Ketamine for Post-Traumatic Stress Disorder

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

100 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety and efficacy of repeated doses of ketamine as compared to placebo to reduce symptoms of Posttraumatic Stress Disorder (PTSD) among Veteran receiving Prolonged Exposure Therapy.

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.

What data supports the effectiveness of the drug ketamine for treating PTSD?

Research shows that ketamine, known for its rapid antidepressant effects, can quickly reduce PTSD symptoms. Studies indicate that repeated intravenous ketamine significantly improved PTSD symptoms in civilian populations, although results were mixed in military populations. ^{1 2 3 4 5}

Is ketamine generally safe for human use?

Ketamine has been used safely in humans for many years, especially in low doses for short-term treatments. However, it can cause side effects like increased blood pressure and heart rate, and its long-term safety is not well established. It is important to monitor for potential addiction and mental effects. ^{6 7 8 9 10}

How does ketamine differ from other drugs for PTSD?

Ketamine is unique for PTSD treatment because it acts rapidly to reduce symptoms, unlike traditional treatments that may take weeks to show effects. It is administered intravenously (through a vein) and has shown potential in cases where other treatments have failed, although its effectiveness can vary among different populations. ^{5 11 12 13 14}

Research Team

Paulo R Shiroma, MD

Principal Investigator

Minneapolis VA Health Care System, Minneapolis, MN

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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, 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, 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. [2021]

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

The emergence of ketamine as a novel treatment for posttraumatic stress disorder. [2020]

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

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

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

Ketamine for Treatment of Posttraumatic Stress Disorder: State of the Field. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]

7. England pubmed.ncbi.nlm.nih.gov

The effect of intravenous administration of variable-dose midazolam after fixed-dose ketamine in healthy awake cats. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England 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. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Immediate ketamine treatment does not prevent posttraumatic stress responses in an animal model for PTSD. [2014]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Assessment of Ketamine and Its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness. [2020]

13. New Zealand 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. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Repeated oral esketamine in patients with treatment resistant depression and comorbid posttraumatic stress disorder. [2023]