Ketamine for Treatment-Resistant Depression

Overseen By Emerson Buse, B.A.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Mark Niciu

Must not be taking: SSRIs, SNRIs, Benzodiazepines, Antipsychotics

Disqualifiers: Psychotic disorders, Substance use, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 1

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, participants will need to stop taking psychiatric medications at least two weeks before the second phase of the study. If you are taking fluoxetine, you must stop at least five weeks before the second phase.

What evidence supports the effectiveness of ketamine as a drug for treatment-resistant depression?

Research shows that ketamine can quickly reduce depression symptoms in people who haven't responded to other treatments. It has been found effective in various forms, like intravenous and nasal spray, and is generally well tolerated with minimal side effects in the short term. ^{1 2 3 4 5}

Is ketamine safe for treating depression?

Ketamine, used for treatment-resistant depression, generally shows rapid antidepressant effects with mostly temporary side effects. However, rare but serious side effects like apnea (temporary stopping of breathing) have been reported, so careful monitoring is recommended during treatment. ^{6 7 8 9 10}

How is the drug ketamine unique in treating treatment-resistant depression?

Ketamine is unique because it acts rapidly to relieve depressive symptoms, including suicidal thoughts, in patients who haven't responded to standard treatments. It works differently from traditional antidepressants by blocking NMDA receptors in the brain and can be administered in various forms, such as intravenous, intranasal, or oral, offering flexibility in treatment. ^{1 2 4 11 12}

What is the purpose of this trial?

A single subanesthetic dose infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and robust antidepressant effects in patients with treatment-refractory major depressive disorder (TRD). A family history of an alcohol use disorder (Family History Positive, FHP) is one of the strongest identified predictors of an improved antidepressant response to ketamine. Like ketamine, alcohol is a functional NMDA receptor antagonist. FHP is associated with differential response to ketamine, e.g. blunted psychotomimetic side effects. One of the primary mechanistic hypotheses for ketamine's antidepressant action is the acute intrasynaptic release of glutamate from major output neurons, e.g. cortical pyramidal cells. Preliminary clinical studies have demonstrated this acute glutamate "surge" in response to subanesthetic dose ketamine. Based on these findings, the investigators hypothesize that ketamine's enhanced antidepressant efficacy in FHP TRD subjects is, at least in part, attributable to increased glutamate release relative to TRD subjects without a family history of alcohol use disorder (Family History Negative, FHN). To test this hypothesis, the investigators have designed a now two-site, open-label study of 18-55-year-old medically and neurologically healthy, currently moderately-to-severely depressed TRD patients. In total, the investigators plan to recruit 25 FHP and 25 FHN TRD subjects. All subjects must not have a current substance use disorder (except nicotine or caffeine). The experimental portion consists of two phases. The preliminary first phase is a medication taper (if needed) and psychotropic medication-free period. The experimental second phase comprises one subanesthetic dose (0.5mg/kg x 40 minute) ketamine infusion. The ketamine infusion will occur during 7T-magnetic resonance imaging (MRI), both resting-state functional MRI (rs-fMRI) and magnetic resonance spectroscopy (MRS) to detect glutamate in the ventromedial prefrontal cortex/ventral anterior cingulate cortex (vmPFC/vACC). The primary outcome measure is group mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from pre-ketamine infusion (baseline) to one-week post-infusion, where the investigators observed ketamine's greatest antidepressant effect in FHP TRD. Additional outcome measures are vmPFC/vACC glutamate change in response to ketamine based on family history status. In summary, this study will provide key mechanistic information on ketamine's improved antidepressant efficacy in a biologically-enriched subgroup. This will contribute to the systematic development of more efficacious, personalized treatments for major depression in an effort to reduce its enormous public health burden.

Research Team

Mark J Niciu, M.D. Ph.D.

Principal Investigator

University of Iowa Health Care (UIHC)

Eligibility Criteria

This trial is for adults aged 21-65 with treatment-resistant major depressive disorder (MDD), who have failed at least one antidepressant trial. Participants must not be pregnant, nursing, or without contraception if of childbearing potential. They should have no lifetime substance use disorders (except nicotine/caffeine), no alcohol use disorder history, and must be social drinkers without significant health issues that MRI can't accommodate.

Inclusion Criteria

Diagnostic and Statistical Manual-4th Edition-Text Revision (DSM-IV-TR)) diagnosis of major depressive disorder (MDD), single-episode (296.30) or recurrent (296.20) without psychotic features based on clinical assessment and confirmed by a Structured Clinical Interview for the DSM-IV- Patient Version (SCID-P). Subjects must be experiencing a current major depressive episode of at least 2 weeks duration

A level of understanding sufficient to agree to all required tests and examinations, sign an informed consent document and verify understanding by a score greater than or equal to 90% on the consent quiz

I have tried at least one antidepressant that didn't work for me.

Exclusion Criteria

Clinically significant abnormal laboratory tests

I have a history of or currently have a severe mental health condition like schizophrenia or bipolar disorder.

I've had seizures of unknown cause or a serious head injury.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Medication Taper and Drug-Free Period

Participants undergo a medication taper if needed and a psychotropic medication-free period of at least two weeks

2 weeks

Ketamine Infusion

Participants receive a single subanesthetic dose of ketamine (0.5mg/kg over 40 minutes) during 7T-MRI to assess antidepressant effects and glutamate changes

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after ketamine infusion, with primary outcome measured at one week post-infusion

1 week

Treatment Details

Interventions

• Alcohol
• Ketamine

Trial Overview The study tests the effects of a single dose of ketamine in those with a family history positive (FHP) or negative (FHN) for alcoholism on depression symptoms and brain glutamate levels using MRI. It involves an initial medication-free period followed by controlled alcohol and ketamine infusions during advanced imaging to observe changes in the brain's response.

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?

Mark Niciu

Lead Sponsor

Trials

2

Recruited

1,100+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

Maintenance ketamine treatment, delivered through various methods such as intravenous and intranasal, shows promise in sustaining antidepressant effects for patients with treatment-resistant depression, based on a review of multiple studies including three randomized controlled trials.

The treatment appears to have a favorable safety profile, with serious side effects like addiction and renal issues being uncommon, although further long-term studies are needed to fully establish its efficacy and role in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Smith-Apeldoorn, SY., Veraart, JK., Spijker, J., et al.[2022]

The FDA has approved S-ketamine nasal spray as a new treatment option for patients with treatment-resistant depression, marking a significant advancement in psychiatric therapies.

Intravenous ketamine has been researched for depression treatment since the 1990s, and this paper outlines the current protocol for its use in patients who do not respond to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ketamine infusion therapy in treatment-resistant depression]. Christodoulakis, ΤΕ.[2022]

Ketamine infusions have shown significant short-term efficacy in reducing depression severity in patients with treatment-resistant depression, as supported by evidence from 10 systematic reviews and randomized controlled trials.

The treatment is generally well tolerated with minimal side effects, but more large-scale studies are needed to evaluate long-term effects and optimal dosing schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine and Treatment-Resistant Depression. Lent, JK., Arredondo, A., Pugh, MA., et al.[2020]

In a study of 53 older adults with treatment-resistant depression, repeated intravenous (IV) ketamine infusions led to significant reductions in depressive symptoms, with 27% of participants showing a response and 10% achieving remission after 4 infusions.

While ketamine was effective, 69% of participants experienced transient hypertension during treatment, highlighting the need for monitoring and potential intervention for this side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series. Lipsitz, O., Di Vincenzo, JD., Rodrigues, NB., et al.[2021]

Ketamine, an NMDA receptor antagonist, has shown rapid and significant antidepressant effects in treatment-resistant depression (TRD), with an (S)-ketamine nasal spray now approved for use alongside oral antidepressants in the U.S. and Europe.

Despite its effectiveness, challenges such as maintaining response, potential side effects, and abuse risk remain, highlighting the need for further research to develop safer, next-generation rapid-acting antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for depression. Jelen, LA., Stone, JM.[2021]

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]

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]

Ketamine shows promise as a treatment for treatment-resistant depression (TRD), but its use can lead to common adverse events, which are usually temporary.

A case of apnea during a slow sub-anesthetic infusion of ketamine highlights a rare but serious potential side effect, emphasizing the need for careful monitoring and management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., et al.[2021]

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]

Ketamine, at sub-anesthetic doses, shows promise as a rapid-acting treatment for patients with treatment-resistant depression (TRD), potentially improving response rates to electroconvulsive therapy (ECT) when used alone or as an adjunct.

While ketamine can enhance the effectiveness of ECT, it may also increase seizure duration and has been associated with cardiovascular and psychotomimetic side effects, necessitating careful monitoring and consideration of concurrent medications to mitigate risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of ketamine's role in ECT and non-ECT settings. Jankauskas, V., Necyk, C., Chue, J., et al.[2020]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. [2022]

2. Greece pubmed.ncbi.nlm.nih.gov

[Ketamine infusion therapy in treatment-resistant depression]. [2022]

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

Ketamine and Treatment-Resistant Depression. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series. [2021]

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

Ketamine for depression. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

7. Germany pubmed.ncbi.nlm.nih.gov

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

8. Netherlands pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. [2021]

10. England pubmed.ncbi.nlm.nih.gov

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

11. New Zealand pubmed.ncbi.nlm.nih.gov

A review of ketamine's role in ECT and non-ECT settings. [2020]

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

Ketamine for the treatment of depression. [2022]