Can gabapentin (GABA analog) or mirtazapine (tetracyclic antidepressant) be prescribed for insomnia?

Gabapentin and Mirtazapine for Insomnia

Neither gabapentin nor mirtazapine is FDA-approved or recommended as a first-line treatment for insomnia, and both should be considered only after CBT-I and approved medications have failed. 1

First-Line Treatment Approach

The American College of Physicians and American Academy of Sleep Medicine strongly recommend Cognitive Behavioral Therapy for Insomnia (CBT-I) as the first-line treatment for all patients with insomnia. 1 This non-pharmacological approach should be tried for 4-8 weeks before considering medication.

If medication becomes necessary after CBT-I proves insufficient, the recommended first-line pharmacological options include:

• Sleep onset insomnia:

  • Ramelteon (8mg)
  • Zolpidem (10mg adults, 5mg elderly)
  • Zaleplon (10mg)

• Sleep maintenance insomnia:

  • Low-dose doxepin (3-6mg)
  • Eszopiclone (2-3mg)
  • Suvorexant (10-20mg)

Mirtazapine for Insomnia

Efficacy

• Recent evidence from the MIRAGE study (2025) shows that mirtazapine 7.5mg significantly reduces insomnia severity in older adults compared to placebo. 2
• Mirtazapine promotes sleep primarily through its antagonism of histamine H1 receptors and serotonin 5-HT2 receptors. 3

Safety Concerns

• Mirtazapine can cause significant adverse effects including:
  • Sedation/drowsiness (23% vs 14% for placebo) 3
  • Increased appetite and weight gain (11% and 10% vs 2% and 1% for placebo) 4
  • Dry mouth (25% vs 16% for placebo) 3
  • Risk of QT prolongation, especially with overdose 4
  • Risk of serotonin syndrome when combined with other serotonergic medications 4
  • Activation of mania/hypomania in patients with bipolar disorder 4

Dosing for Insomnia

• Lower doses (7.5-15mg) appear more effective for insomnia than higher doses 5
• The sedating effects may diminish at higher doses due to increased noradrenergic effects

Gabapentin for Insomnia

Evidence Base

• Limited evidence supports gabapentin for insomnia, particularly in patients with neurological or psychiatric comorbidities 6
• One small study showed promise in treating insomnia in children with neurodevelopmental disorders 7
• Works through modulation of the α2δ subunit of voltage-sensitive calcium channels 6

Safety Considerations

• Potential for dependence and withdrawal symptoms 8
• The Lancet Psychiatry (2019) reports that about 50% of patients prescribed gabapentinoids had been treated continuously for at least 12 months, raising concerns about long-term use 8
• Side effects may include dizziness, somnolence, and peripheral edema

Clinical Decision Algorithm

1. Start with CBT-I for all patients with insomnia (4-8 weeks)

2. If CBT-I is insufficient, consider FDA-approved medications:

   • For sleep onset: Ramelteon, zolpidem, or zaleplon
   • For sleep maintenance: Low-dose doxepin, eszopiclone, or suvorexant

3. Consider mirtazapine only if:

   • Patient has failed first-line treatments
   • Patient has comorbid depression or anxiety
   • Start at 7.5mg at bedtime
   • Monitor for weight gain, daytime sedation, and dry mouth
   • Avoid in patients with bipolar disorder or at risk for QT prolongation

4. Consider gabapentin only if:

   • Patient has failed first-line treatments
   • Patient has comorbid neuropathic pain, restless legs syndrome, or anxiety
   • Start at low doses (100-300mg) at bedtime
   • Be cautious about potential for dependence and withdrawal
   • Plan for limited duration of treatment

Important Caveats

• Both medications carry risks of dependence and withdrawal symptoms 8
• Neither should be used long-term without regular reassessment
• Avoid combining with benzodiazepines or alcohol due to additive sedative effects 4
• Both medications should be tapered gradually when discontinuing
• Monitor for daytime impairment, especially when driving or operating machinery

Special Populations

• Elderly patients: Use lower doses of either medication; mirtazapine has stronger evidence in this population 2
• Patients with substance use disorders: Use caution with both medications due to dependence potential
• Patients with renal impairment: Reduce gabapentin dose
• Patients with hepatic impairment: Reduce mirtazapine dose

In conclusion, while both medications may improve sleep in certain contexts, they should not be considered first-line treatments for insomnia and should be used judiciously after weighing risks and benefits.