PTSD Medication: Evidence-Based Recommendations
First-Line Pharmacotherapy: SSRIs
Sertraline and paroxetine are the medications with the strongest evidence for PTSD treatment, as they are the only two FDA-approved agents for this indication and have demonstrated efficacy in multiple large-scale controlled trials. 1
Why SSRIs Lead the Evidence Base
SSRIs have the most robust clinical trial data with the largest number of double-blind, placebo-controlled trials demonstrating efficacy in 6-12 week studies, showing that 58% of SSRI-treated patients respond compared to only 35% on placebo 2
Sertraline specifically has been extensively studied and offers a favorable tolerability profile with relatively weak effects on the cytochrome P450 system, making it a first-line choice 3, 4
Paroxetine is FDA-approved for PTSD and demonstrated superiority over placebo in multiple 12-week trials, with both 20 mg and 40 mg daily doses showing significant improvement on PTSD symptom scales 1
Fluoxetine has well-controlled evidence of efficacy, though it lacks FDA approval for PTSD specifically 5, 4
Critical Treatment Duration Considerations
Continue SSRI treatment for 6-12 months minimum after symptom remission, as discontinuation leads to high relapse rates of 26-52% when shifted to placebo compared to only 5-16% maintained on medication 6, 7, 8
The high relapse rate after medication discontinuation contrasts sharply with trauma-focused psychotherapy, where relapse rates are substantially lower after CBT completion 7, 8
Important Context: Psychotherapy Should Be Prioritized
While you asked specifically about medication, trauma-focused psychotherapy (Prolonged Exposure, Cognitive Processing Therapy, or EMDR) should be offered as first-line treatment before or alongside medication, with 40-87% of patients no longer meeting PTSD criteria after 9-15 sessions 7, 8
Medication should be considered when psychotherapy is unavailable, the patient refuses psychotherapy, or residual symptoms persist after psychotherapy 7, 8
Many PTSD patients prefer psychotherapy over medication when given a choice, and psychotherapy provides more durable benefits with lower relapse rates 6, 8
Second-Line Medication Options
If SSRIs are not tolerated or ineffective:
Venlafaxine (SNRI) has promising results in open-label studies and is recommended as a first-line option by the 2023 VA/DoD guideline 8, 5
Mirtazapine (NaSSA) showed benefit with 65% response rate versus 22% placebo in one small trial, though this is based on low-certainty evidence 2
Nefazodone and trazodone (serotonin-potentiating agents) have shown promise in open-label studies and should be considered as second-line treatment 5
Medications to AVOID
Benzodiazepines are contraindicated in PTSD treatment, with evidence showing 63% of patients receiving benzodiazepines developed PTSD at 6 months compared to only 23% receiving placebo 7, 8
Propranolol, hydrocortisone, and benzodiazepines for acute stress reactions have been found to be of limited benefit in preventing chronic PTSD 6
Benzodiazepines may worsen PTSD outcomes and should be avoided despite their common use for anxiety 5, 9
Adjunctive Treatments for Specific Symptoms
Prazosin is recommended for PTSD-related nightmares and insomnia, with Level A evidence from the American Academy of Sleep Medicine 8, 9
Atypical antipsychotics (particularly risperidone) can be considered as add-on therapy when SSRIs provide incomplete response, especially when paranoia or flashbacks are prominent 5, 9
Common Pitfalls to Avoid
Do not use psychological debriefing (single-session intervention within 24-72 hours post-trauma), as randomized controlled trials do not support its usefulness and it may be harmful 6, 8
Do not discontinue SSRIs prematurely—the evidence clearly shows high relapse rates with early discontinuation 7, 8
Do not assume medication alone is sufficient—combination with trauma-focused psychotherapy provides superior outcomes 6, 8