Ketamine for PTSD and Depression in TBI

Overseen By Seth Dsiner, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Minneapolis Veterans Affairs Medical Center

Must be taking: Antidepressants, Trazodone, Atypical neuroleptics

Must not be taking: MAO inhibitors, Memantine, Long benzodiazepines

Disqualifiers: Psychosis, Severe TBI, Substance use, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 3 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to examine the use of sedative ketamine to treat depression and post-traumatic stress disorder (PTSD) in Veterans with mild to moderate traumatic brain injury (TBI). The main questions it aims to answer are: * Efficacy of ketamine to reduce symptoms of depression and/or PTSD * Safety of ketamine to treat depression and/or PTSD in TBI Participants will be randomly assigned to receive either ketamine or midazolam (active placebo) twice a week for 3 weeks. During participation, subjects will be interviewed, have lab tests, and complete rating scales, and questionnaires.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you need to have stable treatment with certain medications like FDA-approved antidepressants, trazodone, atypical neuroleptics, prazosin, or clonidine for at least 4 weeks before starting. Some medications, like monoamine oxidase inhibitors and certain benzodiazepines, are not allowed.

What data supports the effectiveness of the drug ketamine for PTSD and depression in TBI?

Research shows that ketamine can rapidly reduce symptoms of PTSD and depression. It has been effective in treating depression, including treatment-resistant cases, and has shown potential in reducing PTSD symptoms, although results can vary based on the population. ^{1 2 3 4 5}

Is ketamine generally safe for use in humans?

Ketamine has been studied for its use in treating depression, showing rapid effects but also some side effects like psychiatric and cardiovascular issues. While it is generally well-tolerated, more research is needed to understand its long-term safety, especially with repeated use. ^{2 6 7 8 9}

How is the drug ketamine unique for treating PTSD and depression in TBI?

Ketamine is unique because it acts rapidly to reduce symptoms of PTSD and depression, unlike traditional antidepressants that can take weeks to work. It works through a novel mechanism by blocking NMDA receptors in the brain, and it can be administered intravenously, providing fast relief. ^{5 10 11 12 13}

Eligibility Criteria

This trial is for Veterans with mild to moderate traumatic brain injury (TBI) who are experiencing depression or PTSD. Participants must be able to attend multiple treatment sessions and complete assessments. Specific criteria for inclusion or exclusion were not provided.

Inclusion Criteria

Willingness/able to sign informed consent

I had a mild to moderate brain injury over 12 weeks ago, meeting specific health guidelines.

I have been on a stable dose of certain mental health medications for at least 4 weeks.

Exclusion Criteria

Imminent risk of suicidal/homicidal ideation and/or behavior with intent and/or plan

Lifetime history of psychosis-related disorder, current episode of mania/hypomania/mixed assessed by the Mini-International Neuropsychiatric Interview (MINI 7.0 for DSM-5)

I have not received ketamine treatment in the past 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ketamine or midazolam (active placebo) twice a week for 3 weeks

3 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketamine

Trial Overview The study tests if ketamine, given as a sedative, can help reduce symptoms of depression and PTSD in TBI patients compared to midazolam (an active placebo). Treatments are administered twice weekly over three weeks while monitoring through interviews, lab tests, and questionnaires.

Participant Groups

Group I: Ketamine Experimental Treatment 1 Intervention

Twice a week ketamine IV 0.5 mg/kg

Group II: Midazolam Active Control 1 Intervention

Twice a week midazolam IV 0.045 mg/kg

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Minneapolis Veterans Affairs Medical Center

Lead Sponsor

Trials

77

Recruited

355,000+

Findings from Research

In a study of 9016 patients receiving ketamine intravenous therapy (KIT) for depression, 53.6% showed a significant response (≥50% reduction in depression scores) within 14-31 days, indicating KIT's efficacy in real-world settings.

While most patients benefited from KIT, a small percentage (8.4%) experienced worsening depressive symptoms, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. McInnes, LA., Qian, JJ., Gargeya, RS., et al.[2023]

Oral ketamine has shown effectiveness in treating severe depression, including treatment-resistant cases and those with suicidal ideation, based on various studies including randomized controlled trials with doses ranging from 0.25 to 7 mg/kg.

Despite its lower bioavailability (20%-25% reaching the bloodstream), oral ketamine is well tolerated and can be adjusted for individual needs, making it a practical option for depression treatment alongside conventional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Andrade, C.[2019]

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]

This systematic review analyzed 60 studies on the safety of ketamine for treating depression, revealing that acute doses of ketamine led to more frequent side effects, including psychiatric and cardiovascular issues, compared to placebo.

There is a notable lack of data on the long-term safety and effects of repeated ketamine dosing, highlighting the need for large-scale clinical trials to better understand its safety profile over extended use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side-effects associated with ketamine use in depression: a systematic review. Short, B., Fong, J., Galvez, V., et al.[2019]

Subcutaneous (SC) administration of racemic ketamine and esketamine has shown rapid and robust antidepressant effects in both unipolar and bipolar patients, with response and remission rates ranging from 50% to 100% after single or multiple doses.

The studies indicated that SC ketamine is generally well-tolerated, with only transitory side effects, making it a promising and cost-effective treatment option for depression, especially in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. Cavenaghi, VB., da Costa, LP., Lacerda, ALT., et al.[2021]

Ketamine and esketamine are effective for rapidly alleviating symptoms of treatment-resistant depression, with esketamine being approved for use in the US and EU, while ketamine is often used off-label.

Both treatments may require repeated doses and the addition of standard antidepressants to sustain their effects, but they also carry risks of adverse effects and potential for abuse, highlighting the need for further research on their long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy: Ketamine and Esketamine. Feeney, A., Papakostas, GI.[2023]

A single intravenous infusion of ketamine has been shown to provide rapid but temporary relief from symptoms of treatment-resistant major depressive disorder (MDD) and bipolar depression, indicating its potential as a quick intervention for severe cases.

While generally safe and well tolerated when administered by trained professionals, concerns exist regarding the long-term side effects, including dissociative symptoms and risk of abuse, highlighting the need for standardized treatment guidelines for ketamine use in psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for Treatment-Resistant Mood Disorders. Park, LT., Falodun, TB., Zarate, CA.[2023]

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, an NMDA receptor antagonist, has shown rapid and significant antidepressant effects in treatment-resistant depression (TRD), with an (S)-ketamine nasal spray now approved for use alongside oral antidepressants in the U.S. and Europe.

Despite its effectiveness, challenges such as maintaining response, potential side effects, and abuse risk remain, highlighting the need for further research to develop safer, next-generation rapid-acting antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for depression. Jelen, LA., Stone, JM.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. [2023]

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

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. [2019]

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

Anxiolytic effects of acute and maintenance ketamine, as assessed by the Fear Questionnaire subscales and the Spielberger State Anxiety Rating Scale. [2021]

4. England pubmed.ncbi.nlm.nih.gov

A systematic review of ketamine for the treatment of depression among older adults. [2021]

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

Side-effects associated with ketamine use in depression: a systematic review. [2019]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021]

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

Pharmacotherapy: Ketamine and Esketamine. [2023]

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

Ketamine for Treatment-Resistant Mood Disorders. [2023]

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

Repeated ketamine infusions for antidepressant-resistant PTSD: Methods of a multicenter, randomized, placebo-controlled clinical trial. [2020]

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. England pubmed.ncbi.nlm.nih.gov

Ketamine for depression. [2021]