Sequenced Treatment Effectiveness for Posttraumatic Stress

NCT ID: NCT04597190

Last Updated: 2025-05-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 700 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-01
• Study Completion Date: 2024-08-01

Brief Summary

Individuals with PTSD are more likely to engage in unhealthy behaviors such as tobacco use, drug use, alcohol misuse, and have high rates of morbidity/mortality. PTSD negatively impacts marriages, educational attainment, and occupational functioning. Some patients with PTSD can be successfully referred to specialty mental health clinics, but most patients with PTSD cannot engage in specialty care because of geographical, financial and cultural barriers and must be treated in primary care. However, policy makers do not know the best way to treat PTSD in primary care clinics, especially for patients who do not respond to the initial treatment choice. There are effective treatments for PTSD that are feasible to deliver in primary care. These treatments include commonly prescribed antidepressants and brief exposure-based therapies. However, because there are no head-to-head comparisons between pharmacotherapy and psychotherapy in primary care settings, primary care providers do not know which treatments to recommend to their patients. In addition, despite high treatment non-response rates, very few studies have examined which treatment should be recommend next when patients do not respond well to the first, and no such studies have been conducted in primary care settings.

This trial will be conducted in Federally Qualified Health Centers and VA Medical Centers, where the prevalence of both past trauma exposure and PTSD are particularly high. The investigators will enroll 700 primary care patients. The investigators propose to 1) compare outcomes among patients randomized to initially receive pharmacotherapy or brief psychotherapy, 2) compare outcomes among patients randomized to treatment sequences (i.e., switching and augmenting) for patients not responding to the initial treatment and 3) examine variation in treatment outcomes among different subgroups of patients. Telephone and web surveys will be used to assessed outcomes important to patients, like self-reported symptom burden, side-effects, health related quality of life, and recovery outcomes, at baseline, 4 and 8 months. Results will help patients and primary care providers choose which treatment to try first and which treatment to try second if the first is not effective.

Detailed Description

Background: In primary care settings, PTSD frequently goes undetected and untreated. When PTSD is diagnosed in primary care, treatment is usually inadequate and outcomes are poor. This is highly problematic because many patients with PTSD prefer receiving care in primary care settings, and less than half are successfully referred to the specialty mental health setting. This is especially a concern for safety net primary settings such as Federally Qualified Health Centers and VA Medical Centers, where the prevalence of both past trauma exposure and PTSD are particularly high. However, there are effective pharmacotherapy and psychotherapy treatments for PTSD that are feasible to deliver in primary care.

Objective: Because there are no head-to-head comparisons of pharmacotherapy and psychotherapy for PTSD among primary care patients, the investigators propose to 1) compare outcomes among patients randomized to initially receive pharmacotherapy or brief psychotherapy, 2) compare outcomes among patients randomized to treatment sequences (i.e., switching and augmenting) for patients not responding to the initial treatment and 3) examine variation in treatment outcomes among different subgroups of patients.

Methods: This multi-site trial will enroll 700 patients meeting clinical criteria for PTSD from 7 Federally Qualified Health Centers and 8 VA Medical Centers. The pharmacotherapy treatments are sertraline, fluoxetine, paroxetine and venlafaxine. The psychotherapy treatment is Written Exposure Therapy. Telephone and web surveys will be used to assessed outcomes (patient treatment engagement, self-reported symptom burden, health related quality of life, and recovery outcomes) at baseline, 4 and 8 months. Patients will be the unit of the intent-to-treat analysis. Multiple imputation will be used for missing data. Mixed-models will be used to test hypotheses.

Significance: Due to a lack of head-to-head comparisons between pharmacotherapy and psychotherapy protocols, clinical practice guidelines for PTSD provide contradictory recommendations about pharmacotherapy and psychotherapy. In particular, PTSD clinical practice guidelines have little to offer primary care providers because so few trials have been conducted in this setting. The proposed large pragmatic trial will compare, head-to-head, FDA approved PTSD medications with a brief trauma-focused psychotherapy that is evidence-based and feasible to deliver in primary care. In addition, despite high treatment non-response rates, very few trials have examined treatment sequencing and none have done so in the primary care setting. For patients not responding to the initial treatment, the proposed research is powered to compare, head-to-head, alternative treatment sequences that are feasible to deliver in primary care.

Conditions

PTSD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

SSRI Then Augmentation by WET

Prescribers will prescribe one of three SSRIs (sertraline, fluoxetine or paroxetine). Patients who do not respond to treatment by four months will have their treatment augmented by Written Exposure Therapy (WET) delivered by an integrated behavioral health consultant.

Group Type: ACTIVE_COMPARATOR

Selective serotonin reuptake inhibitor

Intervention Type: DRUG

Prescribers and patients choose among three selective serotonin reuptake inhibitors (SSRI), sertraline, paroxetine, or fluoxetine based on patient's treatment history (i.e., failed SSRI trials due to side-effects or lack of efficacy) and preference. If a patient experiences problematic side effects after taking their choice of SSRI, the provider may switch them to another of the SSRI options during the first 8 weeks of follow-up. Patients on any antidepressant (including SSRIs) at enrollment will be cross-tapered over four weeks to either fluoxetine, sertraline or paroxetine (i.e., the old drug will be tapered down while the new drug is tapering up).

Written Exposure Therapy

Intervention Type: BEHAVIORAL

Written Exposure Therapy will be delivered during six 30 minute sessions. The first session includes psychoeducation about symptoms of PTSD, provides a treatment rationale for approaching the trauma memory, and discusses the use of writing as a means of doing so. In sessions 2-6, patients will write about the memory of their worst traumatic event for 20 minutes, with a focus on details of the event and thoughts and feelings that occurred during the event. Patients are directed to write about the same trauma memory during each session. The session ends with the therapist instructing the patient to allow themselves to experience any trauma-related memories, images, thoughts, and feelings in the interval between sessions. The therapist reads the narrative between sessions to make sure instructions were followed. Feedback about the narrative is provided to the patient at the beginning of sessions 3-6. This feedback is used to prompt the patient for writing in the current session.

SSRI Then Switch to SNRI

Prescribers will prescribe one of three SSRIs (sertraline, fluoxetine or paroxetine). Patients who do not respond to treatment by four months will have their treatment switched to the SNRI (serotonin-norepinephrine reuptake Inhibitor) venlafaxine.

Group Type: ACTIVE_COMPARATOR

Selective serotonin reuptake inhibitor

Intervention Type: DRUG

Prescribers and patients choose among three selective serotonin reuptake inhibitors (SSRI), sertraline, paroxetine, or fluoxetine based on patient's treatment history (i.e., failed SSRI trials due to side-effects or lack of efficacy) and preference. If a patient experiences problematic side effects after taking their choice of SSRI, the provider may switch them to another of the SSRI options during the first 8 weeks of follow-up. Patients on any antidepressant (including SSRIs) at enrollment will be cross-tapered over four weeks to either fluoxetine, sertraline or paroxetine (i.e., the old drug will be tapered down while the new drug is tapering up).

Serotonin-norepinephrine reuptake inhibitor

Intervention Type: DRUG

Prescribers will prescribe venlafaxine.

WET Then Switch to SSRI

Integrated behavioral health consultants will deliver WET. Patients who do not respond to treatment by four months will be switched to one of three SSRIs (sertraline, fluoxetine or paroxetine).

Group Type: ACTIVE_COMPARATOR

Selective serotonin reuptake inhibitor

Intervention Type: DRUG

Prescribers and patients choose among three selective serotonin reuptake inhibitors (SSRI), sertraline, paroxetine, or fluoxetine based on patient's treatment history (i.e., failed SSRI trials due to side-effects or lack of efficacy) and preference. If a patient experiences problematic side effects after taking their choice of SSRI, the provider may switch them to another of the SSRI options during the first 8 weeks of follow-up. Patients on any antidepressant (including SSRIs) at enrollment will be cross-tapered over four weeks to either fluoxetine, sertraline or paroxetine (i.e., the old drug will be tapered down while the new drug is tapering up).

Written Exposure Therapy

Intervention Type: BEHAVIORAL

Written Exposure Therapy will be delivered during six 30 minute sessions. The first session includes psychoeducation about symptoms of PTSD, provides a treatment rationale for approaching the trauma memory, and discusses the use of writing as a means of doing so. In sessions 2-6, patients will write about the memory of their worst traumatic event for 20 minutes, with a focus on details of the event and thoughts and feelings that occurred during the event. Patients are directed to write about the same trauma memory during each session. The session ends with the therapist instructing the patient to allow themselves to experience any trauma-related memories, images, thoughts, and feelings in the interval between sessions. The therapist reads the narrative between sessions to make sure instructions were followed. Feedback about the narrative is provided to the patient at the beginning of sessions 3-6. This feedback is used to prompt the patient for writing in the current session.

Interventions

Selective serotonin reuptake inhibitor

Prescribers and patients choose among three selective serotonin reuptake inhibitors (SSRI), sertraline, paroxetine, or fluoxetine based on patient's treatment history (i.e., failed SSRI trials due to side-effects or lack of efficacy) and preference. If a patient experiences problematic side effects after taking their choice of SSRI, the provider may switch them to another of the SSRI options during the first 8 weeks of follow-up. Patients on any antidepressant (including SSRIs) at enrollment will be cross-tapered over four weeks to either fluoxetine, sertraline or paroxetine (i.e., the old drug will be tapered down while the new drug is tapering up).

Intervention Type: DRUG

Serotonin-norepinephrine reuptake inhibitor

Prescribers will prescribe venlafaxine.

Intervention Type: DRUG

Written Exposure Therapy

Written Exposure Therapy will be delivered during six 30 minute sessions. The first session includes psychoeducation about symptoms of PTSD, provides a treatment rationale for approaching the trauma memory, and discusses the use of writing as a means of doing so. In sessions 2-6, patients will write about the memory of their worst traumatic event for 20 minutes, with a focus on details of the event and thoughts and feelings that occurred during the event. Patients are directed to write about the same trauma memory during each session. The session ends with the therapist instructing the patient to allow themselves to experience any trauma-related memories, images, thoughts, and feelings in the interval between sessions. The therapist reads the narrative between sessions to make sure instructions were followed. Feedback about the narrative is provided to the patient at the beginning of sessions 3-6. This feedback is used to prompt the patient for writing in the current session.

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

• Screen positive for PTSD (PC-PTSD>=3 AND PCL>=33)
• Screen positive for trauma (Brief Trauma questionnaire)

Exclusion Criteria

• Diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder or dementia
• Current prescription of venlafaxine
• Change in any psychotropic prescription in the past 2 months
• A scheduled specialty mental health appointment or preference for specialty mental health care
• Pregnant
• Terminally ill
• Prisoner
• Unable to communicate in English or Spanish
• <18 years of age
• Impaired decision making capacity

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanford University

OTHER

Sponsor Role: collaborator

Boston University

OTHER

Sponsor Role: collaborator

Washington State University

OTHER

Sponsor Role: collaborator

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

John Cooper Fortney

Professor, School of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Little Rock VA Medical Center

North Little Rock, Arkansas, United States

East Arkansas Family Health Center

West Memphis, Arkansas, United States

Neighborhood Healthcare

San Diego, California, United States

San Diego VA Medical Center

San Diego, California, United States

VA Eastern Colorado Health Care

Aurora, Colorado, United States

Bedford VA Medical Center

Bedford, Massachusetts, United States

Ann Arbor VA Medical Center

Ann Arbor, Michigan, United States

Upper Great Lakes Family Health Center

Hancock, Michigan, United States

Family Medical Center of Michigan

Temperance, Michigan, United States

Partnership Health Center

Missoula, Montana, United States

Cincinnati VA Medical Center

Cincinnati, Ohio, United States

Portland VA Medical Center

Portland, Oregon, United States

Ralph H. Johnson VA Medical Center

Charleston, South Carolina, United States

North Central Texas Community Health Center

Wichita Falls, Texas, United States

Healthpoint

SeaTac, Washington, United States

Countries

United States

References

Fortney JC, Kaysen DL, Engel CC, Cerimele JM, Nolan JP Jr, Chase E, Blanchard BE, Hauge S, Bechtel J, Taylor A, Acierno R, Nagel N, Sripada RK, Painter JT, DeBeer BB, Zimberoff A, Bluett EJ, Teo AR, Morland LA, Grubbs K, Sloan DM, Marx BP, Heagerty PJ. Pragmatic Comparative Effectiveness of Primary Care Treatments for Posttraumatic Stress Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2025 Oct 15. doi: 10.1001/jamapsychiatry.2025.2962. Online ahead of print.

Reference Type: DERIVED

PMID: 41091477 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

STUDY00011185

Identifier Type: -

Identifier Source: org_study_id