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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining a nasal spray form of esketamine (a drug similar to ketamine often used for depression) with Prolonged Exposure (PE) therapy can more effectively treat posttraumatic stress disorder (PTSD). Prolonged Exposure therapy helps individuals confront and process their traumatic experiences. The trial seeks to determine if using both treatments together can improve PTSD symptoms more than therapy alone. Ideal participants are those diagnosed with PTSD who have maintained stable medication doses for at least four weeks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking insights.

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.

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

Research has shown that intranasal esketamine, especially when combined with therapies like Prolonged Exposure (PE), is generally well-tolerated. Various studies have found that esketamine quickly and effectively reduces symptoms of depression and PTSD, even in very ill patients.

One study found that esketamine, when combined with therapy, quickly reduced tension, anxiety, and other common PTSD symptoms, with most participants managing the treatment well. Another study with veterans showed significant improvements in PTSD symptoms. These findings suggest that esketamine, already approved by the FDA for treatment-resistant depression, is safe to use with PE for addressing PTSD symptoms. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for PTSD, which often include medications like SSRIs and SNRIs, Esketamine offers a novel approach by using an active ingredient derived from ketamine, known for its rapid-acting antidepressant effects. This treatment is administered intranasally, which is less invasive and potentially faster-acting than traditional oral medications. Researchers are excited about Esketamine because it targets the brain's glutamate system, offering a different mechanism of action compared to conventional therapies that focus on serotonin pathways. Additionally, when combined with Prolonged Exposure therapy, there is hope for synergistic effects, potentially leading to faster and more robust improvements in PTSD symptoms.

What evidence suggests that this treatment might be an effective treatment for PTSD?

Research has shown that using esketamine with prolonged exposure therapy might help treat PTSD. In this trial, participants will receive a combination of esketamine, a medication approved by the FDA for treatment-resistant depression, and prolonged exposure therapy. Esketamine has shown promise in reducing PTSD symptoms, especially when combined with therapy. Studies have found that esketamine improved PTSD symptoms in patients with treatment-resistant depression. In one study, nearly half of the participants experienced significant improvements in their PTSD symptoms. Additionally, esketamine can enhance the effects of therapy, making it a potentially powerful option for people dealing with PTSD. ^{1 2 3 5 6}

Who Is on the Research Team?

Casey Straud, PsyD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06795659

Combining Esketamine and Prolonged Exposure ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9305073/

Efficacy and Safety of Intranasal Esketamine in Patients ... This study reports the outcomes of 11 severely ill patients with comorbid TRD and PTSD after IN Esketamine treatment. Esketamine significantly improved ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2468749924001133

Esketamine facilitate psychotherapies for Post-Traumatic ... Esketamine treatment associated with psychotherapies appears promising in patients with resistant complex PTSD and TRD.

4. 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.

5. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00169-9/fulltext

Effects of intranasal (S)-ketamine on Veterans with co ... Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in ...

6. mdpi.com mdpi.com/2076-328X/14/8/717

Combined Effects of Nasal Ketamine and Trauma-Focused ... Nasally administered ketamine was well tolerated and resulted in immediate symptom reduction in tension, anxiety, and common PTSD symptoms.