Which antidepressant is least likely to cause insomnia?

Which Antidepressant is Least Likely to Cause Insomnia

If you need an antidepressant that will not worsen insomnia, choose mirtazapine or a tricyclic antidepressant like nortriptyline or desipramine, as these have the lowest risk of causing or exacerbating sleep disturbance.

Antidepressants That Commonly Cause Insomnia

The following antidepressants have activating properties and frequently disrupt sleep, particularly in short-term treatment:

• SSRIs (fluoxetine, paroxetine, sertraline, citalopram) commonly cause insomnia, nervousness, and sleep disturbances as typical side effects 1, 2, 3
• Fluoxetine is particularly activating with a very long half-life, and side effects may not manifest for several weeks 1
• Venlafaxine (SNRI) has activating effects that may disrupt sleep 2, 3
• Bupropion is activating and should not be used in patients with insomnia; the second dose must be given before 3 p.m. to minimize insomnia risk 1
• Reboxetine has activating properties that can worsen sleep 3
• Desipramine tends to be activating and may reduce apathy but can cause sleep disruption 1

In maintenance treatment with these activating antidepressants, 30-40% of patients may still suffer from insomnia 3.

Antidepressants Least Likely to Cause Insomnia

First Choice: Mirtazapine

• Mirtazapine is potent, well-tolerated, and promotes sleep, appetite, and weight gain 1
• It demonstrates important sleep-improving effects related to its pharmacodynamic properties, with specific postsynaptic 5-HT2 and 5-HT3 receptor blockade providing antidepressant effects without serotonin-related sleep side effects 4
• Dosing: Start at 7.5 mg at bedtime, maximum 30 mg at bedtime 1
• The most commonly reported side effect is transient somnolence, which appears less frequent at higher dosages 4

Second Choice: Nortriptyline

• Nortriptyline tends to be sedating and may be useful in patients with agitated depression and insomnia 1
• It has a lower risk for cardiotoxic, hypotensive, and anticholinergic effects compared to other tricyclics 1
• Dosing: 10 mg at bedtime, maximum 40 mg per day given twice daily 1
• Therapeutic blood level window of 50-150 ng/mL 1

Third Choice: Doxepin (Low-Dose)

• Low-dose doxepin (3-6 mg) is specifically recommended for insomnia and has been approved for treatment of insomnia characterized by difficulties maintaining sleep 5, 3
• When used for depression with insomnia, the dose is 25 mg 5
• Doxepin has minimal anticholinergic effects compared to other tricyclics 5
• Moderate quality evidence shows TCAs including doxepin improve subjective sleep quality (SMD -0.39,95% CI -0.56 to -0.21), sleep efficiency (MD 6.29 percentage points), and increase sleep time (MD 22.88 minutes) 6

Important Clinical Considerations

Avoid these common pitfalls:

• Do not use SSRIs if insomnia is a primary concern, as they commonly cause sleep disturbances even though paroxetine is "less activating" than other SSRIs 1, 2
• Do not assume all sedating antidepressants are equivalent—choose based on anticholinergic burden (lower is better in elderly patients) 5
• When using sedating antidepressants for sleep promotion, use the lowest effective dose administered early enough before bedtime 2
• Always combine pharmacotherapy with Cognitive Behavioral Therapy for Insomnia (CBT-I) when possible, as sleep hygiene alone is not effective for chronic insomnia 5

Monitoring requirements:

• A full therapeutic trial requires at least 4-8 weeks 1
• After 9 months, consider dosage reduction to reassess the need for medication 1
• Discontinue antidepressants over 10-14 days to limit withdrawal symptoms 1
• Regular follow-up is essential to monitor for side effects and effectiveness 5