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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how ketamine, an anesthetic, can help people with depression that hasn't improved with standard treatments. By focusing on those with a family history of alcohol use, researchers hope to understand why ketamine might work better for them. Participants will receive a single low-dose ketamine infusion and undergo brain imaging to study changes in brain chemistry. Ideal candidates have experienced major depression for at least two weeks, have tried other antidepressants without success, and do not currently have any substance use issues (except caffeine or nicotine). As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group, offering participants a chance to potentially benefit from an innovative approach to depression.

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.

Is there any evidence suggesting that ketamine is likely to be safe for humans?

Research has shown that ketamine is generally safe and effective for people with treatment-resistant depression (TRD). Studies with TRD patients indicate that ketamine is safe when used in controlled settings. Common side effects include temporary feelings of disconnection from reality or dizziness, but these usually don't last long. The FDA has already approved ketamine for other uses, such as anesthesia, which supports its safety. While some side effects may occur, many patients with difficult-to-treat depression experience significant benefits. ^{1 2 3 4 5}

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

Unlike the standard treatments for depression, such as SSRIs and SNRIs, ketamine acts on a completely different brain chemical. Most antidepressants target serotonin or norepinephrine, but ketamine works on the glutamate system, which is thought to influence mood and cognition more directly. This unique mechanism offers hope for faster relief, often showing results in just hours or days instead of weeks. Researchers are excited because ketamine could provide a rapid-acting option for people who haven't found success with traditional medications.

What evidence suggests that ketamine might be an effective treatment for treatment-resistant depression?

Research has shown that ketamine can quickly and effectively reduce symptoms of depression in people who haven't responded to other treatments. One study found that about 45% of patients experienced significant improvement, and around 30% achieved remission, meaning their depression symptoms greatly improved or disappeared. Unlike many traditional antidepressants that can take weeks to work, ketamine often begins to help within hours to days. Its effects can last from 2 to 6 months after treatment. Ketamine works by rapidly increasing certain brain chemicals that improve mood, especially in people with a family history of alcohol use disorders. This makes ketamine a promising option for those who haven't found relief with other treatments. ^{4 5 6 7 8}

Who Is on the Research Team?

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

Principal Investigator

University of Iowa Health Care (UIHC)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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+

Published Research Related to This Trial

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 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 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]

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 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]

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35688035/

Real-world effectiveness of ketamine in treatment-resistant ... All results suggest that the mean antidepressant effect is substantial (mean ± 95% CI, % responded = 45 ± 10%; p< 0.0001, % remitted = 30 ± 5.9%; p< 0.0001, ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032725016349

Real-world clinical data on the long-term effectiveness and ... The majority of people with TRD in our sample appeared to experience a sustained treatment response with 2-6 months of generic racemic ketamine.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6767816/

Efficacy of ketamine therapy in the treatment of depression Results: There was a significant improvement in depression, anxiety, and the severity of illness after 2 weeks and 1 month of the last dose of ketamine.

4. nature.com nature.com/articles/s41591-024-03063-x

Extended-release ketamine tablets for treatment-resistant ... Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2302399

Ketamine versus ECT for Nonpsychotic Treatment ... Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39721099/

Safety outcomes of ketamine for treatment-resistant ... Ketamine can give rise to acute, cumulative and longer-term side effects (SEs) across a treatment course. The Ketamine Side Effect Tool (KSET) examines adverse ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S016517812400619X

Safety outcomes of ketamine for treatment-resistant ... The Ketamine Side Effect Tool (KSET) was developed to provide a systematised safety monitoring tool for ketamine therapy in psychiatry.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25271445/

Ketamine safety and tolerability in clinical trials for treatment ... Conclusions: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in ...