Doxepin
Sinequan · Silenor
Tricyclic AntidepressantGeneric availableTDM data
Doxepin inhibits reuptake of norepinephrine and serotonin. It is one of the most potent antihistamines known, with H1 receptor affinity exceeding that of conventional antihistamines. At low doses (3-6 mg, Silenor), the H1 antihistamine effect predominates, making it useful for insomnia. At antidepressant doses (75-300 mg), NE/5-HT reuptake inhibition provides antidepressant and anxiolytic effects.
Compare Doxepin →FDA-Approved Indications
- Depression and/or anxiety
- Insomnia characterized by difficulty with sleep maintenance (Silenor 3-6 mg)
What Sets This Drug Apart
- Most potent H1 antagonist known — Ki 0.17 nM exceeds diphenhydramine by >1000-fold, enabling ultra-low dose (3-6 mg Silenor) for insomnia without significant anticholinergic effects
- Dual FDA indications: full-dose TCA for depression/anxiety AND ultra-low-dose (Silenor) for insomnia — functionally two different drugs at different dose ranges
- Extremely sedating even among TCAs — potent H1 antagonism (Ki 0.24 nM) makes it the basis for low-dose insomnia treatment (Silenor 3-6 mg), but at antidepressant doses (150-300 mg) sedation…
- H1 + H2 antagonism makes it useful for chronic urticaria/pruritus — a unique off-label niche among antidepressants
- Also available as topical cream (Prudoxin/Zonalon) for pruritus — systemic absorption can still cause drowsiness
- Lethal in overdose like other TCAs — narrow therapeutic index at antidepressant doses
Boxed Warning
Suicidality in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders (class warning for ant