Ketamine vs Midazolam for Suicidal Thoughts

(TASK Trial)

Overseen By Zach Brown, BA

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Texas Southwestern Medical Center

Must not be taking: CYP3A4 inhibitors, CYP2B6 inducers

Disqualifiers: Psychotic disorder, Mania, Substance use, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

Duration: 2 weeks

114 Participants Needed

Trial Summary

What is the purpose of this trial?

This project aims to examine the signal of efficacy of ketamine, a rapidly acting medication shown to decrease suicidality in adults in as short as hours or days, as opposed to weeks. The study design is a double-blind, randomized, active-control trial of adolescents (ages 13-18 years) with recent suicidal behaviors (suicide attempt or increased suicidal ideation). All participants must be receiving standard of care treatment which may range broadly from both outpatient and inpatient programs which include clinically indicated psychosocial and/or psychopharmacological treatments. Ketamine/midazolam treatment will occur twice weekly during the first two weeks of the study, followed by weekly assessments through week 12.

Will I have to stop taking my current medications?

You may need to stop certain medications that affect how ketamine works in your body, especially those that change heart rate or blood pressure. ADHD medications should not be taken 24 hours before treatment. The study team will review your medications to see if any need to be stopped.

What data supports the effectiveness of the drug ketamine for reducing suicidal thoughts?

Research shows that ketamine can quickly reduce suicidal thoughts, with effects appearing within an hour and lasting up to a week. Studies have found that ketamine is more effective than midazolam in reducing suicidal thoughts in patients with depression and cancer. ^{1 2 3 4 5}

Is ketamine or midazolam safe for treating suicidal thoughts?

Both ketamine and midazolam have been studied for safety in various conditions, including sedation in children and treatment of depression with suicidal thoughts. Research suggests that both drugs have similar safety profiles, but ketamine is often preferred due to its rapid effects on reducing suicidal thoughts. ^{1 3 4 5 6}

How is ketamine different from other drugs for treating suicidal thoughts?

Ketamine is unique because it can rapidly reduce suicidal thoughts and overall depression levels, often within a day, which is faster than many traditional antidepressants. It is administered in a sub-anesthetic dose intravenously (through a vein), and its quick action makes it particularly novel for acute situations. ^{3 4 5 7 8}

Research Team

Madhukar Trivedi, MD

Principal Investigator

University of Texas Southwestern Medical Center

Eligibility Criteria

Adolescents aged 13-18 with recent suicidal behavior and a primary diagnosis of depression are eligible. They must be fluent in English, not have severe substance use issues or unstable medical conditions, and agree to use contraception. Those with certain psychiatric disorders or weighing over 120 kilograms are excluded.

Inclusion Criteria

You have had a serious suicidal event within the past month that required immediate evaluation or hospitalization.

I am receiving recommended mental health care.

My main diagnosis is depression.

Exclusion Criteria

My primary diagnosis is not depression.

Have unstable medical conditions (stable for less than 3 months) or with clinically significant laboratory values or an electrocardiogram (ECG) that would pose significant risk

You have been diagnosed with schizophrenia, a psychotic disorder, a developmental disorder, or mental retardation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either ketamine or midazolam infusions twice weekly for two weeks

2 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with weekly assessments

10 weeks

11 visits (combination of in-person and remote)

Treatment Details

Interventions

• Ketamine Hydrochloride
• Midazolam Hydrochloride

Trial Overview The trial is testing the effectiveness of ketamine compared to midazolam in reducing suicidality among adolescents receiving standard care for depression. It's a double-blind study where treatments are given twice weekly initially, then assessed weekly up to week 12.

Participant Groups

Group I: Midazolam Active Control 2 Interventions

0.02 mg/kg midazolam will be administered 4 times in a 2 week period. Midazolam will be dissolved in 0.9% sodium chloride in a total volume of 100ml and administered with a syringe infusion pump at a constant rate.

Group II: Ketamine Active Control 2 Interventions

0.5 mg/kg intravenous ketamine will be administered 4 times in a 2 week period. Ketamine will be dissolved in 0.9% sodium chloride in a total volume of 100ml and administered with a syringe infusion pump at a constant rate.

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+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

A single dose of ketamine can significantly reduce suicidal thoughts within an hour of administration, with effects lasting up to a week, making it a promising option for patients with severe or treatment-resistant depression.

The antisuicidal effects of ketamine occur independently of its impact on overall depression severity, indicating a unique mechanism of action that warrants further investigation for crisis intervention in suicidal patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk. Andrade, C.[2022]

In a study of 156 suicidal patients, ketamine infusions significantly reduced suicidal ideation, with early remission at day 1 and day 3 being strong predictors of sustained remission at week 6.

Clinical factors like bipolar disorder and lower initial suicidal thoughts were linked to early remission, but overall, no specific clinical factors reliably predicted long-term outcomes, highlighting the need for ongoing monitoring and comprehensive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical predictive factors and trajectories of suicidal remission over 6 weeks following intravenous ketamine for suicidal ideation. Jollant, F., Demattei, C., Fabbro, P., et al.[2023]

A pilot study involving 16 participants with bipolar depression indicated that a sub-anesthetic dose of ketamine (0.5 mg/kg) may lead to a greater reduction in suicidal ideation compared to midazolam, with a mean difference of nearly 6 points on the Scale for Suicidal Ideation, although this was not statistically significant.

The study found promising correlations between memory improvement and reduction in suicidal thoughts after ketamine infusion, as well as a decrease in serum brain-derived neurotrophic factor (BDNF) associated with reduced suicidal ideation, suggesting potential biomarkers for future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Grunebaum, MF., Ellis, SP., Keilp, JG., 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]

In a study involving 151 participants from 10 clinical trials, it was found that the placebo response for suicidal ideation was greater than for other depressive symptoms when participants received saline or midazolam, suggesting that suicidal thoughts may respond differently to treatment than general depression symptoms.

These findings may help explain why intravenous ketamine shows rapid improvements in overall depressive symptoms but has more modest effects on suicidal ideation, indicating a need for further research into targeted treatments for suicidal thoughts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Participant-Level Integrative Data Analysis of Differential Placebo Response for Suicidal Ideation and Nonsuicidal Depressive Symptoms in Clinical Trials of Intravenous Racemic Ketamine. Bloomfield-Clagett, B., Ballard, ED., Greenstein, DK., et al.[2023]

A review of four studies involving children in emergency departments found that both ketamine and midazolam provide similar efficacy and safety for conscious sedation.

Despite their comparable profiles, ketamine is favored by both parents and physicians, suggesting a preference for its use in pediatric sedation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midazolam or ketamine for procedural sedation of children in the emergency department. Munro, A., Machonochie, I.[2018]

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 60 healthy children aged 1.5 to 7 years, a combination of ketamine and midazolam was found to be the most effective pre-surgery sedation method, achieving 100% success in parental separation.

The ketamine and midazolam mixture also showed an 85% success rate for mask induction, significantly outperforming ketamine alone (42%) and midazolam alone (65%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine plus midazolam, a most effective paediatric oral premedicant. Warner, DL., Cabaret, J., Velling, D.[2022]

References

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

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical predictive factors and trajectories of suicidal remission over 6 weeks following intravenous ketamine for suicidal ideation. [2023]

3. Denmark pubmed.ncbi.nlm.nih.gov

Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. [2022]

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

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

5. England pubmed.ncbi.nlm.nih.gov

A Participant-Level Integrative Data Analysis of Differential Placebo Response for Suicidal Ideation and Nonsuicidal Depressive Symptoms in Clinical Trials of Intravenous Racemic Ketamine. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Midazolam or ketamine for procedural sedation of children in the emergency department. [2018]

7. 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]

8. France pubmed.ncbi.nlm.nih.gov

Ketamine plus midazolam, a most effective paediatric oral premedicant. [2022]