Ketamine for Depression

Recruiting at 1 trial location

Overseen By Nicholas Murphy

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must be taking: Psychotropic medications

Must not be taking: NMDA, AMPA, Opioids, others

Disqualifiers: Psychotic disorders, Major medical problems, others

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

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

Compensation: Varies

Number of Visits: 8

100 Participants Needed

Trial Summary

What is the purpose of this trial?

The core objective of this study is to enhance the translational potential of this electroencephalogram (EEG) biomarker by using ketamine(KET)-induced gamma potentiation as a prognostic marker of 4-week treatment outcome. Previous research focused exclusively on KET-induced gamma band potentiation (GBP) in the context of a single infusion. Our study design captures the clinical variation associated with real-world treatment resistant depression (TRD) patients and allows us to analyze the relative importance of GBP to antidepressant symptom reduction across the induction phase of treatment. If successful, it provides a compelling rationale for a larger prospective investigation of gamma dynamics as a moderator of outcome to varied TRD therapies which impact the balance of cortical excitation and inhibition.

Will I have to stop taking my current medications?

Participants must be on a stable dose of their current psychotropic medications for at least 4 weeks before the study. However, certain medications, like those affecting specific brain receptors, benzodiazepines over 6mg/day, prescription opioids, and some dietary supplements, must be stopped before the study.

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

Research shows that intravenous ketamine can quickly and significantly improve depression symptoms, even in patients who haven't responded to other treatments. Studies have demonstrated its rapid antidepressant effects, providing relief for about 2-3 weeks after treatment. ^{1 2 3 4 5}

Is ketamine safe for treating depression?

Ketamine has been shown to have rapid antidepressant effects, but common side effects include a sense of detachment from reality and increased blood pressure. These side effects are generally temporary, and the treatment is considered promising with careful monitoring. ^{6 7 8 9 10}

How is the drug ketamine unique for treating depression?

Ketamine is unique for treating depression because it can produce rapid antidepressant effects, especially when administered subcutaneously (under the skin), which is a convenient and cost-effective method compared to traditional intravenous routes. This makes it particularly beneficial in developing countries, and it has shown promising results with high response rates and manageable side effects. ^{1 7 11 12 13}

Eligibility Criteria

This trial is for individuals with treatment-resistant depression, including those diagnosed with Major Depressive Disorder. Healthy subjects are also included to provide a comparison group. Participants must meet specific criteria not detailed here.

Inclusion Criteria

Level of understanding sufficient to agree to all tests and examinations required by the protocol

My mental health medication doses have been stable for at least 4 weeks.

I have been diagnosed with major depression for at least 4 weeks.

Exclusion Criteria

Patients at serious and imminent risk of suicide and not suitable for an outpatient study

Body mass index (BMI) >=40 kg/m2

I recently started cognitive behavioral therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive ketamine infusions to assess gamma potentiation as a prognostic marker

4 weeks

8 infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Study exit visit (up to a month after infusion)

Treatment Details

Interventions

• Ketamine

Trial Overview The study tests if brain wave patterns (gamma oscillations) can predict how well patients respond to ketamine therapy over four weeks. It involves comparing the effects of saline (a placebo) and ketamine on these brain waves in people with depression.

Participant Groups

Group I: Healthy Controls Active Control 2 Interventions

Healthy controls will receive one saline and ketamine infusion.

Group II: Treatment Resistant Depression Active Control 2 Interventions

Treatment Resistant Depression participants will receive 8 ketamine infusions where their first and fourth infusions are a saline and ketamine infusion.

Group III: Major Depressive Disorder Active Control 2 Interventions

Major Depressive Disorder participants will receive one saline and ketamine infusion.

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?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

A 49-year-old woman with severe treatment-resistant major depression experienced significant improvement after receiving 36 sessions of ketamine intravenous therapy over 10 months, resulting in nearly a 50% reduction in her depressive symptoms.

The case suggests that long-term repeated ketamine therapy could be a viable option for patients with treatment-resistant depression, but further research is needed to determine the best treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. Kwon, JH., Sim, WS., Hong, JP., et al.[2018]

In a European clinical trial, a 55-year-old male with treatment-resistant depression and substance use disorder showed significant improvement in depression symptoms after a single intravenous infusion of ketamine, with reductions in Hamilton Depression Rating Scale (HDRS) scores from 36 to 16 and Beck Depression Inventory (BDI) scores from 26 to 9.

The antidepressant effects of ketamine were rapid, with the patient reporting improvements just 25 minutes into the infusion, and these effects lasted for at least 7 days, demonstrating ketamine's potential as a fast-acting treatment for depression even in patients with co-occurring substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Liebrenz, M., Borgeat, A., Leisinger, R., et al.[2022]

Racemic ketamine and its derivative, S-ketamine, have been shown to provide rapid relief from depressive symptoms, with effects lasting approximately 2-3 weeks after treatment, based on multiple clinical trials.

Further research is needed to optimize dosing strategies, especially for specific populations like obese individuals, and to monitor long-term safety regarding cognitive and organ system effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Key considerations for the use of ketamine and esketamine for the treatment of depression: focusing on administration, safety, and tolerability. Kritzer, MD., Pae, CU., Masand, PS.[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]

Intravenous ketamine has been shown to be safe and effective in rapidly reducing depressive symptoms, including suicidal thoughts, in patients with treatment-resistant unipolar or bipolar depression, based on five controlled studies and additional open-label studies.

While ketamine shows promise as a short-term antidepressant therapy, further research is needed to assess its long-term safety and effectiveness, as well as the efficacy of alternative administration routes like oral or intranasal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for the treatment of depression. Howland, RH.[2022]

Subanaesthetic doses of ketamine have shown substantial efficacy in treating depression, with response rates averaging 77% and remission rates around 43% within 4 to 72 hours after a single dose.

Despite the rapid improvement in mood for many patients, the effects are often short-lived, highlighting the need for further research on dosing regimens and strategies to maintain the antidepressant response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Katalinic, N., Lai, R., Somogyi, A., et al.[2013]

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 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]

A review of 41 treatment arms from 21 studies found that ketamine formulations that maximize first pass metabolism and delay the time to peak concentration (Tmax) are associated with better safety and tolerability, particularly in reducing side effects like dissociation and increased blood pressure.

The study revealed strong correlations between the ketamine:norketamine ratio and both dissociation ratings and blood pressure changes, suggesting that careful formulation can help minimize adverse effects while maintaining the antidepressant efficacy of ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. Glue, P., Russell, B., Medlicott, NJ.[2021]

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]

In a study involving 156 participants with suicidal ideation, ketamine treatment led to a significantly higher rate of full remission of suicidal thoughts at day 3 compared to placebo, with 63% of those receiving ketamine achieving remission versus 31.6% in the placebo group.

The study found that ketamine was safe in the short term, with limited side effects and no occurrences of manic or psychotic symptoms, suggesting it could be a rapid and effective option for acute care in suicidal patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. Abbar, M., Demattei, C., El-Hage, W., et al.[2022]

A Phase I study involving 32 patients showed that esketamine (0.5 mg/kg) is generally safe and well-tolerated for use in painless gastroscopy, with no serious adverse events reported.

Esketamine resulted in a shorter recovery time compared to racemic ketamine (9 minutes vs. 13 minutes), making it a potentially more efficient option for anesthesia without gender differences affecting its pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. Wang, J., Huang, J., Yang, S., et al.[2022]

A 65-year-old male cancer patient experienced significant improvement in depression symptoms and achieved remission within 7 days after receiving subcutaneous esketamine, indicating its rapid antidepressant effect.

Subcutaneous administration of esketamine appears to be a safe and effective option for managing both pain and depression in palliative care, suggesting it could be a valuable alternative to traditional intravenous methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report. Barbosa, MG., Delfino, RS., Sarin, LM., et al.[2021]

References

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

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Intravenous ketamine therapy in a patient with a treatment-resistant major depression. [2022]

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

Key considerations for the use of ketamine and esketamine for the treatment of depression: focusing on administration, safety, and tolerability. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Ketamine for the treatment of depression. [2022]

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

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. [2013]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. Germany pubmed.ncbi.nlm.nih.gov

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

9. Germany pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. [2022]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report. [2021]