What is the mechanism of action (MOA) of Doxepin?

Mechanism of Action of Doxepin

Doxepin primarily works by inhibiting the presynaptic reuptake of both norepinephrine and serotonin in the brain, while also exhibiting potent H1 and H2 histamine receptor antagonism. 1

Primary Mechanisms

• Doxepin is a tricyclic antidepressant (TCA) from the dibenzoxepin family with multiple pharmacological actions 1
• The current hypothesis is that its clinical effects are due, at least in part, to influences on adrenergic activity at synapses, preventing deactivation of norepinephrine by reuptake into nerve terminals 1
• Unlike selective agents, doxepin has a more balanced effect on both serotonin and norepinephrine neurotransmission 2
• Doxepin exhibits potent H1 and H2 antihistamine activity, making it particularly useful in conditions with central nervous system manifestations 3

Secondary Pharmacological Properties

• In animal studies, doxepin demonstrates anticholinergic, antiserotonin, and antihistamine effects on smooth muscle 1
• At higher than usual clinical doses, norepinephrine response was potentiated in animals, though this effect was not demonstrated in humans 1
• Unlike some other psychoactive medications, doxepin is virtually devoid of euphoria as a side effect 1
• Doxepin has not been demonstrated to produce physical tolerance or psychological dependence associated with addictive compounds 1

Clinical Applications Based on MOA

• The combination of antidepressant activity with sedative effects makes doxepin similar to amitriptyline in its clinical action profile 4
• Doxepin's more marked sedative properties make it particularly useful in depressed patients with sleep disturbances 4, 5
• In a recent study comparing sleep medications, doxepin significantly enhanced sleep continuity with better tolerability than trazodone 5
• Doxepin's potent H1 and H2 antihistamine activity with tricyclic antidepressant properties makes it useful for reducing central nervous system manifestations in conditions like mast cell activation syndrome 3

Important Considerations and Cautions

• Doxepin is contraindicated in patients with glaucoma or a tendency toward urinary retention due to its anticholinergic effects 1
• At dosages above 150 mg per day, doxepin may block the antihypertensive effect of guanethidine and related compounds 1
• Doxepin is contraindicated with drugs that inhibit hepatic metabolism via cytochrome P450 and with drugs that have potential arrhythmic properties 3
• Doxepin may cause drowsiness and cognitive decline, particularly in the elderly, and might increase suicidal tendencies in children and young adults with depression 3

Pharmacological Differentiation

• Unlike selective serotonin reuptake inhibitors (SSRIs), doxepin has a more balanced effect on both serotonin and norepinephrine neurotransmission 2
• Unlike selective norepinephrine reuptake inhibitors (SNRIs), doxepin has additional significant antihistaminic and anticholinergic properties 6
• Doxepin's sedative effect is more pronounced than that of imipramine, making it more suitable for patients with anxiety and sleep disturbances 4
• At therapeutic doses, doxepin appears to cause fewer cardiovascular side effects than some other TCAs, though it has similar cardiotoxicity on overdosage 4