Atomoxetine Effect on Attention, Executive Function, and Quality of Life in Veterans With Posttraumatic Stress Disorder
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 2
- 主要终点
- Behavior Rating Inventory of Executive Function-Adult (BRIEF-A)
研究概览
简要总结
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.
详细描述
Aim 1: To examine the impact of ATX in enhancing executive function. Based on preliminary data, the investigators hypothesize that ATX, compared with placebo, will be more effective in improving EF in Veterans with PTSD and AD. To test this hypothesis, 12-week, randomized, double-blind, placebo-controlled trial of ATX will be conducted among Veterans with PTSD. The outcome measure will be the analyses of changes in Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the response inhibition task, GoNogo (GNG), Trail making and digit span tests (TMT and DST). The rationale for this aim is that impaired EF may be a powerful risk for PTSD treatment resistance and poor QoL and psychosocial function (PSF), therefore, improving EF with ATX may ultimately improve Veterans QoL, PSF, and reducing disability rating. The investigators expect that the 12-week treatment with ATX will significantly improve attention, EF, inhibitory function in Veterans with PTSD.
Aim 2: To examine the impact of ATX on improvement of QoL and daily psycho-social function.
Based on literature and preliminary data, the investigators hypothesize that ATX, compared with placebo, will be more effective in improve Veterans' QoL, PSF, and disability rating. The outcome measure will be the analyses of changes in Adult ADHD Quality of Life-29 (AAQOL-29), WHO Disability Assessment Schedule 2.0 (WHODAS 2.0), The Inventory of Psychosocial Functioning (IPF). The investigators expect that the 12-week treatment with ATX will significantly improve QoL and psychosocial function, and significantly reduce EFD and AD related disability.
Aim 3: To examine the impact of ATX on overall AD and PTSD treatment outcomes. The hypothesis for this aim is that successful treatment of attention and executive deficits will be associated with greater reduction of PTSD and AD symptoms. To achieve this goal, more clinical and psychological assessments including depression, anxiety, and other functional scales, such as CAPS-5 scores, BDI, BAI, and CARRS-S:S attention deficit scores will be performed to assess the PTSD overall improvement. The investigators expect that the significant improvement of attention and executive function will lead to a significant improvement of overall PTSD outcomes.
Recruitment:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
- •The project will allow approved standard therapies, including psycho- or/and pharmacotherapies be continued with the condition that the subjects continue to present with PTSD symptoms severe enough to meet the inclusion criteria
- •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
- •Current substance use disorders:
- •DSM-5 alcohol
- •marijuana
- •and/or other drug use disorders in the last 3 months
- •Mild alcohol and marijuana use which does not meet the criteria for mild use disorder, such as occasional or recreational use will be permitted on a case by case basis
- •Females who are pregnant or desired to become pregnant during the clinical trial period
- •Urine pregnancy tests will be performed at each of the visits, including prior to, during, and after the clinical trial
- •Prominent suicidal or homicidal ideation or any suicidal behavior in the past 3 months on the Columbia Suicide Severity Rating Scale (C-SSRS)
研究组 & 干预措施
Placebo
placebo pill appears like real atomoxetine pill but has no therapeutic ingredient and benefit. The same schedule to distribution as Atomoxetine arm.
干预措施: Placebo (Drug)
active atomoxetine
Active ATX (40mg capsules) will be prepared. Initial dose is 40mg, titrated to 80mg if tolerable in one week.
干预措施: Atomoxetine (Drug)
结局指标
主要结局
Behavior Rating Inventory of Executive Function-Adult (BRIEF-A)
时间窗: 15 minutes
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.
次要结局
- 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)