Ketamine for Major Depressive Disorder

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Mayo Clinic

Must not be taking: Benzodiazepines, MAOIs, Glutamate/GABA drugs

Disqualifiers: Schizophrenia, Substance use disorder, 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: 2

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how ketamine might aid individuals with major depressive disorder, particularly those whose depression has not improved with other treatments. Researchers aim to determine if changes in certain brain chemicals, such as GABA and glutamate, correlate with improved symptoms after ketamine use. The study is open to individuals currently experiencing major depressive disorder or bipolar depression who have not found success with at least two other treatments. This includes those voluntarily hospitalized or receiving outpatient care. As an Early Phase 1 trial, this research seeks to understand ketamine's effects in people, providing participants an opportunity to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, medications affecting glutamate or GABA, certain antidepressants, and some other drugs are not allowed within two weeks before starting the study drug. It's best to discuss your current medications with the study team to see if any changes are needed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ketamine is generally safe and well-tolerated in medical settings. For example, one study found that injections of (R)-ketamine hydrochloride were safe for healthy individuals. Initially developed as an anesthetic for surgeries, ketamine is now used in much smaller doses to treat depression, and these low doses are usually safe.

Another study examined oral ketamine for depression and found it both effective and tolerable, meaning participants experienced few negative side effects. Additionally, a small review demonstrated that repeated ketamine treatments reduced symptoms of depression and anxiety without causing serious issues.

Overall, while more research is needed, current studies suggest that ketamine is generally safe for treating depression. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike traditional antidepressants for Major Depressive Disorder, which often take weeks to become effective, ketamine has the potential to show results in just days. Researchers are excited about ketamine because it works differently by targeting the NMDA receptors in the brain, which can rapidly alleviate depressive symptoms. This new mechanism of action offers hope for those who haven't responded to typical therapies, such as SSRIs or SNRIs, providing a much-needed alternative for fast relief.

What evidence suggests that ketamine might be an effective treatment for major depressive disorder?

Research has shown that ketamine, which participants in this trial will receive, can quickly and effectively reduce depression symptoms. Its benefits can appear immediately and may last up to a month. Unlike most traditional antidepressants, ketamine affects the glutamate system in the brain. This unique action helps improve mood and reduce depression symptoms rapidly. Some studies suggest that ketamine can help individuals whose depression hasn't improved with other treatments. While early results are promising, more research is needed to fully understand its mechanisms and long-term effects. ^{2 3 4 6 7}

Who Is on the Research Team?

Balwinder Singh, MD, MS

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with major depressive disorder or bipolar depression, who have not responded to at least two previous treatments. They must score ≥15 on the PHQ-9 depression scale and be able to understand the study's requirements. Exclusions include a BMI >40, certain medication use, recent ketamine treatment for depression, specific medical conditions like GERD or brain injury, and any active substance abuse.

Inclusion Criteria

Ability to provide informed consent

Current psychiatric inpatient (voluntary only) or outpatient treatment

Male or female

Exclusion Criteria

Patients with a BMI >40

Ongoing prescription of > 4 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment

You have received ketamine treatment for depression in the last 2 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single 40-minute infusion of intravenous ketamine

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in GABA and glutamate levels and depression symptoms

24 hours

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine

Trial Overview The study tests if changes in ACC GABA and glutamate levels in the brain after taking ketamine are linked to remission of depression symptoms. It also looks at whether these changes correlate with metabolite levels in the body. Participants will receive ketamine infusions and undergo MRS imaging.

How Is the Trial Designed?

Group I: Ketamine Experimental Treatment 1 Intervention

Open-label, non-randomized

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Ketamine has shown significant antidepressant efficacy in treating major depression, as demonstrated by several open and controlled trials.

Nasal ketamine administration may provide a more convenient alternative to intravenous delivery, potentially improving accessibility and patient compliance in depression treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ketamine as antidepressant: the current study situation]. Ritter, PS., Bauer, M., Pilhatsch, M.[2021]

Intramuscular (I.M.) ketamine at a dose of 0.25 mg/kg is as effective and safe as higher doses (0.5 mg/kg) administered either intramuscularly or intravenously (I.V.) for treating major depression, showing significant symptom relief within just two hours.

The study, involving 27 subjects, demonstrated that the antidepressant effects of ketamine were sustained for three days, with only mild and transient adverse effects reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute antidepressant effects of intramuscular versus intravenous ketamine. Chilukuri, H., Reddy, NP., Pathapati, RM., et al.[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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6767816/

Efficacy of ketamine therapy in the treatment of depression Ketamine has a robust and rapid effect on depression, which was seen immediately after the administration of ketamine and sustained at the end of 1 month.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7113176/

Ketamine in Major Depressive Disorder: Mechanisms and ... Ketamine, although developed as an anesthetic, has been found to produce an antidepressant effect at sub-anesthetic doses via N-Methyl-D-aspartic acid (NMDA) ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0165032725019081

Oral ketamine for the treatment of major depressive and ... Our findings align with recent data from RCTs showing a positive but non-significant trend for antidepressant efficacy of low-dose peroral ...

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. clinicaltrials.gov clinicaltrials.gov/study/NCT01945047

Action of Ketamine in Treatment-Resistant Depression Results from this study will help establish the beneficial effects of a single KET injection as a rapid intervention for major depression, and to ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12298542/

Pharmacokinetics, Safety, and Tolerability of (R)-Ketamine ... Conclusions: In summary, (R)-ketamine hydrochloride injection was safe and well tolerated in healthy Chinese subjects. The clinical study ...

7. 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 ... A small retrospective chart review study29 showed that the reduction in depressive and anxiety symptoms with repeated administration of IM ketamine was not.