Nebulized Ketamine for Depression

Overseen By Theresa Jacob, PhD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Theresa Jacob, PhD, MPH

Must not be taking: Lithium, Lamotrigine, Opioids, others

Disqualifiers: Bipolar, Psychotic disorders, Hypertension, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 4

Duration: 8-10 days

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether nebulized ketamine, an anesthetic, can reduce symptoms in people with moderate to severe depression. Researchers compare ketamine to midazolam, which serves as a placebo. The trial targets individuals in a psychiatric unit diagnosed with major depressive disorder. Participants should not have a history of bipolar disorder, recent substance use issues, or certain medical conditions like uncontrolled high blood pressure. As a Phase 3 trial, this treatment is in the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking therapy for depression.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot participate if you are on lithium, lamotrigine, or more than two medications for high blood pressure. You also cannot have used opioids within 24 hours before the trial.

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

Research has shown that ketamine has been studied for treating depression in various forms, such as a nasal spray or inhaled mist. Some studies indicate it can quickly ease depression symptoms. For instance, nasal ketamine helped people maintain stability for up to 16 weeks when used with regular antidepressants.

Regarding safety, ketamine is generally well-tolerated. Some side effects might occur, but they are usually mild and temporary. Common side effects include dizziness, a faster heartbeat, or feeling detached from reality. These effects often resolve quickly.

Since advanced clinical trials are testing nebulized ketamine, there is already some evidence of its safety for humans. This should help participants feel more comfortable about its safety. However, as with any treatment, discussing potential risks and benefits with a healthcare provider is important. ^{1 2 3 4 5}

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

Researchers are excited about nebulized ketamine for depression because it offers a novel way to deliver an already promising treatment. Unlike traditional oral antidepressants, which can take weeks to show effects, ketamine works rapidly and can relieve depressive symptoms in just a few hours to days. This form of ketamine is administered through a nebulizer, which may provide a more direct and efficient delivery compared to intravenous or nasal spray forms, potentially reducing side effects and improving patient compliance. The rapid action and unique delivery method make it a compelling option, especially for those with treatment-resistant depression.

What evidence suggests that this trial's treatments could be effective for depression?

Research has shown that nebulized ketamine, which participants in this trial may receive, might help reduce depression symptoms. One study significantly lowered depression-like behavior, with up to an 80.9% reduction in certain tests. Other studies on different forms of ketamine, such as intranasal administration, demonstrate its rapid mood-lifting effects. This suggests that inhaling ketamine can quickly improve mood in people with depression. While research continues, the results so far are promising for those with moderate to severe depression. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for inpatients with moderate to severe depression. Specific eligibility criteria are not provided, but typically participants must meet diagnostic criteria for Major Depressive Disorder and be able to give informed consent.

Inclusion Criteria

I am 18 or older with a severe depression score.

Structured Clinical Interview for DSM-5 (SCID-5) will be performed to confirm MDD diagnosis

I have been diagnosed with moderate to severe depression.

Exclusion Criteria

Recent or current homicidal ideation with an intent to act

Acutely intoxicated patients will also be excluded

I am allergic to ketamine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive nebulized ketamine or midazolam as an active placebo, with dosing days requiring in-person visits and monitoring for a minimum of two hours.

8-10 days

4-5 visits (in-person for dosing, otherwise remote)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in depressive symptoms and side effects.

1-2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nebulized Ketamine

Trial Overview The study is testing if nebulized ketamine can alleviate symptoms of depression. It's a double-blind trial, meaning neither the patients nor the researchers know who receives ketamine or a placebo (inactive substance).

How Is the Trial Designed?

Group I: Nebulized Ketamine Experimental Treatment 1 Intervention

Ketamine dosage calculated by body weight at 1.5mg/kg

Group II: Nebulized Midazolam Active Control 1 Intervention

Midazolam used as active placebo. Dosage calculated by body weight at 0.03mg/kg

Who Is Running the Clinical Trial?

Theresa Jacob, PhD, MPH

Lead Sponsor

Trials

1

Recruited

40+

Published Research Related to This Trial

A retrospective analysis of 2758 patients treated with ketamine intravenous therapy (KIT) across ten clinics showed significant reductions in both depression and anxiety symptoms after treatment, with effect sizes indicating strong efficacy (Cohen's d = -1.17 for anxiety and d = -1.56 for depression).

Patients receiving KIT experienced greater reductions in depression symptoms compared to those who were not treated with KIT or who started standard antidepressant therapy, with sustained symptom relief observed for up to a year after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis. Hietamies, TM., McInnes, LA., Klise, AJ., et al.[2023]

Oral ketamine has shown effectiveness in treating severe depression, including treatment-resistant cases and those with suicidal ideation, based on various studies including randomized controlled trials with doses ranging from 0.25 to 7 mg/kg.

Despite its lower bioavailability (20%-25% reaching the bloodstream), oral ketamine is well tolerated and can be adjusted for individual needs, making it a practical option for depression treatment alongside conventional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Andrade, C.[2019]

In a European clinical trial, a 55-year-old male with treatment-resistant depression and substance use disorder showed significant improvement in depression symptoms after a single intravenous infusion of ketamine, with reductions in Hamilton Depression Rating Scale (HDRS) scores from 36 to 16 and Beck Depression Inventory (BDI) scores from 26 to 9.

The antidepressant effects of ketamine were rapid, with the patient reporting improvements just 25 minutes into the infusion, and these effects lasted for at least 7 days, demonstrating ketamine's potential as a fast-acting treatment for depression even in patients with co-occurring substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Liebrenz, M., Borgeat, A., Leisinger, R., et al.[2022]

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]

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]

Intranasal (IN) ketamine treatment for depression was found to have significant acute side effects, including cardiovascular and neurological issues, at doses lower than 100 mg, leading to poor tolerability among participants.

The study indicated that the formulation and delivery method of IN ketamine were not effective, as participants struggled with self-administration and experienced variable absorption, suggesting that these factors greatly influence the treatment's safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial. Gálvez, V., Li, A., Huggins, C., et al.[2022]

Subanaesthetic doses of ketamine have shown substantial efficacy in treating depression, with response rates averaging 77% and remission rates around 43% within 4 to 72 hours after a single dose.

Despite the rapid improvement in mood for many patients, the effects are often short-lived, highlighting the need for further research on dosing regimens and strategies to maintain the antidepressant response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Katalinic, N., Lai, R., Somogyi, A., et al.[2013]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8204747/

Intranasal Ketamine for Depression in Adults: A Systematic ... Our meta-analysis suggests that repeated intranasal ketamine conducted a fast-onset antidepression effect in unipolar depression.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0091305723001612

Nebulized and intraperitoneal ketamine have equivalent ... When depression-like behavior was induced by dexamethasone, nebulization with ketamine reduced immobility by 79.7 %, 49.2 %, and 44.4 % in the FST and 80.9 %, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10747365/

The Efficacy and Safety of Intranasal Formulations ... Lapidus et al. (2014) found a significant improvement in depressive symptoms at day 7 in patients treated with IN ketamine in comparison to the ...

4. news.harvard.edu news.harvard.edu/gazette/story/2025/09/first-study-to-compare-two-ketamine-therapies-for-patients-with-severe-depression/

First study to compare two ketamine therapies for patients ... IV ketamine showed greater overall efficacy, with a 49.22 percent reduction in depression scores by the final dose while IN esketamine resulted ...

5. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/564836

Nebulized Ketamine for the Treatment of Major Depressive ... This is a double blind active placebo controlled clinical trial for individuals within an inpatient setting with moderate to severe ...

6. health.harvard.edu health.harvard.edu/blog/ketamine-for-treatment-resistant-depression-when-and-where-is-it-safe-202208092797

Ketamine for treatment-resistant depression A longer-term study found that nasal ketamine (plus their regular antidepressant) helped people stay in stable remission 16 weeks into treatment ...

7. guidelinecentral.com guidelinecentral.com/clinical-trial/?id=NCT06752759&v=tabular

Nebulized Ketamine for the Treatment of Major Depressive ... Nebulized Ketamine for the Treatment of Major Depressive Disorder in an Inpatient Setting: A Midazolam-controlled Randomized Controlled Trial.