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

 
NCT4414930: Pharmacologic augmentation of targeted cognitive training in schizophrenia  
Study Protocol 
 
October 11, 2019 

SPECIFIC AIMS: Pharmacologic Augmentation of Targeted Cognitive Training in Schizophrenia 
 
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. Antipsychotics are the major therapeutic tool for chronic psychotic disorders, 
including schizophrenia, but do not significantly alter their course or real-life impact. Specific cognitive 
therapies achieve modest symptom reduction and improved function and cognition in psychosis patients, 
including bottom-up sensory-based targeted cognitive training (TCT). While benefits of TCT are evident at the 
group level, almost half of all patients demonstrate little or no cognitive gains after 30-40 hours (h) of TCT. For 
patients and clinicians, the costs and logistical complexities associated with these time- and resource-intensive 
interventions can be prohibitive. Consistent with the scope of this RFA, we propose and will test a novel 
augmentation strategy for using medications to specifically enhance the benefits of TCT in schizophrenia. 
 
Suppressing active psychosis with antipsychotics benefits cognitive interventions for schizophrenia, but 
it is possible that drugs with pro-cognitive effects will specifically, and perhaps synergistically, augment the 
clinical benefits of cognitive therapies. A "proof of concept" for this approach is found in the use of the pro-
extinction drugs to selectively enhance the impact of cognitive therapy for anxiety disorders. In this proof of 
concept, a learning-based therapy is paired with a medication that enhances a brain mechanism (extinction) 
that is both 1) critical to that form of learning, and 2) known to be deficient in some anxiety disorders. In this 
application, we will use the pro-attention drug, amphetamine, to enhance a brain mechanism (attention) that is 
both 1) critical to learning in TCT, and 2) known to be deficient in schizophrenia. We hypothesize that 
amphetamine will augment TCT learning and hence the clinical gains from TCT in schizophrenia patients, and 
that this PACT approach will be particularly effective in biomarker-defined subgroups of patients. A successful 
PACT will produce neurocognitive and clinical gains from TCT that are more robust, more rapidly achieved, 
more durable and/or impact a greater proportion of patients, compared to TCT alone.  
 
Preliminary support for this hypothesis and the proposed experimental design comes from both our 
laboratory- and clinic-based studies. Our laboratory-based studies tested dose and time-course effects of 
amphetamine on TCT learning in antipsychotic-medicated schizophrenia patients (MH59803). Amphetamine 
(2.5 < 5 > 10 mg) significantly enhanced learning in an auditory discrimination task (Posit Science Sound 
Sweeps) -- a key component of the TCT suite of exercises with established efficacy in schizophrenia patients. 
This enhanced learning was 1) not drug state-dependent, 2) retained for at least 1 week, 3) most robust among 
patients with the greatest baseline attentional deficits, and 4) associated with gains in auditory discrimination. 
Our data supported the acute, sub-acute and long-term safety of repeated amphetamine exposure in these 
antipsychotic-medicated patients. However, while amphetamine-enhanced learning during a 1-h Sound 
Sweeps test provides a valuable assay of target engagement, we have no evidence that it predicts greater, 
faster or more lasting clinical, neurocognitive or functional gains with a full course of amphetamine+TCT.  
 
Our clinic-based studies yielded key findings related to Sound Sweeps performance and predictors of 
therapeutic sensitivity to a full course of TCT in a real world psychiatric treatment facility. First, baseline levels 
of early auditory information processing (EAIP) significantly predicted learning during 1-h of Sound Sweeps. 
Second, schizophrenia patients exhibited significant clinical, neurocognitive and functional gains after 30-h of 
TCT, and gains in EAIP during the first hour of Sound Sweeps strongly predicted neurocognitive gains after a 
full course of TCT. In total, these findings with amphetamine, Sound Sweeps, auditory discrimination, EAIP 
and TCT provide a strong empirical and conceptual framework for a mechanistically-based hypothesis to be 
tested via the proposed randomized, placebo-controlled 30-h pilot trial of (amphetamine+TCT) vs. 
(placebo+TCT). We propose that: 1) amphetamine will enhance and/or accelerate the clinical, neurocognitive 
and functional gains after 30-h of TCT in schizophrenia patients, and 2) this PACT effect will be predicted by 
gains in learning and EAIP after 1-h of Sound Sweeps training. Via 3 Aims, this application provides efficient 
pilot testing of this PACT strategy in antipsychotic-medicated schizophrenia patients, using clear Go/No-Go 
criteria to inform a future, fully-powered Confirmatory Efficacy trial:   
    Aim 1  Confirm target engagement: In two, 1-hour tests, determine if amphetamine increases Sound 
Sweeps learning in a cohort of impaired schizophrenia patients (n=54).   
    Aim 2  Efficiently test clinical, neurocognitive and functional impact, and their relationship to target 
engagement: In a 30-session, 10-week course of TCT, determine if amphetamine augments the magnitude, 
rate and/or durability of TCT-induced gains, and whether these gains are associated with target engagement. 
    Aim 3  Biomarkers of AMPH-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 amphetamine-enhanced clinical, neurocognitive or functional gains 
among schizophrenia patients receiving combined amphetamine+TCT. 
Contact PD/PI: SWERDLOW, NEAL R 
Specific Aims
Page 55

Research Strategy: A. Significance:  Chronic psychotic disorders, including schizophrenia (SZ), affect 2% of 
the world’s population, causing suffering and severe disability. Among the consequences of these disorders, 
psychosocial disability is strongly correlated with neurocognitive impairment18,42,118. The primary treatment for 
these disorders over the past 60 years has been antipsychotic (AP) medications, which produce only marginal 
gains in neurocognition49; by contrast, specific cognitive therapies significantly improve neurocognition and 
outcome in SZ patients, with effect sizes of d≈0.40 vs. APs alone8,30,40,110-1. Many studies document the safety, 
acceptability and efficacy of cognitive therapies in SZ with benefits often lasting years30,40,66-9; benefits are 
achieved with both “top-down” therapies, that engage higher order cognitive mechanisms, and “bottom-up” 
cognitive and basic sensory training delivered via computerized cognitive remediation programs31-2,115.  
One “bottom-up” cognitive therapy, Targeted Cognitive Training (TCT), is a “neuroplasticity-based” computerized 
approach to cognitive remediation31. In TCT, the user performs progressively more difficult learning trials to 
improve pitch and temporal acuity of processing in auditory sensory, attention-related and working memory 
systems. The goal of TCT is to foster the recovery of key neurocognitive functions by harnessing mechanisms 
of neuroplasticity under carefully controlled conditions, rather than to promote the development of compensatory 
cognitive or behavioral operations. TCT relies on repetitive practice and procedural learning - mechanisms that 
are relatively intact in SZ patients - by providing auditory training exercises that are: 1) intensive: thousands of 
trials per exercise; 2) attentionally engaging: self-paced initiation of each trial; 3) adaptive: the difficulty of each 
training task adjusts trial-by-trial based on performance; and 4) rewarding: entertaining animations reinforce 
correct responses3. In several reports31-2,115, Vinogradov and colleagues have shown that after 30-50 hours (h) 
of TCT, SZ patients have large effect size gains (d>0.86) in auditory-dependent cognitive domains (verbal 
learning and memory), global cognition and quality of life that persist for at least 6 months post-TCT.  
While TCT is highly efficacious at the group level, individual gains from TCT vary considerably: up to 45% of SZ 
patients fail to benefit (d ≤ 0.2)72, even after an extended 100h course of TCT33. Multi-site findings are more 
promising, with significant gains in MATRICS Consensus Cognitive Battery (MCCB) composite and verbal 
learning scores after 20h of training51. While these gains no longer reached statistical significance after 40h of 
training due to subject attrition, the effect size (d≈0.39) remained non-trivial but modest. Still, given the high rate 
of TCT “non-response”, and the modest overall effect sizes, the costs and logistical impediments associated with 
getting severely ill SZ patients to complete three 1h sessions of TCT per week for 10-20 weeks can be prohibitive. 
Per RFA-MH-18-705, this application seeks to “pilot test” a practical means to augment, accelerate and/or 
prolong the benefits of TCT in SZ patients, in order to inform a future, fully-powered “Confirmatory Efficacy trial”.   
B. Innovation: In Pharmacologically Augmented Cognitive Therapies (“PACTs”) for SZ 24,89-90, as first proposed 
by the PI90, 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 neither 
the proposed use of pro-cognitive drugs, nor TCT, are independently innovative in the treatment of SZ, combining 
these treatments within a PACT design to augment the gains from TCT - as described in this application - is 
highly innovative and responds to the FOA’s goal to support “the development… of novel… interventions… as 
augmentations to a standard treatment.” This application must be limited to the use of one pharmacologic agent, 
and the PI has carefully selected this agent based on > 18 years of meticulous “foundational” parametric dose-
response and time-course studies in healthy subjects and SZ patients, that included several potential neuro- and 
psychophysiological biomarkers95-8,103-4,106. Nonetheless, it is anticipated that the PACT design tested in this 
application will be applied to many other medications, and the PI has studies in progress to establish parametric 
data for other classes of putative pro-cognitive agents. Thus, it is anticipated that findings from this application 
will advance an innovative treatment strategy that will have implications well beyond its focused scope.  
A major challenge to the PACT approach is the availability of drugs with evidence-based pro-cognitive effects in 
SZ patients; in fact, trials of potential pro-cognitive agents in SZ have largely yielded negative results eg. 4,19,35-
7,41. However, these “negative” studies generally share two important weaknesses. First, they were not conducted 
in the context of cognitive therapy, and drugs designed to enhance specific domains of cognition, e.g. attention, 
might not yield clinical benefits unless paired with interventions that access those components, i.e. utilize/place 
demands on enhanced attention. An analogy is seen in the effects of anabolic steroids, which produce minimal 
gains in muscle mass unless paired with an exercise that puts “demands” on that muscle. In many “negative” 
studies, the candidate pro-cognitive agent was simply added to a passive daily medication regimen, without any 
new cognitive “load”35-7. A "proof of concept" for the PACT approach of pairing a drug that has a target pro-
cognitive mechanism with a therapy that demands that mechanism is seen in the use of pro-extinction drugs to 
selectively enhance the therapeutic impact of exposure therapy for anxiety disorders22,84.  
A second weakness of most “negative” studies of pro-cognitive agents for SZ is that these trials suffer from the 
lack of biomarkers that identify sensitive “enriched” clinical subgroups of patients43,47,60. Given the range of 
neurocognitive and symptom profiles across chronic psychotic disorders, reflecting the heterogeneous 
Contact PD/PI: SWERDLOW, NEAL R 
Research Strategy
Page 56

neurobiology of these disorders, it is not surprising that a drug acting through one mechanism to enhance one 
neurocognitive domain 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 PACT 
application proposes to combine a drug that enhances attention with a TCT task that is attentionally demanding, 
and in which performance is associated with attentional capacity105. By pharmacologically enhancing attention, 
we have evidence98,104 (see below) that we can enhance TCT learning in an optimized laboratory setting; if this 
finding is confirmed in Aim 1, we will test the hypothesis that such enhanced learning translates into greater 
clinical gains from TCT (Aim 2). Second, PACT designs 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.  
This application uses an experimental therapeutics approach in an “efficient pilot test” of the hypothesis that 
the pro-attention psychostimulant, amphetamine (AMPH), will augment TCT-induced learning, and thereby 
clinical, neurocognitive and functional gains, in AP-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 (below), this 
application will confirm target engagement and identify predictive biomarkers that predict the effectiveness of 
AMPH-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-stratified 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. 
The proposed use of EEG and objective behavioral biomarkers will produce system-level mechanistic insights, 
e.g. regarding the relationship of early sensory processing, target engagement, auditory discrimination and 
attentional capacity 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 gains, as in108.   
“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. At a mechanistic level, PACT challenges 
existing clinical practice by proposing treatments that target spared, healthy circuitry in patients rather than 
pathological circuitry per se (which is widely distributed and highly variable among psychosis cohorts123). 
Ultimately, treatment choice will be guided by biomarkers that might include laboratory-based measures, perhaps 
including 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 AMPH will enhance the therapeutic benefits of TCT in biomarker-identified SZ patients.  
Approach: The choice of the dopamine (DA)- and norepinephrine (NE)-releaser, AMPH, for this PACT approach 
is based on: 1) extensive experience with AMPH in the treatment of attentional and other cognitive deficits: 
because pro-attentional effects are “known”, it will be easier to interpret “negative” findings; 2) robust evidence 
that AMPH enhances neurocognitive performance in AP-medicated SZ spectrum patients at doses that are safe, 
well tolerated6,38,54,79-80,87,117 and reduce negative symptoms57,73; 3) a rich cross-species literature of AMPH effects 
that can inform us about mechanisms of action; and 4) novel and compelling findings from the PI’s R01 
(MH59803) of AMPH effects in healthy subjects (HS) and SZ patients104 (below, Fig. 2). This choice is also 
informed by the PI’s MH59803 studies in HS with pergolide, bromocriptine, pramipexole, amantadine, memantine 
and tolcapone, in addition to AMPH14,91,97,100,102. Neither “selective” DA- nor NE-receptor agonists have 
comparable evidence-based pro-cognitive effects in SZ patients, and thus cannot yet be used to test the main 
hypothesis in this application. A systematic review and meta-analysis of 22 studies investigating psychostimulant 
effects in patients with SZ determined that methylphenidate but not AMPH worsened symptoms. Exposure to 
AMPH in this study and in the proposed PACT design is very limited: 5 mg, 3 times per week, for approximately 
10 weeks. However, implicit in this choice is the fact that future applications of PACT for SZ – even involving 
Contact PD/PI: SWERDLOW, NEAL R 
Research Strategy
Page 57

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Auditory system “learning” (APS pre- vs. post-training) 210 min post-pill was significantly enhanced by 10 mg 
AMPH (p<0.002), particularly in SZ patients (Fig. 2D); rs4680 status did not moderate AMPH effects on APS. 
Among patients, more APS learning was associated with AMPH-induced increases in attention (MCCB “A/V” 
domain: r=0.34, p<0.05) and shorter latency of the P3a ERP (r=-0.43, p<0.035). There were no significant 
“order effects”: AMPH enhanced APS learning whether it preceded or followed placebo testing. AMPH-enhanced 
learning was not state-dependent: it “carried forward” to the next testing day, 1 week later (Fig. 2E). There were 
no adverse effects of AMPH, consistent with our experience with higher doses of AMPH (20 mg po) in 
HS23,94,97,103,106. Subjectively, participants could not guess pill identity at greater than chance levels, while 
objective / blind measures of alertness, hedonia and autonomic function confirmed AMPH bioactivity.  
Based on these findings, we submitted an R61/R33 application (MH112742); the primary goal of the R61 was to 
both confirm “target engagement” (AMPH effects on APS learning) and optimize AMPH dose and post-AMPH 
time interval for an R33 “pilot” trial of an AMPH/TCT PACT design in SZ patients. The major critiques of this 
application were that the proposed R61 scope (parametric dose- and time-course optimization) was 1) 
“incremental” (not novel); and 2) not “significantly distinct from [the scope of] MH59803”. Seeing no other viable 
path forward, over the next 2 years we used carry-over funds from MH59803 and funds from a NARSAD 
Distinguished Investigator Award to complete the previously proposed R61 parametric studies (target n=36 SZ 
patients; current n=30), in addition to relevant “foundational” studies of TCT in SZ patients, described below. 
These studies (Fig. 3; reported in98) use a within-subject 4-week design to test dose-response effects of AMPH 
(0, 2.5, 5 or 10 mg po) on APS learning, given 60 (current n=12) or 210 min (n=18) prior to Sound Sweeps. 
AMPH significantly enhanced APS learning at both time-points, with an inverted-U dose-function reflecting 
maximal gains with 5 mg (d=0.85; Fig. 3A). APS learning gains with AMPH were greatest among patients in the 
lowest 50% of attention/vigilance (A/V) scores (the highest 50% scored in a “normal” A/V range), consistent with 
our findings that low baseline attention/ vigilance predicts greatest AMPH-enhanced attention23. AMPH-induced 
gains in auditory discrimination (assessed by the QuickSIN “Speech-in-Noise” measure) and sensorimotor gating 
(prepulse inhibition) in SZ patients parallel those in APS learning, both in terms of optimal dose (5 mg) and 
attention-dependence (greatest in patients with low MCCB “A/V” scores) (Fig. 3C,D). We have preliminary92 
evidence for similar findings with memantine, a drug pharmacologically distinct from AMPH, and collectively 
these findings are incorporated into our working mechanistic models for PACT effects on TCT (e.g. Fig. 1). 
 
 
 
 
 
 
   
    
   
    
    
 
\ 
Safety of AMPH in AP-medicated SZ patients: Over the course of studies in Figs. 2-3, we accumulated enough 
experience to publish findings on the safety of AMPH in antipsychotic-medicated SZ patients95. We assessed 
autonomic, subjective and clinical measures after acute (same day) and subacute exposure (across 4 weeks of 
repeated within-subject dosing), and were able to recontact and clinically assess 19 subjects with an average 
post-AMPH interval of 17 months. AMPH was associated with no detrimental subjective, autonomic or clinical 
changes. Symptoms assessed acutely, sub-acutely or long-term were either unchanged or reduced. Reductions 
in BPRS psychosis scores were noted across each test day; long-term, psychosis symptoms declined (SAPS: 
p<0.009) and function increased (Scale of Function: p<0.015). Anecdotally, 4 subjects participated in both single 
and multi-dose studies, resulting in a cumulative AMPH dose of 27.5 mg; in these subjects, long-term reductions 
in SANS and SAPS were d=1.11 and 0.93, respectively. Among the 19 recontacted subjects, antipsychotic dose 
(chlorpromazine equivalents) declined for 6 subjects by an average of 411 mg/d, increased in 2 subjects by an 
average of 146 mg/d, and was unchanged in 11 subjects. No subjects experienced any adverse effects of 
AMPH after 1 dose, 3 weekly doses over 4 weeks, or both, assessed daily, weekly or 17 months later. 
For perspective, the 5 mg dose proposed in this application is a conservative starting dose for children, ages 6 
and older, for the treatment of ADHD, who then titrate to substantially higher doses taken daily for years; this 
application proposes this 5 mg dose for adults who are taking medications (antipsychotics) known to block many 
adverse effects of amphetamine70,95,104, and these patients will have a total exposure of 30 pills over 10 weeks.    
Fig. 3. Preliminary studies: AMPH dose-effects98. A. Maximal APS learning with 5 mg AMPH (d=0.85); hatched bar 
shows 10 mg data from Fig. 2D. Similar effects of 5 mg were detected 60 and 210 min post-pill. B. AMPH gains in APS 
learning in patients with impaired-range A/V scores. C. QuickSIN detected deficits at 5 dB in low-attention patients (*) 
corrected by 5 mg AMPH (!). D. Similar inverted-U AMPH effects on prepulse inhibition (PPI) in low-attention patients.  
(mg po)
(mg po)
(mg po)
Page 59

Prelim. Studies: 2. TCT effects on neurophysiological, neurocognitive and functional measures in SZ patients  
In the past 3 years, the PI and Co-PI (Dr. Light) assessed biomarker predictors of TCT response in 46 severely 
ill SZ patients at a residential treatment facility. Findings from these studies are published45,48,77-8,107,109. In brief, 
patients were assessed in measures of neurocognition and early auditory information processing, and then 
randomly assigned to TCT (1-h, » 3 times/week, total » 30 sessions) or treatment as usual (TAU) groups. As 
seen in Fig. 4, compared to TAU, TCT patients exhibited significant gains in neurocognition (verbal learning, the 
most disabling neurocognitive deficit of SZ), reduced symptoms (auditory hallucinations) and enhanced function 
(engagement and participation in psychosocial groups and activities); compared to TAU, gains in function by 
TCT patients over 10-weeks translated to 1 full extra week of clinical rehabilitation45,107,109. Importantly, gains in 
neurocognition and symptoms correlated significantly with (i.e. were predicted by) 3 EEG-based measures 
(discussed below). As it relates to the feasibility of this application, these findings demonstrate that: 1) a trial of 
TCT is feasible in patients with chronic psychotic disorders; 2) TCT is well-tolerated, even among severely 
disabled, functionally impaired patients; 3) TCT produces quantifiable gains in clinical, neurocognitive and 
functional metrics; 4) adding high-density EEG testing to a TCT protocol is feasible and well-tolerated; and 5) 
changes in functional EEG biomarkers of auditory system target engagement predicted TCT-induced gains.  
 
 
 
 
                                
 
 
 
 
Target Engagement: APS learning is the target to be engaged in this application. Compared to healthy subjects, 
APS learning is impaired in SZ patients104. We hypothesize that this impaired learning is one factor that prevents 
SZ patients from benefiting fully from 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 hypothe-
size and will test in this application that AMPH-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 AMPH-enhanced gains in APS learning reflect processes that will generalize to 
AMPH-enhanced gains in the therapeutic impact of these other auditory sensory-based tasks. Other potential 
measures of target engagement, including “APS plateau”16 will also be explored as secondary outcomes. 
More generally, our findings have led us to develop working mechanistic models of PACT effects on TCT (e.g. 
Fig. 1). PACT works when a medication engages brain substrates regulating neurocognitive resources that are 
demanded by the form of learning being applied in cognitive therapy. With enhanced neurocognitive resources, 
greater learning is possible; in some cases this enhanced learning is associated with (and potentially mediated 
by) an identifiable intermediate neural mechanism. With greater learning, the learning-based therapy has an 
enhanced clinical impact. In the present application, AMPH enhances attention, most prominently among 
patients with the lowest basal attentional levels. Enhanced attention mediates greater auditory discrimination; 
this is evident both in gains in EEG metrics of early auditory information processing, and in enhanced speech 
discrimination in QuickSIN testing98 (Fig. 3C). Patients able to better discriminate sounds are able to more quickly 
discriminate and learn to correctly identify Sound Sweeps (and learn other TCT components), and the 
therapeutic impact of learning to detect tonal frequency modulation (e.g. a critical feature of prosody that allows 
an individual to better interpret the affective content of speech) is augmented. Based on this model, we 
acknowledge that – in addition to gains in APS learning - “target engagement” could be demonstrated either via 
gains in attention (e.g. MCCB scores in “A/V” domain) or 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. 
Fig. 4. TCT effects on symptoms (Scale of Positive Symptoms 
auditory hallucinations (p<.05) and voices conversing p<0.01), 
neurocognition (MCCB verbal learning, p<0.01) and function 
(p<0.005) in SZ patients over 10 weeks of TAU (n=22; blue 
lines) or TAU+TCT (n=24; orange lines) 45,107,109 . Findings 
confirm feasibility of quantifying significant gains from TCT in 
the same population to be used in this application. Larger 
effects were detected in biomarker-identified subgroups, but 
there is clearly “room” for AMPH-enhanced effects on these 
and other symptoms, neurocognitive domains and functional 
metrics, as proposed here, as well as the rate and durability of 
these changes (not assessed in our previous studies).  
Page 60

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Page 61

paradigm is that AMPH enhances attentional engagement with the auditory discrimination task. Anecdotally, test 
subjects (particularly patients) are challenged to maintain full attention throughout the hour-long Sound Sweeps 
task, and conceivably, a low dose of AMPH might help subjects stay “on task”. Nonetheless, both our empirical 
data and conceptual models leave us well short of a neural or molecular mechanistic explanation of AMPH’s 
actions in a PACT model, and it is not realistic 
to suggest that such mechanisms will be fully 
explicated 
via 
the 
present 
application. 
However, if utility of an AMPH PACT regimen is 
confirmed in this R33, we plan to develop these 
models within subsequent clinical trials (of 
AMPH and perhaps memantine), and in a 
separate 
application 
focused 
on 
basic 
mechanistic analyses of TCT learning.   
Critical next step: Our preliminary findings 
from MH59803 provide evidence of target engagement for this PACT model: compared to PBO, AMPH was 
associated with greater APS “learning” across 1-h of TCT. However, this evidence is inadequate to justify a 
Confirmatory Efficacy trial with PACT, since AMPH may enhance TCT-induced APS learning, but still not 
enhance TCT-induced clinical, neurocognitive or functional gains. Even with evidence of target engagement, 
and its replication and optimization in MH59803, it is only a hypothesis that enhanced learning during TCT will 
augment its clinical benefits. 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 from MH59803, to explore (i.e. “learn/confirm”) 
mature hypotheses related to mechanisms (e.g. Fig. 1) and predictors of pro-cognitive therapeutics for SZ.  
Six potential limitations: It is important to acknowledge and address the potential limits of this application. 
Limitation #1? It might not work: Some evidence suggests that drug-enhanced APS learning, symptom reduction 
and neurocognitive gains from TCT may be dissociable phenomena, i.e. AMPH might enhance APS learning but 
have no impact on PACT-induced neurocognitive gains. Cain et al.20 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.24 study in several specific ways, including: 
1) this application uses a detailed conceptual framework for PACT design and implementation; 2) it benefits from 
dose/time optimization studies (Fig. 3) to maximize drug effects on APS learning; 3) AMPH is a pro-attention DA 
releaser, while DCS is a pro-extinction NMDA agonist. Clearly, better attention (after AMPH) might augment the 
neurocognitive effects of TCT, while better extinction (after DCS) might not; 4) the present study uses a suite of 
hypothesis-driven biomarkers to identify potentially sensitive patient subgroups; and 5. The present patient 
cohort might have more “room to move” in outcome metrics. Nonetheless, it is clear that AMPH-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 understanding, we will carefully track and dissect these distinct outcome 
measures over the course of the R33 (Fig. 7), as we have in our published studies45,48,77-8,107,109 .  
One possible basis for a lack of PACT response might be that, over a 30-session trial, enhanced learning with 
AMPH may be state-dependent (to some degree). Evidence from our preliminary study suggests that AMPH-
enhanced APS learning was not “state-dependent”: APS gains from training done under AMPH conditions 
“carried over” to the pre-assessment phase of a subsequent test, 7d later (Fig. 1F). However, this finding does 
not guarantee that clinical, neurocognitive or functional gains from an AMPH PACT regimen would not exhibit 
some state-dependency, i.e. be less robust when patients are assessed in the absence of AMPH. In practical 
terms, it matters less whether there is some degree of state-dependent learning in this process, as long as 
“enough” learning and the associated clinical changes do generalize to a non-AMPH state. Outcome measures 
after sessions 10, 20 and 30, and 12 weeks later (Fig. 7), will be acquired in the absence of AMPH.    
Limitation #2? Even if AMPH is safe in SZ patients after 1-3 doses, is it safe if used 30 times over 10 weeks in 
this R33? Even with the stress of neurochemical imaging, and/or a bolus i.v. infusion1,2,27,56,65,113, in AP-
unmedicated SZ patients, high doses of AMPH have mixed and transient clinical effects, often improving 
symptoms and neurocognition. A recent meta-analysis documents the safety of AMPH in antipsychotic-
medicated SZ patients88, and studies (Fig. 2-3) confirmed that AMPH is well-tolerated and enhances learning in 
such patients. However, our 2 studies involved only 1-3 doses of AMPH, while in this R33 PACT paradigm, 
AMPH will be taken 30 times over »10 weeks, each pill paired with a session of TCT. Thus, it would be reassuring 
Fig. 6. Simplified schematic of a 
system-level mechanistic model 
informed 
by 
this 
application. 
Cognitive constructs and circuits 
map 
onto 
an 
RDoC 
matrix. 
Biomarkers/ outcome measures 
probe different system levels; some 
circuit-level information will come 
from pre- vs. post-TCT changes in 
EEG source dynamics. “+” = con-
vergent gains from TCT and AMPH. 
Page 62

to find evidence that comparable dosing with AMPH, followed by its discontinuation, is safe in AP-medicated SZ 
patients. The recent meta-analysis73 cites many such studies; one recent example is described here: 
Lasser et al.57 reported the safety of daily lisdexamfetamine (ld-AMPH), an AMPH pro-drug (Vyvanse 20-70 
mg/day; equivalent AMPH dose = 5.9–20.8 mg/d), in 92 antipsychotic-medicated SZ outpatients, in a 10-week 
trial, followed by abrupt discontinuation and a 4-week follow-up. Daily ld-AMPH for 10 weeks significantly 
reduced negative symptoms but did not increase adverse events; abrupt discontinuation of ld-AMPH did not lead 
to an increase in adverse events. These data support the safety of 10 weeks of daily AMPH use, in doses that 
far exceed those proposed herein, followed by abrupt drug discontinuation. Total AMPH exposure in that study 
greatly exceeded the amount proposed in this application (e.g. 70 consecutive days of 5.9–20.8 mg/d vs. 30 
days over »10 weeks of 5 mg/d). Still, patients in this application are carefully monitored as described below, 
and assessed by a licensed clinician 3 times each week, and tested on a range of clinical scales including RFA-
mandated suicidality scales, throughout the full course of the study. 
Importantly, while daily AMPH in the Lasser et al.57 study reduced negative symptoms in SZ patients, we do not 
predict that the more limited TCT-paired use of AMPH in the present study will reproduce these effects. In fact, 
we predict that AMPH will primarily exert its therapeutic effects by augmenting the impact of TCT, which should 
result in reduced negative and positive symptoms, as well as neurocognitive and functional gains (see Fig. 4).   
Limitation #3? This application will not pinpoint molecular or neural circuit-level mechanisms of AMPH, TCT or 
PACT effects, in a biologically heterogeneous group of medicated psychotic patients. This is true. Nominally, 
circuit-based models may help frame the PACT construct within the RDoC matrix. In the simplest model, 
neurocognitive deficits in SZ patients caused or exacerbated by low PFC DA tone will be “rescued” by AMPH-
induced PFC DA release; potential adverse effects of AMPH-induced subcortical DA release will be blunted by 
antipsychotics via D2 blockade, with relatively weaker blockade of PFC D1 receptors26,44. In this model, AMPH 
might be most beneficial to patients whose forebrain DA systems, including PFC and subcortical regions working 
in concert, are most sensitive to pro-neuroplastic effects of AMPH. We reported circumstantial support for this 
model, based on levels of positive symptoms, positive hedonic effects of AMPH, AMPH-enhanced PPI and 
attention, AMPH-enhanced APS learning and antipsychotic dosing in SZ subjects, as well as related animal 
models93.  However, the hypothesized ability of AMPH to enhance TCT performance in SZ patients is first and 
foremost based on empirical evidence (e.g. Figs. 2-3), independent of unproven circuit- or pathophysiological 
models involving DA, NE or other brain substrates. The explicit primary goal of this application is to provide the 
first-ever test of a novel, evidence-based therapeutic model, starting with confirmation of target engagement, but 
not to investigate the pathophysiology of SZ; system-level mechanisms will be modeled (e.g. Fig. 6). 
Limitation #4? This PACT is stacked: This R33 design is optimized: a) patients are carefully characterized as 
part of a clinical trial; b) AMPH dose and timing are optimized based on MH59803; c) potential logistical hurdles 
that might cause subject attrition (transportation, food, reimbursement) are minimized; and d) biomarker assess-
ment 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, different PACT 
delivery models are being studied by the PI and Co-PI, and we 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.” 
Limitation #5? Control groups? Adding control “computer game” groups might reveal if PACT benefits reflect 3x/ 
week AMPH use independent of TCT, computer use independent of TCT, and/or interactions of AMPH+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 AMPH 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 AMPH under conditions that are unlikely to have lasting 
clinical value, is not ethically justified. Fisher et al.33 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.   
Limitation #6? Ceiling effects? TCT effects on neurocognitive and clinical metrics might be “at ceiling”, and thus 
insensitive to further gains from AMPH. 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)139a. 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 or SAPS). Thus, despite robust gains in 
some areas after TCT, there is clearly “room to move”93 for added PACT-induced gains. Furthermore, while 
Contact PD/PI: SWERDLOW, NEAL R 
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Page 63

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 AMPH 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.   
Will “negative results… 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 AMPH 
group effects on APS learning. Based on the data (e.g. evidence of AMPH bioactivity), we will develop testable 
hypotheses (e.g. cohort differences) that might account for differential outcomes in the present application vs. 
studies in MH59803. Even if there are not robust AMPH effects on APS learning (target engagement), it is 
possible that heterogeneity in AMPH APS sensitivity might reflect meaningful subgroups of patients (e.g. low vs. 
high attention/vigilance), and that APS AMPH sensitivity might still predict (correlate with) AMPH enhancement 
of TCT therapeutic effects. In other words, a lack of a group difference (placebo vs. AMPH) would not preclude 
the utility of AMPH APS sensitivity as a predictive biomarker. Conversely, even if target engagement is 
confirmed, it is possible that group differences (placebo vs. AMPH) in therapeutic gains might not be detected. 
A “valid” negative outcome (e.g. lack of positive AMPH effects on outcome measures despite evidence of target 
engagement and adequate TCT exposure) will indicate that AMPH-enhanced APS learning is not sufficient to 
enhance TCT effects in a clinically-defined SZ cohort. Analyses will then determine if AMPH 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. Factors 
contributing to this dissociation might include (among other possibilities): 1. Tolerance to the “pro-learning” 
properties of AMPH (unexpected, since AMPH retains pro-attentional effects, even after years of daily use); 2. 
State-dependent learning (discussed above); 3. Adverse effects of AMPH on psychosis, akathisia or other 
symptoms; such effects will be assessed via clinical metrics (below). Analyses of these and other factors that 
might impede AMPH-induced gains will guide further development of both TCT and PACT interventions.  
Feasibility: Our research team includes a Board Certified Psychiatrist (NS) 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 biomarkers to clinical 
function in SZ (MT), a UCSD SZ Research Program with a >25 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-up61), as well as double-blind, PBO-controlled trials of putative pro-cognitive agents (including 
AMPH) in SZ patients and HS13,23,91,104. We have completed and published extensively on a 30-session clinical 
trial of TCT in the same general population and with many of the same biomarkers proposed herein.  
In summary, this application will confirm target engagement by demonstrating that AMPH (5 mg po, 60 min prior 
to TCT) enhances APS learning in a Sound Sweeps session in biomarker-characterized AP-medicated SZ 
patients; these patients will then be randomized to a 30-session RCT of TCT+AMPH (n=27) vs. TCT+PBO 
(n=27). Findings will determine whether AMPH augments the known neurocognitive and clinical benefits of TCT, 
and whether APS “AMPH sensitivity” - based on APS gains in 2 test sessions - predicts the therapeutic impact 
of AMPH over a 30-session TCT regimen. Other predictive biomarkers will be explored, including baseline 
neurocognitive (MCCB A/V scores), ERP (P3a, MMN) / EEG (ASSR, theta band power) measures, and AMPH 
effects on auditory discrimination and on ERP changes across the first Sound Sweeps sessions. 
General Methods: Environment: Subjects are screened, tested and undergo TCT at the UCSD Medical Center. 
Recruitment will enroll » 23 patients/year. Participants are 18-55 y.o. AP-medicated (stable regimen >1 month, 
in active outpatient treatment) patients with a primary diagnosis of SZ or schizoaffective disorder (depressed 
type), recruited and consented at UCSD as per 91,101,104. Study inclusion/exclusion criteria are detailed in 
“Protection of Human Subjects”; all subjects with stimulant abuse or dependence histories are excluded. 
Screening includes a confirmatory diagnostic assessment (M.I.N.I. 6.0), a general medical, psychiatric and 
substance history, physical exam by an M.D., EKG, vision and hearing tests, urine toxicology and pregnancy 
test (UTox/P).  All medications and changes are recorded (AP doses in chlorpromazine equivalents; quantifying 
anticholinergic burden116 as in13,48,91). Medication patterns of our last » 100 SZ subjects are found in91,95,104.  
Design (Fig. 7). Test 1: Enrolled patients complete post-PBO clinical, neurocognitive and functional measures 
and candidate biomarkers (EEG, QuickSIN, WIN); they are tested in Sound Sweeps, and then assigned to PBO 
vs. AMPH arms (n=27/arm) using stratified random sampling (over sex, age and high/low Test 1 (baseline) APS 
learning) blind to arm identity, similar to107. Stratifying for baseline APS learning should increase the sensitivity 
of the primary target engagement metric. Test 2 follows » 5-7 days later, after either PBO or AMPH (5 mg po). 
Tests 1-2 are used to assess target engagement (Aim 1: AMPH-enhanced APS learning) and AMPH effects on 
ERP/EEG, auditory discrimination (QuickSIN, WIN) and neurocognitive measures (Aim 3: Biomarkers). Our 
design allows for 20% attrition from enrollment (n=69) to completion of target engagement testing (n=54).    
Contact PD/PI: SWERDLOW, NEAL R 
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For Aim 2, TCT 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 (» 10-12 weeks). TCT is delivered by trained staff (see 
below). 60 min prior to each TCT session, patients take either PBO or 5 mg AMPH, as per arm assignment. 
Patients and staff are blind to study arm; staff are blind to patients’ baseline or post-intervention assessments.  
 
 
 
 
                        
 
 
 
Assessments:  30 sessions of TCT will be completed, based on our findings (Fig. 4) and evidence that TCT 
efficacy is dose-dependent16,32,114. Assessment dates could be based on either: 1. session # (10, 20 and 30 and 
12 weeks later); or 2. Time (days) since starting TCT. In our experience45,107,109 TCT rates closely match 3/week 
(30 sessions mean = 65 days; 90% of subjects completed their 30 TCT sessions within 11 weeks. Primary 
analyses will be based on session #, but session dates are recorded and confirmatory analyses will define 
assessment points based on time passage. Candidate predictive biomarkers are re-tested after session 30.  
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 PBO-arm 
subject tests positive for amphetamine; any clinical worsening or UTox positive for recreational drugs (other than 
AMPH in AMPH-arm subjects) or a positive pregnancy test is promptly reviewed with the on-site Psychiatrist; 
any “yes” on the Columbia Suicide Severity Rating Scale81 (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 models.    
Outcome and “Go Decisions”. In addition to 
confirming “target engagement”, this application 
tests the hypothesis that SZ patients given AMPH 
+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 AMPH-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 (Fig. 8) – 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, AMPH>PBO, p<0.05); 2) evidence 
of gains from PACT (d > 0.5 (AMPH > PBO)) in primary clinical, neurocognitive and/or functional measures (Fig. 
8), and 3) the absence of adverse effects of AMPH 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.25,63-4 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 
Fig. 7. Study Phases: Baseline & 
Randomization includes 2 Sound 
Sweeps tests: Test 1 with PBO and 
» 5-7 days later Test 2 with either 
AMPH or PBO. Treatment Phase 
includes 30 TCT sessions with 
outcome measures after 10, 20 
and 30 sessions. Post-treatment 
tests 
assess 
both 
immediate 
biomarker changes and 12-week 
durability of outcome gains.   
Fig. 8. “Go” criteria: #1, plus at least one of #’s 2, 3 & 4 (d>0.5) 
1. Target engagement: APS learning, AMPH > PBO, p<0.05  
2. Greater clinical, neurocognitive or functional gains: 
 - ¯PANSSt, ­MCCB-C or ­Fnxn:  AMPH+TCT > PBO+TCT 
3. Faster clinical, neurocognitive or functional gains: 
 - drug group x session interaction (p<0.05) followed by    
 AMPH+TCT > PBO+TCT at specific session # or combination; 
4. More durable clinical, neurocognitive or functional gains: 
 - AMPH+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) 
Page 65

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 total14), 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), all subjects receive a PBO pill and 
complete 1-h of Sound Sweeps to generate a “PBO APS score” as described previously (Fig. 2A,B). Treatment 
group assignment (PBO vs. AMPH) is then made using stratified random sampling (above), and 5-7 days later 
patients ingest either PBO (n=27) or 5 mg AMPH (n=27) 60 min before completing the Sound Sweeps session 
(“Test 2”). AMPH effects on APS learning are assessed both within-subject (APS (Test 1 - Test 2) for AMPH 
group subjects: a key measure of AMPH sensitivity) and between subjects (APS Test 2, PBO vs. AMPH 
groups).  For all other sessions, subjects receive either PBO or AMPH 60 min before TCT, 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) 
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 (Fig. 4B) to track clinical status, and TCT response. TCT reduces both positive and 
negative symptoms of psychosis, and we predict that AMPH will augment these effects via enhanced TCT 
learning (i.e. not via a lasting direct pharmacological effect of AMPH), 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 ideation81; any “yes” in C-SSRS prompts an immediate 
full evaluation/action plan by a study M.D.; and 7) AMPH Cessation Symptom Assessment (ACSA). 
Neurocognition: Change in MCCB Composite performance from baseline is one outcome measure. The MCCB 
measures 7 cognitive domains: SP, A/V, WM (verbal and nonverbal), verbal learning, visual learning, reasoning/ 
problem solving and social cognition. Details are found in50,52,74; past studies by the PI of drug effects on MCCB 
performance include13,23. 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 robust31, and should be augmented by AMPH. Baseline and AMPH-enhanced (Test 2 vs. 1) MCCB 
performance (A/V subscale) will also be tested as potential biomarkers/moderators of AMPH PACT efficacy. 
Function is assessed via the World Health Organization Disability Schedule 2.0 (WHODAS)112 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 recommended by the DSM-5 Task Force committee to replace the global 
assessment of functioning scale55. 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. AMPH-enhanced APS 
learning is both an outcome measure (Aim 1, “target engagement”) and candidate predictor of clinical outcome 
(Aim 2); 2. Baseline and AMPH-enhanced MCCB A/V scores are associated with APS AMPH sensitivity96,98, and 
thus may predict clinical outcome (Aim 2); 3. ERP measures of early auditory information processing variably 
predict response to early APS learning60 , AMPH-enhanced APS learning104, and TCT outcomes45.   EEG/ERPs 
are acquired via 64-channel recording systems and assessed in the same order, as per53,91: 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 
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Page 66

conversation in a noisy environment, and are thought to index peripheral (WIN) vs. more central (QuickSIN) 
auditory processing. AMPH-enhanced auditory discrimination (Test 2 vs. 1) may predict PACT outcome (Aim 2); 
gains in auditory discrimination over 30 hours of TCT, and their augmentation by AMPH, will be tracked to inform 
evolving models of PACT mechanisms (e.g. Figs. 1 & 6). Predictions: First and foremost, target engagement 
(AMPH-enhanced APS learning) will predict AMPH-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 AMPH-enhanced TCT outcome (Aim 2). 
AMPH-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 characterization77. Robust biomarker predictors will be examined as moderators of 
both indirect and direct paths between treatment and outcome in a future Confirmatory Efficacy trial.  
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 
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 AMPH arms, and 
any baseline differences are addressed in the outcome analyses. Differential drop-out rates from PBO vs. AMPH 
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 covariates48,107,116. Sex differences 
are tested for all measures based on known sex differences in AMPH sensitivity10,71. 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 AMPH-enhanced 
APS learning. APS learning is defined as the reduction in Sound Sweeps APS threshold (ms) pre- to post-
assessment. Target engagement was demonstrated in MH5980398,104, and will be confirmed if APS learning is 
increased by AMPH either in a within-subject comparison (AMPH group, “Test 2 vs. 1”), or in a between-subject 
comparison (AMPH group vs. placebo group change “Test 2” vs. “Test 1”) (note that AMPH and PBO groups are 
matched by Test 1 PBO performance via stratified randomized assignment). Effect sizes and inferential statistics 
are based on LME models with random intercepts. A statistically significant main effect of drug (PBO vs. AMPH) 
on APS learning in either within- or between-subject contrasts is a “Go” criteria and confirms target engagement.  
Aim 2 – Test clinical, neurocognitive and functional impact of AMPH on TCT, and its relationship to target 
engagement: We will determine if AMPH+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. AMPH) or drug x session (#10, 20, 30) interaction in an LME model is the 
primary “Go” criteria. The main 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 regression analyses will examine whether change in AMPH-enhanced APS 
learning (“within-subject” target engagement; Aim 1) predicts gains in Aim 2 outcome measures. 
Aim 3 – Biomarkers of AMPH-induced gains: We will determine if baseline levels of specific neurocognitive or 
EEG-based measures, or changes in specific measures with initial AMPH exposure (Test 2 vs. 1), predict greater 
sensitivity to AMPH-enhanced neurocognitive, clinical or functional gains over 30-h of TCT. Regression analyses 
will assess whether specific candidate biomarkers predict AMPH-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 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 amphetamine 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 AMPH sensitivity and biomarkers on both indirect (moderated-
mediation) and direct paths between treatment and outcome.  
Contact PD/PI: SWERDLOW, NEAL R 
Research Strategy
Page 67

Inclusion of Women, Minorities and Children 
 
Inclusion of women: Women will be included in this study. There are sex differences in the DA-releasing 
effects of AMPH10,71, that might impact the effects of AMPH on a number of behavioral measures that are 
relevant to this application. Thus, while no sexual dimorphism has been reported in the therapeutic effects of 
TCT, and none were noted in our study of AMPH effects on APS learning, we will strive to include enough men 
and women in the study to conduct meaningful analyses of sex effects on both AMPH sensitivity and biomarker 
predictors of AMPH effects on APS learning. To control for potential effects of menstrual cyclicity on 
biomarkers or drug sensitivity, Aim 1 drug testing will begin within days 1 - 7 of menses onset (our standard 
protocol for over a decade e.g. 106). There is a strong rationale for assessing the predicted drug effects in both 
men and women, because these findings will have implications in terms of the potential clinical applications of 
this PACT design.  
 
Several steps will be taken to avoid exposure of any fetus to amphetamine. First, females who are pregnant, 
nursing, imminently planning pregnancy or have a positive urine pregnancy test on screen day or any test day 
will be excluded from this study. Second, female subjects of childbearing potential (defined here as any female 
who has not had a total hysterectomy and/or bilateral oophorectomy, or who has had a menstrual cycle within 
the past year) will have urine pregnancy tests weekly through the 10th week of TCT ("Surecheck Early 
Pregnancy Test"). Second, in all subjects of childbearing potential, Aim 1 testing will begin within days 1 - 7 of 
menses onset. Third, to participate in this study, females of childbearing potential must agree to use a double-
barrier method of contraception when participating in sexual intercourse (regardless of other methods of 
contraception). If a female of childbearing potential becomes pregnant during the study, the subject will be 
exited from the study. The investigator will determine whether the subject was exposed to active study drug or 
placebo, and notify the subject of this information.  
 
Inclusion of minorities: Ethnic representation is based on recruitment response, with every effort made to 
include minority groups. Exclusion criteria are not based on ethnicity. Minority participation should thus reflect 
the ethnic make-up of the San Diego community. Based on our experience, the following ethnic percentages 
are expected in the study sample, based on the past 4 years of subject recruitment: White, not of Hispanic 
origin = 54%; Hispanic = 9.5%; Black, not of Hispanic origin = 3.2%; Asian = 32%; American Indian or Alaskan 
native = 0%. The source of recruitment information is recorded for each subject (e.g. website, fliers, newspaper 
advertisements, etc.), providing us with ethnic “success rates” for particular means of recruitment. Ethnic 
representation is then reviewed with annual progress reports. Recruitment efforts are adjusted, based on 
“success rates” of specific recruitment means, to respond to any significant deviation from the projected ethnic 
recruitment rates. The UCSD Medical Center is an equal opportunity employer; pursuant to state legislation, 
the University of California no longer applies affirmative action criteria in the student application process. 
 
Inclusion of Children: Children younger than 18 are not included because of the diagnostic complexities and 
clinical heterogeneity introduced by studying psychosis in that population, as well as the ethical considerations 
involved in the administration of psychoactive drugs to children. The primary therapeutic intervention (TCT) has 
not been thoroughly studied in psychosis spectrum patients younger than 18 years of age; one small report 
was “negative” but likely under-powered; one larger report detected positive effects. Because the key question 
in the present R33 application will be confounded by a lack of therapeutic response to the TCT intervention, it 
was felt that inclusion of this younger cohort should await more definitive evidence for such an effect. In 
addition, several key “biomarker” measures are either highly variable and not fully developed or not established 
in younger children. 
 
Contact PD/PI: SWERDLOW, NEAL R 
Inclusion of Women, Minorities, and Children
Page 72

Recruitment and Retention Plan 
We anticipate that over the course of this study we will consent 69 SZ individuals for screening, from whom we 
will advance 54 individuals to in-laboratory baseline testing and randomization into two arms with n=27 per 
arm. After study attrition, we conservatively expect that 36 individuals will complete 30 hours of TCT and 
longitudinal (12 week post-TCT) testing, and that attrition will be roughly balanced to arrive completed samples 
of n=18 per study arm.   
                                                     
 
 
 
 
Example of CONSORT Diagram of proposed R33 study 
 
 
 
* Conservative estimate of final n=18/arm for Aim 2 analyses 
 
To meet these recruitment and retention needs, men and women with a SZ disorder are recruited from the San 
Diego community using our long-established network and recruiting procedures, as per13,58,61,91,101,104. Our full-
time patient recruiters have established longstanding relationships with club houses and board-and-care 
facilities in San Diego County that serve this patient population. Our laboratory participates in events at these 
facilities (e.g. MHA Visions Clubhouse in Chula Vista recently hosted a “What Wellness Looks Like” Mental 
Health Awareness and Creative Arts show to celebrate Mental Health Awareness Month), as well as 
recruitment events (e.g. “NAMI Walks”) hosted by NAMI-San Diego. The PI is a former member of the NAMI-
SD Board of Directors and Chair of their Medical Advisory Board, and has maintained strong relationships with 
this organization that facilitate recruitment. Study advertisements are placed in local newspapers, and on 
relevant websites, including the PI’s website dedicated to this study. The URL for this site 
(http://www.psychiatry. ucsd.edu/research/Pages/psychiatryresearch.aspx) can be accessed through links 
entitled “Psychiatry Research” on our Department’s website (http://www.psychiatry.ucsd.edu/research/ 
Pages/default.aspx) and on the UCSD CTRI website for “Studies Recruiting Volunteers” (http://ctri.ucsd.edu/ 
community/Pages/studies-recruiting-volunteers.aspx). Our studies are also listed on ResearchMatch, and 
Clinicaltrials.gov. The lead Co-Investigator, Dr. Light, has ongoing funded collaborations with local residential 
treatment facilities, as described in this application, and patients who do not participate in TCT studies at these 
facilities are eligible for participation in this application. Other recruitment sources include the UCSD Medical 
Center Outpatient and Inpatient Psychiatric Services (both of which are staffed by Psychiatry Residents in the 
UCSD Psychiatry Research Residency Training Program, for which the PI serves as Director), as well as 
outlying community clinics staffed by UCSD Residents. 
Assess for 
Eligibility (n=69)
Randomize
(n=54)
Allocate to 
PBO+TCT (n=27)
Allocate to 
AMPH+TCT (n=27)
# lost to 
follow-up or 
discontinued
# lost to 
follow-up or 
discontinued
Analyze Aim 1
(n=27)
Analyze Aim 2
(n=18)*
# excluded:
Ineligible,
decline
Enrollment
Allocation
Analysis
Follow-up
Analyze Aim 1
(n=27)
Analyze Aim 2
(n=18)*
Page 73

Study enrollment is reviewed at weekly diagnostic consensus meetings, and is documented in quarterly 
milestone reports. There are expected seasonal differences in recruitment patterns, based on University 
Holidays (e.g. Winter Holidays, during which time no TCT training takes place), and Resident caseload 
transfers (July, when a “bolus” of referrals can be expected). Nonetheless, any deviation from expected 
recruitment targets is identified, analyzed and addressed. Primary responsibility to track and retain participants 
is delegated to Ms. Joyce Sprock. 
Study retention is enhanced by: 1) transportation provided to and from each laboratory visit; 2) careful attention 
to participant needs including schedule flexibility; 3) a comfortable laboratory environment, including availability 
of healthy meals and snacks; 4) reminder phone calls for all post-TCT visits; 5) careful follow-up protocol for all 
missed visits; 6) subject payment. 
Recruitment of subjects and informed consent procedures will follow Dr. Swerdlow's established methods. For 
all subjects we will have a consent form describing all laboratory measures and any potential side effects they 
may expect from AMPH. Specifically, all subjects will be asked to read a description of AMPH, 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 in SZ patients; and 4) an assessment of the likelihood that they 
will experience significant side effects from this drug, in the dose to be used in this study.  In all cases, fully 
informed consent will be obtained and a study M.D. 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 application 
is under review; in our past protocols for AMPH studies in this population, we have had 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.  
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 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.   
Payment is $15/hr. This equates roughly to $45 for completion of the screening visit, $45 per visit for each of 
the 30 TCT sessions, except sessions 10, 20 and 30 ($75), $60 for post-week 30 biomarker testing and $45 for 
week 22 testing. For the full R33 screening, testing, training and follow-up, subjects are paid a total of $1590. 
This payment is required to: 1) maintain subject flow and thereby avoid cost-ineffective “down time”; 2) attract 
subjects from non-indigent populations, and thereby avoid high rejection rates due to health and drug exclusion 
criteria and subject. 
 
Contact PD/PI: SWERDLOW, NEAL R 
Recruitment and Retention Plan
Page 74

Protection of Human Subjects 
The subject population for the present application will include approximately 69 individuals diagnosed with 
Schizophrenia or Schizoaffective Disorder, Depressed Type (collectively referred to as “SZ” patients) (ages 18-
55). These numbers represent the estimated samples that will be screened in order to yield a final sample size 
of 54 SZ patients who will complete Aim 1, of whom 36 will also complete Aim 2. Subjects are recruited from 
the San Diego community, and their ethnic/ racial characteristics are described elsewhere. 
Specific inclusion and exclusion criteria are as follows:  
Inclusion criteria: 18-55 y.o. AP-medicated (stable regimen > 1 month; current active outpatient treatment) 
outpatients with a primary diagnosis of SZ or schizoaffective disorder (depressed type) for >2 years, clinically 
stable (non-acute phase >12 weeks; not hospitalized in >2 months; all “no” responses on C-SSRS items 1-5 (1 
month) and behaviors (3 months), never treated with TCT.  
Exclusion criteria: premorbid IQ <70, substance abuse (past month; positive UTox), history of stimulant 
dependence, pregnant or nursing (women of childbearing potential consent to double-barrier contraception), 
history of significant medical/ neurologic illness (e.g. cancer, diabetes, CVA, heart disease, HIV, tuberculosis), 
history of seizure, open head injury or closed head injury with loss of consciousness > 10 min, R-hand injury), 
vital signs (VS): SBP<90 or >160; DBP<45 or >95; HR<55 or >95, hearing deficit (>40 dB @ 1000 Hz), 
corrected visual acuity < 20/4012, color blindness; inability to provide informed consent or to complete visits 
needed for this application; past or current treatment with TCT; current medications include psychostimulants, 
monoamine oxidase inhibitors, or dopamine agonists (including bromocriptine and amantadine).  
Patients are typically first screened by a trained laboratory assistant, who will exclude them based on the 
above criteria. Importantly, all SZ participants must be taking an antipsychotic medication on an ongoing basis 
(including depot preparations), with a stable dose for at least 1 month prior to study participation, and must be 
maintained on that medication throughout the study. Dose adjustments by the treating physician will be 
recorded. SZ patients cannot be taking a concomitant dopamine agonist medication (e.g. amantadine or 
bromocriptine). For appropriate subjects, the study is described again, and subjects sign consents for 
participation.  
This age range was selected to avoid ethical and interpretative concerns associated with drug effects on 
symptoms and biomarkers in children and adolescents, as well as diagnostic uncertainties in younger 
individuals exhibiting psychotic symptoms. There will be a roughly equal representation of males and females; 
sample size is based on power analyses described in this application. The difference between the size of the 
anticipated screened population and anticipated final sample size (n=69 vs. n=36 SZ patients) reflects 
predicted rates of subject screen failure and attrition.  
Records and data will be rigorously protected, as described below. Historical and questionnaire data, 
biomarker and related measures will be obtained; urine will be obtained for toxicological analysis as part of the 
subject exclusion process and with each study visit to reduce risk of interactions with the study drug and of 
uncontrolled effects on TCT performance and outcome measures.  
Subject recruitment and informed consent procedures follow the PI’s established methods, approved by the 
UCSD Human Subjects IRB. In all cases, fully informed consent is obtained by a trained technician or the PI, 
and the PI will be directly available to clarify questions. Signed and witnessed consents are kept on file with 
other subject data. The UCSD IRB has authorized no waivers or modifications of normal procedures.  
Study governance follows our successful model: the PI provides study oversight, runs weekly diagnostic 
consensus / clinical monitoring meetings, oversees IRB and DSMB interactions, insures recruitment / testing 
milestones, among other roles; Co-I’s oversee all biomarker testing, data fidelity and analyses (GL, MT), 
participate in clinical consensus meetings (GL). Our DSMB, through the UCSD CTRI, ensures patient safety 
and data validity and integrity (see Letter). 
Potential risks are minimal. The rating scales and questionnaires are innocuous. ERP testing exposes subjects 
to the application of scalp electrodes and to brief sounds, which in >25 years of testing have caused no side-
effects. Alternative measures have been considered; the selection of these specific ERP measures reflects the 
significant advantages of applying towards these studies the substantial body of information generated by > 25 
years of systematic studies of ERPs in healthy and clinical populations. All other measures require only 
computer keyboard or paper-pencil use and involve no risk.  
The AMPH dose (5 mg po) is low in terms of clinical use (“starting dose for a 6 year-old with ADHD”), and 
based on our substantial experience with higher doses in healthy (20 mg) and SZ populations (10 mg) (see 
citations in "Research Strategy"), including studies with multiple doses administered over 4 weeks, adverse 
reactions are not likely (never seen in our experience with over 120 HS given 20 mg p.o., or in > 70 SZ 
patients tested thus far with 10 mg AMPH). Furthermore, higher daily doses of AMPH in SZ patients 
Contact PD/PI: SWERDLOW, NEAL R 
Protection of Human Subjects
Page 79

administered over a 10-week clinical trial followed by rapid discontinuation yielded adverse event rates 
comparable to those of placebo57. No consistent subjective effects have been associated with the 5 mg dose of 
AMPH in our studies, nor has 5 mg produced any statistically significant autonomic changes. Alternative drugs 
have been considered, and the proposed drug was selected, based on a rationale clearly described in 
“Research Strategy”.  
The use of AMPH as a daily augmentation medication for SZ patients has been reviewed in systematic meta-
analyses, revealing no adverse effects (but some benefits) with AMPH; by contrast, methylphenidate was 
associated with adverse effects.88 The use of AMPH to study neurocognition and brain imaging in 
antipsychotic-medicated and unmedicated SZ patients has been described in numerous published reports, 
cited in this application1,2,27,56,65. A 1982 review145 of the use of high doses of AMPH in about 300 unmedicated 
SZ patients – mostly via an i.v. route – produced mixed changes, with most patients having no symptomatic 
changes, and with more patients showing improvement than worsening of symptoms. More recent case 
seriese.g. 21 identify predominant symptomatic improvement in AP-medicated SZ patients prescribed high daily 
doses of AMPH (40-80 mg po) for periods of years. In controlled trials, adverse effects after an oral dose of 10 
mg AMPH, or even with 10 weeks of higher daily doses in antipsychotic-medicated SZ patients57 are extremely 
rare. Our recent review of our laboratory’s experience supports the safety of AMPH in the same population to 
be recruited for the present application95. For perspective, the present study proposes to use 5 mg AMPH, 
about 3 times per week, for about 10 weeks. Nonetheless, clinical state will be carefully monitored in all test 
subjects via symptom ratings scales described in the application. All testing will be monitored by a licensed 
physician, who will remain on site for the entire test day, until subject discharge; R33 patients will be evaluated 
by a trained Research Associate during 3x/week visits for TCT, with a specific focus on suicidality and 
psychotic symptoms via both unstructured and structured clinical assessment (e.g. including use of the 
Columbia Suicide Severity Rating Scale113 (C-SSRS)). Any increase in symptoms is reviewed immediately with 
a study Psychiatrist, who will make appropriate clinical interventions, potentially including an Emergency Room 
evaluation for hospitalization. Electrocardiograms will be administered at the onset, mid-point and end of the 
study. Follow-up contact will be attempted with all patients who miss scheduled visits. These are standard 
practices in the PI’s laboratory, where studies of acute drug effects (e.g. memantine, AMPH) on the proposed 
measures in SZ patients are commonly conducted.  
The overall risks of this proposal are small. AMPH will not be administered to subjects in whom it is medically 
contraindicated, such as subjects with known cardiovascular or neurologic disorders or diagnoses of stimulant 
dependence (although it is notable that oral AMPH, at doses up to 60 mg, has been investigated as a 
treatment for cocaine dependence39). The dose selected for use in these studies is in the low- or below-
therapeutic range for AMPH. Studies will be conducted under the direct supervision of a licensed physician. To 
address the potential for AMPH to produce changes in blood pressure, all subjects’ vital signs will be carefully 
monitored, and subjects will not be released from the laboratory until their vital signs are within normal limits; it 
is notable that the dose of AMPH in this application has been tested in SZ patients in the PI’s laboratory and 
produced minimal autonomic activation. Drugs will be dispensed by a licensed physician or pharmacist, and a 
licensed physician or nurse will be present on the premises at all times during testing to assess and address 
potential adverse drug effects, and if needed, to administer medical assistance to the test subject. 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.  
Risk/benefit ratio: Both study arms include an active intervention with documented efficacy in reducing 
symptoms and improving neurocognition in SZ patients. Thus, it is a reasonable likelihood that many study 
participants will benefit clinically from completing this study, regardless of their arm assignment. The 
hypothesis being tested is that these benefits will be augmented by AMPH. It is anticipated that the proposed 
study will yield important, new information about a new therapeutic approach in SZ patients, as well as 
systems-level neural information of direct relevance to several neuropsychiatric disorders. Thus, this study has 
a significant potential for providing major gains in our treatment and understanding of the brain basis for 
disorders that are severe and common. It is possible that the information obtained, and the treatment 
administered, in this R33 with individual subjects will be of direct benefit to them. In addition, subjects will 
benefit indirectly - through a cascade of familial and societal benefits - from the information generated by these 
studies. Furthermore, based on their awareness of the potential importance of this work to their community, 
subjects will benefit in areas of self-esteem and self-understanding. Information from physical examinations, 
and screening measures, may also be of direct benefit to test subjects. The overall risks of the proposed 
studies are low, as described above. Thus, on balance, the risk/benefit ratio of the proposed studies is very 
low. 
Contact PD/PI: SWERDLOW, NEAL R 
Protection of Human Subjects
Page 80

Data and Safety Monitoring Board and Plan:  
 
The Data and Safety Monitoring Board (DSMB) is an independent group of three UCSD experts established 
through our UCSD CTRI, based on a Data and Safety Monitoring Plan (DSMP) specific to this R33 application. 
Our UCSD CTRI is partially funded by a Clinical and Translational Science Award (CTSA) from the National 
Institutes of Health. The DSMB comes at no cost to this application. 
 
The DSMB consists of 3 CTRI multidisciplinary leaders, free from any conflicts of interest or direct involvement 
with the academic or other credit resulting from this study, who advise both the PI and the NIMH, based on 
their expertise. The primary responsibilities of the DSMB are enumerated below; they include to periodically 
review and evaluate the accumulated study data for participant safety, study conduct and progress, and 
efficacy, and to make recommendations to the NIMH concerning the continuation, modification, or termination 
of the R33 trial. The DSMB considers study-specific data as well as relevant background knowledge about the 
treatments (TCT and AMPH) and patient population under study (chronic psychotic disorder).  
 
The DSMB is also responsible for maintaining the confidentiality of its internal discussions and activities as well 
as the contents of reports provided to it. The DSMB will review cumulative study data to evaluate safety, study 
conduct, and scientific validity and integrity of the trial. The CTRI has specific guidelines that ensure a 
comprehensive study protocol for timely DSMB notification by the PI related to any adverse events (AEs), 
serious adverse events (SAEs) or unanticipated problems (UPs). As part of this responsibility, DSMB members 
must be satisfied that the timeliness, completeness, and accuracy of the data submitted to them for review are 
sufficient for evaluation of the nature of the event and the safety and welfare of the study participants. The 
DSMB will also assess the performance of overall study operations and any other relevant issues, as 
necessary. A letter of support from Dr. Kathryn Gold, DSMB Chair, is attached. The primary 
responsibilities of this DSMB include: 
 
1. Conducting an initial review of the proposed research to assure quality study conduct;  
2. Reviewing study procedures to assure quality of study conduct, including SOPs for data management and 
quality control procedures;  
3. Evaluating the quality of the ongoing study conduct by performing quarterly evaluations of the study accrual, 
compliance with eligibility, participant adherence to study requirements, and accuracy and completeness of 
data;  
4. Considering factors external to the study when relevant information becomes available, such as scientific or 
therapeutic developments that may have an impact on the safety of the participants or the ethics of the study;  
5. Recommending appropriate study review or temporary halting for any SAE, and termination due to the 
occurrence of 3 SAEs (symptom exacerbation or suicidality associated specifically with active treatment vs. 
PBO), or inability of PI to provide necessary assessment information or to answer study questions;  
6. Recommending continuation of ongoing studies at quarterly reviews;  
7. Considering the overall picture, including need to pursue both primary and appropriate secondary analysis, 
and making these recommendations during the final months of PY3 (see Timeline);  
8. Consider modifying sample sizes based on unexpectedly robust therapeutic benefits; and  
9. Reviewing final results, via DSMB report by PI within 90 days of completion of final R33 subject.  
 
The DSMP proposes both the process and content of the DSMB, including its deliberative processes, event 
triggers that would call for an unscheduled review, stopping guidelines, unmasking (unblinding) and voting 
procedures prior to initiating any data review. Elements of the DSMP include: 
 
1. How risks are minimized (e.g. see Protection of Human Subjects section on inclusion and exclusion 
criteria, careful clinical monitoring including specific scales for suicidality and psychosis and specific criteria for 
interventions based on these scales);   
2. How risks are reasonable in relation to anticipated benefits (see Protection of Human Subjects re: 
risk/benefit ratio);   
3. Plan to monitor progress and safety (see below for description of adverse events and related protocol);  
4. Assessments of data quality, timeliness, participant recruitment, accrual and retention; 
5. Plan to assure compliance with reporting of adverse events and/or unanticipated problems involving risk to 
participants or others (see below for details):  
Contact PD/PI: SWERDLOW, NEAL R 
Data and Safety Monitoring Plan
Page 81

 
a. Process for detecting and reporting serious and unexpected adverse events and/or unanticipated 
 
problems involving risk to participants or others;  
 
b. Who will be monitoring and collecting the adverse events;  
 
c. Who will be notified of an adverse event; 
 
d. The timing of reports; 
 
e. Annual reporting of adverse events. 
 
This DSMP will be approved by our UCSD IRB and CTRI DSMB in advance of enrolling any R33 study 
subjects. 
 
Adverse Events 
 
Definition of Adverse Events (AEs): An AE is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
 
Causal relationship of AEs: Medical judgment will be used to determine the relationship, considering all 
relevant factors, including pattern of reaction, temporal relationship, confounding factors such as concomitant 
medication, concomitant diseases and relevant history, and reported as such to the DSMB. 
 
Vital signs (measurements of systolic/diastolic blood pressure and pulse rate as outlined below) will be 
recorded at each study visit and at specific time points after AMPH/PBO ingestion. BP is measured using a 
brachial cuff on the non-dominant arm; pulse is measured manually for 30 seconds and multiplied by 2.  
 
Assessment of suicidality: Suicidality will be monitored closely during the study period. Suicidal thoughts and 
behavior will be assessed by Columbia-Suicide Severity Rating Scale (C-SSRS). The C-SSRS is a 
questionnaire assessing both suicidal behavior and suicidal ideation. It consists of five questions related to 
suicidal behavior and five questions related to suicidal ideation, evaluated as either present or not. The C-
SSRS will be administered by qualified clinicians and will be assessed at the screening visit with the aim to 
exclude patients with active moderate or severe symptomatology prior to the Screen Visit, or recent (or current) 
suicidal or suicide attempt according to the C-SSRS (baseline/screening version). Subsequently, the C-SSRS 
since last visit assessment will be performed at each visit as shown in the study Schematic. If there is a 
positive response of suicide attempt or suicidal ideation by the patient during the administration of the C-SSRS 
during the treatment period, a study MD will immediately interview the patient during the visit and determine if 
the patient will be discontinued from the trial and appropriate actions for the patients safety have to be 
initiated. For assessment of the C-SSRS paper forms will be used and results will be transcribed into the 
DSMB report. 
 
Definition of a Serious Adverse Event (SAE): A serious adverse event is defined as any AE which results in 
death, is life-threatening, requires inpatient hospitalization, results in persistent or significant disability or 
incapacity or is to be deemed serious for any other reason if it is an important medical or psychiatric event 
when based upon appropriate medical judgment which may jeopardize the patient and may require medical, 
psychiatric or surgical intervention.  
 
For AEs not included in the protocol-defined grading system, the following guidelines will be used to describe 
severity: 
 
 
Mild  Events require minimal or no treatment and do not interfere with the participants daily activities. 
 
Moderate  Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
 
Severe  Events interrupt a participants usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
Contact PD/PI: SWERDLOW, NEAL R 
Data and Safety Monitoring Plan
Page 82

The PIs assessment of an AEs relationship to the study interventions - TCT and AMPH - is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event will be reported. All AEs will have their 
relationship to TCT and AMPH assessed. To help this assessment, the following guidelines are used: 
 
 
Related  The AE is known to occur with TCT or AMPH, there is a reasonable possibility that TCT or 
AMPH caused the AE, or there is a temporal relationship between the use of TCT or AMPH and the event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the TCT or 
AMPH and the AE. 
 
 
Not Related  There is not a reasonable possibility that the administration of TCT or AMPH caused the 
event, there is no temporal relationship between the use of TCT or AMPH and the event onset, or an alternate 
etiology has been established. 
 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the known risks of TCT or 
AMPH. 
 
AEs will be identified either 1) if alerted by study subject, their representative (relative, physician) between 
study visits, or 2) by careful clinical assessment at a study visit or follow-up visit. All subjects are evaluated 
clinically at every visit (approx. 3 times per week), and any deviation from their expected baseline clinical state 
will warrant a more detailed clinical assessment, documentation and intervention as necessary. 
 
Any medical or psychiatric condition or symptom that is present at the time that the participant is screened will 
be considered as baseline and not reported as an AE. However, if the study participants condition deteriorates 
at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is obtained 
until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation (12 weeks post-
TCT). At each study visit, the investigators will inquire about the occurrence of AE/SAEs since the last visit. 
Events will be followed for outcome information until resolution or stabilization. 
 
AEs suspected by study staff are immediately reported to a study MD. A study MD (typically the PI, but other 
licensed MDs are also listed on this PIs IRB protocols and can provide back-up coverage) is on the premises 
at all times that experiments and TCT training are in progress, and study staff have cell phone access to study 
clinicians at all times, including weekends and holidays. If an AE is confirmed, the PI is notified immediately; 
study staff and clinicians have cell phone access to the PI at all times, including weekends and holidays.  
 
The PI will convene a phone- or face-to-face meeting of all study clinicians 24 hours to discuss the implications 
of the AE and all necessary follow-up and interventions. A full report to the DSMB and IRB will be made within 
7 days of the AE. The PI is responsible for signing off on all AE reports. Reporting lines are as follows: 
 
Reporting Source → Research Staff → Study MD (PI) → DSMB, IRB 
 
Reporting lines will be as above, for AEs. However, the PI will notify the DSMB and IRB in real-time in the 
event of any SAE; in addition, the PI will complete an SAE Form within the following timelines: 
 
All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on the SAE 
Form and submitted to the NIMH within 24 hours of site awareness. Other SAEs regardless of relationship, will 
be submitted to the NIMH within 72 hours of site awareness. 
 
Contact PD/PI: SWERDLOW, NEAL R 
Data and Safety Monitoring Plan
Page 83

All SAEs will be followed until satisfactory resolution or until the PI deems the event to be chronic or the 
adherence to be stable. Other supporting documentation of the event may be requested by the NIMH as soon 
as possible. 
 
Incidents or events that meet the OHRP criteria for unanticipated problems (UPs) require the creation and 
completion of an UP report form. It is the PIs responsibility to report UPs to the UCSD IRB and to the NIMH. 
The UP report will include the following information: 
 
 
Protocol identifying information: protocol title and number, PIs name, and the IRB project number; 
 
A detailed description of the event, incident, experience, or outcome; 
 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
 
an UP; 
 
A description of any changes to the protocol or other corrective actions that have been taken or are 
 
proposed in response to the UP. 
 
UPs that are SAEs will be reported to the UCSD IRB and to the NIMH within 24 hours of the 
 
investigator becoming aware of the event. 
 
Any other UP will be reported to the UCSD IRB and to the NIMH within 72 hours of the investigator 
 
becoming aware of the problem. 
 
All UPs will be reported in real time to the DSMB 
 
Pregnancy: As described in Protection of Human Subjects, women of childbearing years participate in the 
present study only under specific conditions designed to minimize the possibility of pregnancy, and with weekly 
or more often monitoring of urine pregnancy tests. Any patients testing positive in this surveillance will receive 
further study drug. The study blind will be broken; if the subject was receiving active drug, they will be referred 
for appropriate pregnancy-related care and follow-up will be maintained with the subject through to completion 
of pregnancy.  
 
Amphetamine carries a teratogenic risk classified as Pregnancy Category C.  However, the level of exposure in 
the present study is very low and likely to be greatly exceeded by the teratogenic risk of other medications 
being taken by schizophrenia patients. TCT has no known teratogenic risk. 
 
Study Halting: Administration of study agent will be halted if three grade 3 AEs determined to be probably 
related are reported to the DSMB. The DSMB will notify the NIMH immediately when the third grade-3 event is 
reported and enrollment screens will stop accepting new study participants. The DSMB will convene an ad hoc 
meeting by teleconference or in writing as soon as possible. The DSMB will provide recommendations for 
proceeding with the study to the NIMH. The NIMH will inform the FDA of the temporary halt and the disposition 
of the study. 
 
 
 
 
Contact PD/PI: SWERDLOW, NEAL R 
Data and Safety Monitoring Plan
Page 84

Tracking Number: GRANT12951838
Funding Opportunity Number: RFA-MH-18-705 Received Date:
2019-10-11T12:27:52.000-04:00
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-attention psychostimulant, amphetamine, 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 amphetamine vs. TCT (30
 sessions) plus placebo.
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+AMPH 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. AMPH (5 mg po)) 1 hour prior to Sound Sweeps. Tests 1 and 2 are used to assess target engagement
 (Aim 1: AMPH-enhanced APS learning) and AMPH 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 5 mg AMPH, 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
Thirty, one-hour sessions over approximately 10 weeks, of computerized
 cognitive training modules.
Drug (including
placebo)
amphetamine
The pro-attentional medication, amphetamine (placebo vs. 5 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
Contact PD/PI: SWERDLOW, NEAL R 
Page 87

Tracking Number: GRANT12951838
Funding Opportunity Number: RFA-MH-18-705 Received Date:
2019-10-11T12:27:52.000-04:00
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 amphetamine vs. placebo confirms target
 engagement, which is the primary outcome of Aim
 1.
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 amphetamine
 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.; and 7)
 AMPH Cessation Symptom Assessment
Primary
MATRICS Consensus
Cognitive Battery Global
Composite T-score (MCCB-C)
baseline vs. post-TCT session
10, 20 and 30 (approximately
10 weeks), and 12 weeks post-
TCT
The MCCB measures 7 separable cognitive
 domains. Details are found in cited reports
 including past studies by the PI of drug effects
 on MCCB performance. Since the MCCB is
 assessed multiple times, alternate forms of
 the HVLT-R and BVMT-R are administered 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; specifically,
 TCT effects on verbal learning performance are
 known to be robust, and should be augmented by
 AMPH. Baseline MCCB performance (attention/
vigilance subscale) will also be tested as a
 potential biomarker/ moderator of AMPH efficacy.
Primary
World Health Organization
Disability Schedule (WHODAS
2.0)
baseline vs. post-TCT session
10, 20 and 30 (approximately
10 weeks), and 12 weeks post-
TCT
Function will be assessed via the World Health
 Organization Disability Schedule 2.0 (WHODAS
 2.0)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 6 domains:
 cognition, mobility, self-care, getting along with
 people, life activities, participating in society; it
 was recommended by the DSM-5 Task Force
 committee to replace the global assessment of
 functioning (GAF) scale.
Contact PD/PI: SWERDLOW, NEAL R 
Page 88

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