Best Antidepressant for PTSD
Sertraline or paroxetine are the best antidepressants for PTSD, as they are the only FDA-approved medications specifically for this indication and have the strongest evidence base from multiple large placebo-controlled trials. 1
First-Line Pharmacotherapy
SSRIs are the first-line antidepressant treatment for PTSD, with sertraline and paroxetine having FDA approval based on robust clinical trial data. 1, 2, 3
Sertraline Dosing and Efficacy
- Start at 25 mg/day for the first week, then increase to 50-200 mg/day based on response and tolerability 1, 4
- Mean effective doses in clinical trials ranged from 146-151 mg/day 1
- Demonstrated 60% responder rate versus 38% for placebo in intent-to-treat analysis 4
- Sertraline significantly improves all three PTSD symptom clusters: reexperiencing/intrusion, avoidance/numbing, and hyperarousal 1, 2
- Particularly effective in women (76% of trial participants), though gender interaction requires further study 1
Treatment Duration
- Initial trials demonstrate efficacy at 12 weeks 1, 4
- Continuation treatment for 24-52 weeks significantly reduces relapse rates compared to placebo 1
- Patients who responded during open-label treatment experienced significantly lower relapse rates when continued on sertraline versus switching to placebo 1
Tolerability Profile
- Discontinuation rate due to adverse events is only 9% versus 5% for placebo 4
- Most common side effects: insomnia (35%), diarrhea (28%), nausea (23%), fatigue (13%), and decreased appetite (12%) 4
- Sertraline has minimal cytochrome P450 interactions, making it safer in patients on multiple medications 5
Alternative SSRI Options
Fluoxetine and paroxetine are also FDA-approved for PTSD and represent equivalent first-line choices if sertraline is not tolerated. 2, 3
- All three SSRIs (sertraline, paroxetine, fluoxetine) have demonstrated efficacy in multiple double-blind, placebo-controlled trials 2
- SSRIs may be more effective than older antidepressants for avoidance and numbing symptoms specifically 6
Second-Line Antidepressant Options
If SSRIs are ineffective or not tolerated, consider:
Venlafaxine (SNRI)
- Venlafaxine effectively treats primary PTSD symptoms and should be the next choice after SSRI failure 3
- Serotonin-norepinephrine reuptake inhibition provides dual mechanism of action 2
Other Serotonin-Potentiating Agents
- Nefazodone, trazodone, and mirtazapine show promise in open-label studies but lack controlled trial data 2
- Nefazodone should not be first-line due to hepatotoxicity risk 7
- Trazodone (mean dose 212 mg, range 25-600 mg) reduced nightmare frequency from 3.3 to 1.3 nights per week but caused significant side effects in 60% of patients 7
Third-Line Antidepressant Options
MAOIs and Tricyclic Antidepressants
- Phenelzine (30-90 mg/day) and tricyclic antidepressants should be reserved for treatment-resistant cases 7
- MAOIs appear superior to TCAs in limited comparative studies but both leave residual symptoms 2
- TCAs primarily improve intrusive symptoms and anxiety/depression but have minimal effect on avoidance symptoms 6
- Significant cardiovascular complications and overdose risk limit their use 2
Important Clinical Considerations
Augmentation Strategies
- If SSRIs provide partial response, consider adding prazosin for nightmares and sleep disturbance (though recent large VA trial showed no benefit, many patients still respond clinically) 7, 3
- Atypical antipsychotics (aripiprazole, risperidone, olanzapine) can augment SSRIs for residual symptoms, particularly paranoia or flashbacks 8, 2
- Topiramate (median dose 150 mg/day, range 12.5-500 mg/day) may help as adjunctive therapy but has significant side effects including cognitive impairment 7
Treatment Pitfalls to Avoid
- Benzodiazepines were ineffective in controlled trials and may worsen PTSD; avoid or use only short-term 2, 6
- Bupropion was ineffective in open-label PTSD studies 2
- Do not discontinue effective SSRI therapy prematurely—maintain for at least 6-12 months to prevent relapse 1, 2