Remeron (Mirtazapine) for PTSD
Mirtazapine is not recommended as a first-line treatment for PTSD, but may be considered as an augmentation strategy when combined with SSRIs, or as an alternative when first-line treatments fail or are not tolerated.
Evidence-Based Treatment Hierarchy for PTSD
First-Line Pharmacotherapy
The most recent VA/DoD 2023 guidelines 1 establish that SSRIs (specifically paroxetine, sertraline) and the SNRI venlafaxine are the only medications with strong recommendations for PTSD treatment. These should be prioritized over mirtazapine for initial pharmacotherapy.
Mirtazapine's Role in PTSD
As Monotherapy: The evidence for mirtazapine monotherapy in PTSD is weak and contradictory:
- A 2020 randomized controlled trial in 78 veterans 2 found no significant difference between mirtazapine (up to 45 mg/day) and placebo on the primary PTSD outcome measure during the 8-week controlled phase (P = 0.418)
- Only the Clinical Global Impressions-Improvement scale showed benefit (P = 0.041)
- A 2022 Cochrane review 3 found evidence of beneficial effect for mirtazapine on treatment response (RR 0.45,95% CI 0.22 to 0.94; 65% response vs 22% placebo), but this was based on only one small study with 26 participants and rated as low-certainty evidence
As Augmentation Therapy: Mirtazapine shows more promise when combined with SSRIs:
- A 2015 placebo-controlled trial 4 demonstrated that sertraline plus mirtazapine showed significantly greater remission rates (P = 0.042) and improvement in depressive symptoms (P = 0.023) compared to sertraline plus placebo
- Effect sizes ranged from small to moderate (d = 0.26-0.63) across multiple outcomes
- The combination was well-tolerated with only increased appetite as a significant side effect
Practical Prescribing Algorithm
Step 1: Start with an SSRI (sertraline or paroxetine) or venlafaxine as first-line treatment 1
Step 2: If inadequate response after 8-12 weeks at therapeutic doses, consider:
- Adding mirtazapine 15-45 mg at bedtime as augmentation 4
- Starting dose: 7.5-15 mg at bedtime, titrate to 30-45 mg based on response 5
Step 3: Mirtazapine may be particularly useful when:
- Sleep disturbances are prominent (promotes sleep) 5, 6
- Appetite/weight loss is present (promotes appetite and weight gain) 5, 6
- Patient cannot tolerate SSRIs
- Anxiety symptoms are prominent in comorbid depression 7
Important Caveats
What Mirtazapine Does NOT Treat:
- The 2010 and 2018 American Academy of Sleep Medicine guidelines 8, 9, 8 do not recommend mirtazapine for PTSD-associated nightmares. Prazosin remains the Level A recommendation for this specific symptom 8
Monitoring Requirements:
- Monitor for orthostatic hypotension, especially in elderly patients
- Watch for excessive sedation and weight gain
- Assess for angle-closure glaucoma risk 10
- Avoid in patients taking MAOIs (14-day washout required) 10
Clinical Reality vs. Guidelines
A 2023 Swiss study 11 found that while clinicians frequently prescribe antidepressants for PTSD, mirtazapine (21% of treated patients) was commonly used despite not being in VA/DoD guidelines. This reflects real-world practice where mirtazapine's sedating and anxiolytic properties make it attractive, particularly for patients with prominent sleep and anxiety symptoms.
The bottom line: While mirtazapine has FDA approval only for major depressive disorder 10, it may serve as a reasonable second-line or augmentation option in PTSD when first-line SSRIs/SNRIs are inadequate, particularly when targeting comorbid depression, anxiety, insomnia, or appetite disturbance. However, it should not replace evidence-based psychotherapy or first-line pharmacotherapy with SSRIs/venlafaxine 1.