Ketamine + Buprenorphine for Depression
(AFSP Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: Stanford University
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 5 Jurisdictions
Trial Summary
What is the purpose of this trial?To explore whether intravenous ketamine followed by buprenorphine produces more rapid and sustained anti-suicidal effects than ketamine followed by placebo, investigators will conduct a single study that will take approximately 2.5 years to complete. 60 subjects (60 infusions) or approximately 24 infusions per year.
Do I need to stop my current medications to join the trial?
You must be on a stable dose of an SSRI or SNRI antidepressant for at least 4 weeks before joining the trial. If you are currently using lamotrigine, you need to stop it before receiving ketamine. Other medications are not specifically mentioned, so consult with the trial team for more details.
What data supports the idea that Ketamine + Buprenorphine for Depression is an effective drug?
The available research shows that ketamine, when used alone, has been effective in treating depression. For example, subcutaneous ketamine has shown a rapid and strong antidepressant effect, with response rates between 50% to 100% in various studies. Oral ketamine has also been found effective in treating severe depression and treatment-resistant depression, with similar outcomes to conventional antidepressants. However, there is no specific data provided on the combination of ketamine and buprenorphine for depression, so the effectiveness of this combination remains unclear based on the information available.
12345What safety data exists for ketamine and buprenorphine in treating depression?
Existing safety data for ketamine in treating depression includes findings from systematic reviews and clinical trials. Subcutaneous ketamine has shown rapid antidepressant effects with transitory side effects. The Ketamine Side Effect Tool (KSET) highlights the need for comprehensive safety monitoring. A systematic review identified psychiatric, cardiovascular, and neurological side effects, with a call for more research on long-term safety. However, specific safety data for the combination of ketamine and buprenorphine in depression is not detailed in the provided research.
26789Is Ketamine a promising drug for depression?
Yes, Ketamine is a promising drug for depression. It acts quickly and effectively, showing strong antidepressant effects in various forms, including subcutaneous and oral administration. Studies have shown that it can help reduce depression symptoms and suicidal thoughts, making it a valuable option for those who haven't responded to other treatments.
23101112Eligibility Criteria
Adults aged 18-70 with Major Depressive Disorder currently in a depressive episode of at least 8 weeks, who haven't responded well to two different antidepressants for this episode. They must be generally healthy and women must use effective birth control or be non-childbearing. People with certain physical conditions, drug abuse history, or other mental health disorders are excluded.Inclusion Criteria
You meet the threshold on the total SSI score of >/=11 at both screening and baseline visits.
I am either not able to have children or am using effective birth control.
Your body mass index (BMI), which is a measure of your body fat based on your weight and height, should be between 17 and 35.
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Exclusion Criteria
You have a condition that affects your memory or thinking, such as dementia or delirium.
You have had an eating disorder such as anorexia, bulimia, or other similar disorders within the past five years.
You cannot participate in this study if you have taken part in another research study that involves a new drug or device in the past month or at the same time as this study.
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Participant Groups
The study is testing if ketamine followed by buprenorphine is more effective than ketamine followed by a placebo in reducing suicidal thoughts quickly and for an extended period. Participants will receive intravenous infusions over approximately 2.5 years.
2Treatment groups
Experimental Treatment
Active Control
Group I: KetamineExperimental Treatment1 Intervention
Every eligible participant will receive 0.5mg/kg IV given over 40 minutes
Group II: Buprenorphine or PlaceboActive Control2 Interventions
Buprenorphine or placebo once daily for 4 weeks
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 NearbySelect from list below to view details:
Stanford University School of MedicineStanford, CA
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Who Is Running the Clinical Trial?
Stanford UniversityLead Sponsor
References
Oral Ketamine for Depression, 2: Practical Considerations. [2020]The oral route of administration is probably the least expensive and most convenient way to administer ketamine in indicated contexts in depressed patients. Because only 20%-25% of orally administered ketamine reaches systemic circulation, oral doses of about 2.0-2.5 mg/kg may need to be administered to achieve equivalence to intravenously administered ketamine. In case reports, case series, standard operating practice in ketamine facilities, and randomized controlled trials, oral ketamine has been administered through weight-based dosing and as fixed doses, and the dosing strategy has been one-size-fits-all or individualized through a dose discovery process. Administered doses have ranged from 0.25 to 7.0 mg/kg in weight-based dosing sessions and from 25 mg to 300 mg in fixed dosing sessions. This article reviews strategies for dosing with oral ketamine, dose discovery procedures, rates of dosing during a session, the frequency of dosing sessions and the duration of treatment, treatment in the clinic vs domiciliary treatment, adverse effects and risks, and safety issues. Finally, this article provides a detailed account of practices and experiences with oral ketamine so that readers may know what to expect when the treatment is orally administered. Whereas oral ketamine appears to be a safe and effective treatment and could make ketamine an accessible and affordable intervention in less privileged medical facilities, readers are warned that the literature on oral ketamine is thin and that there are many areas that need more investigation, especially matters related to pharmacokinetics, physiologic effects, abuse potential and strategies to mitigate illicit use, and adverse effects and efficacy relative to other routes of administration. Until studies of a sufficiently high quality become available, the use of oral ketamine to treat depression must be considered experimental.
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.
Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. [2019]Clinical evidence is accumulating to support the use of ketamine as a powerful, quick-acting intervention for depression. Ketamine has been administered by oral, sublingual, transmucosal, intravenous, intramuscular, subcutaneous, intranasal, and even rectal routes. Whereas intravenous ketamine is the best studied approach, common sense dictates that oral ketamine is the most practical. The bioavailability of oral ketamine and interindividual variations thereof have been poorly studied; possibly only 20%-25% of an oral dose reaches the bloodstream. This is not necessarily a limitation because, as with other drugs that have poor oral bioavailability, compensation is possible by administering an appropriately higher dose, and interindividual variations can be addressed through individualized dose up-titration. A quarter- century of experience supports the use of oral ketamine for treating acute and chronic pain in children and adults. Case reports, case series, chart reviews, and 3 recent randomized controlled trials (RCTs) show that oral ketamine is effective in treating severe depression, depression with suicidal ideation, and treatment-resistant depression; that oral ketamine, used as an augmentation agent, improves outcomes in patients receiving a conventional antidepressant; and that oral ketamine reduces depression in patients with chronic pain. Doses of oral ketamine have ranged from 0.25 to 7 mg/kg and from 50 mg per occasion to 300 mg per occasion in multiple daily dosing, daily dosing, and intermittent dosing schedules. Oral ketamine was well tolerated in all studies; dropout and reasons for dropout were similar in ketamine and control arms in the 3 RCTs. These findings suggest that if ketamine is to find a place as an off-label treatment for depression and suicidality in mainstream psychiatry, researchers should study the safety, efficacy, and optimization of oral ketamine. Intravenous and intranasal routes may be monetarily more promising, but the oral route could be of greatest service.
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).
A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. [2023]Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices.
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.
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.
Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. [2022]To assess the pharmacokinetics and safety of pure S-ketamine (esketamine) in Chinese patients undergoing painless gastroscopy and evaluate the potential advantage of esketamine in clinical treatment compared with racemate ketamine hydrochloride injection.
Side-effects associated with ketamine use in depression: a systematic review. [2019]This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria. After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depresssion. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.
Ketamine's rapid antisuicidal effects are not attenuated by Buprenorphine. [2021]Ketamine's rapid antisuicidal action has gathered significant clinical interest in treatment of depression though concerns exist that its actions occur through the Opioid pathway. A recent study additionally reported that Naltrexone blocks antisuicidal effects of Ketamine suggesting that its antisuicidal effects are also due to opioid mechanisms. We present a case of treatment refractory depression with recent suicide attempt and active suicidal ideations who was on an Opioid partial agonist, Buprenorphine, for management of pain. Patient responded to a trial of IV ketamine treatment with rapid improvement in suicidal thoughts. Patient's suicidal ideations decreased after first Ketamine treatment and resolved after second treatment while maintained on Buprenorphine. Our finding shows that Buprenorphine does not block Ketamine's effects on suicidal ideations and therefore Ketamine treatment could be provided safely in controlled environment to those with substance use disorders or with chronic pain while being maintained on Buprenorphine. Additionally, our case suggests that non-Opioid mechanisms may be involved in Ketamine's antidepressant effects and its response to suicidal ideations in those on Opioid partial agonists.
Intranasal Ketamine for Acute Pain: Behavioral and Neurophysiological Safety Analysis in Mice. [2022]Subanesthetic ketamine has been used for treatment-resistant depression and is popular as an opioid-sparing agent.
The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature. [2020]Background: Previous literature suggests that ketamine may be an effective drug in the palliative care population as this drug has been shown to treat multiple conditions that are common in these patients. Objective: This review examines the efficacy of ketamine for the treatment of depression and physical pain in palliative care patients. Methods: Eleven studies were included on the topic of ketamine as an antidepressant in the palliative care population. Additionally, 5 RCT studies were included on the topic of physical pain in this population. Results: All 11 studies, including one RCT, found antidepressant effects of ketamine in this patient population. Ketamine's effect on treating physical pain was mixed with the largest and most recent RCTs suggesting no significant analgesic effect. Discussion: This review suggests that starting qualified patients on intravenous (IV) ketamine and switching to oral or intranasal administration may be the most effective and convenient for treating depression, especially for patients who wish to receive treatment at home. Significant analgesia was found in patients who received epidural or intrathecal ketamine as well as in one study using intravenous administration. More research is necessary to determine which palliative care patients may benefit from ketamine treatment.