appropriate clinical interventions. Patients testing positive for 
recreational drugs will be retested in 1 week; patients with 3 positive tests no longer continue in the study. Data 
from subjects who, for this or other reasons, do not complete the full study are carried forward in an 
“intent to treat” design, and their data are analyzed using linear mixed-effects models.    
Outcome and “Go Decisions”. In addition to 
confirming “target engagement”, this application 
tests the hypothesis that SZ patients given MEM 
+TCT will exhibit greater, faster and/or more 
durable improvements (change from baseline) in 
symptoms, 
neurocognition 
and/or 
function 
compared to patients given PBO+TCT, and that 
this enhanced clinical response will be associated 
with greater MEM-enhanced TCT learning.  
The small “n” necessitated by the 3-year timeline 
and 
demanding 
treatment 
schedule 
greatly 
constrains the total number of outcome measures. 
Moreover, the plan to assess not only magnitude but also rate and durability of PACT gains triples the number 
of primary analyses. Thus, we selected only one primary clinical, neurocognitive and functional outcome 
measure (Table 1) – recognizing that they are relatively “blunt” metrics - but will track several other, more 
focused, measures as well as inter-measure correlations in exploratory analyses to inform future studies.     
A “Go” decision requires: 1) confirmation of target engagement (APS learning, MEM>PBO, p<0.05); 2) evidence 
of gains from PACT (d > 0.5 (MEM > PBO)) in primary clinical, neurocognitive and/or functional measures (Table 
1), and 3) the absence of adverse effects of MEM that are significantly greater than PBO levels. The decision to 
not use traditional statistical significance as “Go” criteria for Aim 2 reflects this RFA’s call for “Pilot” studies, the 
need to identify candidate treatments for a subsequent larger “n” Confirmatory Efficacy R01 study, and the limits 
in sample size resulting from the 3-year R33 duration. Cohen defined a medium effect size (d=0.5) as one that 
is “visible to the naked eye,” and this amount of change is viewed as clinically meaningful in trials targeting 
negative symptoms.99-101 This d=0.5 “Go” threshold for Aim 2 corresponds to a “number needed to treat” (NNT) 
value  3.62. While a “Go” decision does not require identification of a biomarker predicting greater PACT 
sensitivity (Aim 3), the identification of one or more meaningful predictors that could be incorporated into a 
Confirmatory Efficacy trial would favorably impact a “Go” decision. 
Staff assessing outcome measures are blind to treatment arm, and for some measures receive training using 
videotaped and practice interviews until achieving high (ICC>.80) reliability based on 20 assessments by 2 raters. 
We achieve high inter-rater reliability (e.g., ICC>0.85 for PANSS total), and check for rater drift each 90d. 
Specific Procedures: TCT is completed with a dedicated room and equipment. Staff trained with a UCSD-
developed “TCT Clinician Competence Assessment” monitor TCT, clarify instructions and provide encourage-
ment as needed. In the initial “biomarker testing” session (Test 1), subjects complete 1-h of Sound Sweeps 
to generate a “Pre-Training APS score” as described previously (Fig. 3) under identical circumstances and 
timelines as for the Test 2 session described below. Treatment group assignment (PBO vs. MEM) is then made 
using stratified random sampling (above) and 5-7 days later patients ingest either PBO (n=27) or 20 mg MEM 
(n=27) 240 min before completing the Sound Sweeps session (“Test 2”). MEM effects on APS learning are 
assessed both within-subject (APS (Test 1 - Test 2) for MEM group subjects: a key measure of MEM sensitivity) 
and between subjects (APS Test 2, PBO vs. MEM groups).  After Test 2, all subjects are prescribed daily PBO 
or MEM using a standard titration schedule (MEM 5 mg at hs→ 5 mg bid→ 5 mg am/10 mg hs→ 10 mg bid over 
3 weeks). Participants return to the laboratory to complete 1h TCT per our established procedures2,34, which 
includes 5 modules of auditory/verbal processing exercises. Each module increases in difficulty as performance 
improves: 1) Sound Sweeps; 2) Syllable Identification: Patients distinguish between 2 similar phonemes (e.g., 
“ba” vs. “da”), differing only in their voice onset time; 3) Word Matching: Subjects match short similar-sounding 
consonant-vowel-consonant words (e.g., bad, dad); 4) Listen & Do: Subjects reconstruct a spoken series of 
instructions and use a computer mouse to click icons on the screen in a specified order. This exercise is designed 
to stimulate verbal WM processes supported by the lateral PFC as well as premotor and motor processes. 5) 
Table 1. “Go” criteria: #1, plus at least one of #’s 2, 3 & 4 (d>0.5) 
1. Target engagement: APS learning, MEM > PBO, p<0.05  
2. Greater clinical, neurocognitive or functional gains: 
 - PANSSt, MCCB-C or Fnxn:  MEM+TCT > PBO+TCT 
3. Faster clinical, neurocognitive or functional gains: 
 - drug group x session interaction (p<0.05) followed by   
 MEM+TCT > PBO+TCT at specific session # or combination; 
4. More durable clinical, neurocognitive or functional gains: 
 - MEM+TCT > PBO+TCT at post-TCT week 12. 
PANSSt: Positive & Negative Symptom Scale total; MCCB-C: 
MATRICS Composite; Fnxn: Function (assessed via the World 
Health Organization Disability Schedule 2.0 (WHODAS) 
Contact PD/PI: LIGHT, GREGORY A 
Research Strategy
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Rhythm Recall: Subjects listen to and replicate a short rhythmic sequence. This task is designed to stimulate 
both basic auditory processes supported by primary auditory cortex, and non-verbal auditory WM. 
Symptoms are assessed to track clinical status and TCT response. TCT reduces positive symptoms of 
psychosis, and we predict that MEM will augment these effects via enhanced TCT learning (i.e. not via a lasting 
direct pharmacological effect of MEM), detected by the Positive & Negative Syndrome Scale. For this reason, 
and based on the need to limit total outcome measures, PANSS Total Score is the primary clinical outcome 
measure. Positive and negative symptom subscales, as well as PANSS factor-derived measures, will be 
assessed in exploratory analyses. Other secondary clinical measures will include: 1) Psychotic Symptom Rating 
Scales (PSRS; assesses auditory hallucinations); 2) Young Mania Rating Scale; 3) Patient Health Questionnaire-
9 (PHQ-9; current depressive symptoms); 4) Abnormal Involuntary Movement Scale (AIMS); 5) C-SSRS; 
“Lifetime/Recent version” at screen; “Since Last Visit” at follow-up visits). The C-SSRS is a reliable, valid and 
sensitive measure of suicidal ideation98; any “yes” in C-SSRS prompts an immediate full evaluation/action plan 
by a study M.D.; and 7) MEM Cessation Symptom Assessment (ACSA). 
Neurocognition: Change in MCCB Composite performance from baseline is one outcome measure. The MCCB 
measures 7 cognitive domains: speed of processing, attention/vigilance, working memory (verbal and 
nonverbal), verbal learning, visual learning, reasoning/ problem solving and social cognition. Details are found 
in36,102,103; past studies of drug effects on MCCB performance include48,104. Since the MCCB is assessed multiple 
times, alternate forms of the HVLT-R and BVMT-R are used in counterbalanced order. MCCB Global Composite 
T-score (MCCB-C) is the primary neurocognitive outcome measure. Individual MCCB domain T-scores are used 
in secondary analyses to determine whether an overall effect is driven by specific aspects of neurocognition; 
TCT effects on verbal learning performance are known to be robust24, and should be augmented by MEM. 
Baseline and MEM-enhanced (Test 2 vs. 1) MCCB performance (A/V subscale) will also be tested as potential 
biomarkers/moderators of MEM PACT efficacy. 
Function is assessed via the World Health Organization Disability Schedule 2.0 (WHODAS)105 at baseline, after 
sessions 10, 20 and 30, and week 12 post-TCT. WHODAS 2.0 is a 12-item patient-rated measure (< 15 min) 
using a 5-point Likert scale focusing on cognition, mobility, self-care, getting along with people, life activities and 
participating in society; it was selected by the DSM-5 Task Force committee to replace the global assess-ment 
of functioning scale106. NIH “PhenX Toolkit” scales of Impairment, QOL and Social Isolation will also be used. 
After session #30, the assessment will include a 14-item 7-point Likert scale of treatment satisfaction.  
Biomarkers from Tests 1-2 will be assessed as predictors of target engagement (Aim 1) and PACT sensitivity 
(Aim 2); in some cases, these measures will also inform mechanistic models for PACT: 1. MEM-enhanced APS 
learning is both an outcome measure (Aim 1, “target engagement”) and candidate predictor of clinical outcome 
(Aim 2); 2. Baseline and MEM-enhanced MCCB A/V scores are associated with APS MEM sensitivity73, and thus 
may predict clinical outcome (Aim 2); 3. EEG measures of early auditory information processing variably predict 
response to early APS learning87, MEM-enhanced APS learning74, and TCT outcomes31.   EEG/ERPs are 
acquired via 64-channel recording systems and assessed in the same order, as per49,107: MMN/P3a/Theta 
power/Phase locking (25 min; Oddball Paradigm), ASSR (6 min). 4. Auditory discrimination: Words-In-Noise 
(WIN; NIH Toolbox) and Speech-In-Noise (Quick-SIN; Etymotic Research) are acquired at Tests 1-2, TCT hour 
30 and week 22. Both measures assess the ability to recognize speech over background noise, mimicking a 
conversation in a noisy environment, and are thought to index peripheral (WIN) vs. more central (QuickSIN) 
auditory processing. MEM-enhanced APS learning may predict PACT outcome (Aim 2); gains in auditory 
discrimination over 30 hours of TCT, and their augmentation by MEM, will be tracked to inform evolving models 
of PACT mechanisms. Predictions: First and foremost, target engagement (MEM-enhanced APS learning) will 
predict MEM-enhanced TCT outcomes (Aim 2) as described below. Exploratory analyses will test secondary 
predictions: for example, high vs. low baseline P3a amplitude and faster P3a latency will predict greater target 
engagement (Aim 1), and greater MEM-enhanced TCT outcome (Aim 2). MEM-enhanced (Test 2 vs. 1) ERPs, 
auditory discrimination and neurocognitive (A/V) measures will also be explored as outcome (Aim 2) predictors; 
significant pre- vs. post-TCT changes in ERP source dynamics will also be examined for mechanistic 
characterization71. Robust biomarker predictors will be examined as moderators of both indirect and direct paths 
between treatment and outcome in a future Confirmatory Efficacy trial.  
Post-treatment protocol: On completion of 30 TCT sessions, participants will be offered the option of 
maintaining their assigned drug (PBO or MEM) through the 22-week durability assessments. Those who opt to 
discontinue the study drug will titrate off, over a 3-week period. After week 22, study blind will be broken, and 
subjects who continued to receive MEM will again be offered the option of titrating off of MEM vs. maintaining 
MEM treatment coordinated with, and under the supervision of, their primary provider.  
Data Analysis: “Go/No Go” decisions are based on traditional statistical significance (Aim 1) and effect sizes 
(Aim 2). Formal statistical testing is conducted using linear mixed-effects (LME) models; hypothesis tests are 2-
sided (α=.05). Model parameters are estimated via the R lme4 package and Cohen’s d is estimated via the 
Contact PD/PI: LIGHT, GREGORY A 
Research Strategy
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EMAtools package. Type I errors are minimized by constraining the number of primary analyses; secondary 
analyses use false discovery rate corrections. Expected attrition rates are described above. Because outcome 
measures involve a “change from baseline”, baseline metrics are compared between PBO and MEM arms, and 
any baseline differences are addressed in the outcome analyses. Differential drop-out rates from PBO vs. MEM 
arms are monitored. Data are assumed to be missing at random; full information maximum likelihood estimators 
are used, and all data/cases are included in analyses. Clinical follow-up is pursued with all patients exiting the 
study through post-TCT week 12. Cohort differences: For between-subject contrasts (main effect of drug), differ-
ences in age, antipsychotic and anticholinergic loads are tested and used as covariates2,33,95. Sex differences 
are tested for all measures. NIH Data Harmonization: 3 “PhenX Toolkit” (NOT-MH-15-009) measures of function 
are used; see above and “Resource Sharing Plan”. 
Aim 1 – Confirm target engagement: The primary dependent measure of target engagement is MEM-enhanced 
APS learning. APS learning is defined as the reduction in Sound Sweeps APS threshold (ms) Test 1 to Test 2 
assessment. Target engagement was demonstrated in Fig. 3 76, and will be confirmed if APS learning is 
increased by MEM (note that MEM and PBO groups are matched by Test 1 PBO performance via stratified 
randomized assignment). As appropriate, effect sizes and inferential statistics are based on standard regression 
or LME models with random intercepts. A significant interaction between contrast coded drug (PBO vs. MEM) 
and Test (Test 1 vs. Test 2) predictors on APS learning is a “Go” criteria and confirms target engagement.  
Aim 2 – Test clinical, neurocognitive and functional impact of MEM on TCT, and its relationship to target 
engagement: We will determine if MEM+TCT produces greater, faster or more durable clinical, neurocognitive 
or functional gains from baseline, compared to PBO+TCT, over a 30-session course of TCT. A Cohen’s d>0.5 
for the main effect of drug (PBO vs. MEM) or drug x session (#10, 20, 30) interaction in an LME model is the 
primary “Go” criteria. The effect of drug assesses “greater” gains. Reverse Helmert contrasts for session 
assesses “faster” gains. A separate model comparing differences in outcomes at 12-weeks post-TCT assesses 
“more durable” gains. Secondary analyses will examine whether change in MEM-enhanced APS learning 
(“within-subject” target engagement; Aim 1) predicts gains in Aim 2 outcome measures. 
Aim 3 – Biomarkers of MEM-induced gains: We will determine if baseline levels of specific neurocognitive or 
EEG-based measures, or changes in specific measures with initial MEM exposure (Test 2 vs. 1), predict greater 
sensitivity to MEM-enhanced neurocognitive, clinical or functional gains over 30-h of TCT. Regression analyses 
will assess whether specific candidate biomarkers predict MEM-enhanced gains in outcome measures.  
Subject “throughput”: We will enroll and screen 23 subjects/yr, test target engagement in 18 subjects/yr, and 
(conservatively) complete TCT training in 12 subjects/yr. This will yield 2 “target engagement” Aim 1 arms of 
n=27, and (conservatively) 2 TCT completion Aim 2 arms of n=18. Training capacity (2 TCT stations with morning 
and afternoon sessions on M, W and F, with T and Th “make-up” days for missed appointments, 48 weeks/year) 
allows for a “maximum throughput” of 19.2 subjects/yr. To reach the target of 12 TCT-completing subjects 
/year, we would need to maintain training rates of 62.5% capacity. This is well within our historical testing levels. 
Power analyses: Consistent with the FOA, this study will adequately power tests of target engagement (Aim 1) 
for traditional significance, while the “Go” signal for therapeutic impact (Aim 2) is based on effect size (d=0.5). 
To detect target engagement for an LME model with d=0.5, 80% power, alpha=0.05, test-retest correlation=0.8, 
and a linear treatment effect, n=27 randomized participants are required per Hedeker et al (1999). This is a 
conservative estimate of d for target engagement, since empirically, d for target engagement with 20 mg MEM 
was 0.85 (Fig. 3). A future Confirmatory Efficacy trial will be powered to apply more robust approaches to Aim 2, 
e.g. Path Analysis60 to study moderating effects of APS MEM sensitivity and biomarkers on both indirect 
(moderated-mediation) and direct paths between treatment and outcome.  
Innovative ideas raise questions. Here are some answers:  
1. We don’t know how MEM works. MEM is described as an uncompetitive low-affinity NMDA receptor 
antagonist with rapid blocking and unblocking ability. It is widely used to treat Alzheimer’s Disease44,45, but the 
cellular mechanisms responsible for MEM’s clinical effects are a source of controversy, and the present 
application is fully agnostic to such mechanisms. One relevant clinical effect of MEM is to enhance verbal 
communication in Alzheimer’s patients108,109, which might reflect gains in auditory discrimination. It also has 
positive activity in cognitive measures in both healthy animals and a range of human and animal models for 
dementia, depression, ischemia and neuroinflammation110,111. Thus, consistent with an RDoC framework, the 
impact of MEM on disease states is defined more by a dimension of cognition, than by a diagnostic entity. MEM 
enhances hippocampal long-term potentiation (LTP), and reverses an experimentally-induced loss of LTP111; it 
also alters excitation/inhibition (E/I) dynamics in frontal circuitry implicated in models of SZ neuropathology112 
and associated with MMN and cognitive deficits in SZ113. We have also recently shown that acute 20mg of MEM 
normalizes novel measures of E/I balance in SZ patients63.  What we do know about MEM, however, is that it 
acutely increases EAIP (Fig. 2) and Sound Sweeps APS learning in SZ patients (Fig. 3); here, we ask whether 
Contact PD/PI: LIGHT, GREGORY A 
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such gains accompany daily MEM use and translate into an augmentation of TCT’s clinical benefits.  
2. MEM is not ketamine (or PCP, or MK-801). Unlike other NMDA antagonists, MEM has little impact on basal 
NMDA transmission114. In rats, PCP, ketamine and MK801 exhibit inverted-U dose-functions on spontaneous 
gamma power, and adversely impact other frequency bands; in contrast, gamma-enhancing effects of MEM 
follow a linear, positive dose-function and are selective for the gamma band61. In some behavioral measures, 
MEM is similar to ketamine but not PCP115,116, while in others, MEM actually reverses the effects of ketamine43. 
In measures of glutamate-dependent synaptic plasticity, MEM effects are opposite to those of ketamine and MK-
801117. In HS, ketamine reduces MMN118, but MEM increases MMN (d=0.87)62. More generally, prevailing models 
suggest that SZ symptoms reflect NMDA hypoactivity. While these models may be valid at a level of cortical 
microcircuitry, trying to reconcile them with complex effects of oral drugs with differential effects at the NMDA 
receptor complex may not be useful. A cogent critique of current biological models of SZ as they relate to future 
therapeutics is found in, "Are we studying or treating schizophrenia correctly?"41 
3. MEM is safe. The best evidence that MEM is very distinct from the PCP/ketamine class of NMDA antagonists 
is that MEM has been studied in >185 NIH trials, and used clinically by large numbers of elderly, frail dementia 
patients for years, without serious adverse events (SAEs). Unlike ketamine, which has psychotogenic effects in 
SZ patients119, studies of MEM effects in SZ patients (Table 2) have consistently reported no increased SAEs; 
most report beneficial effects on symptoms and cognition (including 3 meta-analyses):  
Table 2.     Citation 
Study Design 
N 
mg/d 
Wks 
Δ Sx? 
Δ Cog? 
SAEs? 
Lieberman et al.120 
D-B RCT + SGAPs 
70 
20 
8 
Ø  
Ø 
no 
Lee et al.121 
D-B RCT + APs 
26 
20 
12 
Ø  
Ø  
no 
Omranifard et al.122  
D-B RCT + APs 
64 
20 
12 
 GAF, QLS 
NA 
no 
Veerman et al.123 
D-B RCT + clozapine 
52 
20 
12 
 neg 
 
no 
Veerman et al.124 
1-y extension of above  
24 
20 
52 
 pos/neg 
Ø 
no 
De Lucena et al.125 
D-B RCT + clozapine 
21 
20 
12 
 pos/neg 
 MMSE 
no 
Krivoy et al.126 
Open label 
7 
5-20 
6 
 pos/neg 
Ø 
no 
Rezaei et al.127 
D-B RCT + risperidone 
40 
20 
8 
 neg 
NA 
no 
Mazinani et al.128  
D-B RCT + risperidone 
22 
20 
12 
 neg 
 MMSE 
no 
John et al.129 
Chart-based retrospective 
26 
10-20 
8-100 
 pos/neg 
 
no 
Fakhri et al.130 
D-B RCT added to olanz. 
30 
20 
6 
 pos/neg 
NA 
no 
Zheng et al.131  
Meta-analysis 
452 
-- 
-- 
 neg 
 MMSE 
no 
Kishi et al.132-134 
Meta-analysis 
226 
-- 
-- 
 neg 
 MMSE 
no 
Zheng et al. 46 
Meta-analysis 
512 
-- 
-- 
 neg 
 MMSE 
no 
D-B: Double-blind; RCT: randomized controlled trial; +: added on; QLS: Quality of life scale; GAF: global 
assessment of functioning; MMSE: Mini-mental State Exam; Sx: Symptoms; SAEs: serious adverse events; 
pos/neg: symptoms. 
In addition to Table 2, many other studies and case reports describe clinical and functional gains after MEM in 
SZ patients135-138. As noted above, none of the studies in Table 2 utilized MEM in concert with a systematic 
cognitive intervention, nor were any specific biomarkers used to predict sensitive patient subgroups. Both 
cognitive intervention and predictive biomarkers139 are part of the treatment model that will ultimately be driven 
by the present application.  
4. MEM is pretty weak, but... We fully acknowledge that, even in its primary clinical use (Alzheimer’s Disease), 
MEM has relatively modest clinical impact.  Importantly, MH94320 identified something that MEM is really good 
at: increasing EAIP in HS and SZ patients47,50,90,107. No other drug is known to do this, and this ability of 
MEM, along with its ability to enhance APS learning (Fig. 3) – provides the basis for the key hypotheses in this 
application: that MEM will enhance the clinical impact of TCT, and that an individual’s sensitivity to this effect will 
be predicted by EAIP-based biomarkers.   
As it relates to MEM’s potency in this PACT model, it is important to acknowledge that the dose selected for the 
Aim 1 “Test 2 MEM challenge” (20 mg; Fig. 5) is based on empirical evidence that this dose – but not 10 mg 
MEM – enhances EAIP in HS and SZ patients, while 30 mg MEM (not tested in SZ patients) failed to enhance 
some EAIP biomarkers (but DID produce some adverse effects)47. In other words, MEM appears to have 
“inverted-U dose-effects” on at least some EAIP measures, and 20 mg produces the most consistent, robust 
effects47,49,50,63,76, in addition to its ability to enhance APS learning in SZ patients (Fig. 3). Also importantly, the 
dose of MEM selected for the 10-week treatment phase of this study (20 mg daily in divided doses) is based on 
the known safety and tolerability of this dose, which is the one most commonly used to target neurocognitive 
deficits in SZ (and all other) patients (Table 2).  
 
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5. MEM offers advantages over other drugs in a PACT “Confirmatory Efficacy” study. Our group has 
studied several potential pro-cognitive drugs for use in a PACT model, including MEM, tolcapone, modafinil and 
amphetamine; based on positive results, we are separately pursuing R33 support to pilot amphetamine/PACT 
studies (see Budget Justification). However, MEM offers some advantages over amphetamine in the PACT 
model, particularly in relation to its “scalability” for larger clinical trials: 1) amphetamine is administered by a staff  
member prior to each TCT session, while MEM is taken daily as part of the patient’s routine regimen; 2) after 
amphetamine administration, subjects remain “on-site” for safety monitoring during training, which is not needed 
with MEM; 3) the literature documenting MEM safety in SZ patients, as it will be used in the present application 
(10 mg bid; Table 2) is substantial; and 4) positive UTox results for amphetamine are not easily interpreted during 
an amphetamine trial. More generally, we anticipate that there will be variable sensitivity to PACT drugs, that no 
single drug will effectively enhance TCT effects in all patients, and that - guided by predictive biomarkers - it will 
be important to have alternative treatment options for use in this model. 
6. Target Engagement. APS learning is the target to be engaged in this application. We hypothesize that 
this learning is critical for the therapeutic benefits of TCT; by enhancing APS learning, patients will benefit more 
from TCT. Consistent with the experimental therapeutics model supported by this RFA, TCT “learning”, as 
detected by gains in APS, is the “factor that an intervention intends to modify, based on a hypothesis that [its] 
modification will result in improvement of symptom, behavior, or functional outcomes.” This choice of targets is 
consistent with this RFA instruction, “Targets might include…potentially modifiable…cognitive processes…” We 
hypothesize and will test in this application that MEM-enhanced learning during TCT – of which APS learning 
is an accessible, quantitative metric - will amplify, accelerate or make more durable the clinical, neurocognitive 
and functional gains after a 30-h course of TCT, i.e. “test the hypothesis that the target is relevant to the clinical 
problem under study.” In addition to TCT Sound Sweeps used in target engagement, clinical delivery of TCT 
involves training modules that engage auditory sensory processing in ways that are distinct from Sound Sweeps. 
Nonetheless, we predict that MEM-enhanced gains in APS learning reflect processes that will generalize to 
MEM-enhanced gains in the therapeutic impact of these other auditory sensory-based tasks. Other potential 
measures of target engagement, including “APS plateau”68 will also be explored as secondary outcomes. 
Based on this model, we acknowledge that – in addition to gains in APS learning - “target engagement” could 
be demonstrated either via gains in EAIP or other behavioral measures of auditory discrimination (QuickSIN 
score), but feel that the target that is most proximal to the therapeutic impact of TCT in this model is learning, 
i.e. gains in APS. Because of its “proximity” to the therapeutic impact of PACT, APS learning should be a target 
that provides a robust engagement signal and that strongly predicts the clinical consequences of the PACT 
intervention. Also, compared to EEG, measures of APS learning are more “scalable” for use in future 
“Confirmatory Efficacy” trials. 
7. This approach might not work: Some evidence suggests that drug-enhanced APS learning, symptom 
reduction and neurocognitive gains from TCT may be dissociable, i.e. MEM might acutely enhance APS learning 
and EAIP biomarkers but have no impact on TCT-induced neurocognitive gains. Cain et al.92 reported that SZ 
patients taking the pro-extinction NMDA agonist, D-cycloserine (DCS) – but not those taking PBO - exhibited 
significant gains in APS learning and negative symptom reduction during an 8-week trial of TCT; DCS-enhanced 
APS learning was evident at the first time point (1 week). Interestingly, PBO- but not DCS-treated patients 
exhibited significant gains in MCCB performance. Thus, enhanced APS learning was associated with symptom 
reduction but not neurocognitive gains. This R33 application differs from the Cain et al.92 study in several specific 
ways, including: 1) this R33 uses a detailed conceptual framework for PACT design and implementation; 2) it 
benefits from previous dose/time optimization studies to maximize drug effects on APS learning; and 3) it uses 
a suite of hypothesis-driven biomarkers to identify potentially sensitive patient subgroups. Nonetheless, it is clear 
that MEM-enhanced TCT gains might be most evident in some but not all metrics (symptoms, neurocognition, 
function), even in the face of robust target engagement. With this awareness, we will carefully track and dissect 
these distinct outcome measures over the course of the R33, as we have in our published studies2,31,33,34,65,71.  
8. Is this PACT “scalable”? This R33 design is optimized: a) patients are carefully characterized as part of a 
clinical trial; b) MEM dose and timing are optimized based on our previous studies; c) potential logistical hurdles 
that might cause subject attrition (transportation, food, reimbursement) are minimized; and d) biomarker 
assessment uses high fidelity lab-based measures that are not readily available in community-based settings for 
mental healthcare delivery. While this optimized design is feasible in our on-site laboratory (see below, 
“Feasibility”), a robust PACT design will face challenges in implementation in the “real world”. Importantly, we 
are studying different PACT delivery models, and are in discussions with a local Intensive Outpatient Program 
(IOP) (comparable to “Day Treatment”). The IOP model has been particularly successful in San Diego, and could 
be adapted to incorporate PACT into an integrated treatment, along with standardized biomarkers for 
personalized regimens, careful monitoring of clinical state and antipsychotic adherence, and individual and group 
supportive therapies. If this and a Confirmatory application support PACT efficacy, it will be “scalable.” 
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9. No control groups. Adding control “computer game” groups might reveal if PACT benefits reflect MEM use 
independent of TCT, computer use independent of TCT, and/or interactions of MEM+computer use. These are 
3 very-low probability outcomes. We opted against this since: 1) efficacy of TCT is already known, so our primary 
aim is to assess the impact of added MEM vs. PBO; 2) recruitment demands for 4 groups will not yield “n’s” 
needed to detect meaningful Go/No-Go criteria; and 3) requiring patients to complete 30-h of non-therapeutic 
games for 10 weeks, or exposing patients to MEM under conditions that are unlikely to have lasting clinical value, 
is not ethically justified. Fisher et al.37 found that patients randomized to computer game groups exhibited 
significant declines in verbal memory. Healthy subjects are not studied since no likely PACT effects on such 
subjects would alter the clinical implications of either positive or negative findings in SZ patients.   
10. There is still “room to move”: TCT effects on neurocognitive and clinical metrics might be “at ceiling”, and 
thus insensitive to further gains from MEM. Compared to treatment as usual, 30-h of TCT in our studies resulted 
in medium-to-large effect size gains in Verbal Learning (d=0.65) and auditory discrimination (“Words-in-Noise”; 
d=0.67), and in reductions of auditory hallucinations (d=-0.64). However, TCT did not produce gains in other 
MCCB domains (e.g. Cohen’s d’s for processing speed, attention/vigilance and working memory were -0.1, -0.3 
and -0.29, respectively), or in broader symptom profiles (e.g. SANS). Thus, despite robust gains in some areas 
after TCT, there is clearly “room to move”51 for added PACT-induced gains. Furthermore, while past studies 
assessed the magnitude of TCT effects at a single point (after 30 sessions), the proposed study will assess both 
the onset and durability of PACT effects. It is possible that MEM will accelerate and/or prolong the gains from 
TCT, in ways that were not assessed in our previous studies, but which are certainly of clinical importance. The 
small sample size of this “pilot” study will not easily detect traditional (p<0.05) statistically significant group 
differences, but “Go/No-Go” decisions will be based on “clinically meaningful” Cohen’s d=0.5.   
11. “Negative results… [will] guide further intervention development”? This R33 has clear ‘Go/No-Go’ 
criteria. If target engagement is not confirmed, we will conclude that this design setting is unsuitable for detecting 
robust MEM group effects on APS learning. Based on the data (e.g. evidence of MEM bioactivity), we will develop 
testable hypotheses (e.g. cohort differences) that might account for differential outcomes in the present 
application. Even if there are not robust MEM effects on APS learning (target engagement), it is possible that 
heterogeneity in MEM APS sensitivity might reflect meaningful subgroups of patients (e.g. low vs. high 
attention/vigilance), and that APS MEM sensitivity might still predict (correlate with) MEM enhancement of TCT 
therapeutic effects. In other words, a lack of a group difference (placebo vs. MEM) would not preclude the utility 
of MEM APS sensitivity as a predictive biomarker. Conversely, even if target engagement is confirmed, it is 
possible that group differences (placebo vs. MEM) in therapeutic gains might not be detected. A “valid” negative 
outcome (e.g. lack of positive MEM effects on outcome measures despite evidence of target engagement and 
adequate TCT exposure) will indicate that MEM-enhanced APS learning is not sufficient to enhance TCT effects 
in a clinically-defined SZ cohort. Analyses will then determine if MEM enhances TCT effects in biomarker-defined 
SZ subgroups. A failure to detect such subgroups would suggest a dissociation between target engagement in 
the first Sound Sweeps session and therapeutic benefit after 30-h of TCT.  
12. This work is feasible. Our study team includes 2 Board Certified Psychiatrists (NS, YJ) with SZ clinical trial 
experience, a licensed Clinical Psychologist/Neurophysiologist and PI of a BBRF-funded trial of biomarker 
predictors of TCT in SZ patients (GL), an expert statistician with a career focus on analytic pathways from biomar-
kers to clinical function in SZ (MT), a UCSD SZ Research Program with a >30 y history of recruiting and testing 
thousands of psychosis patients in studies with ERPs and other biomarkers proposed in this R33 (published 
retest stability with 1-year follow-up140), as well as double-blind, PBO-controlled trials of putative pro-cognitive 
agents (including MEM) in SZ patients and HS48,49,74,104. We completed and published extensively on a 30-
session clinical trial of TCT in SZ patients and with many of the same biomarkers proposed herein.  
13. Why an R33 and not a full Confirmatory Efficacy Trial? While this work provides a strong empirical 
justification for MEM target engagement, this evidence is insufficient to justify moving to a full, large scale, 
Confirmatory Efficacy trial with PACT at this time. We acknowledge that MEM may enhance TCT-induced APS 
learning in a single session, but still not enhance, accelerate, or make more durable TCT-induced clinical, 
neurocognitive or functional gains following a full course of TCT. Even with evidence of target engagement, and 
its replication and optimization, it is still only a hypothesis that enhanced learning during TCT will augment its 
clinical benefits. In fact, MEM has different neurobiological effects after one (as shown in our preliminary results, 
Figs. 2-3) vs. multiple doses141,142 (as proposed in this application); in some models, it is effective after acute but 
not chronic dosing141. Consistent with this RFA-MH-18705 (“replicate target engagement and relate change in 
the… target/mechanism to clinical benefit”), testing this hypothesis, with specific “Go/No Go” criteria, will 
be the most critical development of the present application. Beyond this critical step, this application will 
leverage a substantial foundation of findings to explore (i.e. “learn/confirm”) mature hypotheses related to 
mechanisms and predictors of pro-cognitive therapeutics for SZ. 
 
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Section 4 - Protocol Synopsis (Study 1)
4.1. Brief Summary
Current therapies for chronic psychotic disorders such as schizophrenia include antipsychotic medications, which do not
 significantly improve function or correct cognitive deficits in this disorder, and cognitive therapies, which produce only modest
 benefits to most patients. We hypothesize that medications that specifically target neurocognitive processes like attention and
 vigilance will significantly augment the clinical benefits of cognitive therapies in schizophrenia. Here, we will confirm that the
 pro-cognitive medication, memantine, enhances learning of an auditory processing task in a computerized targeted cognitive
 training (TCT) program in antipsychotic-medicated schizophrenia patients, and complete a randomized, double-blind clinical
 trial in antipsychotic-medicated schizophrenia patients, comparing TCT (30 sessions) plus memantine (MEM) vs. TCT (30
 sessions) plus placebo (PBO).
4.2. Study Design
4.2.a. Narrative Study Description
Screened, eligible patients complete clinical, neurocognitive and functional measures and candidate biomarkers (EEG,
 QuickSIN, WIN). Aim 1 is completed in 2 tests, approximately 1 week apart. In Test 1, Sound Sweeps are tested after
 PBO for all subjects, who are then randomized to TCT+PBO vs. TCT+MEM arms (n=27/arm) using stratified random
 sampling (over sex, age and high/low Test 1 APS learning) blind to arm identity, similar to our previous studies. Test
 2 follows approximately 5-7 d later; this test is identical to Test 1, except that subjects receive their assigned study
 drug (PBO vs. MEM (20 mg po)) 1 hour prior to Sound Sweeps. Tests 1 and 2 are used to assess target engagement
 (Aim 1: MEM-enhanced APS learning) and MEM effects on auditory discrimination (QuickSIN, WIN). Our design allows
 for 20% attrition from enrollment (n=69) to completion of target engagement testing (n=54).   For Aim 2, TCT in these
 same subjects is scheduled 3 d/week (M-W-F) for 1-h/d, recognizing the need for flexibility (T-Th are “make-up days”),
 and continues until a subject completes 30-h (approximately 10-12 weeks). TCT is delivered by trained staff. 60 min
 prior to each TCT session, patients take either PBO or 20 mg MEM, as per arm assignment. Patients and staff are
 blind to study arm; staff are blind to patients’ baseline or post-intervention assessments. Outcome metrics assess
 symptom, neurocognitive and functional changes after 10, 20 and 30 TCT sessions, and 12 weeks post-TCT. Candidate
 biomarkers are re-tested after completion of 30 sessions of TCT.
4.2.b. Primary Purpose
Treatment
4.2.c. Interventions
Type
Name
Description
Behavioral (e.g.,
Psychotherapy,
Lifestyle
Counseling)
Targeted Cognitive Training
(TCT)
Thirty, one-hour sessions over approximately 10 weeks, of computerized
 cognitive training modules.
Drug (including
placebo)
memantine
The pro-cognitive medication, memantine (placebo vs. 20 mg) will be
 administered orally, 1 hour prior to targeted cognitive training, in a double-
blind, randomized design.
4.2.d. Study Phase
Phase 2/3
Is this an NIH-defined Phase III Clinical Trial?
❍
Yes
●
No
4.2.e. Intervention Model
Parallel
4.2.f. Masking
●
Yes
❍
No
❏
✔Participant
❏
✔Care Provider
❏
✔Investigator
❏
✔Outcomes Assessor
4.2.g. Allocation
Randomized
4.3. Outcome Measures
Tracking Number:
Funding Opportunity Number:  Received Date:
Contact PD/PI: LIGHT, GREGORY A 
Page 94

Type
Name
Time Frame
Brief Description
Primary
Auditory Processing Speed
(APS) learning
Test 1 and Test 2, one week
apart
APS is measured before and after the TCT
 "Sound Sweeps" frequency modulation session,
 to determine the amount of "learning", based
 on the reduction in detection gap (ms). More
 learning (greater gain in processing speed)
 with memantine vs. placebo confirms target
 engagement, which is the primary outcome of Aim
 1.
Primary
MCCB Composite
baseline vs. post-TCT session
10, 20 and 30 (approximately
10 weeks), and 12 weeks post-
TCT
Change in MCCB Composite performance
 from baseline is one outcome measure. The
 MCCB measures 7 cognitive domains: speed of
 processing, attention/vigilance, working memory
 (verbal and nonverbal), verbal learning, visual
 learning, reasoning/ problem solving and social
 cognition. Details are found in[25, 89, 90]; past
 studies of drug effects on MCCB performance
 include[37, 91]. Since the MCCB is assessed
 multiple times, alternate forms of the HVLT-R
 and BVMT-R are used in counterbalanced order.
 MCCB Global Composite T-score (MCCB-C) is
 the primary neurocognitive outcome measure.
 Individual MCCB domain T-scores are used in
 secondary analyses to determine whether an
 overall effect is driven by specific aspects of
 neurocognition; TCT effects on verbal learning
 performance are known to be robust[13], and
 should be augmented by MEM. Baseline and
 MEM-enhanced (Test 2 vs. 1) MCCB performance
 (A/V subscale) will also be tested as potential
 biomarkers/moderators of MEM PACT efficacy.
Primary
PANSSt: Positive & Negative
Symptom Scale total
baseline vs. post-TCT session
10, 20 and 30 (approximately
10 weeks), and 12 weeks post-
TCT
TCT reduces both positive and negative symptoms
 of psychosis; we predict that memantine will
 augment these effects via enhanced TCT
 learning, detected by the PANSS. For this reason,
 and based on the need to limit total outcome
 measures, PANSS Total Score is the primary
 clinical outcome measure. Positive and negative
 symptom subscales, as well as PANSS factor-
derived measures, will be assessed in exploratory
 analyses. Other secondary clinical measures
 will include: 1) Psychotic Symptom Rating
 Scales (assesses auditory hallucinations); 2)
 Young Mania Rating Scale; 3) Patient Health
 Questionnaire-9 (current depressive symptoms);
 4) Abnormal Involuntary Movement Scale; 5)
 Columbia Suicide Severity Rating (C-SSRS);
 “Lifetime/Recent version” at screen; “Since
 Last Visit” at follow-up visits). The C-SSRS is a
 sensitive measure of suicidal ideation; any “yes”
 in C-SSRS prompts an immediate full evaluation/
action plan by a study M.D.
Tracking Number:
Funding Opportunity Number:  Received Date:
Contact PD/PI: LIGHT, GREGORY A 
Page 95

Primary
World Health Organization
Disability Schedule 2.0
(WHODAS)
baseline, after sessions 10, 20
and 30, and 12 weeks post-
TCT
Function is assessed via the World Health
 Organization Disability Schedule 2.0 (WHODAS)
 at baseline, after sessions 10, 20 and 30, and
 week 12 post-TCT. WHODAS 2.0 is a 12-item
 patient-rated measure (< 15 min) using a 5-point
 Likert scale focusing on cognition, mobility, self-
care, getting along with people, life activities and
 participating in society; it was selected by the
 DSM-5 Task Force committee to replace the
 global assess-ment of functioning scale. NIH
 “PhenX Toolkit” scales of Impairment, QOL and
 Social Isolation will also be used. After session
 #30, the assessment will include a 14-item 7-point
 Likert scale of treatment satisfaction.
Primary
EEG biomarkers
baseline,visit 2 and after
session 30
Biomarkers from Tests 1-2 will be assessed as
 predictors of target engagement (Aim 1) and
 PACT sensitivity (Aim 2).EEG measures of
 early auditory information processing variably
 predict response to early APS learning[74],
 MEM-enhanced APS learning[62], and TCT
 outcomes[18].   EEG/ERPs are acquired via 64-
channel recording systems and assessed in the
 same order, as per[38, 94]: MMN/P3a/Theta
 power/Phase locking (25 min; Oddball Paradigm),
 ASSR (6 min). Exploratory analyses will test
 secondary predictions: for example, high vs. low
 baseline P3a amplitude and faster P3a latency
 will predict greater target engagement (Aim
 1), and greater MEM-enhanced TCT outcome
 (Aim 2). MEM-enhanced (Test 2 vs. 1) ERPs,
 auditory discrimination and neurocognitive (A/
V) measures will also be explored as outcome
 (Aim 2) predictors; significant pre- vs. post-TCT
 changes in ERP source dynamics will also be
 examined for mechanistic characterization[20].
 Robust biomarker predictors will be examined as
 moderator
4.4. Statistical Design and Power
4.4_Statistical_Design_and_Power.pdf
4.5. Subject Participation Duration
approximately 24 weeks
4.6. Will the study use an FDA-regulated intervention?
❍
Yes
●
No
4.6.a. If yes, describe the availability of Investigational
Product (IP) and Investigational New Drug (IND)/
Investigational Device Exemption (IDE) status
4.7. Dissemination Plan
4.7_Dissemination_Resource_Sharing.pdf
Tracking Number:
Funding Opportunity Number:  Received Date:
Contact PD/PI: LIGHT, GREGORY A 
Page 96

auxiliary variables to our models, nonrandom dropout is corrected by conditioning treatment 
effects on the predictors of dropout. 
Primary Efficacy Endpoint(s): Aim 1: Target engagement  APS learning will be significantly 
greater under MEM vs. PBO conditions. Aim 2: Pilot trial - Compared to PBO arm patients, 
MEM arm patients will exhibit greater clinical benefit, as indicated by one or more of the 
following: greater, faster or more durable improvements in PANSSt (reduced scores; see below, 
Go/No-Go), MCCBc (increased scores) or WHODAS (reduced scores).  
Secondary Efficacy Endpoint(s): Aim 3: Biomarkers - baseline levels of specific neurocognitive 
or EEG-based measures, or changes in specific measures with initial MEM exposure, predict 
greater sensitivity to MEM-enhanced neurocognitive, clinical or functional gains over 30 
sessions of TCT. 
Analyses testing primary and secondary hypotheses will include all subjects clinical, 
neurocognitive and functional assessments. Data from subjects who do not complete the full 
study are carried forward in an intent to treat design, and their data are analyzed using linear 
mixed models.   Separate analyses will compare completion / drop-out rates across arms, as 
well as a 14-item 7-point Likert scale assessing treatment satisfaction.  
Go/No-Go decision and primary and secondary endpoints 
Go/No-Go decisions are based on traditional statistical significance (Aim 1) and effect sizes 
(Aim 2). Formal statistical testing is conducted using linear mixed-effects (LME) models; 
hypothesis tests are 2-sided (α=.05). Model parameters are estimated via the R lme4 package 
and Cohens d is estimated via the EMAtools package. Type I errors are minimized by 
constraining the number of primary analyses; secondary analyses use false discovery rate 
corrections. 
PANSSt scores will be assessed at specific intervals. Because TCT is associated with 
improvements in both positive and negative symptoms, our a priori hypothesis is that a PACT 
effect will be evident in both positive and negative symptoms. Hence, PANSSt is used as the 
primary metric of symptomatic gains. A greater reduction in PANSSt score will be detected 
using data from baseline through TCT 30h, by a significant main effect of group (arm) or a 
significant interaction of group x session, with post-hoc contrasts revealing significant group 
differences at TCT 30h. A faster reduction in PANSSt scores will be detected using these same 
data by a significant interaction of group x session and a significant group difference at a point 
prior to TCT 30h. A more durable reduction in PANSSt scores will be detected using data from 
TCT 30h through 12 weeks post-TCT, by a significant main effect of arm or a significant 
interaction of group x post-TCT day, with post-hoc contrasts revealing significant group 
differences 12 weeks post-TCT. 
Comparable analytic approaches will be used for neurocognition (MCCBc) and function 
(WHODAS) as described in Research Strategy. Data will be described as means with SEM. 
Tests for normalcy will be applied to all data and non-parametric comparisons will be used if 
normalcy is not demonstrated. The Analysis Set for these data will be all subjects who have 
completed 30h of TCT and post-TCT clinical, neurocognitive and function assessments. When 
appropriate, missing data are handled via multiple imputation or full information maximum 
likelihood estimation.  
Secondary regression analyses assess the predictive value of putative biomarkers on clinical, 
neurocognitive or functional gains from the addition of MEM to TCT. Future studies with larger 
samples will assess potentially more informative models, e.g. Path Analysis to study moderating 
effects of APS MEM sensitivity and biomarkers on both indirect (moderated-mediation) and 
direct paths between treatment and outcome.  
Power analyses  
Contact PD/PI: LIGHT, GREGORY A 
Statistical Design and Power
Page 98

Consistent with the FOA, this study will adequately power tests of target engagement (Aim 1) for 
traditional significance, while the Go signal for therapeutic impact (Aim 2) is based on effect 
size (d=0.5). To detect target engagement with d=0.5, 80% power, alpha=0.05, test-retest 
correlation =0.8, and a linear treatment effect, n=27 randomized participants are required per 
group. This is a very conservative estimate of d for target engagement, since empirically, d for 
target engagement with 5 mg MEMetamine was 0.85 (Fig. 3A). A future Confirmatory Efficacy 
trial will be powered to apply more robust approaches to Aim 2, e.g. Path Analysis108 to study 
moderating effects of APS MEM sensitivity and biomarkers on both indirect (moderated-
mediation) and direct paths between treatment and outcome. 
 
 
 
Contact PD/PI: LIGHT, GREGORY A 
Statistical Design and Power
Page 99