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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether ketamine, an anesthetic and potential antidepressant, can reduce symptoms of depression and PTSD in Veterans with mild to moderate traumatic brain injury (TBI). Participants will receive either ketamine or midazolam, a similar drug acting as a placebo, twice a week for three weeks. The trial aims to assess ketamine's effectiveness and safety for these conditions. Veterans with a TBI who have not responded well to at least one antidepressant may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that ketamine might be a promising treatment for PTSD and depression. A large study involving over 8,000 PTSD patients found that ketamine significantly reduced their symptoms. Many of these patients also experienced improvements in depression, suggesting ketamine could help with both conditions.

Regarding safety, ketamine is generally well-tolerated. Some individuals might feel dizzy or notice an increased heart rate or higher blood pressure. These side effects are usually brief and not serious. As this trial is in a middle phase, existing evidence supports its safety, but more research is needed to understand long-term effects. Prospective participants should discuss potential risks and benefits with the medical team. ^{1 2 3 4 5}

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

Unlike the standard treatments for PTSD and depression in traumatic brain injury (TBI), such as antidepressants and psychotherapy, ketamine offers a rapid onset of action. Most treatments take weeks to show effectiveness, but ketamine can provide relief in just a few days. Ketamine works uniquely by targeting the brain's NMDA receptors, which is different from the common approach of altering serotonin levels. Researchers are excited about ketamine because it not only offers faster results but also opens up new pathways for treating these complex conditions.

What evidence suggests that ketamine might be an effective treatment for PTSD and depression in TBI?

Research has shown that ketamine can effectively reduce symptoms of PTSD and depression. In a study involving over 8,000 PTSD patients, 87% of whom also had depression, ketamine therapy significantly eased their symptoms. Another study found that repeated intravenous doses of ketamine provided quick and lasting relief for PTSD symptoms. In this trial, participants will receive either ketamine or midazolam. For individuals with traumatic brain injury (TBI), ketamine may help with mental health issues, though it requires careful use. The evidence highlights ketamine's potential to improve mental health conditions, making it a promising treatment option for those dealing with PTSD and depression, even if they have TBI. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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 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 (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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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. clinicaltrials.gov clinicaltrials.gov/study/NCT06228391

Ketamine Treatment for PTSD and MDD in TBI 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 ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165178125003373

A retrospective analysis of ketamine intravenous therapy ... In a large real-world sample of 8,136 PTSD patients (87 % with comorbid depression), Ketamine Intravenous Therapy (KIT) significantly reduced PTSD and ...

4. 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 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8858880/

Long-term increase in sensitivity to ketamine's behavioral ... The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12529321/

Ketamine for treatment-resistant post-traumatic stress disorder Ketamine is a promising treatment for post-traumatic stress disorder (PTSD), but further research is required to extend early findings.