Prolonged Exposure Therapy + Medication for PTSD

Recruiting at 6 trial locations

Overseen By Michael Thase, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Pennsylvania

Must not be taking: MAO inhibitors

Disqualifiers: Suicidal ideation, Active psychosis, Manic episodes, 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

Compensation: Varies

Number of Visits: 41

300 Participants Needed

Trial Summary

What is the purpose of this trial?

Posttraumatic Stress Disorder (PTSD) remains a salient and debilitating problem, in the general population and for military veterans in particular. Several psychological and pharmacological treatments for PTSD have evidence to support their efficacy. However, the lack of comparative effectiveness data for PTSD treatments remains a major gap in the literature, which limits conclusions that can be drawn about which of these treatments work best. The current study will compare the effectiveness of PTSD treatments with the strongest evidentiary support - Prolonged Exposure (PE) therapy and pharmacotherapy with paroxetine or venlafaxine - as well as the combination of these two treatments. A randomized trial will be conducted with a large, diverse sample of veterans with PTSD (N = 300) recruited from 6 VA Medical Centers throughout the US. Participants will complete baseline assessments, followed by an active treatment phase (involving up to 14 sessions of PE and/or medication management) with mid (7 week) and posttreatment (14 week) assessments, and follow-up assessments at 27 and 40 weeks. Study outcomes will include PTSD severity, depression, quality of life and functioning, assessed via clinical ratings and self-report measures. Further, a range of demographic and clinically relevant variables (e.g., trauma type/number, resilience) will be collected at baseline and examined as potential predictors or moderators of treatment response, addressing another gap in the PTSD treatment literature. These data will be used to develop algorithms from predicting the optimal treatment for individual patients (i.e., "personalized advantage indices"; PAIs). Effectiveness of the treatments will be compared using multilevel modeling. PAIs will be developed by conducting bootstrapped analyses to select variables that predict or moderate outcomes (clinician rated PTSD severity at Week 14), followed by jacknife analyses to determine the magnitude of the predicted difference (representing an individual's "predicted advantage" of one treatment over the others).

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that ongoing treatments that could interact with the trial medications (paroxetine and venlafaxine) may exclude you from participating. It's best to discuss your current medications with the trial team.

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

Research shows that Prolonged Exposure Therapy (PE) is highly effective for PTSD, with strong evidence supporting its use. Medications like paroxetine and venlafaxine XR have also shown promise in treating PTSD, and combining these with PE may enhance treatment outcomes, although more research is needed to compare their combined effectiveness. ^{1 2 3 4 5}

Is the combination of Prolonged Exposure Therapy and medications like Paroxetine and Venlafaxine XR safe for treating PTSD?

Paroxetine and Venlafaxine XR have been studied for PTSD and other anxiety disorders, showing they are generally safe and effective in both short-term and long-term use. These medications are well-tolerated in adults, although individual responses can vary. ^{1 2 3 6 7}

How does the treatment of Prolonged Exposure Therapy combined with Paroxetine or Venlafaxine XR differ from other PTSD treatments?

This treatment is unique because it combines Prolonged Exposure Therapy, which is a well-supported psychological approach, with medications like Paroxetine or Venlafaxine XR, which are antidepressants. This combination aims to enhance the effectiveness of therapy for those who do not fully respond to therapy alone, offering a potentially more comprehensive approach to managing PTSD symptoms. ^{1 4 5 8 9}

Eligibility Criteria

This trial is for military veterans who have been diagnosed with PTSD, can give informed consent, and speak English. They must be willing to undergo Prolonged Exposure therapy or take medications like paroxetine or venlafaxine XR, or both. Veterans who've had a failed trial of these therapies, active psychosis, certain medical conditions that conflict with the treatments, recent suicidal behavior, or history of manic episodes cannot participate.

Inclusion Criteria

I have been diagnosed with PTSD.

I am able to understand and agree to the study's procedures and risks.

fluent in English

Exclusion Criteria

I have had episodes of mania in the past.

I am not on any treatments that clash with paroxetine or venlafaxine.

I have tried Prolonged Exposure therapy or medications like paroxetine and venlafaxine XR without success.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants complete baseline assessments to collect demographic and clinically relevant variables

1 week

Active Treatment

Participants receive up to 14 sessions of Prolonged Exposure therapy and/or pharmacotherapy with paroxetine or venlafaxine

14 weeks

Up to 14 sessions (in-person or via telehealth)

Mid-treatment Assessment

Mid-treatment assessments conducted to evaluate progress

1 week

Post-treatment Assessment

Post-treatment assessments conducted to evaluate treatment outcomes

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

26 weeks

Assessments at 27 and 40 weeks

Treatment Details

Interventions

• Paroxetine
• Prolonged Exposure Therapy
• Venlafaxine XR

Trial Overview The study compares the effectiveness of Prolonged Exposure (PE) therapy and pharmacotherapy using paroxetine or venlafaxine XR against their combination in treating PTSD. Participants will receive up to 14 sessions of PE and/or medication management over several weeks with follow-up assessments to measure treatment impact on PTSD severity and quality of life.

Participant Groups

Group I: Prolonged Exposure Therapy Active Control 1 Intervention

8-14 sessions of psychotherapy, each lasting 60-90 minutes, focused on imaginal exposure to trauma memories and in vivo exposure to trauma reminders

Group II: Pharmacotherapy Active Control 1 Intervention

20-60mg of paroxetine daily, or 75-300mg of venlafaxine XR daily

Group III: Combined treatment (Prolonged Exposure and Pharmacotherapy) Active Control 2 Interventions

8-14 sessions of psychotherapy, each lasting 60-90 minutes, focused on imaginal exposure to trauma memories and in vivo exposure to trauma reminders AND 20-60mg of paroxetine daily, or 75-300mg of venlafaxine XR daily

Paroxetine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paxil for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Panic disorder
• Social anxiety disorder
• Generalized anxiety disorder
• Posttraumatic stress disorder

Approved in European Union as Seroxat for:

• Major depressive episodes
• Obsessive-compulsive disorder
• Panic disorder with or without agoraphobia
• Social anxiety disorder
• Generalized anxiety disorder
• Posttraumatic stress disorder

Approved in Canada as Paxil for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Panic disorder
• Social anxiety disorder
• Generalized anxiety disorder
• Posttraumatic stress disorder

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Birmingham VA Health Care System

Collaborator

Trials

4

Recruited

630+

San Diego Veterans Healthcare System

Collaborator

Trials

38

Recruited

5,500+

VA Palo Alto Health Care System

Collaborator

Trials

97

Recruited

58,500+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Corporal Michael J. Crescenz VA Medical Center

Collaborator

Trials

31

Recruited

9,900+

Coatesville VA Medical Center

Collaborator

Trials

1

Recruited

300+

Milwaukee VA Medical Center

Collaborator

Trials

4

Recruited

390+

North Texas Veterans Healthcare System

Collaborator

Trials

39

Recruited

4,005,000+

Findings from Research

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]

Venlafaxine XR, a serotonin and norepinephrine re-uptake inhibitor, shows both short- and long-term efficacy in treating PTSD, supported by recent randomized, double-blind, placebo-controlled trials.

While venlafaxine XR is primarily approved for other anxiety disorders and major depression, it demonstrates potential as a treatment for PTSD, although more extensive studies are needed compared to its use in other anxiety conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release formulation of venlafaxine in the treatment of post-traumatic stress disorder. Pae, CU., Lim, HK., Ajwani, N., et al.[2015]

In a study of 6,839 VA outpatients with PTSD, no significant differences in medication efficacy were found among fluoxetine, paroxetine, sertraline, topiramate, and venlafaxine, suggesting that these medications are similarly effective in real-world settings.

Patients with higher baseline PTSD checklist scores and those receiving evidence-based psychotherapy showed better improvement, while those with high disability levels were less likely to experience meaningful benefits, highlighting the importance of combined treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient and Clinical Factors Associated With Response to Medications for Posttraumatic Stress Disorder. Shiner, BR., Gui, J., Rozema, L., et al.[2022]

A randomized clinical trial involving 450 veterans with PTSD will compare the effectiveness of Prolonged Exposure therapy, pharmacotherapy with paroxetine or venlafaxine, and a combination of both treatments, assessing PTSD severity and other outcomes over multiple time points.

The study aims to develop personalized advantage indices to identify which treatment may be most beneficial for individual patients, potentially guiding future clinical practice and treatment planning for PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of prolonged exposure therapy, pharmacotherapy, and their combination for PTSD: What works best and for whom; study protocol for a randomized trial. Bredemeier, K., Larsen, S., Shivakumar, G., et al.[2022]

Prolonged exposure (PE) therapy has the strongest evidence supporting its effectiveness for treating PTSD, particularly in combat-related cases, while other therapies like EMDR and cognitive processing therapy (CPT) also show strong efficacy.

Pharmacological treatments, especially paroxetine, sertraline, and venlafaxine, are promising, but more research is needed to compare the effectiveness of medications versus psychotherapy and to explore the benefits of combined treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Clinician's Guide to PTSD Treatments for Returning Veterans. Sharpless, BA., Barber, JP.[2021]

Paroxetine is effective for the short-term treatment of PTSD, showing significantly better response and remission rates compared to placebo in three 12-week studies.

The medication improves sleep disturbances and reduces all symptom clusters of PTSD, demonstrating efficacy in both male and female patients, regardless of the presence of comorbid conditions like depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paroxetine in the treatment of post-traumatic stress disorder: pooled analysis of placebo-controlled studies. Stein, DJ., Davidson, J., Seedat, S., et al.[2022]

In a study of 834 VA outpatients with PTSD, venlafaxine was found to be significantly more effective than fluoxetine, paroxetine, sertraline, and topiramate in achieving remission of PTSD symptoms during the acute treatment phase.

Continuing medication during the continuation phase was associated with a lower risk of needing acute psychiatric services, highlighting the importance of ongoing treatment for managing PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing Medications for DSM-5 PTSD in Routine VA Practice. Shiner, B., Leonard, CE., Gui, J., et al.[2022]

Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, paroxetine, and sertraline show a statistically significant but small effect in reducing PTSD symptoms compared to placebo, based on a systematic review of 115 randomized controlled trials.

Prazosin and risperidone also demonstrate small positive effects when used to augment other treatments, but no single pharmacological intervention was found to be superior to others in head-to-head comparisons.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological therapy for post-traumatic stress disorder: a systematic review and meta-analysis of monotherapy, augmentation and head-to-head approaches. Hoskins, MD., Bridges, J., Sinnerton, R., et al.[2023]

Prolonged exposure (PE) therapy significantly reduced PTSD symptoms in five patients with severe chronic combat-related PTSD, showing a mean decrease of 48% in PTSD Symptom Scale scores after 10-15 sessions.

Four out of five patients maintained or continued to improve their symptoms 6-18 months post-treatment, indicating the long-term efficacy of PE therapy for combat-related PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged exposure therapy for chronic combat-related PTSD: a case report of five veterans. Nacasch, N., Foa, EB., Fostick, L., et al.[2019]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Extended-release formulation of venlafaxine in the treatment of post-traumatic stress disorder. [2015]

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

Patient and Clinical Factors Associated With Response to Medications for Posttraumatic Stress Disorder. [2022]

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

A comparison of prolonged exposure therapy, pharmacotherapy, and their combination for PTSD: What works best and for whom; study protocol for a randomized trial. [2022]

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

A Clinician's Guide to PTSD Treatments for Returning Veterans. [2021]

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

Paroxetine in the treatment of post-traumatic stress disorder: pooled analysis of placebo-controlled studies. [2022]

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

Comparing Medications for DSM-5 PTSD in Routine VA Practice. [2022]

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

Pharmacological therapy for post-traumatic stress disorder: a systematic review and meta-analysis of monotherapy, augmentation and head-to-head approaches. [2023]

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

Prolonged exposure therapy for chronic combat-related PTSD: a case report of five veterans. [2019]