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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores ketamine as a fast-acting treatment for major depressive disorder, which typically requires more time for other medications to address. The researchers aim to determine if repeated doses can sustain the antidepressant effects of a single ketamine dose. Healthy volunteers and individuals experiencing a major depressive episode for at least two weeks are eligible to participate. Participants will undergo various tests and procedures, including brain scans and mood assessments, to understand ketamine's impact on depression and brain chemistry. As a Phase 1 trial, this research focuses on understanding ketamine's effects in people, offering participants the opportunity to be among the first to receive this treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketamine is generally safe and effective for individuals with depression that hasn't improved with other treatments. Some studies find that many patients experience rapid relief from depression symptoms. In one study with 25 patients, more than half felt significantly better within 24 hours after taking ketamine.

However, some people have reported side effects, such as dizziness or headaches. In certain cases, participants stopped studies due to these side effects. No serious problems were reported in studies where patients received lower doses of ketamine, suggesting that while side effects can occur, they are usually manageable.

For those considering joining a trial, this information can help weigh the potential benefits and risks. Always discuss any concerns with the research team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Researchers are excited about ketamine for major depressive disorder because it offers a novel mechanism of action compared to traditional antidepressants. While most antidepressants target serotonin, norepinephrine, or dopamine pathways, ketamine works by blocking NMDA receptors in the brain, which can rapidly alleviate depressive symptoms. Additionally, ketamine has the potential to show results within hours or days, unlike standard treatments that often take weeks to become effective. This rapid action could be a game-changer for individuals who need quick relief from severe depression symptoms.

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

Research has shown that ketamine can quickly help treat major depression. In this trial, participants may receive different doses or forms of ketamine, such as a single dose or repeated doses, to evaluate its effectiveness. One study found that infusions of racemic ketamine effectively reduced depression symptoms in hospitalized patients. Another study indicated that ketamine works at least as well as electroconvulsive therapy (ECT), with 55% of ketamine patients showing significant improvement. Additionally, ketamine has proven more effective than a placebo, with more patients feeling better after treatment. These findings suggest that ketamine could be a promising option for those seeking fast relief from depression symptoms. ^{4 6 7 8 9}

Who Is on the Research Team?

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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 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 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]

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Treatment was well-tolerated, with no serious adverse events reported, potentially due to the lower exposure to ketamine compared to its ...

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Study Finds Ketamine is at Least as Effective as ECT ...

The researchers found that 55 percent of those receiving ketamine and 41 percent of those receiving ECT reported at least a 50 percent ...

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Ketamine in Major Depressive Disorder: Mechanisms and ...

Ketamine produced a stronger and superior effect than placebo, as 10 out of 27 patients had a response after ketamine infusion, while only 1 out ...

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Rigorous clinical trials suggest ketamine is safe and well-tolerated in patients with treatment-resistant depression (TRD).

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Ketamine for treatment-resistant major depressive disorder

Overall, 14/25 patients (56%) were responders (⩾50% reduction at 24 h compared with baseline) for either ketamine dose for the Hospital Anxiety and Depression ...

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For ketamine versus placebo, both dropout and incidence rates of adverse events (AEs) were statistically significant, with number needed to harm ...

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Efficacy and Safety of Ketamine vs Electroconvulsive ...

This systematic review and meta-analysis of 6 trials with 340 patients suggests that ECT may be superior to ketamine in improving depression severity.