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

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This is a feasibility study and the goal of this project is to evaluate whether peak ACC GABA and glutamate, quantified as a CSF-corrected absolute concentration percent change from baseline, is associated with clinical remission, Montgomery Asberg Depression Rating Scale (MADRS) total score of \<10, to the anti-glutamatergic antidepressant ketamine. As MRS is expensive, we also aim to study a correlation between change in peripheral metabolites (GABA and glutamate) and central GABA and glutamate levels.

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 ketamine safe for treating depression?

Ketamine and esketamine have shown rapid antidepressant effects, but they can cause side effects like dissociation (feeling detached from reality) and increased blood pressure. While they are generally considered safe for short-term use, more research is needed to understand their long-term safety. ^{1 2 3 4 5}

How is the drug ketamine unique in treating major depressive disorder?

Ketamine is unique because it can provide rapid relief from depressive symptoms, often within hours, unlike traditional antidepressants that can take weeks to work. It can be administered in various ways, including intravenously, intranasally, and subcutaneously, offering flexibility and convenience, especially in settings with limited resources. ^{1 6 7 8 9}

What data supports the effectiveness of the drug ketamine for treating major depressive disorder?

Research shows that ketamine can quickly reduce symptoms of depression, even in people who haven't responded to other treatments. Studies have found that both intravenous and subcutaneous forms of ketamine provide rapid and strong antidepressant effects, with many patients experiencing significant relief. ^{1 6 7 9 10}

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

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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

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

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

Ketamine for the treatment of depression. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

[Ketamine as antidepressant: the current study situation]. [2021]

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

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

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

Pharmacotherapy: Ketamine and Esketamine. [2023]

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

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

9. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Acute antidepressant effects of intramuscular versus intravenous ketamine. [2022]