What is the mechanism of action of doxepin (tricyclic antidepressant) for treating sleep disorders, particularly insomnia?

Mechanism of Action of Doxepin for Sleep

At low doses (3-6 mg), doxepin works primarily through highly selective antagonism of histamine H1 receptors, which promotes both the initiation and maintenance of sleep. 1, 2

Primary Mechanism: Selective H1 Receptor Antagonism

• Doxepin binds with subnanomolar affinity to the histamine H1 receptor, demonstrating high specificity compared to other receptor types 1, 2
• At low doses (1-6 mg), doxepin selectively antagonizes H1 receptors without significantly affecting other receptor systems that are active at higher antidepressant doses 1, 2
• This selective H1 antagonism blocks the wake-promoting effects of histamine in the central nervous system, thereby facilitating sleep 3

Dose-Dependent Receptor Activity

• Low doses (3-6 mg): Predominantly H1 receptor antagonism with minimal effects on other receptor systems 1, 2
• Higher antidepressant doses (>25 mg): Additional anticholinergic, antinoradrenergic, and antiserotonin effects become clinically significant, along with effects on norepinephrine reuptake 4, 5
• The therapeutic window for insomnia specifically exploits the H1 selectivity while avoiding the dose-limiting side effects seen at higher doses 3

Clinical Implications of the Mechanism

• The H1 antagonism produces preferential effects on sleep maintenance rather than sleep initiation, given histamine's role in the sleep-wake cycle 3
• Polysomnographic studies show minimal disruption of sleep architecture, unlike many other sedative-hypnotics 2
• The mechanism results in rapid onset of action, with significant improvements evident after a single dose 1, 6
• No evidence of tolerance development, physical dependence, or rebound insomnia has been observed, likely due to the specific H1 mechanism without broader receptor effects 1, 2

Distinction from Antidepressant Mechanism

• The antidepressant effects at higher doses are hypothesized to involve prevention of norepinephrine reuptake at nerve terminals, influencing adrenergic activity at synapses 4
• At the low doses used for insomnia (3-6 mg), these monoaminergic effects are not clinically relevant 5, 3
• This explains why low-dose doxepin is effective for insomnia without producing antidepressant effects 5