What is this study of ketamine and Esketamine (Spravato) trying to find out about treatment-resistant depression?

This study is comparing ketamine given through an IV and Esketamine nasal spray to see how well they work, how acceptable they are to patients, and how manageable their side effects are for people with treatment-resistant depression. Researchers want to learn which treatment might be better for certain patients. The study is sponsored by Yale University and involves multiple sites.

Who may be eligible for this depression clinical trial?

Adults aged 18 or older with major depressive disorder that has not improved after at least two antidepressant treatments may be eligible. Both men and women can join, but women of childbearing potential must use effective contraception. People with bipolar disorder, recent substance use issues, or certain heart or blood vessel conditions cannot participate. Please review eligibility criteria for more details.

Is there any cost to participate in this depression clinical trial?

Study-related care, including the study drug or procedure and all trial visits, is provided at no cost. However, personal travel expenses to and from the study sites may vary and are not guaranteed to be covered. Participants should plan accordingly for any travel costs.

Actively Recruiting

Phase 3

Age: 18Years +

All Genders

ID06713616

Comparative Effectiveness of Racemic Ketamine Versus Esketamine SpravatoAE for Treatment-Resistant Depression

Led by Yale University · Updated on 2026-05-05

400

Participants Needed

Research Sites

N/A

Total Duration

AI-Summary

What this Trial Is About

Researchers are evaluating two treatments for adults with treatment-resistant depression TRD to compare their effectiveness, comfort, and side effects. The study focuses on ketamine given through an IV drip, which is not yet FDA approved for this use, and Esketamine Spravato, a nasal spray approved by the FDA for TRD. The trial aims to understand which treatment works better for different patients and how well each is tolerated. Participants will be randomly assigned to receive either intravenous ketamine or intranasal Esketamine. Ketamine doses will be up to 60 mg per day, infused over 40 minutes, with a lifetime limit of eight doses. Esketamine doses range from 56 to 84 mg per session, with adjustments allowed for those who have difficulty tolerating the medication, including a lower dose option of 28 mg if needed. The study will last about five years and enroll around 400 patients across multiple sites. Throughout the study, participants will be monitored for depression symptoms and side effects using self-reports and clinician evaluations over four weeks of treatment. Researchers will assess changes in depression severity, suicidal thoughts and behaviors, quality of life, disability levels, and healthcare use. Safety and tolerability will be carefully tracked during this period. The primary outcome will be self-reported effectiveness at 30 days, with additional assessments continuing until the end of treatment.

CONDITIONS

Brief Title

PCORI Comparative Effectiveness Study-Esketamine (Spravato) vs. Ketamine-Equivalence Study

Who Can Participate

Age: 18Years +

All Genders

Eligibility Criteria

You may qualify if you...

Signed and dated informed consent form
Willingness to follow all study procedures and availability for the study duration
Adults aged 18 years or older
Diagnosis of major depressive disorder that has not improved after two or more antidepressant trials
Moderate or severe depression with a MADRS score of 25 or higher
Clinician judgment supports ketamine or esketamine treatment regardless of study participation
Female participants must either not be of childbearing potential or use highly effective contraception and agree to maintain it during and for one week after treatment
Female participants agree not to donate eggs during the study period

You will not qualify if you...

Diagnosis of bipolar disorder or psychotic disorders such as schizophrenia or schizoaffective disorder
Active or recent (within 12 months) substance use disorder except nicotine
Pregnant or breastfeeding women
History of intracerebral hemorrhage or aneurysmal vascular disease
Allergy or hypersensitivity to ketamine, esketamine, or study ingredients
Known personal or family history of ketamine use disorder or prior exposure exceeding eight lifetime doses
Uncontrolled high blood pressure above 145/90 at screening
Known cardiovascular or cerebrovascular conditions increasing risk from ketamine or esketamine
Conditions posing serious risk from acute blood pressure rise
Arteriovenous malformation
Positive urine drug test for unprescribed substances or recent cannabis use within 24 hours
Positive alcohol test or clinical signs of intoxication at screening
Unable or unwilling to arrange safe transportation home after treatment sessions and to avoid driving until the next day following sleep

Research Team

Cindy Voghell

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