What is the evidence for using mirtazapine (an antidepressant medication) for post-traumatic stress disorder (PTSD)?

Evidence for Mirtazapine in PTSD Treatment

Mirtazapine has limited evidence supporting its use in post-traumatic stress disorder (PTSD), with only small pilot studies showing modest efficacy. Based on the available evidence, mirtazapine should be considered a second-line or adjunctive treatment option for PTSD, particularly when insomnia, anxiety, or depression are prominent symptoms.

Efficacy Evidence for Mirtazapine in PTSD

Controlled Trials

• A small placebo-controlled, double-blind pilot trial showed mirtazapine (up to 45 mg/day) had response rates of 64.7% compared to 20% for placebo on the SPRINT Global Improvement measure 1
• Mirtazapine demonstrated favorable effects on PTSD symptoms and general anxiety compared to placebo 1

Open-Label Studies

• An open-label prospective study in combat veterans (n=17) showed significant improvement in PTSD symptoms after 12 weeks of mirtazapine treatment (15-45 mg/day) 2
  • CAPS scores decreased from 87.5 to 64.4 (p=0.01)
  • Four participants achieved remission of PTSD symptoms
  • Anxiety scores improved, though depression scores did not change significantly

Mechanism of Action Relevant to PTSD

Mirtazapine has a unique pharmacological profile that may be beneficial in PTSD:

• Dual enhancement of noradrenergic and serotonergic neurotransmission via α2-adrenergic receptor blockade 3, 4
• Blocks 5-HT2 and 5-HT3 receptors, which may reduce anxiety and improve sleep 3, 4
• Demonstrated anxiolytic and sleep-improving effects 3
• Faster onset of action compared to SSRIs (citalopram, fluoxetine, paroxetine, sertraline) 5

Comparison to First-Line Treatments

SSRIs remain the first-line pharmacological treatment for PTSD:

• Sertraline and paroxetine are FDA-approved for PTSD 6
• SSRIs have the largest evidence base with multiple double-blind, placebo-controlled trials 6
• Fluoxetine has also been extensively studied for PTSD 6

Treatment Algorithm for PTSD

1. First-line treatments:

   • SSRIs (particularly sertraline and paroxetine) 6
   • Trauma-focused psychotherapy (CBT with exposure) 5

2. Second-line treatments (if SSRIs are ineffective or not tolerated):

   • Serotonin-potentiating non-SSRIs including mirtazapine, venlafaxine, nefazodone, and trazodone 6

3. Third-line treatments:

   • Tricyclic antidepressants (TCAs)
   • Monoamine oxidase inhibitors (MAOIs) 6

Advantages of Mirtazapine in PTSD Treatment

• Rapid onset of action compared to SSRIs 5
• May be particularly helpful when insomnia is a prominent symptom 3
• Does not appear to be associated with sexual dysfunction, unlike SSRIs 3
• Anxiolytic effects may help address comorbid anxiety 3

Adverse Effects and Considerations

• Common side effects include:

  • Somnolence (most common, appears less frequent at higher doses) 3
  • Weight gain and increased appetite 3, 2
  • Potential for metabolic effects (increased blood glucose) 2

• All participants in the combat veteran study experienced weight gain, with one participant gaining 8.75 kg (8.4%) 2

• One participant developed elevated fasting blood glucose consistent with diabetes mellitus 2

Limitations of Current Evidence

• Small sample sizes in available studies
• Limited number of controlled trials specific to PTSD
• Lack of direct comparisons with established PTSD treatments
• Short duration of available studies

Clinical Implications

When considering mirtazapine for PTSD:

• Use as a second-line option after SSRIs have failed or are not tolerated
• Consider mirtazapine when sleep disturbance is a prominent symptom
• Monitor weight and metabolic parameters during treatment
• Initial dosing typically starts at 15 mg at night, titrated to 15-45 mg based on response 2
• May be particularly useful in patients with comorbid depression and anxiety

The evidence for mirtazapine in PTSD is promising but limited. More robust clinical trials are needed to definitively establish its place in PTSD treatment algorithms.