Highlight
This pragmatic clinical trial compared the effectiveness of selective serotonin reuptake inhibitors (SSRIs) to brief trauma-focused psychotherapy (written exposure therapy, WET) in treating PTSD among primary care patients. Both modalities showed similar PTSD symptom reduction in adherent patients over 4 months. For patients not responding to initial SSRI treatment, switching to a serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine was significantly more effective than augmenting with WET. The findings support feasibility and benefit of both treatments in primary care and suggest SNRI switch as a preferred second-step strategy after SSRI failure.
Study Background
Posttraumatic stress disorder (PTSD) represents a considerable clinical burden with substantial morbidity, affecting quality of life and functioning. First-line treatments include trauma-focused psychotherapies and pharmacotherapies such as SSRIs, yet robust head-to-head comparisons remain sparse, especially in the primary care setting where most patients initially present. Additionally, evidence regarding optimal second-step treatments for those who do not respond to initial therapies is limited. Addressing these gaps is critical to optimizing PTSD management in real-world clinical practice, particularly in federally qualified health centers and Veterans Affairs medical centers where PTSD prevalence is high.
Study Design and Methods
This pragmatic comparative effectiveness trial (NCT04597190) enrolled 700 adults with clinically diagnosed PTSD from 7 federally qualified health centers and 8 Veterans Affairs medical centers across the United States between April 2021 and June 2024. Participants were randomized into three treatment sequences:
1. SSRI (choice of sertraline, fluoxetine, or paroxetine) followed by WET augmentation if no response;
2. SSRI followed by SNRI (venlafaxine) switch if no response;
3. WET followed by SSRI.
The primary outcome was PTSD symptom severity measured by the DSM-5 PTSD Checklist (PCL-5) at baseline and 4 months.
Effectiveness assessments incorporated real-world considerations of treatment engagement and adherence to reflect pragmatic clinical practice. Treatment fidelity and adherence were monitored and reported.
Key Findings
The cohort’s mean age was 45.1 years with 62.1% men; baseline mean PCL-5 score was 52.8, indicating severe symptomatology. At 4 months:
- Among patients starting with SSRIs, approximately 51.8% were adherent, showing a mean 14.0-point reduction in PCL-5 scores.
- In patients starting with WET, 31.5% completed the full therapy course, with a mean 12.1-point reduction in PCL-5 scores.
The adjusted mean difference between SSRI and WET initial treatment groups was 1.79 (95% CI, -0.76 to 4.34; P = .17), indicating no statistically significant difference in PTSD symptom improvement favoring either treatment.
For the subset of patients (41.4%) who did not respond to SSRIs:
- Those switched to the SNRI venlafaxine showed a significant 9.2-point PCL-5 symptom reduction.
- Those receiving WET augmentation had a more modest 2.3-point decrease.
The adjusted mean difference was 10.19 (95% CI, 4.97-15.41; P < .001), favoring an SNRI switch as a second-step treatment after SSRI failure.
The study demonstrated that both pharmacotherapy and brief trauma-focused psychotherapy are feasible and yield clinically meaningful symptom reductions when delivered in primary care contexts.
Expert Commentary
This trial addresses critical clinical questions regarding first-line and second-step PTSD treatment sequencing in primary care—an area previously lacking randomized head-to-head data. The analogous PTSD symptom reduction with SSRIs and WET in adherent patients underscores the value of providing personalized treatment options based on patient preference, accessibility, and resource availability.
Importantly, the lower completion rate of WET compared to SSRI adherence highlights the challenges of engaging patients in psychotherapy in real-world primary care. Clinicians should anticipate and address barriers to therapy completion.
The marked superiority of SNRI venlafaxine switching over psychotherapy augmentation in SSRI nonresponders offers new evidence to guide second-step treatment strategies. While trauma-focused psychotherapies remain core interventions, pharmacologic stepwise adjustment should be considered when initial SSRIs do not yield sufficient benefit.
Limitations include reliance on adherence and self-reported symptom scales, with potential variance in treatment fidelity despite pragmatic design. Generalizability to specialty mental health settings may be limited but the focus on primary care is a significant strength given this setting’s predominance in PTSD management.
Conclusion
This pragmatic randomized trial demonstrates that both SSRIs and brief trauma-focused psychotherapy (WET) are effective and feasible first-line treatments for PTSD in primary care. For patients who do not respond to an initial SSRI, switching to an SNRI rather than psychotherapy augmentation yields greater symptom improvement. These findings inform evidence-based sequencing of PTSD treatments in primary care, promoting individualized treatment selection and enhancing recovery prospects.
Further research should explore long-term outcomes, strategies to improve psychotherapy engagement, and evaluation of combined modality approaches to optimize symptom remission and functional recovery for PTSD patients in diverse clinical settings.
Funding and Trial Registration
This study was supported by the Department of Veterans Affairs and federally qualified health center collaborations. The trial is registered under ClinicalTrials.gov Identifier: NCT04597190.
References
Fortney JC, Kaysen DL, Engel CC, et al. 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. Epub ahead of print. PMID: 41091477.