Ketamine for Post-Traumatic Stress Disorder

No longer recruiting at 1 trial location

Overseen By Paulo R Shiroma, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Disqualifiers: Pregnancy, Suicide risk, Head injury, Psychosis, Mania, Substance use, others

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

Compensation: Varies

Number of Visits: 10

Duration: 10 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of ketamine in reducing PTSD symptoms in Veterans undergoing Prolonged Exposure Therapy. Researchers will compare ketamine, typically used for anesthesia, to midazolam, a sedative, to determine which better alleviates PTSD symptoms. Veterans with a PTSD diagnosis who can consent to participate might be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to important findings.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that ketamine is generally safe and well-tolerated for treating post-traumatic stress disorder (PTSD) and depression that doesn't respond to other treatments. Common side effects in these studies included dizziness, mild confusion, or increased blood pressure, but these effects were usually temporary and manageable.

Although ketamine is not yet specifically approved for PTSD, its use in depression provides some confidence in its safety. However, more research is needed to fully understand its effects on PTSD.

For any concerns about joining a trial, discussing them with a healthcare professional is important. They can provide personalized information and assist in making an informed decision. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PTSD?

Researchers are excited about using ketamine for treating PTSD because it works differently from most current treatments. Unlike standard options that typically involve SSRIs or therapy, ketamine acts rapidly, potentially providing relief within hours by targeting the brain's glutamate system rather than serotonin. Additionally, ketamine is administered intravenously, which might enhance its quick action compared to oral medications. This unique mechanism and delivery method could offer new hope for individuals who haven't responded well to traditional therapies.

What evidence suggests that this trial's treatments could be effective for PTSD?

Research has shown that ketamine can help reduce PTSD symptoms. One study found that repeated ketamine infusions through an IV significantly improved patients' PTSD symptoms, as measured by a PTSD-specific checklist. Another study found that ketamine therapy had lasting effects, with benefits observed up to six months later. Although the exact mechanism remains unclear, ketamine is believed to quickly affect certain brain pathways, easing symptoms. In this trial, participants will receive either ketamine or midazolam, both combined with prolonged exposure therapy, to evaluate their effectiveness in treating PTSD. Overall, these findings suggest that ketamine could be a promising treatment for PTSD. ^{1 2 4 6 7}

Who Is on the Research Team?

Paulo R Shiroma, MD

Principal Investigator

Minneapolis VA Health Care System, Minneapolis, MN

Are You a Good Fit for This Trial?

This trial is for male and female Veterans aged 18-75 with PTSD. Participants must be able to consent to the study. It's not suitable for those with a history of severe head injury, mania/hypomania, psychosis, recent severe substance/alcohol abuse, or women who are pregnant/breastfeeding. High suicide risk individuals are also excluded.

Inclusion Criteria

I am a Veteran aged between 18 and 75.

ability to provide written informed consent

I have been diagnosed with PTSD.

Exclusion Criteria

You have had a serious head injury in the past.

You are currently experiencing a period of extreme excitement or irritability.

You have a history of mental illness that includes losing touch with reality.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ketamine or midazolam via intravenous infusion once per week for 3 weeks, followed by 7 additional Prolonged Exposure (PE) therapy sessions

10 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine
• Midazolam

Trial Overview The study tests if ketamine can help reduce PTSD symptoms more effectively than a placebo when given alongside Prolonged Exposure Therapy—a common treatment for PTSD—to Veterans.

How Is the Trial Designed?

Group I: Ketamine and prolonged exposure (PE) Experimental Treatment 1 Intervention

Single IV ketamine 0.5 mg/kg 24-72 hrs prior to PE session at week 1,2, and 3 followed by 7 additional PE sessions.

Group II: Midazolam and prolonged exposure (PE) Placebo Group 1 Intervention

Single IV midazolam 0.045 mg/kg 24-72 hrs prior to PE session at week 1,2, and 3 followed by 7 additional PE sessions.

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

An extended release oral ketamine tablet was found to be safe and well tolerated in a study of seven patients with treatment-resistant depression/anxiety, with no significant changes in vital signs and only one brief report of dissociation.

All patients experienced over 50% improvements in mood ratings over 96 hours, suggesting that while the onset of mood improvement is slightly delayed compared to injectable forms, this oral formulation could be a promising option for treating resistant depression and anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Glue, P., Medlicott, NJ., Neehoff, S., et al.[2022]

Ketamine, an NMDA receptor antagonist, shows promising rapid antidepressant effects in PTSD, with evidence from various studies including case reports and randomized trials, indicating its potential as a treatment option for this challenging condition.

Despite the variability in clinical presentation and treatment approaches, ketamine demonstrates encouraging safety and efficacy signals, suggesting it could be a valuable off-label intervention for patients with chronic, refractory PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence. Ragnhildstveit, A., Roscoe, J., Bass, LC., et al.[2023]

Ketamine, a noncompetitive NMDA receptor antagonist, shows promise as a rapid-onset treatment for chronic PTSD, with initial clinical trials indicating its potential to quickly reduce symptoms in patients.

Ongoing research is exploring the efficacy of repeated ketamine infusions and its ability to enhance psychotherapeutic interventions, suggesting that ketamine may help modify fear responses and improve neural connectivity in individuals with PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emergence of ketamine as a novel treatment for posttraumatic stress disorder. Feder, A., Rutter, SB., Schiller, D., et al.[2020]

Ketamine, when administered in subanesthetic doses, does not significantly impair cognitive functions in patients with depression or PTSD in the short term, contrasting with the cognitive dysfunction observed in healthy subjects.

The drug may have procognitive effects, particularly in executive function, suggesting that it could enhance psychotherapy interventions for PTSD and depression, warranting further research into its cognitive benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of Neurocognitive Effects of Subanesthetic Doses of Intravenous Ketamine in Major Depressive Disorder, Post-Traumatic Stress Disorder, and Healthy Population. Shiroma, PR., Velit-Salazar, MR., Vorobyov, Y.[2022]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

Ketamine has shown promise as a rapid-acting treatment for PTSD, with a single intravenous dose leading to a quick reduction in symptoms, particularly in civilian populations.

In a study involving repeated IV ketamine administration, significant improvements in PTSD symptoms were observed compared to midazolam, but this effect was not seen in veteran and military populations, indicating the need for further research on its efficacy across different groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for Treatment of Posttraumatic Stress Disorder: State of the Field. Fremont, R., Brown, O., Feder, A., et al.[2023]

In a study involving twelve healthy unmedicated cats, the combination of ketamine and midazolam showed that midazolam doses between 0.05 mg/kg and 0.5 mg/kg had beneficial effects, such as reducing muscle rigidity and nociceptive responses, without significantly delaying recovery compared to ketamine alone.

However, higher doses of midazolam (5.0 mg/kg) prolonged recovery times and led to adverse behavioral effects like restlessness and vocalization, indicating a need for careful dosing to avoid negative outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of intravenous administration of variable-dose midazolam after fixed-dose ketamine in healthy awake cats. Ilkiw, JE., Suter, CM., McNeal, D., et al.[2019]

Ketamine has shown rapid antidepressant effects in several well-controlled studies and is also beneficial for conditions like post-traumatic stress disorder and obsessive-compulsive disorder, although these effects are often short-lived after single infusions.

While ketamine is considered safe for occasional use at sub-anesthetic doses, concerns about neurotoxicity, psychotomimetic effects, and potential for addiction highlight the need for further research on the safety of prolonged use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Has psychiatry tamed the "ketamine tiger?" Considerations on its use for depression and anxiety. Rasmussen, KG.[2015]

In a study involving 367 patients with mood disorders, ketamine demonstrated significant efficacy in improving clinical outcomes compared to both midazolam and saline, with effect sizes of 0.7 and 1.8 respectively, indicating strong therapeutic potential.

Using midazolam as a control in ketamine studies resulted in smaller observed effects of ketamine compared to using saline, suggesting that midazolam may enhance the perceived effectiveness of ketamine due to its own impact on mood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Wilkinson, ST., Farmer, C., Ballard, ED., et al.[2021]

Ketamine, traditionally used in anesthesia, shows promise as a treatment for major depression and PTSD in combat veterans, as demonstrated in a case report of a patient with treatment-resistant symptoms.

The patient experienced significant short-term relief from debilitating depression and PTSD symptoms following intravenous ketamine infusion, suggesting its potential efficacy in psychiatric settings when side effects are managed appropriately.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ketamine on major depressive disorder in a patient with posttraumatic stress disorder. Womble, AL.[2013]

In a study involving 107 animals, administering ketamine immediately after exposure to stress did not alleviate PTSD-like behaviors 30 days later and may have worsened symptoms, as indicated by increased freezing behavior when exposed to trauma cues.

Ketamine treatment was associated with suppressed corticosterone levels in stressed animals, suggesting a disruption in the stress response system, which could contribute to the long-term ineffectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immediate ketamine treatment does not prevent posttraumatic stress responses in an animal model for PTSD. Juven-Wetzler, A., Cohen, H., Kaplan, Z., et al.[2014]

A study on male Sprague-Dawley rats exposed to organophosphates showed symptoms similar to Gulf War Illness (GWI), indicating a potential model for studying GWI-related depression.

Treatment with ketamine at sub-anesthetic doses significantly improved depressive-like behaviors in these rats, with effects observed as early as 1 hour and lasting up to 24 hours, suggesting ketamine may be a promising intervention for GWI-related depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Ketamine and Its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness. Zhu, J., Hawkins, E., Phillips, K., et al.[2020]

In a study involving five patients with treatment-resistant depression (TRD) and comorbid PTSD, repeated oral esketamine treatment led to improvements in depressive symptoms and increased receptiveness to psychotherapy over a duration of six weeks to a year.

While most patients showed positive responses, one individual experienced symptom worsening in a stressful situation, emphasizing the importance of administering esketamine in a safe environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated oral esketamine in patients with treatment resistant depression and comorbid posttraumatic stress disorder. Veraart, JKE., van Westenbrugge, M., van Wulfften Palthe, JE., et al.[2023]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10979792/

Effectiveness of Ketamine for the Treatment of Post- ... Outcomes. The primary outcome of interest was the improvement in PTSD symptoms, assessed using the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) ...

2. cda-amc.ca cda-amc.ca/sites/default/files/pdf/htis/2022/RC1420-Ketamine-for-treatment-resistant-depression-and-PTSD.pdf

Ketamine for Adults With Treatment-Resistant Depression ... One randomized controlled trial with small sample size found that repeated IV ketamine infusions significantly improved post-traumatic stress disorder symptoms ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02397889

Study Details | NCT02397889 | Ketamine as a Treatment ... The purpose of this study is to see whether ketamine, when given repeatedly intravenously can produce a quick and persistent improvement in PTSD symptoms. At ...

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/ibra.12094

Ketamine as a therapeutic agent in major depressive ... In this article, the effectiveness of ketamine as a potential therapeutic for PTSD and MDD along with its mechanisms of action, clinical trials, and possible ...

5. researchgate.net researchgate.net/publication/367222323_Ketamine-assisted_psychotherapy_provides_lasting_and_effective_results_in_the_treatment_of_depression_anxiety_and_post_traumatic_stress_disorder_at_3_and_6_months_Findings_from_a_large_single-arm_retr

Ketamine-assisted psychotherapy provides lasting and ... Ketamine-assisted psychotherapy provides lasting and effective results in the treatment of depression, anxiety and post traumatic stress disorder at 3 and 6 ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK602384/

Ketamine for Adults With Treatment-Resistant Depression or ... A 2022 CADTH report 24 on the use of ketamine for PTSD or TRD found insufficient evidence to provide definitive conclusions about its clinical effectiveness.

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK551873/

Intravenous Ketamine for Adults with Treatment-Resistant ... Three randomized controlled trials reported that intravenous ketamine was significantly more effective than placebo or midazolam for the treatment of adults ...