What are the first‑line pharmacologic treatments for an adult with post‑traumatic stress disorder?

First-Line Pharmacologic Treatment for PTSD

Sertraline or paroxetine are the first-line pharmacologic treatments for adults with PTSD, with 53-85% of patients classified as treatment responders versus 32-62% with placebo. 1

Evidence-Based Medication Hierarchy

Primary Pharmacotherapy Options

The 2023 VA/DoD Clinical Practice Guideline recommends three specific medications as first-line pharmacotherapy 2:

• Sertraline – FDA-approved for PTSD; demonstrated efficacy in two 12-week placebo-controlled trials 3, 4
• Paroxetine – FDA-approved for PTSD; established efficacy in two 12-week placebo-controlled trials 5, 4
• Venlafaxine – Recommended as an alternative first-line option when SSRIs are not tolerated 2, 1

Dosing Strategy

Sertraline dosing for PTSD 1, 3:

• Start: 50 mg daily
• Titrate to: 100-200 mg daily based on response
• Maximum: 200 mg daily

Paroxetine dosing for PTSD 5, 4:

• Start: 20 mg daily
• Titrate to: 20-50 mg daily
• Maximum: 50 mg daily

Treatment Duration

Continue SSRI treatment for at least 9-12 months after symptom improvement to prevent relapse 1. Discontinuation studies demonstrate 26-52% relapse rates when sertraline is stopped versus only 5-16% when continued 1, 6. This represents a critical treatment milestone that must not be shortened prematurely 1.

Adjunctive Medications for Specific Symptoms

PTSD-Related Nightmares

Prazosin is strongly recommended (Level A evidence) as first-line adjunctive treatment for PTSD-associated nightmares 2, 1:

• Starting dose: 1 mg at bedtime
• Titration: Increase 1-2 mg every few days
• Average effective dose: 3 mg (range 1-13 mg)
• Monitor for orthostatic hypotension 1

Important caveat: A large 2018 VA study (304 participants) showed no significant benefit of prazosin over placebo, leading to downgrading of the recommendation 2. However, the Task Force noted that many patients respond very well clinically, and prazosin remains the first choice for pharmacologic treatment of nightmares 2. There may be an interaction with concurrent antidepressant use that diminishes prazosin's efficacy 2.

If prazosin is ineffective or not tolerated, clonidine is recommended as first-line replacement 1:

• Starting dose: 0.1 mg twice daily
• Titration: 0.2-0.6 mg/day in divided doses

Prominent Irritability and Anger

Topiramate may be beneficial for PTSD symptoms including irritability and anger 1:

• Starting dose: 12.5-25 mg daily
• Titration: Increase in 25-50 mg increments every 3-4 days
• Median effective dose: 150 mg/day (range 12.5-500 mg/day)
• Warning: 26% discontinuation rate due to side effects including urticaria, nausea, acute narrow-angle glaucoma, severe headaches, and memory concerns 2

Treatment Algorithm

Step 1: Initiate sertraline 50 mg daily or paroxetine 20 mg daily 1, 4

Step 2: Titrate to therapeutic dose (sertraline 100-200 mg, paroxetine 20-50 mg) over 2-4 weeks 1

Step 3: If partial response with prominent nightmares/hyperarousal at 4-8 weeks, add prazosin 1 mg at bedtime and titrate to effect 1

Step 4: If SSRI fails after adequate 8-12 week trial at therapeutic dose, switch to venlafaxine ER 1

Step 5: If refractory with flashbacks/paranoia, augment with risperidone or aripiprazole 1

Step 6: If prominent irritability/anger persists, consider topiramate augmentation 1

Critical Medications to Avoid

Benzodiazepines

The 2023 VA/DoD guideline strongly recommends AGAINST benzodiazepines for PTSD treatment 2, 6. Evidence demonstrates 63% of patients receiving benzodiazepines developed PTSD at 6 months compared to only 23% receiving placebo 6. Benzodiazepines were ineffective in controlled trials and may worsen PTSD outcomes 1, 7.

Cannabis

The 2023 VA/DoD guideline recommends against use of cannabis or cannabis-derived products for PTSD 2.

Bupropion

Bupropion is not recommended for PTSD treatment 6. It failed to demonstrate efficacy in controlled trials and is omitted from current evidence-based PTSD treatment guidelines 6, 7.

Important Clinical Context

Trauma-focused psychotherapy is superior to pharmacotherapy as first-line treatment 2, 1, 6. The 2023 VA/DoD guideline strongly recommends specific manualized psychotherapies (Prolonged Exposure, Cognitive Processing Therapy, or EMDR) over pharmacotherapy, with 40-87% of patients no longer meeting PTSD criteria after 9-15 sessions 1, 6. Relapse rates are lower after CBT completion compared to medication discontinuation 6.

Pharmacotherapy should be considered when 6:

• Psychotherapy is unavailable or has long wait times
• Patient refuses psychotherapy
• Residual symptoms persist after psychotherapy
• Patient strongly prefers medication

Combine pharmacotherapy with trauma-focused psychotherapy when available, as medication discontinuation leads to higher relapse rates than CBT completion 1.