Methylphenidate for Post-Traumatic Stress Disorder

(IMPACT Trial)

Recruiting at 2 trial locations

Overseen By Carolyn L Fort, BS

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: VA Office of Research and Development

Must not be taking: Antipsychotics, Mood stabilizers, MAOIs, others

Disqualifiers: Bipolar, Schizophrenia, Substance use, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

Posttraumatic stress disorder (PTSD) is frequently accompanied by difficulty concentrating, poor memory, and inability to keep up with tasks, which negatively impacts a person's ability to function at work and in relationships. Currently available treatments do not fully relieve all symptoms. A published research report showed positive evidence that the stimulant medication methylphenidate was beneficial in treating these problems. This study will evaluate the ability of methylphenidate to treat PTSD and associated neurocognitive complaints in Veterans. An innovative feature is the study's N-of-1 design. In this design, every participant will move back and forth every 4-5 weeks between treatment with methylphenidate and treatment with placebo, in random order and under double-blind conditions, over a 20-week period. The investigators will compare the aggregated change in PTSD and neurocognitive symptoms between periods of treatment with methylphenidate versus placebo. Results will help clinicians to better choose the best treatment for Veterans living with PTSD.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as antipsychotics, mood stabilizers, monoamine oxidase inhibitors, stimulants, atomoxetine, or bupropion, at least 2 weeks before starting. If you are receiving trauma-focused therapy for PTSD, you must complete it before joining the study.

What evidence supports the effectiveness of the drug Methylphenidate for treating PTSD?

A small pilot study found that Methylphenidate led to significant improvements in cognitive complaints and PTSD symptoms compared to a placebo, suggesting it may help with emotional and cognitive issues in PTSD. However, larger studies are needed to confirm these findings. ^{1 2 3 4 5}

Is methylphenidate generally safe for use in humans?

Methylphenidate, used in various forms for treating ADHD, is generally considered safe and well-tolerated in children and adolescents. Common side effects include decreased appetite, insomnia, and irritability, but serious adverse events are rare. Safety studies show no unexpected safety concerns, and the drug is comparable to other stimulant treatments. ^{6 7 8 9 10}

How does the drug methylphenidate differ from other drugs for PTSD?

Methylphenidate, commonly used for ADHD, is being explored for PTSD due to its potential to improve cognitive and emotional symptoms, which is different from the more commonly used antidepressants like SSRIs. This drug showed promising results in a small study, suggesting it might help with cognitive complaints and PTSD symptoms, but more research is needed to confirm its effectiveness. ^{1 2 4 11 12}

Research Team

Rebecca C. Hendrickson, MD PhD

Principal Investigator

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Eligibility Criteria

This trial is for US military Veterans aged 18-65 with PTSD, who have trouble concentrating or remembering things. They must be able to consent and not be pregnant, planning pregnancy, or breastfeeding. Participants need a certain score on PTSD and cognitive tests but can't join if they have dementia, severe mental health issues like bipolar I or schizophrenia, recent substance abuse (except caffeine/nicotine), are at high risk of suicide, or are taking excluded medications.

Inclusion Criteria

CAPS-5 past month total score greater than or equal to 26

Subjective neurocognitive impairment, defined as a total score of greater than or equal to 25 (1 standard deviation below the mean) on the NeuroQoL Cognitive Function 8-item self-report form.

I have been diagnosed with PTSD according to DSM-5.

Exclusion Criteria

I have completed a trauma-focused therapy for PTSD within the last 2 weeks.

Prior allergic reaction to any MPH formulation

Current enrollment in another interventional trial for PTSD

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sequential 4-week periods of methylphenidate and placebo, in randomized order, separated by 1-week washout periods, for a total of 20 weeks

20 weeks

Weekly or biweekly assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Methylphenidate (Central Nervous System Stimulant)
• Placebo (Behavioural Intervention)

Trial Overview The study tests Methylphenidate's effectiveness in treating PTSD-related cognitive issues in Veterans using an N-of-1 design. Each participant alternates between the drug and placebo every 4-5 weeks over 20 weeks under double-blind conditions to compare changes in symptoms during different treatment periods.

Participant Groups

Group I: N-of-1 crossover study enrollment: start with placebo Experimental Treatment 2 Interventions

All participants spend time receiving both active study drug (methylphenidate) and placebo (sham study drug), in randomized order, across 4 treatment blocks separated by 1 week washout periods (where no study drug is given).

Group II: N-of-1 crossover study enrollment: start with methylphenidate Experimental Treatment 2 Interventions

All participants spend time receiving both active study drug (methylphenidate) and placebo (sham study drug), in randomized order, across 4 treatment blocks separated by 1 week washout periods (where no study drug is given).

Methylphenidate is already approved in Canada for the following indications:

Approved in Canada as Methylphenidate for:

• Attention Deficit Hyperactivity Disorder (ADHD)
• Narcolepsy

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

In a 12-week trial involving 32 participants with PTSD and/or TBI, methylphenidate significantly improved cognitive complaints compared to placebo, indicating its potential efficacy for these conditions.

The treatment was well tolerated, suggesting a favorable safety profile, but further research with a larger sample size is needed to confirm these promising results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury. McAllister, TW., Zafonte, R., Jain, S., et al.[2018]

Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, paroxetine, and sertraline show a statistically significant but small effect in reducing PTSD symptoms compared to placebo, based on a systematic review of 115 randomized controlled trials.

Prazosin and risperidone also demonstrate small positive effects when used to augment other treatments, but no single pharmacological intervention was found to be superior to others in head-to-head comparisons.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological therapy for post-traumatic stress disorder: a systematic review and meta-analysis of monotherapy, augmentation and head-to-head approaches. Hoskins, MD., Bridges, J., Sinnerton, R., et al.[2023]

A review of 18 clinical trials found that atypical antipsychotics, particularly risperidone and quetiapine, provide a modest benefit in treating PTSD symptoms, especially intrusive thoughts and hypervigilance.

The effect sizes from double-blind placebo-controlled trials were small, indicating that while there is some positive response, larger studies are necessary to better understand the effectiveness and potential side effects of these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of atypical antipsychotic medications for posttraumatic stress disorder. Ahearn, EP., Juergens, T., Cordes, T., et al.[2015]

Pharmaceutical treatments, particularly amitriptyline, imipramine, and quetiapine, significantly improve symptoms of combat-related PTSD compared to placebo, with a moderate effect size across various PTSD symptoms.

While there was no significant increase in overall adverse events from these medications, higher discontinuation rates due to adverse effects were noted, indicating the need for careful monitoring in patients, especially those with severe PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness, Acceptability and Safety of Pharmaceutical Management for Combat-Related PTSD in Adults Based on Systematic Review of Twenty-Two Randomized Controlled Trials. Yan, JZ., Liu, JL., Li, XZ., et al.[2022]

Selective serotonin reuptake inhibitors (SSRIs) are supported by the largest body of evidence for both short- and long-term efficacy in treating PTSD, while initial findings for venlafaxine and risperidone also show promise.

There is insufficient evidence for the effectiveness of benzodiazepines in treating PTSD, despite their common use, and alternative treatments like prazosin and atypical antipsychotics may help in treatment-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-based pharmacotherapy of post-traumatic stress disorder (PTSD). Ipser, JC., Stein, DJ.[2022]

In a study involving 308 patients aged 6-17 with ADHD, 65% showed significant improvement after 3 weeks of treatment with Metadate CD, indicating its effectiveness in real-world clinical practice.

The majority of patients (87%) reported satisfaction with Metadate CD, and those switching from other methylphenidate formulations found it to be as effective or better, with adverse events aligning with existing safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A postmarketing clinical experience study of Metadate CD. Dirksen, SJ., D'Imperio, JM., Birdsall, D., et al.[2019]

In a 1-year study involving 282 children aged 6-12 with ADHD, SDX/d-MPH was found to be safe and well tolerated, with 60.1% of participants experiencing treatment-emergent adverse events, mostly mild to moderate.

The treatment led to significant reductions in ADHD symptoms, demonstrating sustained efficacy over the year, comparable to other methylphenidate products, with no unexpected safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Tolerability of Serdexmethylphenidate/Dexmethylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder: A 12-Month, Open-Label Safety Study. Childress, AC., Marraffino, A., Cutler, AJ., et al.[2023]

In a study involving 149 children aged 6-12 with ADHD, the once-daily medication SDX/d-MPH significantly improved ADHD symptoms compared to placebo, showing a rapid onset and extended duration of efficacy.

The treatment was found to be safe, with no serious adverse events reported, although common side effects included insomnia and decreased appetite, similar to those seen with other stimulant medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Controlled Laboratory Classroom Study of Serdexmethylphenidate and d-Methylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder. Kollins, SH., Braeckman, R., Guenther, S., et al.[2021]

The study involved 119 preschool children aged 4 to <6 years with ADHD, showing that the methylphenidate hydrochloride extended-release capsule (MPH-MLR) significantly reduced ADHD symptoms, with mean ADHD-RS-IV scores dropping from 40.8 to 19.5 during the open-label phase.

In a double-blind phase, children receiving MPH-MLR had a significantly greater improvement in ADHD symptoms compared to those on placebo, with common side effects including decreased appetite and insomnia, consistent with known effects of methylphenidate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Titration Study of Methylphenidate Hydrochloride Extended-Release Capsules (Aptensio XR) in Preschool Children with Attention-Deficit/Hyperactivity Disorder. Childress, AC., Kollins, SH., Foehl, HC., et al.[2021]

Controlled-delivery methylphenidate (methylphenidate CD) is effective and well tolerated for treating ADHD in children aged 6 and older, showing superior control of symptoms compared to osmotic release methylphenidate during a typical school day.

In clinical trials lasting 3 weeks, methylphenidate CD was found to be more effective than a placebo and equally effective as immediate-release methylphenidate, making it a strong option for managing ADHD symptoms during school hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methylphenidate controlled-delivery capsules (EquasymXL, Metadate CD): a review of its use in the treatment of children and adolescents with attention-deficit hyperactivity disorder. Anderson, VR., Keating, GM.[2018]

Post-traumatic stress disorder (PTSD) can lead to long-lasting symptoms like intrusive thoughts and emotional numbing, affecting social and occupational functioning, and is linked to higher suicide risk.

While psychotherapy, especially cognitive behavioral therapy, is effective for PTSD, there is a significant need for proven pharmacological treatments to address core symptoms and prevent the disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-traumatic stress disorder: emerging concepts of pharmacotherapy. Baker, DG., Nievergelt, CM., Risbrough, VB.[2021]

Current pharmacologic treatments for PTSD, such as antidepressants and anxiolytics, are based on drugs developed for other conditions, highlighting a need for more targeted therapies.

Future drug development for PTSD may focus on novel classes of compounds that directly address the disorder's unique biological mechanisms, including corticotropin-releasing factor antagonists and neuropeptide Y enhancers, which could lead to more effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy? Friedman, MJ.[2013]

References

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

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury. [2018]

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

Pharmacological therapy for post-traumatic stress disorder: a systematic review and meta-analysis of monotherapy, augmentation and head-to-head approaches. [2023]

3. England pubmed.ncbi.nlm.nih.gov

A review of atypical antipsychotic medications for posttraumatic stress disorder. [2015]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness, Acceptability and Safety of Pharmaceutical Management for Combat-Related PTSD in Adults Based on Systematic Review of Twenty-Two Randomized Controlled Trials. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Evidence-based pharmacotherapy of post-traumatic stress disorder (PTSD). [2022]

6. England pubmed.ncbi.nlm.nih.gov

A postmarketing clinical experience study of Metadate CD. [2019]

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

Safety and Tolerability of Serdexmethylphenidate/Dexmethylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder: A 12-Month, Open-Label Safety Study. [2023]

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

A Randomized, Controlled Laboratory Classroom Study of Serdexmethylphenidate and d-Methylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder. [2021]

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

Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Titration Study of Methylphenidate Hydrochloride Extended-Release Capsules (Aptensio XR) in Preschool Children with Attention-Deficit/Hyperactivity Disorder. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Methylphenidate controlled-delivery capsules (EquasymXL, Metadate CD): a review of its use in the treatment of children and adolescents with attention-deficit hyperactivity disorder. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Post-traumatic stress disorder: emerging concepts of pharmacotherapy. [2021]

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

What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy? [2013]