From the Guidelines
Doxepin, a tricyclic antidepressant, exhibits a higher affinity for histamine H1 receptors at low doses, typically below 10mg, making it an effective treatment for insomnia and anxiety 1.
Key Points
- At low doses, doxepin's antihistaminic properties are more pronounced, contributing to its sedative effects 1.
- In contrast, at higher doses, typically above 50mg, doxepin's affinity for other receptors, such as serotonin and norepinephrine, becomes more significant, contributing to its antidepressant effects.
- Studies have shown that doxepin at doses of 3mg and 6mg is effective in treating sleep maintenance insomnia with minimal adverse events 1.
- The benefits of using doxepin for insomnia treatment are deemed to be greater than the harms, with weak evidence for efficacy and minimal evidence of adverse events in excess of placebo 1.
Dosage Considerations
- Low doses of doxepin (below 10mg) are recommended for treating insomnia and anxiety due to its higher affinity for histamine H1 receptors 1.
- Higher doses (above 50mg) may be more effective for treating depression, but may also increase the risk of adverse events.
From the Research
Doxepin and Histamine Receptors
- Doxepin is a tricyclic antidepressant that binds to the histamine H1 receptor (H1R) with high affinity 2, 3.
- The Z-isomer of doxepin has a higher affinity for the H1R than the E-isomer, with a 5.2-fold higher affinity for the wild-type H1R 2.
- At low doses, doxepin selectively antagonizes H1 receptors, which is believed to promote the initiation and maintenance of sleep 4, 5.
Low-Dose Doxepin and Insomnia
- Low-dose doxepin (3 or 6 mg) has been shown to improve wake time after sleep onset, total sleep time, and sleep efficiency in patients with chronic primary insomnia 4, 5.
- Low-dose doxepin has been found to be effective in modeling transient insomnia in healthy adults, according to polysomnographic recordings 4.
- The use of low-dose doxepin for insomnia has been supported by several studies, with minimal effects on sleep architecture and no signal for tolerance, psychomotor impairment, or rebound insomnia 4, 5, 6.
Binding Characteristics
- The binding characteristics of doxepin to the H1R have been studied using receptor-bound ligand analysis and molecular dynamics simulations 2.
- The hydroxyl group of Thr1123.37 in the H1R binding pocket contributes to the formation of a chemical environment that is slightly more favorable for the Z-isomer of doxepin 2.
- The high-affinity binding site of doxepin to the H1R has a dissociation constant (KD) of 3.1 +/- 0.3 X 10(-10) M, as determined by Scatchard analysis 3.