Doxepin for PTSD: Not Recommended
Doxepin, a tricyclic antidepressant, should not be used for PTSD treatment as it lacks evidence of efficacy and has been superseded by safer, more effective alternatives with established benefit for core PTSD symptoms. 1, 2
Evidence Against Tricyclic Antidepressants in PTSD
Early medication studies utilizing tricyclic antidepressants (including doxepin) in male veterans showed limited effect and have been replaced by more successful approaches using SSRIs in broader trauma populations. 1
Tricyclic antidepressants as a class appear effective only for intrusive symptoms and anxiety/depressive symptoms, while having little effect on avoidance symptoms—a critical PTSD symptom cluster. 3
TCAs have significant adverse effects including cardiovascular complications and safety concerns with overdose, relegating them to third-line treatment status at best. 4
When compared to MAOIs in limited studies, TCAs showed inferior results, and even MAOIs left patients with substantial residual symptoms. 4
First-Line Treatment: Trauma-Focused Psychotherapy
The 2023 VA/DoD Clinical Practice Guideline strongly recommends trauma-focused psychotherapies over any pharmacotherapy as first-line treatment, with 40-87% of patients no longer meeting PTSD criteria after 9-15 sessions. 2
The three evidence-based psychotherapies are Prolonged Exposure (PE), Cognitive Processing Therapy (CPT), and Eye Movement Desensitization and Reprocessing (EMDR), all demonstrating more durable benefits than medication alone. 2
Relapse rates are substantially lower after CBT completion compared to medication discontinuation (26-52% relapse when shifted from sertraline to placebo versus only 5-16% maintained on medication). 2
First-Line Pharmacotherapy When Needed
If psychotherapy is unavailable, declined, or insufficient, SSRIs—not tricyclics—are the established first-line medications. 2, 4
The 2023 VA/DoD guideline recommends three specific first-line medications: Paroxetine, Sertraline, and Venlafaxine. 2
Sertraline and paroxetine are FDA-approved for PTSD and have demonstrated efficacy in multiple placebo-controlled trials with favorable adverse effect profiles. 4, 5
SSRIs show consistent positive results across all three PTSD symptom clusters (intrusive, avoidance, and hyperarousal), unlike tricyclics which miss avoidance symptoms entirely. 1, 4
Fluoxetine at doses in the upper normal range (mean 57 mg/day) showed statistically significant improvement by week 6 in PTSD symptoms including intrusive and hyperarousal subscores. 6
Critical Medication to Avoid
The 2023 VA/DoD guideline strongly recommends AGAINST benzodiazepines for PTSD treatment, as evidence shows 63% of patients receiving benzodiazepines developed PTSD at 6 months compared to only 23% receiving placebo. 2
Treatment Algorithm for PTSD
Refer immediately for trauma-focused psychotherapy (PE, CPT, or EMDR) as first-line treatment, scheduling 9-15 sessions. 2, 7
If psychotherapy unavailable or patient refuses: Start SSRI (sertraline 50-200 mg/day or paroxetine 20-60 mg/day), titrating to upper therapeutic range over 5-8 weeks. 4, 5
If SSRI not tolerated: Switch to venlafaxine (serotonin-norepinephrine reuptake inhibitor) 75-300 mg/day as second-line agent. 2, 4
For persistent nightmares despite SSRI: Add prazosin 1-13 mg at bedtime (start 1 mg, increase 1-2 mg every few days, average effective dose 3 mg). 2
Continue successful medication for 6-12 months minimum after symptom remission before considering discontinuation due to high relapse rates. 2, 4
Common Pitfalls
Avoid psychological debriefing within 24-72 hours post-trauma, as it is not supported by evidence and may be harmful. 2
Do not delay trauma-focused therapy for prolonged stabilization phases—patients with complex presentations including multiple traumas, severe comorbidities, and dissociation benefit from direct trauma processing. 2
Recognize that many PTSD patients prefer psychotherapy to medication when given a choice, and video/telehealth delivery produces similar outcomes to in-person treatment. 2