PTSD - Post Traumatic Stress Disorder
Conditions
Keywords
Post Traumatic Stress Disorder, methylphenidate, Written Exposure Therapy, fear extinction, Veteran
Brief summary
Many Veterans with post-traumatic stress disorder (PTSD) do not fully benefit from the best current treatments, some of which focus on helping the brain regulate trauma memories. While therapies like Prolonged Exposure and Written Exposure Therapy work for many, about half of Veterans still struggle with symptoms even after treatment. Research suggests that methylphenidate (commonly known as Ritalin), a safe and widely used medication, may improve PTSD symptoms and related mechanisms. This project will test whether adding methylphenidate to Written Exposure Therapy will result in a greater reduction in PTSD symptoms compared to Written Exposure Therapy alone. The investigators will also study body and behavior markers to better understand how and why some Veterans respond to treatment. If successful, this approach could give providers a new, practical tool to improve recovery from PTSD. Ultimately, this work could lead to more personalized, effective care for Veterans, helping them return to fuller and healthier lives.
Detailed description
There is a critical need for novel, and efficacious treatment strategies for post-traumatic stress disorder (PTSD) in Veterans. Gold standard treatments at the VA include evidence-based therapies that leverage fear extinction mechanisms such as Prolonged Exposure and Written Exposure Therapy (WET). Although these treatments are effective, \ 50% of Veterans do not show remission after treatment, indicating efforts to further enhance treatment efficacy are critical. Preclinical, translational, and clinical studies support the potential success of using methylphenidate (MPH; Ritalin) to improve PTSD symptoms and augment fear extinction. However, methylphenidate (MPH) has not been tested as an adjunctive treatment for exposure-based therapy (or any therapy) in those with PTSD. This project aims to (1) conduct a Phase 2a randomized controlled trial (RCT) of MPH to assess initial safety, tolerability, and potential to enhance efficacy of Written Exposure Therapy, and (2) to identify physiological and behavioral markers of treatment response. If successful, this work will provide clinically actionable information on the feasibility and efficacy of a scalable, mechanism-informed enhancement to behavioral therapies for PTSD in Veterans, supporting more efficient VA care delivery, precision medicine approaches, and improved clinical outcomes. This study evaluates the efficacy of WET plus MPH (WET+MPH) versus WET plus placebo (WET+PBO) to treat Veterans with PTSD. Specifically, this design tests the ability of serial, acute, pre-session doses of 40mg of MPH, relative to PBO, to augment PTSD symptom recovery in the context of Written Exposure Therapy, using a double-blind, placebo-controlled, randomized controlled trial design in n=138 Veterans. The primary objective is to assess PTSD symptom reduction, hypothesizing superior outcomes with WET+MPH. Additional aims examine safety and tolerability of WET+MPH and psychophysiological markers of fear extinction learning. The investigators expect that measures of safety and tolerability will be comparable across groups, and that WET+MPH will enhance extinction learning compared to WET+PBO. This study will advance our mechanistic understanding of therapeutic change by incorporating validated clinical, behavioral, and physiological assessments to enable precise characterization of how MPH alters learning processes central to PTSD recovery.
Interventions
BEHAVIORALWritten Exposure Therapy (WET)
WET will administered per manualized protocol, either in-person or via telehealth technology
active medication
DRUGplacebo (PBO)
non-active medication
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomization will occur using a code corresponding to an intervention arm. Only study statistician and pharmacist will have access to code-condition link.
Intervention model description
Two group randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Veteran 2. Current post-traumatic stress disorder (PTSD) symptoms 3. Medically healthy 4. Body weight of ≥ 120 pounds (55 kilograms) 5. Participants must be able to participate and willing to give written informed consent and to comply with the study restrictions
Exclusion criteria
1. Major medical issues 2. Medical conditions that could alter the absorption, metabolism or elimination of study drug 3. Family history of sudden death or ventricular arrhythmia 4. History of glaucoma 5. History, including family history, of motor tic or diagnosis of Tourette's syndrome 6. Pregnancy or lactation 7. Lifetime history of a chronic psychotic disorder or bipolar disorder type I 8. Lifetime history of stimulant use disorder 9. Current moderate or severe substance use disorder for any other substances 10. High suicidal risk 11. Marked anxiety, tension, or agitation, based on clinical observation, that is not due to an outside identifiable, transient, or modifiable cause 12. Unable to abstain from alcohol the evening before or day of study drug administration 13. History of a traumatic brain injury (TBI) resulting in loss of consciousness for more than 30 minutes 14. Drugs of abuse as determined by a positive urine test, excepting THC 15. Current use of any psychotropic medication that has not been at a stable dose 16. Current or recent use of a monoamine oxidase inhibitor or any other medication deemed by the study physician to exhibit an unsafe interaction with methylphenidate (MPH) 17. Past intolerance to methylphenidate (MPH) or any other psychostimulant 18. Current uncontrolled hypertension 19. Current heavy smoker and/or heavy caffeine consumption and unable to limit on study days 20. Abnormal Electrocardiogram, per study physician 21. Participation in a clinical trial with an investigational drug or a device within 30 days prior to dosing. 22. Concurrent participation in an evidence-based behavioral therapy treatment for PTSD 23. Volunteers who are unable to understand the informed consent form(s) and complete the study procedures including clinical testing 24. Any other reason, per study investigators, that would put the participant at undue risk or interfere with the conduct of the study per protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) | Change from pre-treatment to 4-weeks post-treatment | Post-traumatic stress disorder (PTSD) symptom severity will be measured via the diagnostic interview, the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), where the CAPS-5 score range = 0 - 80. Higher scores = more severe PTSD symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event Checklist (AE Checklist) | The Modified-FIBSER is collected at every WET session (sessions 1-5), over a timeframe of up to 10 weeks | The Adverse Event Checklist (AE Checklist) is a list of standard complaints that includes frequent side effects of methylphenidate. The AE Checklist will be used to guide evaluation of adverse events and to help determine AE occurrence, AE-related medication dose adjustments, AE-related medication discontinuation, or AE-related study withdrawal. Greater number of items endorsed = greater occurrence of adverse events. |
| Modified Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) Scale | The Modified-FIBSER is collected at every WET session (sessions 1-5), over a timeframe of up to 10 weeks | Self-rated severity of within session side effects as measured by a Modified Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) Scale . The FIBSER scale is a self-report measure providing 3 global ratings of frequency, intensity, and burden to assess side effects of pharmacotherapy. The scale was modified to measure perceived within-session medication side-effects and the degree to which they interfere with Written Exposure Therapy session goals. The M-FIBSER will be used to guide evaluation of side effects and to help determine study medication tolerability. The M-FIBSER score has three items ranging 0 - 6. Higher scores = more severe frequent/severe/or burdensome side effects. |
| Fear Extinction learning | Change from pre-treatment to 4-weeks post-treatment | Fear potentiated startle is a behavioral indicator of conditioned fear responses, collected during extinction, measured using eyeblink electromyogram (EMG) response. Extinction learning (change in response to conditioned fear cue) as measured by EMG during extinction training session is the secondary outcome measure. EMG responses are measured as arbitrary digital units 0-4095 AU (0.5 mV input unit=2500 mV output unit). |
Countries
United States
Contacts
CONTACTAndrea Townsend, PhD
CONTACTVictoria B Risbrough
PRINCIPAL_INVESTIGATORAndrea Townsend, PhD
VA San Diego Healthcare System, San Diego, CA
PRINCIPAL_INVESTIGATORVictoria B Risbrough
VA San Diego Healthcare System, San Diego, CA
Outcome results
None listed