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

PTSD Medications

First-Line Treatment: SSRIs

Sertraline and paroxetine are the only FDA-approved medications for PTSD and should be your first-line pharmacologic treatment. 1, 2, 1

FDA-Approved SSRIs

• Sertraline is FDA-approved for treating PTSD in adults, with efficacy established in two 12-week placebo-controlled trials demonstrating significant improvement in reexperiencing, avoidance/numbing, and hyperarousal symptoms 1
• Paroxetine is FDA-approved for PTSD treatment, with efficacy established in two 12-week placebo-controlled trials in adults 2
• Both medications demonstrated 53-85% of patients classified as treatment responders versus 32-62% with placebo 3

Treatment Duration and Maintenance

• Continue SSRI treatment for at least 9-12 months after symptom improvement to prevent relapse 4
• Sertraline demonstrated efficacy in maintaining response for up to 28 weeks following 24 weeks of open-label treatment 1
• Discontinuation studies show 26-52% relapse rates when sertraline is stopped versus 5-16% when continued 3
• Paroxetine discontinuation led to 34% relapse versus 17% when maintained on fluoxetine 3

Other SSRIs (Off-Label)

• Fluoxetine has demonstrated efficacy in multiple controlled trials for PTSD, though it lacks FDA approval for this indication 3, 5
• Fluoxetine showed only 17% relapse when continued versus 34% when discontinued 3

Second-Line Treatment: SNRIs

Venlafaxine extended-release is an effective alternative when SSRIs fail or are not tolerated, demonstrating superior efficacy to placebo with mean CAPS-SX17 score improvements of -41.8 versus -33.9 for placebo 6

• Venlafaxine ER achieved 30.2% remission rates versus 19.6% with placebo at 12 weeks 6
• Dosing range: 37.5-300 mg/day, with mean maximum daily dose of 225 mg 6
• Particularly effective for hyperarousal symptoms compared to placebo 6

Adjunctive Medications for Specific PTSD Symptoms

For Nightmares, Irritability, and Hyperarousal

Prazosin is strongly recommended (Level A evidence) as first-line adjunctive treatment for PTSD-associated nightmares, irritability, and anger 4

• Start prazosin at 1 mg at bedtime, increase by 1-2 mg every few days until effective (average dose 3 mg, range 1-10 mg) 4
• Mechanism: reduces elevated CNS noradrenergic activity contributing to hyperarousal and nightmares 4
• Monitor for orthostatic hypotension as a critical side effect 4

Alternative Alpha-Adrenergic Agents

If prazosin is ineffective or not tolerated, clonidine is the recommended first-line replacement 7

• Start clonidine 0.1 mg twice daily, titrate to 0.2-0.6 mg/day in divided doses 7, 8
• Level C evidence for PTSD-associated nightmares 7, 8
• Demonstrated efficacy in female civilian PTSD patients for reducing nightmare frequency 7
• Monitor blood pressure carefully due to hypotension and bradycardia risk 8
• Taper gradually to avoid rebound hypertension 8

Atypical Antipsychotics for Refractory Symptoms

When SSRIs alone are insufficient, particularly with prominent flashbacks or paranoia:

• Risperidone 0.5-2.0 mg/day: 80% of patients reported nightmare improvement 7
• Aripiprazole 15-30 mg/day: substantial improvement in 4 of 5 veterans at 4 weeks, better tolerability than olanzapine 7

Mood Stabilizers for Irritability and Anger

Topiramate may be beneficial for PTSD symptoms including irritability and anger 4

• Start 12.5-25 mg daily, increase in 25-50 mg increments every 3-4 days 4
• Most responders achieve benefit at ≤100 mg/day 4
• Reduced nightmares in 79% of patients, with full suppression in 50% 4
• Monitor for cognitive impairment, weight loss, and paresthesias 4

Treatment Algorithm

1. Initiate sertraline or paroxetine as first-line monotherapy 1, 2, 5, 9
2. If partial response with prominent nightmares/hyperarousal: add prazosin 4
3. If prazosin not tolerated: switch to clonidine 7
4. If SSRI fails after adequate trial: switch to venlafaxine ER 6
5. If refractory with flashbacks/paranoia: augment with risperidone or aripiprazole 7
6. If prominent irritability/anger persists: consider topiramate augmentation 4

Critical Pitfalls to Avoid

• Never use benzodiazepines as primary treatment - they were ineffective in controlled trials and may worsen PTSD 5
• Avoid nefazodone as first-line therapy due to hepatotoxicity risk 7
• Do not discontinue SSRIs prematurely - relapse rates are significantly higher than with continued treatment 3
• Always combine pharmacotherapy with trauma-focused CBT when available, as medication discontinuation leads to higher relapse rates than CBT completion 3, 4

Comorbidity Considerations

• When PTSD coexists with bipolar disorder or prominent impulsivity, anticonvulsants (carbamazepine, valproic acid, topiramate, gabapentin) should be considered earlier in the treatment algorithm 5
• The choice of medication is often determined by prominent PTSD symptom clusters and comorbid psychiatric conditions 10