Ketamine-Enhanced Psychotherapy for PTSD

Recruiting at 1 trial location

Overseen By Charles Gordon, MA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must be taking: Antidepressants, Trazodone, Atypical neuroleptics, Prazosin

Must not be taking: MAOIs, Memantine, Long-acting benzodiazepines

Disqualifiers: Borderline personality, Schizophrenia, Suicidal risk, 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: 10

Duration: 1 week

162 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining ketamine, an anesthetic, with intensive trauma-focused psychotherapy can relieve PTSD symptoms more effectively than midazolam. The researchers hope to achieve significant therapeutic effects within a week, a process that typically takes months. The study will also examine brain changes during treatment. Individuals with severe PTSD for over a year, who are not experiencing active psychotic symptoms, might be suitable candidates for this trial. As a Phase 2 trial, it focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you must stop MAOIs and memantine 4 weeks before, and long-acting benzodiazepines 2 weeks before. Some medications are allowed if you've been on a stable dose for at least 4 weeks, but others are not permitted within 8 hours of treatment sessions.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketamine is generally safe and well-tolerated for treating PTSD. One study found that repeated ketamine infusions were safe, with only brief episodes of feeling disconnected from reality as a side effect. Most participants handled the treatment well.

Midazolam, commonly used for sedation in medical settings, is considered safe under medical supervision. During the trial, doctors and nurses will closely monitor participants' vital signs, such as heart rate and blood pressure, to ensure safety.

Overall, both treatments have been studied, and safety measures are in place to protect participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for PTSD because they use ketamine, which acts differently than typical options like SSRIs and psychotherapy. Ketamine works rapidly, potentially offering relief in just days by targeting the NMDA receptors in the brain, unlike standard treatments that often take weeks to show effects. The study is exploring two doses of ketamine—0.2 mg/kg and 0.5 mg/kg—each combined with trauma-focused psychotherapy, which may enhance their therapeutic effects. Additionally, there's an active comparator group using midazolam, providing a unique opportunity to compare its effects against ketamine in this innovative approach.

What evidence suggests that this trial's treatments could be effective for PTSD?

Research shows that ketamine, especially when combined with therapy, might effectively treat PTSD. In this trial, participants will receive either a 0.5 mg/kg or 0.2 mg/kg ketamine infusion along with trauma-focused psychotherapy. Previous studies have shown that ketamine infusions greatly reduce PTSD symptoms. One study found that patients experienced significant improvements in their PTSD symptoms just 24 hours after starting ketamine treatment. Additionally, ketamine has provided quick and lasting relief from PTSD symptoms. These findings suggest that ketamine could be an effective option for managing PTSD symptoms more rapidly. ^{1 3 4 6 7}

Who Is on the Research Team?

Ilan Harpaz-Rotem, PhD ABPP

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

Adults aged 21-70 with severe PTSD who can read and write English may join this trial. They must not be pregnant, agree to birth control if applicable, have stable mental health without certain disorders like schizophrenia or bipolar mania recently, and no recent substance abuse. Participants should not have medical conditions that make ketamine unsafe.

Inclusion Criteria

I don't have any health issues or take medications that make ketamine unsafe for me.

Able to read and write English

I am between 21 and 70 years old.

Exclusion Criteria

Resting blood pressure lower than 90/60 or higher than 150/90, or resting heart rate lower than 45/min or higher than 100/min

I don't take sedatives or similar medications within 8 hours before treatment, unless approved by my doctor.

My doctor found something unusual during my physical exam.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants receive ketamine or midazolam infusions combined with trauma-focused psychotherapy over a 7-day period

1 week

7 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with MRI scans and clinical evaluations

90 days

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine
• Midazolam

Trial Overview The study is testing whether a week-long intensive psychotherapy combined with either ketamine or midazolam is more effective for treating PTSD. It aims to achieve results faster than traditional methods and will also examine changes in brain function as a result of the treatment.

How Is the Trial Designed?

Group I: 0.5mg/kg ketamine with psychotherapy Experimental Treatment 1 Intervention

2\. Two infusions of Ketamine combined with trauma-focused psychotherapy. Low dose ketamine infusion will take place on day 2 and day 4, of the psychotherapy intervention. A physician will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady state of ketamine infusion of 0.5 mg/kg for 40 minutes.

Group II: 0.2mg/kg ketamine with psychotherapy Experimental Treatment 1 Intervention

Two infusions of low dose Ketamine combined with trauma-focused psychotherapy. Low dose ketamine infusion will take place on day 2 and day 4, of the psychotherapy intervention. A physician will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady state of ketamine infusion of 0.2 mg/kg for 40 minutes.

Group III: Midazolam with psychotherapy Active Control 1 Intervention

Midazolam combined with trauma-focused psychotherapy. Midazolam infusion procedure will take place on day 2 and day 4, of the psychotherapy intervention. A physician will oversee administer the Midazolam infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following midazolam infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady midazolam infusion at a rate 0.045 mg/kg for 40 minutes.

Ketamine is already approved in 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

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

In a randomized controlled trial with 30 participants suffering from chronic PTSD, repeated intravenous ketamine infusions significantly reduced PTSD symptoms compared to a placebo (midazolam), with 67% of the ketamine group showing treatment response.

The ketamine infusions were well tolerated, with no serious adverse events reported, suggesting a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. Feder, A., Costi, S., Rutter, SB., et al.[2021]

A qualitative analysis of 29 online discussion threads about ketamine use for depression and PTSD revealed that users frequently reported rapid mood enhancement, with many experiencing a return of pleasure and motivation after use.

While there were some negative effects reported, such as dizziness and potential urinary bladder damage from misuse, only two posts indicated a lack of mood improvement, suggesting that ketamine may be an effective option for some individuals dealing with these mental health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of ketamine to cope with depression and post-traumatic stress disorder: A qualitative analysis of the discourses posted on a popular online forum. Chaves, TV., Wilffert, B., Sanchez, ZM.[2021]

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]

The RTT-KaT program, which combines ketamine-assisted therapy with group psychotherapy, was well tolerated by all 128 participants, with no dropouts reported during the 12-week program.

While 49.16% of sessions noted elevated blood pressure post-treatment, most adverse effects were mild and transient, including nausea (12.05%), vomiting (2.52%), headaches (3.35%), and dizziness, indicating a good safety profile for ketamine use in this community setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of intramuscular and sublingual ketamine for psychiatric treatment in the Roots To Thrive ketamine-assisted therapy program: a retrospective chart review. Tsang, VWL., Tao, B., Dames, S., et al.[2023]

In a randomized controlled trial with 30 participants suffering from chronic PTSD, repeated intravenous ketamine infusions significantly reduced PTSD symptoms compared to a placebo (midazolam), with a notable improvement in clinician-rated scores after two weeks.

The study found that 67% of participants receiving ketamine were treatment responders, and the infusions were generally well tolerated, indicating a promising safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. Feder, A., Costi, S., Rutter, SB., et al.[2023]

An extended release oral ketamine tablet was found to be safe and well tolerated in a study of seven patients with treatment-resistant depression/anxiety, with no significant changes in vital signs and only one brief report of dissociation.

All patients experienced over 50% improvements in mood ratings over 96 hours, suggesting that while the onset of mood improvement is slightly delayed compared to injectable forms, this oral formulation could be a promising option for treating resistant depression and anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Glue, P., Medlicott, NJ., Neehoff, S., et al.[2022]

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 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]

In a study involving five patients with treatment-resistant depression (TRD) and comorbid PTSD, repeated oral esketamine treatment led to improvements in depressive symptoms and increased receptiveness to psychotherapy over a duration of six weeks to a year.

While most patients showed positive responses, one individual experienced symptom worsening in a stressful situation, emphasizing the importance of administering esketamine in a safe environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated oral esketamine in patients with treatment resistant depression and comorbid posttraumatic stress disorder. Veraart, JKE., van Westenbrugge, M., van Wulfften Palthe, JE., et al.[2023]

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]

Ketamine has shown promise as a rapid-acting treatment for PTSD, with a single intravenous dose leading to a quick reduction in symptoms, particularly in civilian populations.

In a study involving repeated IV ketamine administration, significant improvements in PTSD symptoms were observed compared to midazolam, but this effect was not seen in veteran and military populations, indicating the need for further research on its efficacy across different groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for Treatment of Posttraumatic Stress Disorder: State of the Field. Fremont, R., Brown, O., Feder, A., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10979792/

Effectiveness of Ketamine for the Treatment of Post- ... Our study suggests that ketamine could be a promising option for the treatment of PTSD, particularly when paired with various psychotherapy approaches.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165178125003373

A retrospective analysis of ketamine intravenous therapy ... In a large real-world sample of 8,136 PTSD patients (87 % with comorbid depression), Ketamine Intravenous Therapy (KIT) significantly reduced PTSD and ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38559428/

Effectiveness of Ketamine for the Treatment of Post- ... Results: Ketamine demonstrated significant improvements in PCL-5 scores, both 24 hours after the initial infusion and at the endpoint of the treatment course, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02397889

Study Details | NCT02397889 | Ketamine as a Treatment ... The purpose of this study is to see whether ketamine, when given repeatedly intravenously can produce a quick and persistent improvement in PTSD symptoms. At ...

5. nature.com nature.com/articles/s41386-023-01606-3

Long term structural and functional neural changes ... Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (−0.33, sd = 0.13, 95%HDI [− ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12529321/

Ketamine for treatment-resistant post-traumatic stress disorder Blinded safety data were reviewed during the study by an independent data safety monitoring board. Summary statistics were calculated and ...

7. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.focus.20230006

Ketamine for Treatment of Posttraumatic Stress Disorder In this study, repeated ketamine infusions were also found to be safe and well tolerated in PTSD, with only transient emergence of dissociative ...