Atomoxetine in Comorbid ADHD/PTSD: A Pilot, Placebo-Controlled Feasibility Study
Phase: PHASE4
Conditions: Post Traumatic Stress Disorder, Attention Deficit Hyperactivity Disorder
Sponsor: VA Office of Research and Development

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A. 
BACKGROUND AND SIGNIFICANCE 
A1.  
Significance: PTSD is a debilitating disorder that is common among veterans returning from 
Iraq and Afghanistan (OIF/OEF) due to the high risk of exposure to combat and other trauma. Recently, 
emerging evidence suggest a strong link between PTSD and ADHD. The co-occurring ADHD 
symptoms are likely to reflect the impairment in cognitive function, which often expressed as reduced 
attention span, concentration difficulties, impaired decision-making abilities, and memory problems 
(LaGarde et al, 2010). Co-occurring ADHD cognitive impairments add another layer of complexity to the 
disease process and pose more severe impairments in daily function. While treatments for the 
avoidance, arousal, and re-experiencing symptoms associated with PTSD for military personnel are 
readily available, substantial gaps exist in the treatment of the cognitive deficits associated with PTSD. 
Further, ADHD cognitive symptoms are associated with poorer patient attendance to medical 
appointments, poorer medication compliance and increased risk for psychotherapy resistance and 
medication abuse or diversion (Kolar et al., 2008). Consistent attendance is the best predictor of patient 
functional recovery from PTSD (Tarrier et al., 2000). Subsequently, untreated co-occurring ADHD 
cognitive symptoms that increase the risk for problems in patients’ PTSD treatment engagement, PTSD 
treatment responses, functional impairment, and quality of life have tremendous negative impact on 
treatment outcome. However, in so far, studies have not examined the impact that treating ADHD 
cognitive symptoms have on PTSD treatment engagement, outcome, and functional recovery. The 
proposed study directly addresses this knowledge gap by testing the feasibility and preliminary efficacy 
of atomoxetine (ATX) in treatment of ADHD cognitive symptoms among those with comorbid 
ADHD/PTSD. Our research is directly responsive to the mission of RR&D-SPiRE “to maximize 
functional recovery” of cognitive function in PTSD. The outcome of the proposed research will be 
significant, because it will provide a knowledge base to help determine who is at risk for developing 
problems with treatment engagement among PTSD patients, thereby allowing for development of early 
intervention strategies before drop-out. More importantly, the new knowledge may lead to discovering 
new targets for novel and more effective treatments for PTSD. This novel clinical trial may have 
immediate benefit to Veterans by enhancing their cognitive function, reducing ADHD symptom related 
disabilities and further improving quality of life for veterans with comorbid ADHD/PTSD.  
A2.   
Review of the Literature Relevant to This Application 
Cognitive Impairments in Comorbid ADHD/PTSD: Combat Veterans with PTSD often show cognitive 
impairments in attention, working memory, executive functions, and inhibitory control (Vasterling, 2007), 
a cluster of symptoms overlapping with symptoms of adult ADHD. It has been proposed that the 
cognitive deficits in PTSD may be related to the same disturbance of fronto-temporal systems observed 
in ADHD. This hypothesis has been supported by several imaging research findings that indicate 
functional alteration in the medial frontal and lateral prefrontal cortex in PTSD (Nee et al 2007, Shin et 
al 2006). Further, impaired response inhibition task, Go-NoGo (GNG), a measure of executive function 
has been observed both in ADHD and in PTSD patients (Fisher et al 2011; Swick et al 2012). Finally, 
there is substantially higher rates of PTSD development in individuals with ADHD (Hanson et al 2012), 
suggesting that both may share common biological risks. Although the exact mechanisms of co-
occurrence of cognitive symptoms in both ADHD and PTSD is not yet fully known, research has 
suggested that this cognitive impairment plays an important role in PTSD development, treatment 
response, and prognostic outcomes (Aupperle et al, 2012). Cognitive Function and PTSD Treatment 
Outcome: Many cross-sectional studies have documented strong evidence that PTSD is associated 
with significant cognitive impairment, and the presence of cognitive impairments is related to poorer 
treatment outcome (Verwoerd et al, 2009; Wild and Gur, 2008; Walter et al, 2010). As a result, the 
DSM-5 diagnostic criteria for PTSD have expanded the cognitive symptom criteria associated with 
PTSD. In the past 2 decades, extensive psychological and pharmacological treatments have been 
developed for PTSD, but as many as 50% of individuals with PTSD do not fully respond to the standard 
interventions and drop-out rates are often cited around 30%. Many of these standard treatments are 
developed predominantly to address re-experiencing and avoidance symptoms, but not cognitive 
impairment. However, in patients with PTSD, the impairment in occupational, academic, and social 
functioning often persists after receiving specialized treatment, including successful treatment of PTSD 
symptoms of avoidance and re-experiencing (Westphal et al, 2011). It is well documented that intact 
cognitive function is essential for activities of daily living, including self-care. However, problematic 
treatment behaviors commonly associated with impaired cognitive functioning are not targeted as part 

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of PTSD interventions but are regularly indicated as the best predictors of outcome for exposure-based 
PTSD treatment (Tarrier et al., 2000). Given that up to 50% of patients do not respond well to first line 
treatments for PTSD, it is imperative to identify potential risk factors for poor outcome and seek novel 
treatment strategies to improvement rehabilitation. The standard treatments do not directly target 
cognitive deficits, which may account for poor treatment compliance as well as the failure of functional 
recovery even after successful treatment in PTSD. Cognitive Deficit and Risk of PTSD: Recent 
prospective longitudinal studies have started to emerge and have documented evidence that pre-
trauma subtle cognitive deficits were related to the development of PTSD (Vasterling et al, 2006). A 
veteran twin study suggests that lower pre-trauma cognitive function may constitute a risk for the 
development of PTSD after trauma exposure (Gilbertson et al, 2006). In summary, the cognitive deficit 
is at least partially responsible for PTSD susceptibility, treatment resistance, and poor functional 
recovery. The proposed study will investigate the potential mechanisms of cognitive function in the 
initiation, maintenance, and recovery of combat and other trauma related PTSD, in an effort to inform 
approaches to improve in primary, secondary, and tertiary treatment of PTSD in Veterans.  
A3. 
ATX and Treatment of Cognitive Impairment in ADHD/PTSD: ATX is a selective 
norepinephrine reuptake inhibitor (SNRI). By blocking norepinephrine transporters (NET), ATX 
enhances noradrenergic and dopaminergic signaling in the pre-frontal cortex (PFC), but not striatum 
(Bymarster et al 2002). This feature explains why ATX reduces ADHD symptoms and improves PFC 
cognitive function but has no abuse potential. Therefore, it becomes more preferred therapeutic agent 
in patients where substance abuse is a problem or concern. Given the increased risk for substance 
abuse documented in patients with PTSD (Terriar et al, 2000), the reduced risk for abuse poses a 
substantial benefit to this drug. Currently, ATX is the only non-stimulant medication approved by FDA 
for treatment of ADHD. Studies have shown that ATX is safe, effective, and well tolerated with mild side 
effects profile in acute and long-term treatment of ADHD in children, adolescent, and adult (reviewed by 
Vauphan et al, 2009). Compared to MPH, ATX showed similar efficacy in the improvement of ADHD 
symptoms (Wang et al, 2007). In addition, ATX also exhibited beneficial effect on comorbid anxiety and 
depression in ADHD patients (Geller et al, 2007; Deviss, 2008), both of which are highly comorbid with 
PTSD. Further, the ATX may have potential to improve PTSD as similar SNRI, reboxetine, has shown 
efficacy in reducing PTSD symptoms in motor vehicle accident related PTSD (Spivak et al 2006). The 
above literature review provides strong rational for choosing ATX to treat cognitive symptoms in 
Veterans with ADHD/PTSD.   
A4. 
Relevance to Veterans Health: PTSD is a debilitating condition that develops following 
exposure to traumatic events. Exposure to potentially life threatening events increases dramatically in 
military service, particularly for those directly engaged in combat. As such, PTSD is highly prevalent in 
military personnel and Veterans, estimated at between 11 and 18% of those returning from wars (True 
et al, 1993; Hoge et al, 2004). The primary mental health symptoms and secondary comorbid disorders 
associated with PTSD create a tremendous burden for the Veteran, their families, and for the VA health 
care delivery system, as well as incurring great society burden due to lack of workforce productivity that 
can result from this condition. Despite numerous efforts to develop effective treatments, many patients 
do not or only partially respond to current treatment or withdraw from treatment (Fontana and 
Rosenheck 1997; Johnson et. al. 1999; Prigerson et. al. 2001). The evidence from our research and 
others indicates that comorbid ADHD cognitive impairment is an additional additive risk for the 
development and maintenance of PTSD symptoms (Aupperle et al, 2012). However, as yet, the 
mechanism for this is unknown. This study serves to be the first to both address the lack of research on 
both the shared mechanism of cognitive dysfunction and preliminary trial of a treatment for improving 
PTSD treatment response. The proposed study will conduct a novel clinical trial to assess efficacy of 
ATX to improve treatment outcome and compliance as assessed by patient 1) functional impairment 
and quality of life and 2) reduce the cognitive impairment symptoms observed in both ADHD and 
comorbid PTSD. The outcome of this study will improve the understanding how cognitive deficit 
influence PTSD symptoms after exposure to trauma, and will provide the means to intervene through 
either primary preventive or secondary treatment strategies. The trial will immediately benefit Veterans 
and military personnel who suffer from comorbid ADHD/PTSD, since they will provide more direct 
treatment of cognitive symptoms that will improve their occupational and academic function more 
immediately, improve efficacy of PTSD treatments, and help prevent long-term disability. A long-term 
benefit of this research is that once an association is established among cognitive function and 

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ADHD/PTSD, methods can be developed to target the early intervention and treatment strategies and 
treatment retention enhancements. As a result, the approaches of prevention or early intervention may 
increase individual resilience to traumatic events, and enhance Veteran’s ability to continue their 
performance and engagement in the workforce. 
 
B. 
PRELIMINARY DATA 
B1. 
Experiences: PI, Dr. Wang and Co-investigators, Dr. Hamner, Dr. Sallee, and Dr. Acierno have 
extensive experiences in genetic and treatment research in PTSD and ADHD. Dr. Wang has conducted 
numerous candidate gene research studies in various psychiatric disorders. Dr. Wang moved to 
Charleston VA Medical Center in 2007, and that same year he was awarded a Meirt Review Award to 
study monoamine genotypes in Veterans with and without PTSD. He recruited 388 subjects and 
performed. The project found an association between homozygote short (S) genotype of 5-HTTLPR 
and PTSD (Wang et al, 2011). Recently, Dr. Wang’s research has been focused on identifying 
biomarkers for various psychiatric disorders (Wang et al, 2006; Gilbert et al, 2006; Wang et al, 2007). In 
2011, he won another Merit Review Award titled “Cortical Excitability: Biomarker and Endophenotype in 
Combat Related PTSD”. The on-going project provided essential preliminary data for this application. 
Dr. Kirstin Gros, co-investigator, has extensive history as co-investigator and researcher on social 
impact on the etiology and course of externalizing disorders and modification of interventions to reduce 
barriers to engagement, will help to develop psychological assessments and with statistical analysis. 
Dr. Mark Hamner, Dr. Sallee, and Dr. Acierno have recently joined this research team as co-
investigators to aid in pharmaceutical trial design, 
cognitive assessment, diagnostic assessment, and 
recruitment. Combined, the PI and co-investigators 
are well prepared to undertake the proposed 
research, as they have the scope, breadth of 
expertise, and resources needed to complete the 
research successfully.  
B2.  Preliminary Data:  
B2.1. PTSD, Cognitive Deficit, and ADHD: In our 
on-going project, we evaluated combat veterans with and without PTSD with Clinician Administered 
PTSD Scale (CAPS), Conners' Adult ADHD Rating Scales–Self Report: Short Version (CAARS–S:S, 
score > 65 is regarded clinical significant cognitive impairment; Conner et al 1999). We included 47 
participants, 29 PTSD subject (13 with CAARS > 65, 45%) and 18 controls (2 with SAARS > 65, 
11%).The results indicated PTSD diagnosis is associated with significantly higher self-reported 
attentional and executive dysfunction symptoms (χ2 = 5.81, p = 0.16). This was also evident in the 
significant correlations between CAPS and CAARS-S:S scores (R=0.497 p < 0.01), and CAPS PTSD 
symptoms (β=.26, t =1.88, p =.05), and PTSD patient cognitive deficit severity as measured by the 
CAARS-S:S (β=.59, t=4.81, p<.001, R2 =.34). These findings further support available literature 
suggesting that cognitive symptoms associated with PTSD diagnosis are highly corelated with patients’ 
functional outcome.                                                                               
B2.2. MPH Improves Cognitive Function: Further, we conducted additional preliminary analyses with 
8 PTSD individuals with cognitive symptoms who were treated with MPH. Analyses conducted on 
clinical assessments of patients’ PTSD and ADHD symptoms (CAPS and CAARS-S:S) before and after 
MPH treatment revealed significant reductions in both PTSD and self-reported cognitive deficit 
symptoms (see Fig1 and Fig2; F (1, 7) = 22.39, p =.002).  
 
C. 
RESEARCH DESIGN AND METHODS:  
C1. Overview: The proposed project is a pilot, feasibility double-blind crossover study to investigate the 
efficacy and safety of ATX with comorbid PTSD/ADHD patients to reduce cognitive symptoms, improve 
treatment retention and response, and improve patient’s activities of daily living. A prospective, 10-
week, fixed-dose, randomized, double-blind, placebo-controlled, and cross-over trial of ATX as an 
adjunctive medication to other therapies will be conducted among veterans with comorbid 
PTSD/ADHD. The short-duration, crossover design, and blind enable the study to be feasible in both 
time and funding level. The Primary Objective is to assess the efficacy of fixed dose of ATX (80mg) 
(compared with placebo) in reducing cognitive symptoms in comorbid ADHD/PTSD such that functional 

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impairment and treatment retention are both improved, while The Secondary Objective is to replicate 
the our preliminary finding of negative impact of cognitive symptoms of ADHD on PTSD clinical 
outcomes. The Tertiary Objective is to assess the efficacy of ATX in reducing broad spectrum of 
PTSD symptoms. The proposed study will take 10 weeks and include two phases (Phase I: Initial 
Phase, 5 weeks; Phase II: Crossover Phase, 5 weeks). The crossover design was employed to both 
achieve study objectives while minimizing costs. Each phase consists two periods: Period I (week1 in 
Phase I and week6 in phase II) consist of psychological and physical assessments and placebo lead-
in/wash-out, in which subjects take 6 days placebo; Period II (weeks 2-5 in Phase I and week7-10 in 
Phase II) consist of treatment with either atomoxetine 80mg daily or placebo daily). This project will 
take advantage of established on-going PTSD assessment and treatment clinical trials currently 
performed at the Ralph H. Johnson VA Medical Center (RHJVAMC) to facilitate recruitment. The 
proposed 50 veterans with ADHD/PTSD will be recruited from these on-going trials enabling both 
comprehensive assessment and evaluation of patients’ engagement in ongoing PTSD treatments. 
Subjects will be randomized and assigned by the study investigator (Dr. Floyd Sallee) into crossover 
group 1 (ATX at Phase I, then placebo at Phase II) or 2 (placebo at Phase I, then ATX at Phase II) with 
both placebo and medication administered through pharmacy. Subjects and other investigators are thus 
able to remain blinded to the order of treatment assignment throughout the study. The 1-week interval 
was based on published pharmacokinetic data for 4 week doses of ATX (Witcher et al, 2003). After 
crossover, patients will be unblinded and data will be cleaned and analyzed. Final follow up will be 30-
days after last visit. 
C2. Investigational Agent: ATX is a non-stimulant, FDA approved agent for treatment of ADHD. ATX 
80mg is the most common adult dose used in ADHD with and without comorbid condition (Adler et al, 
2009). In this project, 80 mg ATX and placebo will be prepared in capsules with identical appearance 
and similar taste by Eli Lilly and Company, Indianapolis, Indiana.  
Adverse effects (AE): Typical adverse events reported significantly more frequently with atomoxetine 
than placebo included dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, 
sweating, dysuria, sexual problems and palpitations. Modest increases in heart rate and blood pressure 
were well tolerated and gradually decreased on cessation of treatment.  
Contraindications: ATX is contraindicated in patients known to be hypersensitive to the drug and 
during treatment with monoamine oxidase inhibitors (hypertensive crises may result). Medication will be 
stored and dispensed from the Charleston VAMC investigational drug pharmacy.  Records will be 
maintained of all doses dispensed, and Veterans will be asked to return all unused tablets and empty 
prescription vials to the clinic for assessment of treatment compliance. 
C3. Method 
Subject Recruitment: All the subjects will be recruited through Charleston VAMC Mental Health 
Service Line. The Charleston VAMC has a large base of potential comorbid PTSD and ADHD 
participants. Many clinical trials, including pharmaceutical and psychotherapeutic trials are currently 
conducted in conjunction with the Charleston VAMC PTSD Clinical Team (PCT) clinic and the PCT 
team receives numerous PTSD evaluation consults from OIF/OEF program and Primary Care. 
Currently the PCT clinic receives 200 to 250 new referrals yearly of OIF/OEF Veterans who meet full 
criteria for PTSD based on a comprehensive initial intake interview that includes CAPS and functional 
impairment assessments. PI, Dr. Wang currently manages pharmacological consults for OIF and OEF 
Veterans. A HIPAA waiver of authorization will be on file with the IRB giving the research team 
permission to recruit from prior study populations. Veterans with PTSD from OIF/OEF are uniquely 
suited for this study because statistically they have fewer confounding variables for this clinical trial, 
including medical conditions such as hypertension or glaucoma and cognitive impairments such as 
dementia. Interested veterans who participate in clinical trials are explained the nature, purpose, and 
procedure of the study and asked to sign an informed consent that will explain in detail the purpose of 
the study, potential risks and benefits of pharmacotherapy study participation and alternative treatments 
that may be available. 
Inclusion Criteria: 1) OIF/OEF Veterans age 20 to 60 with PTSD and significant ADHD symptoms 
(CAARS-S:S > 65); 2) Good physical health. 3) Trauma exposure sufficient to meet Category A of 
PTSD criteria (Breslau and Kessler 2001) 
Exclusion Criteria: 1) Age younger than 20 or greater than 60. 2) Known sensitivity to ATX. 3) 
Presence of disorders that could conceivably be exacerbated by atomoxetine (specifically, narrow 

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angle closure glaucoma, urinary outflow obstruction, hypertension, and neurological disorders, 
particularly tics and Tourette's syndrome, or a history of epilepsy or seizures). 4) use of concomitant 
medication that could potentially interact with atomoxetine including monoamine oxidase inhibitors 
(MAOI), antihypertensive medication, or any concomitant medication that was a cytochrome 2D6 
inhibitor (CYP2D6) as atomoxetine's elimination involves the CYP2D6 system. 5) An active or lifetime 
major mental health diagnosis as determined by DSM-IV Axis I Disorders, including schizophrenia, 
schizoaffective disorder, psychotic disorder not otherwise specified, bipolar I disorder, bipolar II 
disorder, bipolar disorder not otherwise specified. The project will allow presence of depressive 
disorders if the depressive episodes are secondary to PTSD. 6) Current substance dependence and 
abuse (within 3 month). 7) Females who are pregnant or likely to become pregnant. 8) Active suicidal 
thoughts and behavior.                                          
Suicide Screen: A screen for recent or current suicidal thought and/or attempts will be conducted 
before the interview. If a subject reports suicidal thought at the time of interview, his physician or 
psychiatrist will be informed and the subject will be escorted to the ER immediately for further 
evaluation and treatment.         
Screening/Baseline Evaluation:  During this visit subjects will review and sign the Informed Consent. 
Eligibility to participate in this portion of the study will be determined by a minimum 6-month duration of 
PTSD illness, CAARS-S:S score of 65 or higher as well as a positive ADHD score for the adult section 
of the Conners ADHD interview, a total CAPS severity score of 55 or higher at the baseline visit. If the 
subjects qualify, then a medical/psychiatric history will be obtained along with laboratory safety 
measures, including electrocardiogram (EKG), liver and renal panel (SMA-12), complete blood count 
with differential, urine toxicology screen and concomitant meds.  If the veteran is female, urine 
pregnancy test will be obtained.    
PTSD Medication Stabilization:  Those patients meeting inclusion criteria will be asked to maintain 
medications at current dosages where medically possible.  Participants who have not initiated new 
prescription medications in the previous 4 weeks will initiate treatment one week following the 
assessment battery.  However, those potential participants who have recently begun trials of 
prescription medication will be required to wait 4 weeks post-assessment to ensure medication 
stabilization, at which point the assessment battery will be re-administered.  
Efficacy Assessments and Outcome Measurement:  Primary outcome measures will be conducted 
at baseline and all subsequent visits by a qualified research clinician using the CAARS-S:S, with the 
Barkley Adult ADHD Rating Scale-IV (BAARS-IV) and Adult ADHD Quality of Life-29 (AAQoL-29) 
conducted at follow up visits. Clinical Global Impression Severity (CGI-S, at baseline only) and Clinical 
Global Impression Improvement (CGI-I, at all visits except baseline and W1) will be done as well.  
Additional assessments for evaluating secondary outcomes will include the Clinician Administered 
PTSD Scale (CAPS), Hamilton Depression Scale (HAM-D). Quality of life will be assessed using the 
Veteran’s version of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF36-V). In 
addition to subjective measures, the response inhibition task Go/NoGo (GNG) and Stop Signal (SST) 
will be used as objective assessments to measure ATX treatment outcomes. 
Key Assessment Measures: 
Mini-International Neuropsychiatric Interview (MINI, Sheehan et al., 1998): The MINI is an abbreviated 
structured psychiatric interview that takes approximately 10-20 minutes to complete. The MINI has 
shown good inter-rater reliability and test-retest reliability for screening psychiatric disorders.   
CAADID Part II: Diagnostic Criteria (CAADID, Epstein et al., 2001) The CAADID is a structured 
interview that assists in the process of diagnosing adult ADHD. This assessment is appropriate for 
those 18 and older. It is most effective when used with other types of ADHD measures, such as the 
CAARS™.  
Clinician Administered PTSD scale (CAPS, Weathers et al., 2000): The CAPS is a structured interview 
that assesses both frequency and intensity of PTSD symptoms according to DSM-IV criteria. It provides 
both a dichotomous index for PTSD diagnoses and a continuous index of PTSD symptom severity. 
Conners’ Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S, Conner et al, 1999):  The 
CAARS-S:S is a 26-item questionnaire that assesses symptoms of ADHD in persons aged ≥18 years. 
T-scores above 65 indicate a likelihood of moderate to severe ADHD symptoms and impairment.  

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The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006): AAQoL-29 is a participant-reported 
outcome measure used to examine disease specific functional impairments and quality of life for adults 
with ADHD. The AAQOL-29 includes Life Productivity, Psychological Health, Quality of Relationships, 
and Life Outlook subscales. Higher scores on the AAQOL-29 indicate better functioning. 
The Barkley Adult ADHD Rating Scale-IV (BAARS-IV, Barkley, 2011): BAARS-IV offers an essential tool 
for assessing current ADHD symptoms and domains of impairment and recollections of childhood 
symptoms. BAARS-IV is empirically based, reliable, and valid for diagnosis and cognitive evaluation of 
adult ADHD.    
Response Inhibition Task: The Go-NoGo (GNG) and Stop-Signal Task (SST) are classical paradigm 
to investigate response inhibition and response execution (higher-order motor and attention control) 
processing, and a reliable marker reflecting medial prefrontal functioning (Fallgatter and Strik, 1999). 
Further, ATX has been found to improve GNG and SST performance in ADHD patients (Nandam et al 
2014; Chamberlain et al, 2007). GNG/SST require participants to implement their response to one kind 
of stimuli (Go/Start) and to withhold the responses to the other kind of stimuli (NoGo/Stop). Therefore, 
GNG commission errors SST time are a reliable marker to examine individual executive function and to 
measure ATX treatment response. GNG and SST will be performed at Dr. Wang’s TMS Laboratory. 
 
 
Table 1:  Outline of study procedures and assessments of the study. 
 
 
 
Initial Assessments 
Screening/ 
Baseline 
Phase I 
Start 
Phase I 
Treatment 
visit 
Phase I 
Follow up, 
Crossover 
lead in 
Phase II 
Start 
Phase II 
Treatment 
visit 
Phase II 
Follow up 
Final Follow 
up visit 
visit (week) 
1  
2 (W1) 
3 (W2) 
4 (W5) 
5 (W6) 
6 (W7) 
7 (W10) 
8 (W14) 
Consent 
X 
  
  
  
  
  
  
  
MINI 
X 
  
  
  
  
  
  
  
CAADID Part II 
X 
  
  
  
  
  
  
  
CES 
X 
 
 
 
 
 
 
 
DTS 
X 
 
 
 
 
 
 
 
CGI-S 
X 
  
  
  
  
  
CGI-I 
  
X 
X 
X 
X 
X 
  
CAARS-S:S 
X 
X 
X 
X 
X 
X 
X 
X 
BAARS 
X 
  
X 
  
  
X 
X 
AAQoL-29 
X 
  
  
X 
  
  
X 
  
SF-36-V 
X 
  
  
X 
  
  
X 
  
CAPS-IV 
X 
  
  
X 
  
  
X 
  
Ham-D 
X 
  
X 
X 
X 
X 
X 
X 
Ham-A 
X 
  
X 
X 
X 
X 
X 
  
GNG/SST 
X 
X 
X 
  
X 
  
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
  
Labs, EKG 
X  
X 
X 
  
UDS 
X 
  
  
X 
  
  
  
  
Dispense med 
  
X 
X 
  
X 
X 
  
  
Compliance 
  
  
X 
X  
X 
X 
  
  
Concom meds 
X 
X 
X 
  
X 
X 
  
  
AEs 
  
  
X 
  
X 
  
  

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Safety assessments:  At each study visit, safety will be assessed by measuring: weight, sitting blood 
pressure, heart rate, adverse events (except baseline), and use of concomitant medications.  
Laboratory and EKG assessments will be performed at baseline, one and seven weeks. Anxiety, 
depression, and suicidal ideation will be assessed with Ham-A, Ham-D, and suicide screen in each of 
the visits. Compliance will be assessed by pill counts and appointment attendance.  Referrals to the 
Charleston PTSD clinic will be conducted at the final study visit for any remaining PTSD symptoms and 
the CBT clinic for remaining ADHD symptoms.   
                  
Follow-up:   The final visit, 30-days after study completion, will include safety assessments, along with 
follow-up of any unresolved adverse events.  This visit will also provide assurance that veterans who 
participated in this medication study will have adequate follow-up care in the Charleston VAMC PTSD 
or Mental Health Outpatient Clinic either with continued medication or psychotherapy. This visit may be 
done over the phone or by mail. 
 
 
        
Diagnostic Procedures: After obtaining the informed consent, a trained research assistant will perform 
the initial interview and administer all of the diagnostic scales to the participants. Dr. Floyd Sallee, Dr. 
Mark Hamner (MD, Co-Investigator) and Dr. Zhewu Wang (PI) will make the final diagnosis based on 
all the data collected. The DSM-IV diagnostic criteria will be used to ascertain each phenotype.  
Database Management:  All collected clinical, demographic, and geographic data will be stored in 
Research Database Storage in the Charleston VAMC PTSD Program. The genotyping data will be 
stored in Dr. Wang’s laboratory Research Database. For each patient, the clinical database will provide 
information as following: age, gender, ethnic origin, medical and psychiatric diagnosis, family history, 
developmental history, and existence of comorbidity. The genotyping data will be separately entered 
without knowledge of clinical data.   Strict confidentiality is maintained regarding database information, 
which is secured and for research purposes only. All the specimens from the subjects will be labeled by 
code at the clinic. Names will not appear on specimens, nor will they be available in the laboratory. The 
person conducting the genotyping is blind to the clinical profile of the subject. No names or identifiable 
information will be used in any data presentation.  
Statistical Analyses and Power Estimation: As a pilot feasibility study with double-blind crossover 
design, the design affords greater power and need for enrollment of fewer subjects. Similar design with 
this medication has suggested sample size of 40 was sufficient for effect sizes typically observed with 
this medication in similar populations (Bain et al 2013). To account for patient dropouts, the study will 
enroll/consent up to 50 patients. This will ensure 40 subjects complete the entire study. This design will 
allow initial pilot feasibility data, improved control and testing of causation, and greater power in the 
allotted time-frame and funding level. The primary consideration is difference in outcome between 
baseline and endpoint with ATX treatment as compared to placebo. The primary outcome measure a 
priori will be the change in total CAARS-S:S scores, AAQoL-29 and BAARS-IV. Secondary measures 
include the remaining efficacy and safety measures as delineated above. The primary outcome of 
interest is the moderating impact of ATX treatment (medication ×ADHD TAU) on treatment response 
(pre- and post-treatment measures of cognitive symptoms of ADHD and PTSD, functional impairment 
in daily living domains, and global functioning). A mixed model, repeated-measures multivariate 
analysis of variance with pre- and post-ADHD TAU treatment ADHD symptoms, functioning, and global 
functioning entered as repeated measures; and ATX treatment entered as the between factors. Pre-
treatment PTSD severity scores (CAPS) will also be entered into the model as a potential explanatory 
covariate. Simple slopes using repeated measures ANOVA will be used to probe significant interactions 
C4. 
Expected Results, Potential Problems and Alternative Strategies:  Upon completion of the 
two objectives, we expect to find treatment with ATX enhances cognitive function, improve quality of life 
and treatment outcome among Veterans with ADHD/PTSD. We predict that the GNG and Stop Signal 
correlate with self-reported cognitive function in PTSD and can be used as biomarkers to measure 
treatment response. Despite the consolidate design, there is a remote possibility that some of the 
measures might not reach to statistically significance in our small sample size, short treatment duration 
and slower action of atomoxetine. The length of treatment has varied in previous atomoxetine studies 
from 3 to 11 weeks. Spencer et al were able to show efficacy on a cognitive test after 3 weeks. 
Because this was a pilot crossover study, a treatment period toward the shorter end of the range was 
most cost-effective and most likely to maximize subject participation and retention, so 4 weeks was 
chosen. We strongly believe that the primary objective will be accomplished using our design, as 
literature support robust significant improvement of ADHD symptoms, cognitive function, and quality of 

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life even at 2 weeks of treatment with ATX 80mg daily compared with placebo (Spencer et al 1998; 
Durell et al 2013; Epperson et al 2011; Tsang et al 2011). Due to the funding and time-frame limits, 
some of the secondary measure may not reach to significance, but we believe the study will provide 
data showing the improvement and that will provide direction for future studies.  
C5. 
Future Direction: The current available treatments for PTSD are not fully effective for cognitive 
symptoms of PTSD and have high drop-out and poor engagement, two factors found to be most 
indicative of overall return to functioning for patients with PTSD. Successful completion of this pilot 
clinical trial may build a platform for future large scale double-blind, placebo-controlled studies using 
either ATX or psycho-stimulants or other cognitive enhancing medications. The response inhibition 
related measurements are sensitive to psychotropic medications. Therefore it is advantageous for us to 
use GNG and Stop Signal approaches to investigate individual treatments response in our future 
research. We believe GNG and Stop signal approaches together with pharmacogenetic approach will 
provide valuable information to direct future individualized medicine.  
 
HUMAN SUBJECTS RESEARCH 
1.  
Protection of Human Subjects 
1.1 
Risks to Subjects 
a. 
Human Subjects Involvement and Characteristics:  
Totally, up to 50 veterans with comorbid ADHD and PTSD will be recruited for this pilot clinical trial. All 
subjects will be Veterans from Operation Iraq Freedom / Operation Enduring Freedom (OIF/OEF). Our 
record review showed age range from 20 to 60 in this OIF/OEF group, and statistically they have fewer 
confounding variables for this clinical trial, including medical conditions such as hypertension or 
glaucoma (described detail in exclusion criteria) and cognitive impairments such as dementia, which 
meet criteria for our research study. PTSD subjects with and without ADHD cognitive symptoms will be 
recruited from the Charleston VAMC Mental Health Service Line. Examining and treatment of ADHD 
cognitive symptoms among Veterans with PTSD is scientifically and ethically justified to further 
understand the mechanism of developing PTSD after trauma exposure, and what is the best treatment 
for Veterans with comorbid PTSD and ADHD. Specific inclusion and exclusion criteria are listed below: 
Inclusion Criteria: 1) OIF/OEF Veterans age 20 to 60 with PTSD and significant ADHD symptoms 
(CAARS-S:S > 65); 2) Good physical health. 3) Trauma exposure sufficient to meet Category A of 
PTSD criteria (Breslau and Kessler 2001) 
Exclusion Criteria: 1) Age younger than 20 or greater than 60. 2) Known sensitivity to ATX 3) 
Presence of disorders that could conceivable be exacerbated by atomoxetine (specifically, narrow 
angle closure glaucoma, urinary outflow obstruction, hypertension, and neurological disorders, 
particularly tics and Tourette's syndrome, or a history of epilepsy or seizures). 4) use of concomitant 
medication that could potentially interact with atomoxetine including monoamine oxidase inhibitors 
(MAOI), antihypertensive medication, or any concomitant medication that was a cytochrome 2D6 
inhibitor (CYP2D6), since atomoxetine's elimination involves the CYP2D6 system. 5) An active or 
lifetime major mental health diagnosis as determined by DSM-IV Axis I Disorders, including 
schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified, bipolar I disorder, 
bipolar II disorder, bipolar disorder not otherwise specified. The project will allow presence of 
depressive disorders if the depressive episodes are secondary to PTSD. 6) Current substance 
dependence and abuse (within 3 month). 7) Females who are pregnant. 8) Suicidal thoughts and 
behavior.                                          
b. Sources of Material 
c.     Potential Risks 
Therapeutic Risk:  
Pharmaceutical agent:  Atomoxetine (ATX) is a norepinephrine reuptake inhibitor that blocks 
norepinephrine and dopamine transporters and increases dopamine and norepinephrine availability in 
the synaptic cleft at the pre-frontal cortex. ATX is one of the first line treatments for children and adult 
attention deficit hyperactivity disorder (ADHD). Efficacy and safety of ATX are well established by 
numerous clinic trials in the past 15 years. However, there have been no trials of ATX for treating 
ADHD cognitive complaints associated with PTSD, possibly because of the less awareness of high 
comorbid rate of ADHD and PTSD, and concern about the abuse potential of commonly used stimulant 
medications and concern about interventions that increase catecholamine release may exacerbate 

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anxiety symptoms. Currently, ATX is the only non-stimulant medication approved by FDA for treatment 
of ADHD. Studies have shown that ATX is safe, effective, and well tolerated with mild side effects 
profile in acute and long-term treatment of ADHD in children, adolescent, and adult (reviewed by 
Vauphan et al, 2009). Unlike psycho-stimulants, ATX does not show abuse potential (Bymarster et al 
2002). A couple of studies have also shown efficacy of ATX in treatment of ADHD cognitive symptoms 
in patients with comorbid ADHD and anxiety and/or depression. ATX were very well tolerated in 
individual with comorbid ADHD and anxiety, or ADHD and depression (Geller et al, 2007; Deviss, 
2008). There is not excessive anxiety or other symptoms among subjects with comorbid anxiety and 
depression, who were taking ATX. Although ATX has not been tested in PTSD, a similar selective 
norepinephrine reuptake inhibitor, reboxetine has been studied in PTSD and shown safety and efficacy 
in reducing PTSD symptoms in motor vehicle accident related PTSD (Spivak et al 2006). The above 
literature review provides strong rational for choosing ATX to treat cognitive symptoms in Veterans with 
ADHD/PTSD.   
 
Adverse Effects:  
Common 
▪ 
Cardiovascular: Increased diastolic arterial pressure (adult, 4.8% to 12.6%; pediatric, 9.3% to 
21.5% ), Increased systolic arterial pressure (adult, 4.2% to 12.4%; pediatric, 4.9% to 12.5% ), 
Tachycardia (adult, 1.5% to 22.4%; pediatric, 0.3% to 23.4% ) 
▪ 
Endocrine metabolic: Weight decreased (adults, 2%; pediatric, 7.1% to 29.1% ) 
▪ 
Gastrointestinal: Abdominal pain (adult, 7%; pediatric, 17% to 18% ), Constipation (adult, 8%; 
pediatric, 1% to 2% ), Decrease in appetite (adult, 16%; pediatric, 16% ), Nausea (adult, 26%; 
pediatric, 7% to 13% ), Vomiting (adult, 4%; pediatric, 11% ), Xerostomia (adult, 20% ) 
▪ 
Neurologic: Headache (pediatric, 19% ), Insomnia (adult, 15%; pediatric, at least 2% ), 
Somnolence (adult, 8%; pediatric, 11% ) 
▪ 
Renal: Delay when starting to pass urine (adult, 6% ) 
▪ 
Reproductive: Dysmenorrhea (adult, 3% ), Erectile dysfunction (adult, 9% ) 
▪ 
Other: Menopausal flushing (adult, 3% ) 
Serious: 
▪ 
Cardiovascular: Myocardial infarction, Prolonged QT interval, Sudden cardiac death 
▪ 
Hepatic: Injury of liver (Severe), Liver failure 
▪ 
Neurologic: Cerebrovascular accident, Dyskinesia, Seizure (adult, 0.1%; pediatric, 0.2% ) 
▪ 
Psychiatric: Mania, Psychotic disorder, Suicidal thoughts (pediatric, 0.4% ) 
▪ 
Reproductive: Priapism (rare ) 
▪ 
Other: Angioedema 
 
Contraindications 
▪ 
cardiac or vascular disorders, severe; at risk for deterioration with clinically important increase of 
blood pressure (15 to 20 mm Hg) or heart rate (20 beats per minute); monitoring recommended.  
▪ 
hypersensitivity to atomoxetine or to other components of the product.  
▪ 
MAO inhibitor use; do not administer atomoxetine during therapy with or within 2 weeks of 
discontinuing an MAO inhibitor; do not administer MAO inhibitor within 2 weeks of discontinuing 
atomoxetine.  
▪ 
narrow angle glaucoma; increased risk of mydriasis  
▪ 
pheochromocytoma, current or history of; increased risk for serious reactions, including 
tachyarrhythmia and elevated blood pressure. 
 
Psychological Risks: There is a minor chance that participant will experience anxiety, discomfort or 
embarrassment during the data collection process, the investigational team will make every effort to 
minimize potential psychological risks by maintaining a pleasant and professional manner, conducting 
interviews and physical assessments in a private clinical office, encouraging dialogue regarding the 
research process, and allowing participants to discuss any reactions or feelings that they may have 
throughout study participation. Additionally, in order to avoid or minimize any further discomfort, the 
participants are allowed to take breaks during the interviews and assessment, or reschedule the 

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appointment for completion at a later time. Participants can refuse to answer any question during an 
interview or on the questionnaire if it makes the participant uncomfortable. 
Legal, Social and Economic Risks: In order to prevent the risk of developing feelings of being 
“labeled” or “stigmatized”, participants will be ensured that confidentiality safeguards will be strictly 
maintained throughout the study. Such safeguards include the conduction of all interviews and clinical 
visits within private and secure areas or offices. Additionally, all study documents will be kept in a 
locked office or on a computer located in a secure area, with limited password access. Confidential 
hospital medical records will document participation in the study through mental health progress notes. 
Additionally, participants’ name will not be identified in the data analysis, publications, or presentations 
of the research results. A Health Insurance Portability and Accountability Act (HIPAA) authorization 
page is included with the informed consent to notify the participants of the use of identifiable personal 
health information.  The informed consent and HIPAA authorization page provide a detailed outline of 
the provisions utilized to protect the confidentiality of research data. The methods used to obtain 
information about the participants include medical record review and assessments described above.   
In order to minimize any economic risk related to having to miss work or having to pay for transportation 
to and from the research visits, the study team will coordinate with the participants to schedule 
appointments at the most convenient time, including seeing participant outside working hours and 
limiting the frequency of visits to those necessary to adhere to the protocol.   
1.2.   Adequacy of Protection Against Risks 
a. 
      Recruitment and Informed Consent 
Subjects will be recruited from Charleston VAMC OIF/OEF Screening Clinic.  Additionally, Veterans 
with or without PTSD may be recruited through Savannah CBOC referrals if Charleston VAMC does not 
have a sufficient number of participants. The study will be open to all Veterans from Iraq Freedom 
Operation and Afghanistan who meet eligibility criteria regardless of ethnicity, gender or socioeconomic 
status.  No charge will be incurred for the participant for any aspect of this study.  Written consent will 
be obtained for each participant who meets the inclusion criteria prior to assessment.  Veterans will be 
given as much time as needed to make a decision whether to participate.  All participants will be 
informed that their participation is voluntary, and that reluctance to participate will not compromise 
availability of care, or the eligibility to participate in other studies.  Participants may discontinue 
assessment at any time during the study.   
b.     Protection against Risk 
Potential risks involve loss of time at work and the psychological stress involved in assessment 
procedures.  These risks will be minimized in several ways.  Breaks and encouragement will be given 
as needed during testing procedures.  There is some flexibility in the on site assessment schedule to 
allow for completion of measures not finished during the scheduled testing time.  In addition, some 
weekend/holiday assessment times will be offered to minimize loss of time of participants. 
ATX is a widely used treatment for ADHD. It is generally well tolerated clinically. Subjects who meet the 
contraindications for ATX listed in section “Therapeutic Risk” will be excluded. Common side effects of 
ATX are dry mouth, insomnia, nausea, decreased appetite, and sweating. Insomnia and sweating are 
of some concern for individuals with PTSD; however, as noted above the ATX has been safely used in 
comorbid ADHD and anxiety. Subjects can also withdraw at any time without penalty. 
The risk of venipuncture is minimal. The mild discomfort of venipuncture and very low possibility of local 
infection will be minimized by using experienced phlebotomists and standard blood drawing techniques. 
Universal precautions for the handling of human blood developed by the Centers for Disease Control 
will be followed at all times when working with blood as well as DNA isolated from blood.  
All assessment information will be considered confidential.  Data will be organized in code-labeled 
binders and stored in locked cabinets.  No participant will be identified by name in any presentation of 
the results.  Identification numbers will code data entered for computer analysis, and the data 
coordinator will keep all names and code numbers.  Findings will be made available to legitimate 
agents of the participants (parents, schools, treating psychologists, physicians), and only with the 
express, written consent of the participants. 
1.3.   Potential Benefits of the Proposed Research to the Subjects and Others 
The immediate benefit is the treatment effect on cognitive function enhancement that may improve 
individual occupational, academic performance, and daily quality of life. The other anticipated benefits 
for participating Veterans include individual neuropsychological assessments and interpretation of the 

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results.  Neuropsychological test information (including psychoeducational assessment) and written 
feedback will be provided to participants. This information may be shared by physicians, educators, and 
other professionals involved with the patients care, as needed.  The importance of the results to the 
fields of PTSD neurophysiology, neuropsychology, and genetics are significant due to the large 
numbers of PTSD participants and even larger number of Veterans returning from the OIF/OEF 
theatres affected with PTSD.  
1.4.    Importance of the Knowledge To Be Gained 
The findings from this proposed study will contribute to the understanding of the neurophysiologic and 
genetic basis of PTSD. The establishment of effective treatment will provide an advanced and viable 
approach for further PTSD diagnostic, genetic, and treatment studies. These physiological and genetic 
markers may be useful in pharmacological treatment selection, and can be used in vulnerability 
assessment for risk population. The procedures in the proposed study all involve minimal risk, and are 
therefore reasonable in relation to the importance of the knowledge that is expected to result. 
1.5      Data and Safety Monitoring 
All collected clinical, demographic, and geographic data, as well as genotyping data will be stored in 
Psychiatric Genetic Research Database, a branch of Psychiatric Data Management. We will use 
computerized systems to collect, create, modify, maintain, archive, retrieve, and transmit clinical data. 
The genotyping data will be separately entered without knowledge of clinical data. Data of cortical 
inhibition will be stored in Charleston VAMC TMS Laboratory data bank.  
All assessment information will be considered confidential.  Data will be organized in code-labeled 
binders and stored in locked cabinets.  Identification numbers will code data entered for computer 
analysis, and the data coordinator will keep all names and code numbers in a separate locked area.  
Findings will be made available to legitimate agencies, such as local IRB, and related research 
personnel. No names or identifiable information will be used in any data presentation. Strict 
confidentiality is maintained regarding database information, which is for research purpose only. All the 
specimens from the subjects will be labeled by code at the clinic. Names will not be used on specimens 
nor available in the research laboratory. The person conducting the sequencing and genotyping is blind 
to the clinical profile of the subject. 
2 
        Inclusion of Woman and Minorities 
Charleston VA Medical Center has traditionally served Veterans both in Charleston as well as 
neighboring counties.  With the exception of occasional out-of-state referrals, the population served 
reflects that of the Charleston metropolitan area.  Participation in this research is open to all Veterans 
who meet eligibility criteria regardless of race, gender, ethnicity, or socioeconomic status.  We expect 
PTSD to affect Veterans of all races and ethnicities across a range of socioeconomic status.  We had 
approximately 35% African American participants in our previous recruitment, which is proportional to 
our surrounding area. As for male to female ratio, our previous studies have shown a higher incidence 
of PTSD in male Veterans because a higher percentage of male soldiers have participated in combat. 
We expect a greater percentage of female Veterans from Iraq Freedom Operation and Afghanistan 
given we have found that more female soldiers have participated in the two wars. All possible effort will 
be made to recruit female Veterans. 
3       Inclusion of Children 
The proposed research study will include Veterans from 20 to 60 (NIH definition of children), and will be 
conducted at Charleston VA Medical Center. We expect less than 10% participants will be under the 
age 21 since the majority of Veterans participating to the screening clinic are older than 21. We will 
assure that the percentage of Veterans age 20 to 60 who participate in this research will reflect the age 
of soldiers in proportion to those who participated in the Iraq Freedom Operation and Afghanistan War.