Ketamine for Major Depressive Disorder

Recruiting in Palo Alto (17 mi)

Overseen by Carlos A Zarate, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Reversible MAOIs, Opioids

Disqualifiers: Bipolar, Schizophrenia, Substance abuse, others

Approved in 5 Jurisdictions

Trial Summary

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 ...

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.

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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.

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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.

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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.

Trial 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)

Participant Groups

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.

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, 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH) Lead Sponsor

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] Ketamine in a subanaesthetic dose has been shown to produce rapid antidepressant effects. Here, we describe a long-term follow-up case of a Korean patient with severe major depression who received repeated ketamine intravenous therapy (KIT).

2. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021] Background: Ketamine has been shown to produce a rapid and robust antidepressant effect. Though numerous routes of administration have been studied, subcutaneous (SC) has proven to be a convenient and cost-effective route making its use particularly relevant in developing countries. Here we provide a systematic review covering the use of SC racemic ketamine and esketamine in depression, including its efficacy, safety and tolerability. Methods: A systematic literature search was carried out, from inception through March, 2021, using PubMed/MEDLINE, EMBASE and Web of Science, with no limits of language. After identifying 159 potentially relevant articles, 12 articles were selected after applying our inclusion/exclusion criteria. These comprised two randomized clinical trials, five case-reports and five retrospective studies. Given the small number of studies found and their heterogeneous nature, a meta-analysis was not considered appropriate. Here we provide a synthesis of these data including participant characteristics, dose range, efficacy, safety/ tolerability. Risk of bias was accessed using the Cochrane risk of bias tool. Results: SC Ketamine was administered to unipolar and bipolar patients a single or multiple doses, weekly or twice-weekly, a dose-titration approach was made in major studies, dose ranged from 0.1 to 0.5 mg/Kg of racemic ketamine and 0.5-1 mg/Kg of esketamine. Across all studies, SC ketamine showed a rapid and robust antidepressant effect, with response/ remission rates from 50 to 100% following both single or multiple doses, with transitory side effects. Conclusion: SC racemic ketamine and esketamine in depression is a promising strategy showing beneficial efficacy and tolerability. Future studies exploring the SC route, its cost-effectiveness, and a direct comparison with IV and intranasal (IN) protocols are warranted. Systematic Review Registration: CRD42019137434.

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] Racemic ketamine, a derivative of phencyclidine, has been used as a dissociative anesthetic since 1970. In 2000, the first randomized controlled trial showed a rapid relief of depressive symptoms. Since then, intravenous ketamine and intranasal S-ketamine have been validated for the treatment of depression and suicidal ideation following dose-response and double-blind placebo-controlled clinical trials. In clinical practice, after dose titration and with repeated treatments, patients may experience approximately 2-3 weeks of symptomatic relief from depression.

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

Ketamine for the treatment of depression. [2022] Ketamine (Ketalar®) is an anesthetic agent derived from the hallucinogenic drug phencyclidine (PCP). It is a high-affinity antagonist at N-methyl-D-aspartate receptors and also binds to opioid mu and sigma receptors. Ketamine is being intensively investigated as an antidepressant therapy. To date, five short-term controlled studies and other open-label studies in patients with unipolar or bipolar depression have demonstrated that intravenous ketamine is safe and has a rapid and profound short-term effect on depressive symptoms, including suicidal thoughts, even among patients considered treatment-resistant to standard medications or electroconvulsive therapy. Before ketamine can be incorporated into clinical practice, however, its long-term safety and effectiveness need to be evaluated. Although the effectiveness of alternative routes of ketamine administration (i.e., oral, intranasal, or intramuscular) needs to be determined, intravenous ketamine could be conceptualized as a clinic-based procedural therapy for treatment resistant forms of depression.

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

[Ketamine as antidepressant: the current study situation]. [2021] The treatment of depressive episodes is characterized by a delay in response of antidepressant medications and high rates of therapeutic failure. In recent years several open and five controlled trials have demonstrated the antidepressant efficacy of ketamine for major depression. In addition a recent study established the utility of nasal ketamine which may render the necessity of intravenous administration obsolete. The current state of evidence is reviewed and discussed.

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

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021] Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects.

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

Pharmacotherapy: Ketamine and Esketamine. [2023] Ketamine and esketamine have rapid-onset antidepressant effects and may be considered for the management of treatment-resistant depression. Intranasal esketamine has regulatory approval in the United States and European Union. Intravenous ketamine is often administered off-label as an antidepressant, though no standard operating procedures exist. Repeated administrations and the use of a concurrent standard antidepressant may maintain antidepressant effects of ketamine/esketamine. Possible adverse effects of ketamine and esketamine include psychiatric, cardiovascular, neurologic and genitourinary effects, and the potential for abuse. The long-term safety and efficacy of ketamine/esketamine as antidepressants require further study.

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

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022] To summarize the evidence of efficacy and safety of the use of ketamine and esketamine for depression.

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] On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice.

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

Acute antidepressant effects of intramuscular versus intravenous ketamine. [2022] Conventional antidepressants take two weeks before their therapeutic action begins. Recent studies have reported on the rapid antidepressant effect of ketamine when given as an intravenous (I.V.) infusion. Little is known about its intramuscular (I.M.) use in depression. Hence this study was conducted to compare the safety, tolerability and efficacy of I.M. versus. I.V. ketamine in Major Depression (ICD-10).