Atomoxetine and Executive Function in PTSD

NCT06573970 | Not Yet Recruiting Phase 4 FDA Drug

• 2 other identifiers: D4823-RI01RX004823-01A2
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 1

Brief Summary

Attention deficits (AD) frequently co-occur with posttraumatic stress disorder (PTSD). The presence of AD is associated with greater PTSD clinical severity and poorer clinical outcomes. Knowledge regarding the mechanism underlying this association is limited, though the emerging evidence has indicated that executive function deficit (EFD) is strongly correlated with AD and PTSD symptoms. While treatments developed for PTSD have existed for years, a substantial portion of individuals do not fully respond to conventional treatment. Accumulating evidence suggest that attention deficit (AD) and EFD may be a driving force for PTSD treatment resistance. However, treatment of executive impairment in PTSD is very limited. As a result, untreated co-occurring AD and EFD in PTSD poses severe negative impacts on patients' functional recovery, treatment outcomes, and quality of life (QoL). Given that up to 50% of patients do not respond well to the first-line pharmacological PTSD treatments, it is imperative to seek novel treatment strategies to improve EF that may improve both standard treatment response and QoL, social function. The proposed study directly addresses this knowledge gap by testing the efficacy of atomoxetine (ATX) in improving EF and attention among Veterans with PTSD, which will further improve Veterans' QoL and social function. ATX represents a promising novel candidate pharmacotherapy for individuals with PTSD. ATX is a non-stimulant selective norepinephrine reuptake inhibitor (SNRI), approved by the FDA for the treatment of ADHD. Studies suggest that ATX, unlike stimulants, lacks addictive properties and shows efficacy in the treatment of comorbid depression and anxiety, which is ideal in the treatment of PTSD. Data from the investigators' preliminary study provides encouraging support for the therapeutic potential of ATX in improving EF in Veterans with comorbid PTSD/ADHD. The investigators' recent research uncovered a higher rate of ADHD among Veterans with PTSD, and the comorbid AD symptoms were correlated with PTSD severity and poorer treatment outcomes. Treatment with ATX showed significant symptoms reduction in ADHD and improvement in inhibitory function in Veterans with ADHD/PTSD. In the proposed study, the investigators will focus on ATX in improvement of EF and attention, and further psycho-social life function and QoL. The investigators will (1) employ a randomized, double-blind design that will consist of 12 weeks of treatment with ATX or placebo medication; (2) use standardized, repeated dependent measures to rigorously assess AD and EFD symptomatology; (3) measure impairment in associated mental and behavioral health problems (e.g., attention deficit, depression, anxiety, suicidality, QoL, family/social functioning); and (4) use response inhibition task GoNogo, working memory and attention tests Digit Span and Trail Making to investigate the underlying pathophysiology of PTSD and prognostic indicators of treatment outcome. To achieve these goals, the investigators have assembled a multidisciplinary team with expertise in PTSD, ADHD clinical trials, and human laboratory paradigms who have successfully collaborated in the past and are uniquely qualified to implement this type of investigation. The proposed project is directly responsive to the mission of the VA-RRD "to maximize Veterans' functional independence, quality of life and participation in their lives and community." Successful completion of this study will provide a platform for a large multi-center trial to further confirm the important role of EF in PTSD treatment outcomes. The findings from this study will provide critically needed evidence to help inform clinical practice guidelines on the treatment of PTSD. The outcome of the proposed research will be significant, because it provides a knowledge base to allow for development of new PTSD intervention strategies. More importantly, this clinical trial may immediately benefit Veterans by enhancing their cognitive function, reducing AD related disability, and further improving quality of life for Veterans who suffer from PTSD.

Conditions

Posttraumatic Stress Disorder With Attention Defic

Keywords

PTSD; ADHD; Executive function; Quality of life

Outcome Measures

Primary Outcomes (1)

• Behavior Rating Inventory of Executive Function-Adult (BRIEF-A)

  The BRIEF-A is a 75-item questionnaire that assesses adult executive functioning and self-regulation. It's suitable for adults ages 18-90 with a wide range of developmental, neurological, psychiatric, and systemic disorders. BRIEF-A uses a 3-point scale to rate items on a frequency basis, with 0 indicating "never", 1 indicating "sometimes", and 2 indicating "often". The raw scores, range from 0 to 150, of each scale are added together to calculate T scores. The higher T scores reflecting greater degree of executive dysfunction and levels of impairment, with scores at or above 65 suggestive of clinical significance.

  15 minutes

Secondary Outcomes (2)

• Conners' Adult ADHD Rating Scales-Self Report: Short Version (CAARS-S:S)

  10 to 15 minutes

• Clinician Administered PTSD Scale 5 (CAPS-5)

  20 minutes

Other Outcomes (1)

• The Adult ADHD Quality of Life-29 (AAQOL-29)

  15 minutes

Study Arms (2)

active atomoxetine

EXPERIMENTAL

Active ATX (40mg capsules) will be prepared. Initial dose is 40mg, titrated to 80mg if tolerable in one week.

Drug: Atomoxetine

Placebo

PLACEBO COMPARATOR

placebo pill appears like real atomoxetine pill but has no therapeutic ingredient and benefit. The same schedule to distribution as Atomoxetine arm.

Drug: Placebo

Interventions

Atomoxetine DRUG

Atomoxetine is a selective norepinephrine reuptake inhibitor medication used to treat attention deficit hyperactivity disorder (ADHD), and executive dysfunction. Dispensing of blinded medication (40mg to 80mg ATX or placebo) will begin at randomization and will be dispensed at weeks 2, 4, 8, and 12. The initial dose of ATX is 40mg or placebo and will be given for one week, the dose will be titrated to 80mg if tolerated in the second week through week 12.

Also known as: Strattera

active atomoxetine

Placebo DRUG

placebo pill appears like real atomoxetine pill but has no therapeutic ingredient and benefit. The same schedule to distribution as Atomoxetine arm.

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Veterans ages 18 to 75 with PTSD and AD (CAPS \> 35 for age 18 to 64, CAPS \> 25 for age 65 to 75; CAARS-S:S \> 60)
• The cut-score of 25 used for participants age 65 to 75 because lower cut-score has been recommended for older Veterans (Yeager and Magruder, 2014)
• ADHD has been recognized as a neurobehavioral impairment in executive function (Brown, 2008)
• Veterans with PTSD at this age range are 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
• Physical health good enough to be able to participate in the study
• Competent to give informed consent

You may not qualify if:

• Age younger than 18 or greater than 75
• Age becomes the main risk factor for major neurocognitive disorder, especially after 75 (Sousa et al, 2020)
• Known sensitivity to ATX
• Presence of disorders that could conceivably 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
• Subjects with major traumatic brain injury (TBI) determined by Ohio State University Traumatic Brain Injury Identification Method (OSU-TBI ID)
• However, mild TBI, assessed with OSU-TBI ID and review of record will be allowed to participate in this trial
• Use of concomitant medication that could potentially interact with atomoxetine including monoamine oxidase inhibitors (MAOI), antihypertensive medication, or any concomitant medication that is a cytochrome 2D6 (CYP2D6) inhibitor, such as paroxetine, venlafaxine, fluoxetine, because atomoxetine's elimination involves the CYP2D6 system
• Subjects who are currently taking psycho-stimulants, other NRIs such as duloxetine, and venlafaxine will be excluded
• However, the investigators will allow subjects who stopped the psycho-stimulant or other NRI or other SSRIs 2 weeks prior to the start of the trial
• Subjects receiving active ongoing therapy with good response at the point of recruitment
• An active or lifetime major mental health diagnosis as determined by DSM-5 major psychiatric disorders, including:
• schizophrenia
• schizoaffective disorder
• psychotic disorder not otherwise specified

Sponsors & Collaborators

• VA Office of Research and Development: lead
• Medical University of South Carolina: collaborator

Study Sites (1)

Ralph H. Johnson VA Medical Center, Charleston, SC

Charleston, South Carolina, 29401-5703, United States

Location

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Attention Deficit Disorder with Hyperactivity

Interventions

Atomoxetine Hydrochloride

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals

Study Officials

• Zhewu Wang, MD

  Ralph H. Johnson VA Medical Center, Charleston, SC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zhewu Wang, MD

CONTACT

(843) 789-7949; zhewu.wang@va.gov

Mark B Hamner, MD BS

CONTACT

(843) 789-7799; Mark.Hamner@va.gov

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: The study is a standard placebo-controlled, double-blind clinical trial. Within each stratum, participants will be block randomized with random block sizes of 2 and 4. Participant age and sex are randomization stratum and should retain balance.

Study Record Dates

• First Submitted: August 23, 2024
• First Posted: August 27, 2024
• Study Start: April 1, 2026
• Primary Completion (Estimated): June 29, 2029
• Study Completion (Estimated): September 28, 2029
• Last Updated: February 12, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Records will be maintained and destroyed per the VHA Records Control Schedule (RCS 10-1). The paper data collected from this study will be kept in a locked cabinet in a locked office, while the electronic data will be coded and stored without personal identifiers. The data will be available from January 2025 until 6 month after the trial completion.
• Access Criteria: The Investigator will make study data accessible to the monitor, other authorized representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request. A file for each subject must be maintained that includes the signed Informed Consent, HIPAA Authorization and copies of all source documentation related to that subject.

Locations

US (1)