Ketamine-Assisted Psychotherapy for Depression

(KAP Trial)

Overseen By Mackenzie Brown, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Icahn School of Medicine at Mount Sinai

Must be taking: Antidepressants

Must not be taking: ECT, TMS, VNS

Disqualifiers: Substance use disorder, Schizophrenia, Bipolar, others

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

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: 1

Duration: 4 weeks

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial compares two treatments for adults with severe depression. One treatment uses ketamine combined with therapy, and the other uses only ketamine. Ketamine helps improve mood by changing brain chemistry, and therapy might make these improvements last longer. Ketamine, originally a dissociative anesthetic, has been increasingly used for treatment-resistant depression due to its rapid antidepressant effects.

Will I have to stop taking my current medications?

You can continue taking your current medications for depression as long as you stay on a stable dose.

What data supports the effectiveness of the drug Ketamine-Assisted Psychotherapy for Depression?

Research suggests that Ketamine-Assisted Psychotherapy (KAP) is effective in reducing depression and anxiety, especially in older patients and those with severe symptoms. Studies also indicate that KAP can lead to rapid improvements in adolescents with various mental health issues, showing promise as a treatment for those who do not respond to conventional therapies. ^{1 2 3 4 5}

Is ketamine-assisted psychotherapy generally safe for humans?

Ketamine has been used safely for decades, and its safety profile is well-established, making it suitable for supervised use in treating depression. However, some adverse effects, like temporary breathing issues, have been reported, so careful monitoring is recommended. ^{1 6 7 8 9}

How is Ketamine-Assisted Psychotherapy different from other depression treatments?

Ketamine-Assisted Psychotherapy is unique because it combines the psychedelic effects of ketamine with psychotherapy, unlike traditional treatments that often use ketamine alone and view its psychedelic effects as side effects. This approach does not require intravenous administration, making it more accessible for office or supervised at-home use. ^{1 2 3 4 10}

Research Team

James M Murrough, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for adults with major depressive disorder (MDD). Participants will be randomly assigned to receive either ketamine-assisted psychotherapy or just ketamine without psychotherapy over four weeks, followed by an 8-week observation period.

Inclusion Criteria

Written informed consent (and assent when applicable) obtained from subject and ability for subject to comply with the requirements of the study

Women of child-bearing potential must have a negative pregnancy test at screening and prior to ketamine infusion

I am in good physical health.

Exclusion Criteria

Substance drug or alcohol use disorder in the prior 12 months

History of suicide attempt or self harm in the prior 2 years

Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Ketamine-Assisted Psychotherapy (KAP) or standard ketamine treatment (KET) over a period of four weeks.

4 weeks

KAP: 1-2 sessions per week; KET: 2 sessions per week

Follow-up

Participants are monitored for safety and effectiveness after treatment over an 8-week period.

8 weeks

Treatment Details

Interventions

• Ketamine
• Ketamine-Assisted Psychotherapy

Trial Overview The study compares two treatments for depression: one combines ketamine with psychotherapy (KAP), and the other uses only ketamine (KET). The effectiveness of each treatment will be measured through changes in depression severity and wellness.

Participant Groups

Group I: Ketamine Assisted Psychotherapy (KAP) Experimental Treatment 2 Interventions

KAP sessions will occur once a week for a total of 4 weeks with the potential for a second session the first week for dose-finding purposes. Participants will have a ketamine exposure of at least 0.3 mg/kg and a maximum of 1.0mg/kg, at each treatment session, personalizing dose to patient experience. Each of the treatment sessions will last 120-180 min and will be conducted by a single therapist who has completed the KAP training as specified in the standard operating procedures.

Group II: Ketamine (KET) Active Control 1 Intervention

Standard medicalized ketamine administration consisting of twice weekly treatment for 3 weeks, followed by a 4th week with a single ketamine infusion serving as a down-titration period before discontinuation. Participants will have a ketamine exposure of at least 0.3 mg/kg administered via intravenous infusion at each treatment session. Patients may be up-titrated over the course of subsequent treatment sessions, as indicated clinically up to 1.0 mg/kg25. No formal psychotherapy will be provided in the KET arm, though study participants will have matched basic psychoeducation related to depression and treatment with ketamine prior to the first dosing session, during the ketamine treatment period, and post-treatment, in order to match the KAP arm. All individuals will be followed over an eight week follow up period and undergo clinical study assessments.

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

Approved in United States as Esketamine for:

• Treatment-resistant depression
• Major depressive disorder with acute suicidal ideation or behavior

Approved in European Union as Ketamine for:

• Anesthesia
• Not specifically approved for psychiatric indications but used off-label

Approved in Canada as Esketamine for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Findings from Research

Ketamine Assisted Psychotherapy (KAP) is an effective treatment for reducing depression and anxiety, particularly in older patients and those with severe symptoms, based on data from 235 patients.

Unlike traditional intravenous ketamine treatments that view its psychedelic effects as side effects, KAP utilizes these effects in a therapeutic context, making it suitable for office and supervised at-home use due to ketamine's proven safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. Dore, J., Turnipseed, B., Dwyer, S., et al.[2020]

Ketamine, traditionally used as an anesthetic since the 1970s, shows significant potential as a treatment for depression when combined with psychological therapies, based on both anecdotal evidence and clinical research.

The review proposes a novel approach to using esketamine (a specific form of ketamine) alongside Acceptance and Commitment Therapy (ACT), highlighting the importance of ketamine's psychoactive effects in enhancing therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toward Synergies of Ketamine and Psychotherapy. Mathai, DS., Mora, V., Garcia-Romeu, A.[2022]

A systematic review of 19 studies involving 1006 patients found that combining psychotherapy with ketamine treatment for psychiatric disorders generally leads to positive outcomes, particularly for conditions like substance use disorders and treatment-resistant depression.

Despite the promising results, the significant variability in psychotherapy types and ketamine protocols across studies means that more standardized and larger randomized controlled trials are needed to determine the best ways to integrate these treatments effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review. Kew, BM., Porter, RJ., Douglas, KM., et al.[2023]

Ketamine-assisted psychotherapy (KAP) shows promise as a treatment for adolescents with various mental health disorders, with four cases demonstrating symptomatic and functional improvements after treatment.

The treatment was well-tolerated, and family involvement was highlighted as crucial for success, suggesting that KAP could significantly enhance the options available for adolescent psychiatric care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine-assisted psychotherapy in adolescents with multiple psychiatric diagnoses. Wolfson, PE., Andries, J., Ahlers, D., et al.[2023]

In a study involving five participants with eating disorders and comorbid mood and anxiety disorders, weekly group-based ketamine-assisted psychotherapy (G-KAP) over 4 weeks led to significant improvements in depression and anxiety symptoms for most participants, with four showing notable reductions in depression scores and two in anxiety scores.

The ketamine treatment was well tolerated with no serious adverse events reported, indicating its safety and feasibility as an adjunct therapy in intensive residential eating disorder treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case series of group-based ketamine-assisted psychotherapy for patients in residential treatment for eating disorders with comorbid depression and anxiety disorders. Robison, R., Lafrance, A., Brendle, M., et al.[2022]

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]

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]

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-assisted psychotherapy (KAP) shows a significant positive effect on treatment outcomes for substance use disorders (SUD), based on five randomized-controlled trials, although the results for treatment-resistant depression (TRD) were not beneficial in one study.

The efficacy of KAP may be linked to temporary neural changes from ketamine, such as NMDAR inhibition and increased synaptic neuroplasticity, but more research is needed to understand the mechanisms and to conduct larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active mechanisms of ketamine-assisted psychotherapy: A systematic review. Joneborg, I., Lee, Y., Di Vincenzo, JD., et al.[2022]

References

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

Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Toward Synergies of Ketamine and Psychotherapy. [2022]

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

Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Ketamine-assisted psychotherapy in adolescents with multiple psychiatric diagnoses. [2023]

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

A case series of group-based ketamine-assisted psychotherapy for patients in residential treatment for eating disorders with comorbid depression and anxiety disorders. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

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

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. [2021]

9. England pubmed.ncbi.nlm.nih.gov

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

10. Netherlands pubmed.ncbi.nlm.nih.gov

Active mechanisms of ketamine-assisted psychotherapy: A systematic review. [2022]