Summary

The combination of doxepin (a tricyclic antidepressant) and paroxetine (an SSRI) can lead to increased doxepin levels due to CYP2D6 enzyme inhibition by paroxetine. This interaction may result in enhanced anticholinergic effects, sedation, and potential serotonin syndrome, requiring careful monitoring and possible dose adjustments.

Introduction

Doxepin is a tricyclic antidepressant (TCA) primarily used to treat depression, anxiety disorders, and chronic insomnia. It works by blocking the reuptake of norepinephrine and serotonin while also having antihistaminic and anticholinergic properties. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for depression, anxiety disorders, panic disorder, and obsessive-compulsive disorder. It selectively blocks serotonin reuptake and is known for its potent inhibition of the CYP2D6 enzyme, which metabolizes many medications including tricyclic antidepressants.

Mechanism of Interaction

The primary mechanism of interaction between doxepin and paroxetine involves cytochrome P450 enzyme inhibition. Paroxetine is a potent inhibitor of CYP2D6, the enzyme responsible for metabolizing doxepin. When paroxetine inhibits CYP2D6, it significantly reduces the clearance of doxepin, leading to increased plasma concentrations of the tricyclic antidepressant. This can result in elevated levels of both the parent compound and its active metabolites. Additionally, both medications affect serotonin levels, which may contribute to additive serotonergic effects and increase the risk of serotonin syndrome, particularly at higher doses or in susceptible patients.

Risks and Symptoms

The combination of doxepin and paroxetine presents several clinical risks. Increased doxepin levels can lead to enhanced anticholinergic effects including dry mouth, constipation, urinary retention, blurred vision, and confusion, particularly in elderly patients. Cardiovascular risks may include prolonged QT interval, arrhythmias, and orthostatic hypotension. Enhanced sedation and cognitive impairment are common, increasing fall risk and impairing daily functioning. The most serious concern is serotonin syndrome, characterized by altered mental status, autonomic instability, and neuromuscular abnormalities. Patients may also experience increased gastrointestinal side effects, sexual dysfunction, and withdrawal symptoms if either medication is discontinued abruptly.

Management and Precautions

Doxepin interactions with food and lifestyle

Alcohol: Avoid alcohol while taking doxepin as it can increase drowsiness, dizziness, and impair thinking and motor skills. The combination may also increase the risk of respiratory depression. Grapefruit: Grapefruit and grapefruit juice may increase doxepin levels in the blood by inhibiting CYP3A4 metabolism, potentially leading to increased side effects. Driving and Operating Machinery: Doxepin may cause drowsiness, dizziness, and blurred vision. Patients should avoid driving or operating heavy machinery until they know how the medication affects them. Sun Exposure: Doxepin may increase sensitivity to sunlight (photosensitivity). Use sunscreen and protective clothing when outdoors to prevent sunburn and skin reactions.

Paroxetine interactions with food and lifestyle

Alcohol: Paroxetine may increase the sedative effects of alcohol. Patients should avoid or limit alcohol consumption while taking paroxetine, as the combination can enhance drowsiness, dizziness, and impair cognitive and motor functions. This interaction is consistently warned against in clinical guidelines due to the potential for increased central nervous system depression.