Can mirtazapine (Remeron) be used for insomnia?

Mirtazapine for Insomnia

Mirtazapine can be used off-label for insomnia, but it is not FDA-approved for this indication and should be considered a third-line option after benzodiazepine receptor agonists and ramelteon, with efficacy that is not well-established according to major sleep medicine guidelines. 1

Guideline Recommendations and Evidence Quality

The American Academy of Sleep Medicine explicitly states that certain antidepressants including mirtazapine are employed in lower than antidepressant therapeutic dosages for insomnia, but these medications are not FDA approved for insomnia and their efficacy for this indication is not well established. 1

• Mirtazapine is positioned as a third-line pharmacologic option after short-intermediate acting benzodiazepine receptor agonists and ramelteon have been considered. 2
• The evidence supporting mirtazapine for chronic primary insomnia is limited in quality and generalizability. 1

When Mirtazapine May Be Appropriate

Despite limited evidence, mirtazapine has specific clinical contexts where it may be beneficial:

• In palliative care patients with refractory insomnia, mirtazapine 7.5-30 mg at bedtime is listed as an acceptable pharmacologic option. 1
• In patients with comorbid depression and insomnia, particularly those with anorexia and sleep disturbances, mirtazapine may address multiple symptoms simultaneously. 1
• In children with autism spectrum disorders, mirtazapine has shown effectiveness for sleep disorders, though this is a specialized population. 1
• In older adults with chronic insomnia, recent evidence shows mirtazapine 7.5 mg significantly reduces insomnia severity compared to placebo, though adverse events led to discontinuation in 20% of patients. 3

Dosing Considerations

Start with 7.5 mg at bedtime, as lower doses are typically more sedating due to greater histaminergic effects. 1, 2

• The dose can be titrated up to 15-30 mg at bedtime if needed. 1
• In elderly or debilitated patients, maintain lower doses (7.5 mg) to minimize sedation and other adverse effects. 1, 2
• Take once daily, preferably in the evening at bedtime. 4

Critical Safety Concerns and Adverse Effects

The FDA label and clinical guidelines highlight several important safety issues:

• Somnolence is extremely common (54% vs 18% placebo) and led to discontinuation in 10.4% of patients in controlled trials. 4
• Increased appetite and weight gain occur frequently: 17% report appetite increase and 7.5% gain ≥7% body weight. 4
• Avoid concurrent use with benzodiazepines and alcohol due to additive sedative effects. 4
• QTc prolongation has been reported, particularly in overdose or with other QTc-prolonging medications. 4
• Serotonin syndrome risk when combined with other serotonergic medications (MAOIs, SSRIs, SNRIs, triptans, tramadol, fentanyl). 4
• Hyponatremia can occur, particularly in elderly patients, and may lead to falls, confusion, or seizures. 4
• Abrupt discontinuation can cause withdrawal symptoms including dizziness, anxiety, insomnia, and electric shock sensations. 4

Practical Clinical Algorithm

Step 1: Confirm chronic insomnia diagnosis and rule out primary sleep disorders (sleep apnea, periodic limb movements). 1

Step 2: Ensure cognitive behavioral therapy for insomnia (CBT-I) has been attempted or offered as first-line treatment. 2

Step 3: If pharmacotherapy is needed, consider FDA-approved options first (benzodiazepine receptor agonists, ramelteon). 1, 2

Step 4: Consider mirtazapine if:

• Patient has comorbid depression or anxiety 1
• Patient has failed or cannot tolerate first-line agents 2
• Patient has poor appetite or unintended weight loss 1
• Patient is in palliative care with refractory insomnia 1

Step 5: Start 7.5 mg at bedtime, warn about somnolence and weight gain. 1, 2, 4

Step 6: Reassess after 4-8 weeks for efficacy and tolerability. 1

Common Pitfalls to Avoid

• Do not use mirtazapine as first-line monotherapy for primary insomnia without considering FDA-approved options or CBT-I first. 1, 2
• Do not combine with benzodiazepines or alcohol due to excessive sedation risk. 4
• Do not abruptly discontinue after prolonged use; taper over 10-14 days to avoid withdrawal. 1, 4
• Monitor weight closely, as weight gain can be significant and may lead to discontinuation. 4, 3, 5
• Screen for bipolar disorder before initiating, as mirtazapine can precipitate manic episodes. 4
• Caution in elderly patients due to increased risk of falls from sedation and hyponatremia. 4

Alternative Strategy: Combination with Melatonin

Emerging evidence suggests that adding prolonged-release melatonin 2 mg to mirtazapine may allow for mirtazapine tapering while maintaining sleep benefits and avoiding weight gain, particularly in perimenopausal women. 5 This strategy warrants consideration when weight gain becomes problematic during mirtazapine treatment.