What are the best medications for treating Post-Traumatic Stress Disorder (PTSD)?

Best Medications for PTSD

Sertraline and paroxetine are the first-line pharmacologic treatments for PTSD, with 53-85% of patients achieving treatment response compared to 32-62% with placebo, and both are FDA-approved for this indication. 1, 2, 3

First-Line Treatment: SSRIs

• Start with either sertraline or paroxetine as monotherapy for primary PTSD symptoms including intrusive thoughts, avoidance behaviors, negative mood alterations, and hyperarousal 1, 2, 3

• Sertraline is FDA-approved for PTSD and demonstrated efficacy in two 12-week placebo-controlled trials, with effectiveness across all three PTSD symptom clusters (reexperiencing, avoidance/numbing, hyperarousal) 2

• Paroxetine is FDA-approved for PTSD with demonstrated superiority in 12-week trials using doses of 20-50 mg/day, showing significant improvement on CAPS-2 total scores and CGI-I responder rates 3

• Continue SSRI treatment for at least 9-12 months after symptom improvement to prevent relapse, as discontinuation studies show 26-52% relapse rates when sertraline is stopped versus only 5-16% when continued 1

• Fluoxetine is also effective for PTSD though not FDA-approved, with extensive study data supporting its use as a first-line option 4, 5

Second-Line Treatment: SNRI

• If SSRIs fail after an adequate trial, switch to venlafaxine ER (37.5-300 mg/day, mean effective dose 225 mg/day) 1, 6

• Venlafaxine ER demonstrated superior efficacy to placebo with mean CAPS-SX17 score reduction of -41.8 versus -33.9 for placebo (P<0.05), and achieved 30.2% remission rate versus 19.6% for placebo 6

• Venlafaxine ER showed particular effectiveness for avoidance/numbing and hyperarousal symptom clusters 6, 5

Adjunctive Treatment for PTSD-Associated Nightmares and Hyperarousal

• Prazosin is strongly recommended (Level A evidence) as first-line adjunctive treatment for PTSD-associated nightmares, irritability, and anger 7, 1

• Start prazosin at 1 mg at bedtime and titrate by 1-2 mg every few days until effective response is achieved 7

• The average effective dose is approximately 3 mg, though the range is 1-13 mg/day, with higher doses (mean 9.5-13.3 mg/day) used in some studies of combat-related PTSD 7

• Three Level 1 placebo-controlled trials (98 patients total) demonstrated statistically significant reduction in trauma-related nightmares, with CAPS Item #2 scores improving from 4.8-6.9 at baseline to 3.2-3.6 after prazosin treatment 7

• Monitor for orthostatic hypotension as the primary side effect requiring clinical attention 7, 1

• If prazosin is ineffective or not tolerated, switch to clonidine (0.2-0.6 mg/day in divided doses) as an alternative alpha-2 adrenergic agent 7, 1

Augmentation for Refractory PTSD with Psychotic Symptoms

• If PTSD is refractory to SSRIs and presents with prominent flashbacks or paranoia, augment with risperidone or aripiprazole 1, 8

• Risperidone 0.5-2 mg/day showed 80% improvement in acute stress symptoms including trauma-related hallucinations in burn center patients with PTSD 8

• Aripiprazole 15-30 mg/day reduced auditory hallucinations in PTSD patients, with four of five veterans reporting substantial improvement in nightmares and hallucinations 8

Augmentation for Prominent Irritability and Anger

• Consider topiramate augmentation if prominent irritability and anger persist despite adequate SSRI trial 1

• Start topiramate at 12.5-25 mg daily and increase in 25-50 mg increments every 3-4 days until therapeutic response is achieved 7, 1

• The final dosage for 91% of full responders was 100 mg/day or less, with topiramate reducing nightmares in 79% of patients and achieving full suppression in 50% 7

• Be aware of significant side effects including urticaria, nausea, acute narrow-angle glaucoma, severe headaches, emergent suicidal ideation, and memory concerns, which led to discontinuation in 9 patients in one case series 7

Alternative Second-Line Options (If SSRIs Not Tolerated)

• Trazodone (mean effective dose 212 mg/day, range 25-600 mg) reduced nightmare frequency from 3.3 to 1.3 nights/week in 72% of veterans, though 60% experienced side effects (daytime sedation, dizziness, headache, priapism, orthostatic hypotension) 7, 8

• Nefazodone (386-600 mg/day) reduced nightmares by 30-58% in veterans and showed comparable efficacy to sertraline in head-to-head comparison, but carries hepatotoxicity risk requiring careful monitoring and is not recommended as first-line therapy 7, 8, 9

Critical Medications to Avoid

• Never use benzodiazepines as primary treatment for PTSD, as they were ineffective in controlled trials and may worsen PTSD symptoms 1

• Clonazepam specifically showed no improvement in nightmare frequency or intensity compared to placebo in a randomized crossover trial 8

• Avoid premature discontinuation of SSRIs, as relapse rates are significantly higher (26-52%) than with continued treatment (5-16%) 1

Treatment Algorithm

1. Initiate sertraline or paroxetine as first-line monotherapy for primary PTSD symptoms 1

2. Add prazosin if partial response with prominent nightmares/hyperarousal, starting at 1 mg at bedtime and titrating to effect 1

3. Switch to clonidine if prazosin not tolerated, using 0.1 mg twice daily and titrating to 0.2-0.6 mg/day 1

4. If SSRI fails after adequate trial (8-12 weeks), switch to venlafaxine ER 1, 6

5. If refractory with flashbacks/paranoia, augment with risperidone or aripiprazole 1, 8

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

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