Esketamine + Prolonged Exposure for PTSD

Overseen By Casey Straud, PsyD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: The University of Texas Health Science Center at San Antonio

Must not be taking: Antidepressants, Benzodiazepines

Disqualifiers: Manic episode, Substance use disorder, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 11

Duration: 2 weeks

8 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you have been on stable doses of your current medications for at least 4 weeks before participating. However, if you are a young adult (18-24 years old), you must not be taking any antidepressants.

What data supports the effectiveness of the treatment Esketamine + Prolonged Exposure for PTSD?

Prolonged exposure (PE) therapy is a well-established treatment for PTSD, shown to reduce symptoms and improve mental health in veterans and military personnel. It is effective across various types of trauma and can also help with related issues like anger and depression. ^{1 2 3 4 5}

Is the combination of Esketamine and Prolonged Exposure therapy safe for treating PTSD?

Esketamine has been associated with some neurological side effects like sedation, dizziness, and changes in taste, and it may increase the risk of nausea and dissociation. These side effects have been observed in studies for other conditions, such as treatment-resistant depression. There is no specific safety data available for the combination of Esketamine and Prolonged Exposure therapy for PTSD. ^{2 6 7 8 9}

How is the treatment of Esketamine + Prolonged Exposure for PTSD different from other treatments?

This treatment is unique because it combines Esketamine, a medication that works on brain chemicals to quickly reduce symptoms, with Prolonged Exposure therapy, a well-established method that helps patients face and process traumatic memories. This combination aims to enhance the effectiveness of PTSD treatment by addressing both the chemical and psychological aspects of the disorder. ^{1 2 4 5 10}

What is the purpose of this trial?

This study is being done to see if Prolonged Exposure (PE), a well-researched, very effective individual (one-to-one) behavioral therapy designed to help people to directly deal with traumatic events they have suffered in the past, can be combined with intranasal esketamine (ketamine) for the treatment of posttraumatic stress disorder (PTSD) to enhance treatment benefits. Ketamine nasal spray is a drug approved by the U.S. Food \& Drug Administration (FDA) for treatment resistant depression. Combined with PE, intranasal ketamine may help to augment PE and further reduce participants' PTSD symptoms.

Research Team

Casey Straud, PsyD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Eligibility Criteria

This trial is for individuals with PTSD who can undergo Prolonged Exposure therapy, a one-to-one behavioral treatment. Participants must be able to tolerate nasal spray medication and have no history of conditions that esketamine could worsen.

Inclusion Criteria

Able to speak and read English (due to standardization of outcome measures)

My current medications have not changed in the last 4 weeks.

I weigh between 110 and 220 pounds.

Exclusion Criteria

A history of ketamine or phencyclidine abuse

Moderate or greater severity for alcohol or substance use disorder (DSM-5) in the previous six months

I am not currently experiencing a severe manic or psychotic episode.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phone screen and baseline assessment

Treatment

Participants receive 10 sessions of Prolonged Exposure therapy and 6 doses of intranasal esketamine over 2 weeks

2 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person) at 1-month follow-up

Treatment Details

Interventions

• Esketamine
• Massed Prolonged Exposure (PE)

Trial Overview The study tests if combining Esketamine (a nasal spray approved for depression) with Prolonged Exposure therapy offers greater relief from PTSD symptoms than the therapy alone.

Participant Groups

Group I: Esketamine combined with Prolonged Exposure for PTSD Experimental Treatment 2 Interventions

Esketamine (intranasal ketamine) will be administered 6 times over a 2-week period after administering PE sessions

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

Institute for Integration of Medicine & Science-UT Health San Antonio

Collaborator

Trials

1

Recruited

8+

Findings from Research

In a study of 31 combat veterans with PTSD undergoing prolonged exposure therapy, 9 out of 24 completers achieved complete remission from PTSD, indicating the therapy's potential efficacy.

The study found that successful remission from PTSD was associated with decreased activation in the left anterior insula during negative image anticipation and increased connectivity with other brain regions, suggesting that effective treatment may involve better regulation of anticipatory anxiety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurosubstrates of remission following prolonged exposure therapy in veterans with posttraumatic stress disorder. Simmons, AN., Norman, SB., Spadoni, AD., et al.[2021]

Prolonged exposure (PE) therapy was found to be effective in reducing PTSD and depression symptoms in a small group of 10 Veterans with mild to moderate traumatic brain injury (TBI) and chronic PTSD, showing large effect sizes from pre- to posttreatment.

The therapy was safely adapted for Veterans with cognitive impairments, indicating that PE can be a viable treatment option for this population, with significant symptom improvements observed after 8 to 18 sessions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A preliminary examination of prolonged exposure therapy with Iraq and Afghanistan veterans with a diagnosis of posttraumatic stress disorder and mild to moderate traumatic brain injury. Wolf, GK., Strom, TQ., Kehle, SM., et al.[2022]

In a study involving 44 adults with PTSD, initial prolonged exposure therapy (PE) significantly improved symptoms, but those who remained symptomatic showed no added benefit from adding paroxetine CR to continued PE during the second phase of treatment.

The results suggest that paroxetine CR does not enhance the effectiveness of PE for patients who do not fully respond to initial therapy, indicating a need for new treatment strategies for PTSD that is resistant to standard approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paroxetine CR augmentation for posttraumatic stress disorder refractory to prolonged exposure therapy. Simon, NM., Connor, KM., Lang, AJ., et al.[2022]

Prolonged exposure (PE) therapy is an effective first-line treatment for PTSD in Veterans and military personnel, significantly reducing symptoms and comorbid issues like anger and depression, supported by extensive research and clinical guidelines.

The PE protocol includes key components such as psychoeducation and exposure techniques, and the Veterans Health Administration has trained over 1,300 mental health providers to deliver this therapy, indicating a strong commitment to improving PTSD treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of exposure therapy: a gold standard for PTSD treatment. Rauch, SA., Eftekhari, A., Ruzek, JI.[2021]

A study involving 160 active-duty military personnel with PTSD found that 60-minute prolonged exposure (PE) therapy sessions are just as effective as the standard 90-minute sessions, making treatment more accessible in settings that typically use shorter appointment times.

Both the Clinician Administered PTSD Scale (CAPS-5) and the PTSD Checklist (PCL-5) showed that the efficacy of 60-minute sessions was noninferior to 90-minute sessions, suggesting that shorter sessions can be effectively implemented without compromising treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy of 90-min versus 60-min sessions of prolonged exposure for PTSD: A randomized controlled trial in active-duty military personnel. Foa, EB., Bredemeier, K., Acierno, R., et al.[2022]

A study analyzing 720 cases of esketamine-related neurological adverse events (AEs) from 2019 to 2021 identified 21 safety signals, with sedation being the most concerning (ROR of 204.00), indicating potential long-term safety issues with esketamine.

The severity of neurological AEs was influenced by factors such as esketamine dosage and co-prescription with other medications, highlighting the need for careful monitoring and management of these risks in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System. Guo, H., Wang, B., Yuan, S., et al.[2022]

Esketamine has been shown to induce antidepressant effects in patients with Major Depression Disorder (MDD), based on a meta-analysis of four randomized controlled trials involving 551 patients.

However, the analysis revealed a significant increase in adverse effects compared to placebo, including nausea, dissociation, dizziness, and sedation, indicating that while esketamine can be effective, it also carries specific risks that need to be considered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Effects of Esketamine for the Treatment of Major Depression Disorder: Findings from Randomized Controlled Trials. Yang, S., Wang, J., Li, X., et al.[2022]

Prolonged Exposure (PE) therapy was found to be feasible and well-accepted among Japanese patients with PTSD, with 10 out of 12 participants completing the treatment over 9 to 15 sessions.

Participants showed significant reductions in PTSD and depression symptoms from before treatment to after, with these improvements maintained at 3- and 6-month follow-ups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study on prolonged exposure of Japanese patients with posttraumatic stress disorder due to mixed traumatic events. Asukai, N., Saito, A., Tsuruta, N., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Neurosubstrates of remission following prolonged exposure therapy in veterans with posttraumatic stress disorder. [2021]

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

A preliminary examination of prolonged exposure therapy with Iraq and Afghanistan veterans with a diagnosis of posttraumatic stress disorder and mild to moderate traumatic brain injury. [2022]

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

Paroxetine CR augmentation for posttraumatic stress disorder refractory to prolonged exposure therapy. [2022]

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

Review of exposure therapy: a gold standard for PTSD treatment. [2021]

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

The efficacy of 90-min versus 60-min sessions of prolonged exposure for PTSD: A randomized controlled trial in active-duty military personnel. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System. [2022]

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

Adverse Effects of Esketamine for the Treatment of Major Depression Disorder: Findings from Randomized Controlled Trials. [2022]

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

Longitudinal Course of Adverse Events With Esketamine Nasal Spray: A Post Hoc Analysis of Pooled Data From Phase 3 Trials in Patients With Treatment-Resistant Depression. [2022]

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

Massed v. standard prolonged exposure therapy for PTSD in military personnel and veterans: 12-month follow-up of a non-inferiority randomised controlled trial. [2023]

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

Pilot study on prolonged exposure of Japanese patients with posttraumatic stress disorder due to mixed traumatic events. [2022]