Which selective serotonin reuptake inhibitors (SSRIs) have the strongest evidence for treating post-traumatic stress disorder (PTSD)?

SSRIs for PTSD: Evidence-Based Recommendations

Sertraline and paroxetine have the strongest evidence for treating PTSD and are the only FDA-approved medications for this condition. 1

Evidence for SSRIs in PTSD

SSRIs are the most extensively studied medication class for PTSD treatment, with the largest number of double-blind, placebo-controlled trials. The evidence hierarchy for specific SSRIs is:

1. First-line options (FDA-approved):

   • Sertraline (Zoloft)
   • Paroxetine

2. Second-line SSRI options:

   • Fluoxetine

Efficacy Data

• Treatment with SSRIs results in 53-85% of participants being classified as treatment responders, significantly higher than placebo (32-62%) 1
• A 2022 Cochrane review found SSRIs improved PTSD symptoms in 58% of participants compared with 35% in placebo groups (RR 0.66,95% CI 0.59 to 0.74) based on moderate-certainty evidence 2

Comparative Evidence Between SSRIs

While all SSRIs show efficacy for PTSD, sertraline offers several advantages:

• FDA approval specifically for PTSD 3
• Favorable tolerability profile
• Relatively weak effect on the cytochrome P450 system, reducing drug interactions 3
• Transfers in lower concentrations to breast milk with undetectable infant plasma levels 1

Paroxetine is also FDA-approved for PTSD and has demonstrated efficacy in controlled trials 1, 4.

Treatment Algorithm for PTSD

1. First-line treatment:

   • Sertraline (start 25-50mg daily, target up to 200mg daily) or
   • Paroxetine (FDA-approved)

2. If first-line treatment fails:

   • Switch to the other FDA-approved SSRI
   • Consider fluoxetine (has evidence but not FDA-approved for PTSD)

3. If SSRIs are ineffective or not tolerated:

   • Consider SNRIs (venlafaxine) or other serotonin-potentiating agents (mirtazapine, nefazodone, trazodone) 5

4. Third-line options:

   • TCAs (amitriptyline has shown efficacy in limited studies) 2
   • MAOIs (have shown promise but with significant side effects) 5

Important Clinical Considerations

Monitoring

• Evaluate initial response after 2-3 weeks
• Assess full effect at 4-6 weeks 6
• Monitor for suicidality, especially in the first months of treatment and following dosage adjustments 6
• Watch for behavioral activation/agitation, which may occur early in SSRI treatment or with dose increases 6

Duration of Treatment

• Continuation and maintenance treatment for 6-12 months decreases relapse rates 5
• Upon discontinuation of medication, relapse is a frequent occurrence 1
• Gradual tapering (10-14 days) is recommended when discontinuing sertraline after long-term use to minimize withdrawal symptoms 6

Common Side Effects

• Sertraline: Nausea, diarrhea, headache, insomnia, sexual dysfunction 1
• Paroxetine: Sexual effects, with higher risk compared to some other SSRIs 1

Pitfalls to Avoid

1. Abrupt discontinuation: Never abruptly discontinue SSRIs due to risk of discontinuation syndrome (dizziness, fatigue, sensory disturbances, anxiety, irritability) 6

2. Overlooking psychotherapy: While this question focuses on medication, cognitive behavioral therapy (CBT), particularly exposure therapy, has strong evidence for PTSD and should be considered alongside pharmacotherapy 1, 6

3. Benzodiazepines: Despite encouraging case reports, these should be avoided or used only short-term due to potential depressogenic effects and the possibility they may worsen PTSD 5

4. Inadequate duration: Short-term treatment is insufficient; continuation for at least 6-12 months is recommended to prevent relapse 5