Atomoxetine for PTSD

Overseen By Mark B Hamner, MD BS

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must not be taking: Psycho-stimulants, MAOIs, SSRIs, others

Disqualifiers: Glaucoma, Hypertension, Epilepsy, TBI, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

160 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that could interact with atomoxetine, such as monoamine oxidase inhibitors (MAOIs), antihypertensive medications, and some antidepressants like paroxetine, venlafaxine, and fluoxetine. If you are on psycho-stimulants or other similar medications, you must stop them at least 2 weeks before starting the trial. However, you can continue with approved standard therapies if your PTSD symptoms are still severe enough to meet the trial's criteria.

What data supports the effectiveness of the drug Atomoxetine for PTSD?

Atomoxetine is a drug that has been shown to be effective in treating ADHD by improving symptoms in both children and adults. Additionally, a study suggests that Atomoxetine may be safe and effective for people with both ADHD and PTSD, indicating potential benefits for PTSD treatment. ^{1 2 3 4 5}

Is atomoxetine generally safe for humans?

Atomoxetine, also known as Strattera, is generally considered safe for humans, but it can cause side effects like stomach pain, decreased appetite, and sleepiness. Serious side effects may include increased heart rate, blood pressure changes, and in rare cases, increased suicidal thoughts. Most side effects are mild to moderate and temporary. ^{6 7 8 9 10}

How does the drug Atomoxetine differ from other treatments for PTSD?

Atomoxetine is unique because it is a non-stimulant drug that works by selectively inhibiting the norepinephrine transporter, which is different from many other PTSD treatments that often focus on serotonin pathways. Additionally, it has shown potential effects on the NMDA receptor, which may influence its impact on PTSD symptoms. ^{2 3 5 11 12}

What is the purpose of this trial?

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.

Research Team

Zhewu Wang, MD

Principal Investigator

Ralph H. Johnson VA Medical Center, Charleston, SC

Eligibility Criteria

This trial is for veterans with PTSD who also have attention deficits and executive function difficulties. Participants should not be fully responsive to conventional PTSD treatments and are looking for new strategies to improve their quality of life and social functioning.

Inclusion Criteria

I am between 65 and 75 years old, meeting the specific age criteria.

ADHD has been recognized as a neurobehavioral impairment in executive function (Brown, 2008)

I am a veteran aged 18-75 with PTSD and AD, meeting the required CAPS and CAARS-S:S scores.

Exclusion Criteria

Known sensitivity to ATX

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, bipolar I disorder, bipolar II disorder, bipolar disorder not otherwise specified, the project will allow the presence of depressive disorders if the depressive episodes are secondary to PTSD

I stopped taking psycho-stimulants or SSRIs at least 2 weeks before the trial starts.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive atomoxetine or placebo for 12 weeks to assess improvement in executive function and attention

12 weeks

4 visits (in-person), weekly phone calls

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (virtual or in-person)

Treatment Details

Interventions

• Atomoxetine

Trial Overview The study tests Atomoxetine (ATX), a non-stimulant medication approved for ADHD, on improving attention and executive functions in individuals with PTSD. It's a double-blind trial, meaning neither the researchers nor participants know who gets ATX or placebo during the 12-week treatment period.

Participant Groups

Group I: active atomoxetine Experimental Treatment 1 Intervention

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

Group II: Placebo Placebo Group 1 Intervention

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

Atomoxetine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in European Union as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in Canada as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Medical University of South Carolina

Collaborator

Trials

994

Recruited

7,408,000+

Findings from Research

Atomoxetine is an effective non-stimulant treatment for ADHD in children and adolescents, showing significant improvements in ADHD symptoms compared to placebo across six clinical trials involving over 3,000 participants.

The drug is well tolerated with minimal side effects, primarily gastrointestinal issues and decreased appetite, and it does not appear to have abuse potential, making it a safe long-term option for managing ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Atomoxetine (Strattera), an alternative in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children]. Gaillez, C., Sorbara, F., Perrin, E.[2020]

Atomoxetine (Strattera) is an effective nonstimulant treatment for adults with ADHD, showing greater symptom improvement compared to placebo in two large 10-week trials, with mean reductions in ADHD symptoms of 28.3% to 30.1%.

Atomoxetine is generally well tolerated, with a low risk of abuse or diversion, making it a suitable option for patients who may be at risk for substance abuse; it is not a controlled substance in the US.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. Simpson, D., Plosker, GL.[2018]

Atomoxetine significantly reduces ADHD symptoms in children and adolescents, especially in those with co-existing conditions like anxiety and depression, with a number needed to treat of 3.4-5.

While most side effects are mild and temporary, serious risks include increased vascular tone, decreased growth rate, and heightened suicidal behavior, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Atomoxetine for treatment of children and adolescents with ADHD]. Resen, K., Pagsberg, AK., Jörgens, G.[2017]

A case of a 17-year-old girl who overdosed on 2840 mg of atomoxetine resulted in a seizure and mild cardiac issues, highlighting the potential risks associated with high doses of this medication.

Despite the overdose, the patient showed significant improvement within 24 hours, indicating that while atomoxetine can cause serious effects in overdose situations, recovery is possible with appropriate medical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolated atomoxetine overdose resulting in seizure. Kashani, J., Ruha, AM.[2015]

In a safety analysis of 15 clinical trials involving 4829 adults with ADHD, atomoxetine was associated with a higher rate of treatment-emergent adverse events compared to placebo (81.3% vs. 68.3% for acute trials), but no new adverse events were identified, confirming its known safety profile.

Atomoxetine led to modest increases in heart rate and blood pressure, but there was no increased risk of serious adverse events or suicidal ideation, indicating it is a safe treatment option for adults with ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials. Camporeale, A., Porsdal, V., De Bruyckere, K., et al.[2015]

Atomoxetine, a nonstimulant medication approved for ADHD, works as a selective norepinephrine reuptake inhibitor and is structurally related to fluoxetine, an antidepressant.

While common side effects include gastrointestinal disturbances, this case highlights potential cardiovascular issues such as syncope, orthostatic hypotension, and tachycardia, which may arise from increased noradrenergic activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular side effects of atomoxetine and its interactions with inhibitors of the cytochrome p450 system. Kasi, PM., Mounzer, R., Gleeson, GH.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

A 12-week nursing support programme for carers of children and adolescents in the UK with attention deficit hyperactivity disorder prescribed atomoxetine. [2021]

2. France pubmed.ncbi.nlm.nih.gov

[Atomoxetine (Strattera), an alternative in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children]. [2020]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Atomoxetine in comorbid ADHD/PTSD: A randomized, placebo controlled, pilot, and feasibility study. [2022]

6. Denmark pubmed.ncbi.nlm.nih.gov

[Atomoxetine for treatment of children and adolescents with ADHD]. [2017]

7. United States pubmed.ncbi.nlm.nih.gov

Isolated atomoxetine overdose resulting in seizure. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular side effects of atomoxetine and its interactions with inhibitors of the cytochrome p450 system. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Atomoxetine use during a period of FDA actions. [2015]

11. United States pubmed.ncbi.nlm.nih.gov

Postmortem tissue distribution of atomoxetine following fatal and nonfatal doses--three case reports. [2015]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain--an in vivo study. [2021]