Ketamine for Major Depressive Disorder

Overseen By Carlos A Zarate, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Reversible MAOIs, Opioids

Disqualifiers: Bipolar, Schizophrenia, Substance abuse, others

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

Compensation: Varies

Number of Visits: 13

150 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

Yes, you will need to gradually stop your current medications during Phase I, which lasts 2-7 weeks. There are specific exceptions for Fluoxetine and Aripiprazole, which require a longer discontinuation period before Phase II.

What data supports the idea that Ketamine for Major Depressive Disorder is an effective drug?

The available research shows that Ketamine can rapidly reduce symptoms of major depressive disorder. For example, intravenous ketamine has been shown to provide quick relief from depression symptoms, even in patients who haven't responded to other treatments. One study found that subcutaneous ketamine had a strong antidepressant effect, with 50 to 100% of patients experiencing improvement after treatment. Another study noted that patients could experience relief for 2-3 weeks after repeated treatments. These findings suggest that Ketamine is a promising option for treating depression, especially for those who haven't found success with other medications. ^{1 2 3 4 5}

What safety data is available for ketamine treatment in depression?

Existing safety data for ketamine treatment in depression indicates that it has rapid antidepressant effects but can cause side effects such as dissociation and increased blood pressure. Subcutaneous administration has shown promising efficacy and tolerability with transitory side effects. Intranasal esketamine is approved in the US and EU, while intravenous ketamine is used off-label. Potential adverse effects include psychiatric, cardiovascular, neurologic, and genitourinary issues, and there is a risk of abuse. Long-term safety and efficacy require further study. ^{2 6 7 8 9}

Is the drug Ketamine a promising treatment for Major Depressive Disorder?

Yes, Ketamine is a promising treatment for Major Depressive Disorder. It has been shown to work quickly and effectively, providing relief from depression symptoms much faster than traditional antidepressants. Different ways of taking Ketamine, like through a nasal spray or under the skin, have also been found to be convenient and effective. ^{1 2 3 5 10}

What is the purpose of this trial?

Background: Most medications that treat depression take weeks or months to work. Researchers want to develop fast-acting treatments. One dose of ketamine has a rapid antidepressant effect. For most people, this lasts a week or less. Repeated doses of ketamine may help maintain this effect. Objective: Main Study: To study the effects of ketamine in treating depression. Ketamine Metabolites Substudy: To study how ketamine effects brain chemistry. To study how ketamine effects the brain. This is done by looking at metabolites, which are created when a drug is broken down. Eligibility: Main Study: People ages 18-65 with major depressive disorder and healthy volunteers Ketamine Metabolites Substudy: Healthy volunteers ages 18-65 Design: Main Study: Participants will be screened in another study, with: * Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests Participants will be inpatients at NIH for 4 phases totaling 14-20 weeks. Phase I (2-7 weeks): * Gradually stop current medications * MRI: Participants lie and perform tasks in a machine that takes pictures of the body. * Mood and thinking tests * Blood and urine tests * Sleep test: Monitors on the skin record brain waves, breathing, heart rate, and movement during sleep. * Transcranial magnetic stimulation: A coil on the scalp gives an electrical current that affects brain activity. * Stress tests: Electrodes on the skin measure reactions to loud noises or electric shocks. Phase I tests are repeated in Phases II and III and in the final visit. Phase II (4-5 weeks): * 4 weekly IV infusions of ketamine or a placebo during an MRI or MEG. For the MEG, a cone over the head records brain activity. Phase III (optional): * 8 infusions of ketamine over 4 weeks Phase IV (optional): * Symptoms monitoring for 4 weeks * Participants will have a final visit. They will be offered standard treatment at NIH for up to 2 months. Ketamine Metabolites Substudy: Participants will be screened in another study, with: * Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests Participants will be inpatients at NIH for 4 days. Study Procedures: Mood and thinking tests Blood and urine tests 1 infusion of ketamine Spinal tap and spinal catheter: Used to get samples of cerebrospinal fluid (CSF). This is a fluid that moves around and within the brain and spinal cord. Studying CSF will help us learn how ketamine effects brain chemistry

Research Team

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

Adults aged 18-65 with major depressive disorder currently experiencing a depressive episode, and healthy volunteers. Participants must understand the study procedures and consent to them, have no bipolar or psychotic disorders, no recent substance abuse (except caffeine/nicotine), not be at serious suicide/homicide risk, not pregnant or nursing, and without unstable illnesses.

Inclusion Criteria

I have been diagnosed with major depression and am currently experiencing an episode lasting at least 2 weeks.

I have depression that didn't improve after trying at least one antidepressant or ECT.

All subjects must have undergone a screening assessment under either protocol 01-M-0254, 'The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers' or protocol 17-M-0181 ('Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies').

Exclusion Criteria

A current NIMH employee/staff or their immediate family member

Subjects with a history of DSM-IV or DSM-V drug or alcohol dependency or abuse (except for caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects who currently are using drugs (except for caffeine or nicotine) must not have used illicit substances or known drugs of abuse in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines or stimulants) urine test at screening.

I have not had seizures, epilepsy, stroke, brain surgery, head injury, or known brain issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase I

Medication taper, drug-free period, and baseline assessments including MRI, mood and thinking tests, and sleep tests

2-7 weeks

Multiple visits (inpatient)

Phase II

4 weekly IV infusions of ketamine or placebo with concurrent fMRI+EEG or MEG

4-5 weeks

4 visits (inpatient)

Phase III (optional)

8 infusions of ketamine over 4 weeks for patients whose symptoms relapsed

4 weeks

8 visits (inpatient)

Phase IV

Follow-up evaluations to determine durability of response

4 weeks

Final visit (in-person)

Treatment Details

Interventions

• Ketamine

Trial Overview The trial is testing the rapid antidepressant effects of ketamine infusions compared to placebo in treating depression. It includes MRI scans during treatment phases and optional extended monitoring. A substudy examines how ketamine affects brain chemistry through cerebrospinal fluid analysis after spinal taps.

Participant Groups

Group I: Phase III Experimental Treatment 3 Interventions

Double-blind, repeated dose of 0.5 mg/kg or 0.1 mg/kg IV ketamine

Group II: Phase II, Arm 1b Experimental Treatment 3 Interventions

Double-blind, single dose of 0.5 mg/kg IV ketamine, concurrently with fMRI+EEG or MEG

Group III: Phase II, Arm 1 Experimental Treatment 3 Interventions

Double-blind, single dose of 0.5 mg/kg IV ketamine

Group IV: Phase I Experimental Treatment 1 Intervention

Medication taper, drug-free period, and baseline assessments

Group V: Metabolites Substudy Experimental Treatment 3 Interventions

Open-label, single dose of 0.5 mg/kg IV ketamine

Group VI: Phase IV Active Control 1 Intervention

Follow-up evaluations

Group VII: Phase II, Arm 2 Placebo Group 3 Interventions

Double-blind, single dose of 0.5 mg/kg IV saline

Group VIII: Phase II, Arm 2b Placebo Group 3 Interventions

Double-blind, single dose of 0.5 mg/kg IV saline, concurrently with fMRI+EEG or MEG.

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?

National Institute of Mental Health (NIMH)

Lead Sponsor

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]

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]

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

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]