Attention Deficit Hyperactivity Disorder, Post Traumatic Stress Disorder
Conditions
Keywords
PTSD, ADHD, Atomoxetine, Combat Trauma, Cognitive Deficit
Brief summary
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. The proposed study directly addresses this knowledge gap by conducting a pilot, fixed-dose, randomized, double-blind, placebo-controlled, and cross-over trial using atomoxetine (ATX) as an add-on medication to other therapies to testing the efficacy of ATX in reducing ADHD cognitive symptoms among veterans with comorbid ADHD/PTSD. Successful completion of this pilot clinical trial may build a platform for future large scale double-blind, placebo-controlled studies using either atomoxetine or other cognitive enhancing medications.
Detailed description
Combat Veterans with posttraumatic stress disorder (PTSD) often show cognitive impairments in attention, working memory, executive functions, and inhibitory control, a cluster of symptoms resembling symptoms of ADHD. The presence of comorbid ADHD cognitive symptoms is often associated with greater PTSD clinical severity and poorer treatment outcomes. 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. As a result, untreated co-occurring ADHD cognitive symptoms in PTSD may have severe negative impacts on patients' functional recovery, treatment outcome, and quality of life. 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. This is a small prospective, 10-week, fixed-dose, randomized, double-blind, placebo-controlled, and cross-over trial of ATX as an add-on medication to other therapies in Veterans with comorbid ADHD/PTSD. Primary outcome measures will be ADHD cognitive symptom reduction and quality of life improvement as measured by the Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S) and the Adult ADHD Quality of Life-29 (AAQoL-29). Secondary outcome measures will be PTSD and depressive symptoms reduction as measured by the Clinician Administered PTSD Scale (CAPS), the Hamilton Depression Scale (HAM-D). In addition to subjective measures, the response inhibition task Go/NoGo (GNG) will be used as objective assessments to measure ATX treatment outcomes. The proposed work is innovative; it applies novel therapeutic agent to treat cognitive symptoms in PTSD. To our knowledge, this is the first study to apply a SNRI to address an often overlooked PTSD-cognitive deficit. This study 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 provides a knowledge base to help determine who is at risk for developing treatment resistance among PTSD patients, thereby allowing for development of early intervention strategies. More importantly, this clinical trial may immediate benefit Veterans by enhancing their cognitive function, reducing ADHD symptoms related disability, and further improving quality of life for veterans suffer from comorbid ADHD/PTSD.
Interventions
Subjects will be randomized and assigned by the study investigator into crossover group 1 (Atomoxetine 80mg at Phase I, then placebo at Phase II) or group 2 (placebo at Phase I, then Atomoxetine at Phase II) with both placebo and medication administered through pharmacy. There was a 1-week interval between the two phases.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
randomized, double-blind, placebo-controlled, and cross-over trial
Intervention model description
A small prospective, 10-week, fixed-dose, randomized, double-blind, placebo-controlled, and cross-over trial of atomoxetine as an add-on medication to other therapies in Veterans with comorbid ADHD/PTSD.
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Veterans age 20 to 60 with PTSD and significant ADHD symptoms (CAARS-S:S \> 65); * Good physical health. * Evidence of combat as defined by: * Trauma exposure sufficient to meet Category A of PTSD criteria (Breslau and Kessler 2001)
Exclusion criteria
* Age younger than 20 or greater than 60. * Known sensitivity to ATX * 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). * 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. * 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. * Current substance dependence and abuse (within 3 month). * Females who are pregnant. * Suicidal thoughts and behavior. b. Sources of Material
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S, Conner et al, 1999) | Visit 1, (Day1), Visit 4(Day 36), Visit 7 (Day 71) | 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 or older. T-scores above 65 indicate a likelihood of moderate to severe ADHD symptoms and impairment. The range for the CAARS-S:S is from 0 to 78. A score of 78 would resemble the worst symptoms of ADHD with a score 0 having no symptoms. |
| The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006) | Visit 1 (Day1), 4(Day 36), 7 (Day 71) | The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006): AAQoL-29 is a 29-item questionnaire designed to assess quality of life and was a secondary efficacy measure in this trial. It is a participant-reported outcome measure used to examine disease specific functional impairments and quality of life for adults with ADHD. The AAQoL is scored as an overall total score, measuring Life Productivity, Psycholofical Health, Relationship, and Life Outlook. Each item is rated by patients on a 5-point Likert scale ranging from Not at all/Never (1) to Extremely/Very Often (5). To derive overall scores, item scores are transformed to a 0-100-point scale (1=0; 2=25; 3=50; 4=75; 5=100). Then, the item scores are summed up and divided by item count to generate overall scores. The score range from 0 to 100. A higher score indicates greater QoL and better functioning. |
Countries
United States
Participant flow
Recruitment details
The participants are explained the nature, purpose, and procedure of the study and asked to sign an informed consent that will explain the potential risks and benefits of the study participation. Primary, secondary outcome measures, and physical examination will be conducted at baseline and all subsequent visits by a qualified research clinician.
Pre-assignment details
Week 1: Screening; Week 2 to 5: Phase 1 (ATX in group 1 and placebo in group2); Week 6: Wash-out; Week 7 to 10: Phase 2 (Crossover, Placebo in group1 and ATX in group2).
Participants by arm
| Arm | Count |
|---|---|
| Group1 Group 1: Atomoxetine during the first phase ( 4 Weeks), the Wash-out (1week), followed by a second phase (4 Weeks) of placebo. | 23 |
| Group 2 Group 2: Placebo during the first phase ( 4 Weeks), the Wash-out (1week), followed by a second phase (4 Weeks) of Atomoxetine. | 21 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal ECG after starting medication | 1 | 0 |
| Overall Study | Anxiety after starting medication | 0 | 1 |
| Overall Study | Nausea after starting medication | 1 | 0 |
| Overall Study | Stopped attending appointments | 3 | 2 |
Baseline characteristics
| Characteristic | Group1 | Group 2 | Total |
|---|---|---|---|
| Age, Customized | 41.2 years | 41.0 years | 41 years |
| CAARS-S:S | 74.78 units on a scale STANDARD_DEVIATION 9.54 | 69.33 units on a scale STANDARD_DEVIATION 9.89 | 72.06 units on a scale STANDARD_DEVIATION 9.97 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 20 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 19 Participants | 18 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 36 |
| other Total, other adverse events | 2 / 36 | 0 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S, Conner et al, 1999)
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 or older. T-scores above 65 indicate a likelihood of moderate to severe ADHD symptoms and impairment. The range for the CAARS-S:S is from 0 to 78. A score of 78 would resemble the worst symptoms of ADHD with a score 0 having no symptoms.
Time frame: Visit 1, (Day1), Visit 4(Day 36), Visit 7 (Day 71)
Population: The 36 patients that completed at least one phase of the study were included in the final analyses. The 8 participants did not finish the first phase, and data were not collected on those 8 subjects on the week 4 and week 7. Therefore, the 8 subjects were not entered to the final analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm1: Atomoxetine | Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S, Conner et al, 1999) | Before the intervention | 75.12 units on a scale | Standard Deviation 9.23 |
| Arm1: Atomoxetine | Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S, Conner et al, 1999) | After the intervention | 67.79 units on a scale | Standard Deviation 8.79 |
| Arm 2: Placebo | Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S, Conner et al, 1999) | Before the intervention | 68.56 units on a scale | Standard Deviation 9.34 |
| Arm 2: Placebo | Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S, Conner et al, 1999) | After the intervention | 72.80 units on a scale | Standard Deviation 8.91 |
Primary
The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006)
The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006): AAQoL-29 is a 29-item questionnaire designed to assess quality of life and was a secondary efficacy measure in this trial. It is a participant-reported outcome measure used to examine disease specific functional impairments and quality of life for adults with ADHD. The AAQoL is scored as an overall total score, measuring Life Productivity, Psycholofical Health, Relationship, and Life Outlook. Each item is rated by patients on a 5-point Likert scale ranging from Not at all/Never (1) to Extremely/Very Often (5). To derive overall scores, item scores are transformed to a 0-100-point scale (1=0; 2=25; 3=50; 4=75; 5=100). Then, the item scores are summed up and divided by item count to generate overall scores. The score range from 0 to 100. A higher score indicates greater QoL and better functioning.
Time frame: Visit 1 (Day1), 4(Day 36), 7 (Day 71)
Population: The 36 patients that completed at least one phase of the study were included in the final analyses. The 8 participants did not finish the first phase, and data were not collected on those 8 subjects on the week 4 and week 7. Therefore, the 8 subjects were not entered to the final analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm1: Atomoxetine | The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006) | Before intervention | 33.61 units on a scale | Standard Deviation 11.52 |
| Arm1: Atomoxetine | The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006) | After Intervention | 43.51 units on a scale | Standard Deviation 9.8 |
| Arm 2: Placebo | The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006) | Before intervention | 36.51 units on a scale | Standard Deviation 11.18 |
| Arm 2: Placebo | The Adult ADHD Quality of Life-29 (AAQOL-29, Brod et al, 2006) | After Intervention | 37.23 units on a scale | Standard Deviation 11.12 |