Ketamine + Midazolam for Depression

(UNIKET Trial)

Overseen By Beth Dedrick

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Must not be taking: Antidepressants, Antipsychotics, Benzodiazepines, others

Disqualifiers: Schizophrenia, Bipolar, Substance use, others

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: 6

Duration: 2 weeks

165 Participants Needed

Trial Summary

What is the purpose of this trial?

The study is investigating dysfunctions in neurocircuitry in regards to irritability with healthy controls (HC) and individuals with Major Depressive Disorder (MDD) by performing MRIs. The MDD group will also be randomized to receive ketamine or midazolam to investigate changes post-treatment in neurocircuitry with regards to irritability.

Do I need to stop my current medications to join the trial?

You must either be free of certain medications like antidepressants and antipsychotics or be stable on them for four weeks before the trial starts.

What data supports the effectiveness of the drug combination of ketamine and midazolam for depression?

Research shows that the combination of ketamine and midazolam is effective in managing pain and sedation in children, suggesting it may have potential benefits for depression treatment due to its calming and pain-relieving effects. ^{1 2 3 4 5}

Is the combination of ketamine and midazolam safe for use in humans?

Research shows that the combination of ketamine and midazolam is generally safe for use in humans, particularly in children undergoing pain procedures, with no major complications observed. Some minor side effects like nausea, vomiting, and salivation were noted, but overall, the combination was well-tolerated. ^{2 6 7 8 9}

How is the drug Ketamine + Midazolam unique for treating depression?

The combination of Ketamine and Midazolam is unique for treating depression because Ketamine acts rapidly to relieve symptoms, including suicidal thoughts, which is different from traditional antidepressants that often take weeks to work. Additionally, the use of Midazolam, a benzodiazepine, may help manage anxiety and enhance the sedative effects, making the treatment potentially more effective for immediate relief. ^{1 2 10 11 12}

Eligibility Criteria

This trial is for adults aged 18-65 with Major Depressive Disorder (MDD) who can undergo MRI scans and are willing to receive ketamine or midazolam infusions. Healthy controls without psychiatric conditions can also participate. All must understand English, not be on certain medications, agree to use contraception, and not have a high risk of substance abuse or suicidal behavior.

Inclusion Criteria

I agree to use birth control during the study and for 3 months after.

I haven't taken any psychotropic or certain anticonvulsant medications, or have been stable on them for 4 weeks.

Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process

Exclusion Criteria

I am not taking any medications that are not allowed in the study.

I do not have any unstable illnesses affecting my organs or immune system.

Any claustrophobia or other conditions which may result in inability to lie still in the MRI scanner for 1 hour or more

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo baseline assessments including pre-treatment fMRI scans

1 week

1 visit (in-person)

Treatment

MDD participants receive twice-weekly intravenous infusions of either ketamine or midazolam for 2 weeks

2 weeks

4 visits (in-person)

Post-Treatment Assessment

Clinical assessments and fMRI scans are repeated after the last infusion

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketamine Hydrochloride
• Midazolam injection

Trial Overview The study examines brain function related to irritability in people with MDD using MRIs before and after administering either ketamine or midazolam. It aims to identify how these treatments affect the neurocircuitry associated with irritability compared to healthy individuals.

Participant Groups

Group I: Healthy Controls Active Control 1 Intervention

Healthy controls will undergo clinician assessments and fMRI to compare to MDD group.

Group II: MDD - Ketamine Active Control 1 Intervention

Participants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four ketamine infusions.

Group III: MDD - Midazolam Placebo Group 1 Intervention

Participants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four midazolam infusions.

Ketamine Hydrochloride is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Pain management
• Depression
• Suicidal ideation

Approved in European Union as Ketamine Hydrochloride for:

• Anesthesia
• Pain management
• Treatment-resistant depression

Approved in Canada as Ketamine Hydrochloride for:

• Anesthesia
• Pain management
• Depression

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Findings from Research

A systematic review of five randomized controlled trials involving 346 uncooperative children found that the combination of midazolam and ketamine was significantly more effective for sedation, achieving an 84% success rate compared to midazolam alone.

Children receiving the midazolam and ketamine combination exhibited calmer behavior (50%) compared to those receiving midazolam alone (37%), with only modest adverse effects that did not require special treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Evaluation of Ease of Dental Treatment and Clinical Efficiency of Midazolam vs Midazolam and Ketamine Combination for Sedation in Young Uncooperative Pediatric Patients: A Systematic Review. Rathi, GV., Padawe, D., Takate, V., et al.[2023]

In a study involving 92 pediatric oncology patients undergoing 226 procedures, the combination of midazolam and ketamine was found to be safe and effective for managing pain, with no complications reported.

The treatment provided satisfactory analgesia in 89 out of 92 patients and induced brief unconscious sedation lasting an average of ten minutes, demonstrating its efficacy in a clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of intravenous ketamine-midazolam association for pain procedures in children with cancer. A prospective study. Pellier, I., Monrigal, JP., Le Moine, P., et al.[2022]

In a study of 60 children aged 1-10 years requiring laceration repair, the combination of oral midazolam and ketamine provided deeper sedation compared to midazolam alone, as indicated by a higher Sedation Score.

The combination treatment also resulted in fewer children needing intravenous sedation (6% vs. 27%), while pain assessment during local anesthetic injection showed no significant difference between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, randomised, placebo-controlled trial of oral midazolam plus oral ketamine for sedation of children during laceration repair. Barkan, S., Breitbart, R., Brenner-Zada, G., et al.[2022]

In a study of 100 children, both oral midazolam alone and a combination of midazolam with ketamine were found to be effective for preoperative sedation, with no serious side effects reported.

The combination of midazolam and ketamine resulted in a higher percentage of children being calm and easily separated from their parents (73.46% vs 41% for midazolam alone), indicating improved emotional readiness for anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative evaluation of midazolam and ketamine with midazolam alone as oral premedication. Ghai, B., Grandhe, RP., Kumar, A., et al.[2022]

The combination of midazolam and ketamine is explored for its effectiveness in emergency medicine, particularly for sedation and pain management.

This combination may benefit specific patient populations, although the abstract does not provide detailed data on the number of subjects or specific outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midazolam with ketamine: Who benefits? Kennedy, RM., McAllister, JD.[2017]

Ketamine hydrochloride has shown rapid and significant antidepressant effects in patients with treatment-resistant mood and anxiety disorders, although the studies supporting this have small sample sizes and limited long-term data.

While ketamine may offer benefits for some patients, there are important safety concerns and limitations in the existing research that must be considered when using it as an off-label treatment for psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. Sanacora, G., Frye, MA., McDonald, W., 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]

A new sedation technique using nasal midazolam and rectal ketamine in 32 children showed good sedation in 23 patients, with minimal severe respiratory depression and excellent cardiovascular stability.

The method resulted in significant anterograde amnesia for the procedure in most patients, with common side effects including nausea and vomiting, and an average recovery time of 40 minutes, indicating it is a relatively safe and effective option for pediatric sedation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of midazolam in diagnostic and short surgical procedures in children. Saint-Maurice, C., Landais, A., Delleur, MM., et al.[2019]

In a phase II feasibility study involving 10 participants with major depressive disorder and advanced life-limiting illnesses, subcutaneous ketamine infusions (0.1-0.4 mg/kg) were well-tolerated and showed promising antidepressant effects, with 50% of participants achieving a significant reduction in depression scores.

The study found no clinically relevant harms associated with the treatment, suggesting that further research into the effectiveness of ketamine in palliative care settings is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous ketamine infusion in palliative patients for major depressive disorder (SKIPMDD)-Phase II single-arm open-label feasibility study. Lee, W., Sheehan, C., Chye, R., et al.[2023]

In a study of 87 children undergoing ophthalmologic surgeries, a combination of low-dose midazolam and ketamine provided effective sedation and reduced anxiety, similar to high-dose midazolam and ketamine.

The low-dose combination resulted in faster recovery times and a lower incidence of excessive salivation compared to the high-dose group, making it a safer option for premedication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low- versus high-dose combination of midazolam-ketamine for oral premedication in children for ophthalmologic surgeries. Darlong, V., Shende, D., Singh, M., et al.[2022]

In a randomized clinical trial involving 99 participants with treatment-resistant depression, higher doses of oral benzodiazepines were found to reduce the effectiveness of a single intravenous ketamine infusion on depression scores at 24 hours post-treatment.

While benzodiazepine use did not affect overall treatment response to ketamine compared to midazolam, it significantly impacted depression ratings at day 1, suggesting that careful management of benzodiazepine dosage may be important when using ketamine for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study. Feeney, A., Hoeppner, BB., Freeman, MP., et al.[2022]

In a study of 42 newly-diagnosed cancer patients, a single dose of ketamine significantly reduced suicidal ideation and overall depression levels compared to midazolam, with improvements noted as early as day 1 and continuing to day 3.

The findings highlight ketamine's potential as a rapid antidepressant for patients facing acute depression and suicidal thoughts, suggesting it may be an effective intervention in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine rapidly relieves acute suicidal ideation in cancer patients: a randomized controlled clinical trial. Fan, W., Yang, H., Sun, Y., et al.[2022]

References

1. India pubmed.ncbi.nlm.nih.gov

Comparative Evaluation of Ease of Dental Treatment and Clinical Efficiency of Midazolam vs Midazolam and Ketamine Combination for Sedation in Young Uncooperative Pediatric Patients: A Systematic Review. [2023]

2. France pubmed.ncbi.nlm.nih.gov

Use of intravenous ketamine-midazolam association for pain procedures in children with cancer. A prospective study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

A double-blind, randomised, placebo-controlled trial of oral midazolam plus oral ketamine for sedation of children during laceration repair. [2022]

4. France pubmed.ncbi.nlm.nih.gov

Comparative evaluation of midazolam and ketamine with midazolam alone as oral premedication. [2022]

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

Midazolam with ketamine: Who benefits? [2017]

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

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. [2013]

8. England pubmed.ncbi.nlm.nih.gov

The use of midazolam in diagnostic and short surgical procedures in children. [2019]

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

Subcutaneous ketamine infusion in palliative patients for major depressive disorder (SKIPMDD)-Phase II single-arm open-label feasibility study. [2023]

10. India pubmed.ncbi.nlm.nih.gov

Low- versus high-dose combination of midazolam-ketamine for oral premedication in children for ophthalmologic surgeries. [2022]

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

Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study. [2022]

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

Ketamine rapidly relieves acute suicidal ideation in cancer patients: a randomized controlled clinical trial. [2022]