Esketamine vs. Ketamine for Depression

Recruiting at 3 trial locations

Overseen By Lisa Harding, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Yale University

Disqualifiers: Bipolar, Psychotic disorder, Substance use, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to compare the relative effectiveness, acceptability, and side effects of ketamine delivered through an IV (a drip into the arm) which is not currently FDA approved for use in the treatment of treatment-resistant depression (TRD) and Esketamine (Spravato®), taken as a nasal spray which has received FDA approval for use in the treatment of treatment-resistant depression (TRD) in the treatment of patients with treatment-resistant depression (TRD). The study will look at the following: * How well the treatment helps with symptoms of depression (effectiveness), * How comfortable and willing people are to use the treatment (acceptability), and * How well people can deal with any side effects from the treatment (tolerability). The study will also examine factors that may predict which treatment works better for certain patients.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, a positive urine toxicology screen for prescribed substances like benzodiazepines and stimulants is allowed, suggesting some medications may be continued. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug Esketamine (Spravato) for depression?

Esketamine, a form of ketamine, has been shown to produce rapid antidepressant effects and was approved by the FDA for treatment-resistant depression in 2019. Studies indicate that both esketamine and racemic ketamine can provide a quick and strong antidepressant effect, with response rates ranging from 50 to 100% in patients with depression. ^{1 2 3 4 5}

Is esketamine and ketamine safe for treating depression?

Both esketamine (Spravato) and racemic ketamine have been studied for their safety in treating depression. They are generally considered safe with transitory side effects, and esketamine has been approved by the FDA for treatment-resistant depression. However, ongoing safety monitoring is important as their use expands. ^{1 2 3 4 6}

How is the drug Esketamine different from other depression treatments?

Esketamine (Spravato) is unique because it is a rapid-acting antidepressant that works differently from traditional antidepressants, targeting the brain's NMDA receptors. It is administered as a nasal spray, offering a new option for those with treatment-resistant depression. ^{2 3 4 7 8}

Research Team

Samuel Wilkinson, MD

Principal Investigator

[e-mail]

Eligibility Criteria

This trial is for individuals with treatment-resistant depression (TRD), meaning their depression hasn't improved after trying other treatments. Participants must be comfortable receiving medication through an IV or as a nasal spray. Specific eligibility criteria are not provided, but typically include factors like age, health status, and prior treatments.

Inclusion Criteria

I have moderate to severe depression.

I am 18 years old or older.

A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study

Exclusion Criteria

Hypersensitivity to ketamine, esketamine or any of the excipients

My blood pressure is not well-controlled.

Positive urine toxicology at screening visit, except for substances that are prescribed

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Spravato® (Esketamine) intranasally or Racemic Ketamine intravenously for treatment-resistant depression

4 weeks

8 treatment sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Racemic Ketamine (NMDA Receptor Antagonist)
• Spravato (Esketamine) (NMDA Receptor Antagonist)

Trial Overview The study compares two forms of ketamine: IV racemic ketamine, which isn't FDA-approved for TRD yet, and Esketamine (Spravato®) nasal spray, which is approved. It will assess how effective they are at easing symptoms of depression, patient comfort with the treatments, and side effect management.

Participant Groups

Group I: Spravato (Esketamine) Experimental Treatment 1 Intervention

Spravato® (Esketamine) will be given intranasally. For esketamine, the dose will be between 56 and 84mg, according to the FDA label for the drug. Allowances will be made for patients who have difficulty tolerating these doses to be dosed at 28mg in subsequent treatment sessions.

Group II: Racemic Ketamine Experimental Treatment 1 Intervention

Ketamine will be given intravenously. Per FDA guidance, the max dose of ketamine will be 60mg per day, with a total lifetime limit of 8 doses. Ketamine will be infused over 40 minutes.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Findings from Research

This clinical trial aims to compare the efficacy and safety of esketamine and racemic ketamine in treating treatment-resistant depression, involving adults aged 18 and older who will receive either esketamine (0.25 mg/kg) or ketamine (0.5 mg/kg) in a controlled setting.

The primary outcome will assess remission rates at 24 and 72 hours post-infusion, providing crucial data on whether esketamine is noninferior to ketamine, which could enhance treatment accessibility for depression globally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial. Correia-Melo, FS., Leal, GC., Carvalho, MS., et al.[2022]

Esketamine, approved for treatment-resistant depression, has been shown to have generally mild and transient side effects, such as dissociation and nausea, with no severe bladder issues reported when used according to guidelines.

Long-term use of esketamine does not appear to impair cognition, contrasting with high doses of racemic ketamine, which can lead to cognitive impairments, indicating that esketamine may be safer for long-term use in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of ketamine and esketamine in treatment of depression. Nikayin, S., Murphy, E., Krystal, JH., et al.[2022]

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]

r/s-ketamine has shown rapid and strong antidepressant effects for individuals with treatment-resistant depression, leading to significant advancements in understanding how antidepressants work.

The FDA has approved the s-isomer of ketamine, known as Esketamine (Spravato), marking it as the first new treatment for depression in over 60 years, highlighting its importance in modern psychiatric care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A New Rapid-Acting Antidepressant. Krystal, JH., Charney, DS., Duman, RS.[2020]

This study is the first randomized controlled trial investigating the efficacy and safety of repeated oral administration of esketamine in patients with treatment-resistant depression (TRD) over a 6-week period, followed by a 4-week follow-up.

If effective, oral esketamine could offer significant advantages over intravenous administration, potentially improving treatment accessibility and patient comfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. Smith-Apeldoorn, SY., Veraart, JKE., Kamphuis, J., et al.[2020]

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]

A review of 36 studies involving 2903 participants found that both racemic ketamine and esketamine significantly improve response and remission rates in patients with depression compared to placebo, with a response rate ratio of 2.14 and a remission rate ratio of 1.64.

The treatments were found to be safe, with no significant increase in treatment retention issues or dropouts due to adverse events, indicating that ketamine and esketamine are acceptable options for managing depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Bahji, A., Zarate, CA., Vazquez, GH.[2023]

In a Phase 2b study involving 202 Japanese patients with treatment-resistant depression, esketamine nasal spray did not show a statistically significant improvement in depressive symptoms compared to placebo, despite reductions in MADRS scores across all esketamine doses.

Esketamine was found to be safe and well-tolerated, although it was associated with a higher incidence of certain side effects, such as increased blood pressure and dissociation, compared to the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study. Takahashi, N., Yamada, A., Shiraishi, A., et al.[2021]

References

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

Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Long-term safety of ketamine and esketamine in treatment of depression. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

A New Rapid-Acting Antidepressant. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study. [2021]