Continuing Education Activity

Doxepin is a medication used in the treatment of major depressive disorder, anxiety, insomnia, as well as in the management of skin pruritus. It is in the tricyclic antidepressant class of medications. This activity describes the indications, dosing, side effects, and contraindications for doxepin as a valuable agent in treating depression. This activity will highlight the mechanism of action, adverse effects, toxicity, and dosing, and the importance of using a team-based approach to manage patients with major depressive disorder.

Objectives:

• Explain the most common side effects associated with doxepin therapy used in major depressive disorder.
• Describe the presentation of a patient with doxepin intoxication.
• Summarize the mechanism of action associated with the administration of doxepin.
• Review the importance of communication and teamwork among healthcare professionals to improve the outcomes of individuals affected by mental illness such as depression treated with doxepin.

Indications

Doxepin is a tricyclic antidepressant that was FDA approved in 1969 to treat the major depressive disorder. Doxepin was primarily approved to treat depression; however, it can also target multiple receptors and is beneficial in treating other disorders. Doxepin displays antagonist effects on alpha-adrenergic, muscarinic, and histaminic receptors.

• The oral tablet formulation of doxepin has been FDA approved for the treatment of insomnia.[1]
• Oral capsule formulation and oral solution formulation have been FDA approved to treat insomnia and anxiety; topical formulations to manage skin pruritus.[2][3][4] 
• In literature and research studies, doxepin has proven to be an effective analgesic in treating neuropathic pain.[5][6] 
• It also has been used as a prophylactic agent against migraines.[7][8] 
• Doxepin has not yet received FDA approval for the treatment of neuropathic pain and migraines.
• Topical creams of doxepin work as a local anesthetic in managing pain and have been useful in the treatment of urethral irritation and dysuria.[9][10][11]

Mechanism of Action

Depression appears to result from a chemical imbalance and a lack of neurotransmitters in the brain. The different classes of antidepressant medications have been formulated to perform unique mechanisms by targeting different receptors and increasing the availability of neurotransmitters. Doxepin is in the tricyclic antidepressants (TCA) drug class; these agents work by increasing the concentration of the neurotransmitter’s serotonin (5-HT) and norepinephrine (NE) in the brain. This action prolongs the availability of the neurotransmitters (5-HT and NE) within the synaptic cleft and enhances their neurotransmission by preventing their reuptake back into the presynaptic terminal. 

Doxepin also displays antagonistic properties in the central nervous system by blocking the following receptors: histamine (H1), alpha-1 adrenergic, and muscarinic. It also inhibits sodium and potassium channels in cardiomyocytes.[12][13] Doxepin has H1 and H2 histamine receptor blocking actions, which explains the antipruritic effect of doxepin.

Pharmacokinetics for Oral Formulation

• Time for peak plasma concentration: 3.5 hours
• Food effects: AUC increased by 41% and Cmax by 15% after a high-fat meal
• Distribution: Highly distributed in other body tissue compartments, the apparent volume of distribution is about 11,930 L for tablets
• Plasma protein bindings: approximately 80%
• Metabolism: Hepatic; active metabolite is desmethyldoxepin
• Apparent terminal half-life: Doxepin: approximately 15 hours; desmethyldoxepin: 31 hours
• Excretion: Less than 3% urine as unchanged drug or N-desmethyldoxepin

Pharmacokinetics for Topical Formulation

• Absorption: Percutaneous absorption
• Plasma concentration : Nondetectable to 47 ng/mL
• Metabolism: Hepatic; primary metabolite is desmethyldoxepin (active)
• Half-life elimination: Doxepin: 28 to 52 hours for desmethyldoxepin

Administration

Doxepin antidepressant formulations are commercially available in the form of oral tablets, capsules, and solutions. Oral administration is the most common method used by patients with depression.

• Doxepin tablets are available in two strengths; 3 mg, and 6 mg.
• Oral capsules are available in 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg.
• Oral solutions are available as 10 mg/mL.
• Other forms available include topical creams (5%) and transdermal patches.
• Transbuccal delivery of doxepin has been a topic of research, but not enough data has been reported to support its effectiveness.[14] Methods such as intranasal, sublingual, and rectal administration have yet to be studied.[15]

Adult Dosing

Tablets: For treatment of insomnia doxepin tablets, 3 to 6 mg are used once daily within 30 minutes of bedtime, for a short duration(less than 4-8 weeks).

Capsule and Oral Concentrate: For Major depressive disorder (unipolar) and treatment-resistant depression initial dose is 25-50 mg at bedtime. The dose is increased every third day or more by 25-50 mg to reach a total daily dose of 100 mg - 300 mg It is preferred to be given into divided doses of two to three times.

Withdrawal: Doxepin should be tapered gradually like other antidepressants although abrupt discontinuation usually does not precipitate symptoms as it has a long half-life.

Specific Patients Population 

• Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment. However, doxepin is converting into active metabolite desmethyldoxepin in the liver, so the drug should be used with caution in these patients. 
• Patient with Renal Impairment: There is no dose adjustment guidance in the manufacturer label for patients with renal impairment. 
• Pregnant women: It is considered as pregnancy category C medicine. 
• Breastfeeding Women: Doxepin is not recommended in nursing mothers as the drug and its active metabolite presents in breast milk.[16]
• Pediatric Patients: The safety and efficacy of doxepin are not established in pediatric patients. As per box warnings, it is not recommended to use in pediatric patients below 12 years of age.
• Geriatric Patients: The safety and efficacy of doxepin are not systematically studied for adults versus geriatric patients. It is listed as potential inappropriate medicine which should be avoided in patients 65 years and older. However, the usual starting dose in geriatric patients should be the low end of the dosing range as they have a greater probability of decreased hepatic, renal, or cardiac functions. Moreover. doxepin may cause confusion and oversedation in geriatric patients so close monitoring is recommended.

Adverse Effects

Doxepin is a unique antidepressant because it produces different adverse effects based on the receptor it antagonizes. Doxepin antagonizes three different receptors, which include: histamine, adrenergic, and muscarinic.

Doxepin blocks histamine H1 receptor and causes sedation and somnolence; therefore, FDA has approved low-dose doxepin, 3 mg, and 6 mg dosages to be used as a first-line agent in depressed patients with sleep disturbances and depression associated with anxiety. Proper education is necessary to prevent patients from self-medicating and overdosing on such pills.[17][18]

Doxepin also has the potential to cause a significant increase in weight and was assessed in a study of 329 patients treated with doxepin and amitriptyline.[19]

Doxepin blocks alpha-adrenergic receptors and should be carefully monitored in those with cardiovascular disorders because it can cause orthostatic hypotension.[20]

Lastly, doxepin blocks muscarinic receptors and produces anticholinergic side effects such as dry mouth, constipation, dizziness, lightheadedness, tachycardia, and prolonged QT interval.[21][22][23]

Patients prescribed an antidepressant, such as doxepin, require careful observation due to the black box warning that states a possible increase in suicidality.[24]

There are significant drug interactions with doxepin which requires dose adjustment, frequency modification, or avoidance for a certain time. Allow 14 days between treatment with doxepin and MAO Inhibitors (selegiline, phenelzine, etc.).

Contraindications

Clinicians must get a thorough medical history and medication history from patients before prescribing medications such as antidepressants. Antidepressants may cause serious adverse effects when combined with other medications such as different classes of antidepressants, opioids, alcohol, herbal medication, and even psychedelics. An interaction between two different classes of antidepressants may lead to excess serotonin in the central nervous system. This effect leads to a condition known as serotonin syndrome, sometimes described as serotonin toxicity. Serotonin toxicity induces symptoms such as mental status changes, autonomic stimulation, and neuromuscular excitation. Patients experience symptoms such as agitation, confusion, vital sign changes such as tachycardia, hyperthermia, flushing, tremor, and neuromuscular changes such as rigidity, increased reflexes, and clonus.[25][26] 

Another contraindication to prescribing doxepin is in patients with cardiovascular disorders such as preexisting bundle branch blocks. Literature has reported cases where patients developed atrioventricular heart block, orthostatic hypotension, and abnormalities in conduction after taking doxepin.[27][28] 

Lastly, doxepin has a poor safety profile in postpartum lactating mothers and is contraindicated in breastfeeding due to its sedative and respiratory depressive effects.[29][30]

Overdose can result in a fatality, so avoid using in patients at risk of intentional overdose or known history of suicidal attempts.

Patients with hypersensitivity to doxepin or excipients should also avoid doxepin.

Monitoring

Therapeutic drug monitoring is a valuable guide used to measure the concentration of a medication and its breakdown products in the blood. Its goal is to maintain a constant concentration in the blood and optimize its therapeutic outcomes, effectiveness, and safety while minimizing its potential for serious adverse effects.[31] Drug monitoring is useful in medications with a narrow therapeutic index; this is a ratio between the toxic and therapeutic dose of the medication. Using such a method has proven effective in many drugs, including antidepressants because it has provided a more reliable index of target drug concentration compared to using dosage. Research cites doxepin as having a therapeutic range of 150 to 250 ng/mL. However, one study found that only 9% of samples displayed plasma levels between 150 to 250 ng/mL, while 88% remained subtherapeutic.[32] Side effects occurred more often when the serum levels were above the therapeutic range.[33] Although there is no definite recommendation, therapeutic drug monitoring of doxepin requires more research to maximize its effectiveness and benefits.

Toxicity

Tricyclic antidepressants are one of the most frequently ingested substances used for self-poison in an attempt to commit suicide. A case fatality index is a tool used to measure ratios and compare toxic levels of drugs to one another.[34] Tricyclics have a greater level of toxicity when compared to other classes of antidepressants, and doxepin is two to three times more toxic when compared to amitriptyline.[35][36] 

Symptoms of intoxication and overdose can be grouped based on the organ system it affects. Overdose on doxepin can affect the central nervous system and cardiovascular system. Doxepin is known to block sodium and potassium channels on cardiomyocytes and can reduce cardiac action potential and depolarization and lead to cardiac arrhythmias.[37] It can increase heart rate and widen the PR, QRS, and QT interval as assessed in a study of an individual who overdosed on 5000 mg of doxepin, developed cardiac arrest and was persistently hypotensive.[38] 

Doxepin can also cause neurological effects such as coma, grand mal seizures, and respiratory depression.[13][39][40][41]

Treatment options that are beneficial in patients with doxepin intoxication include sodium bicarbonate, hemodialysis/hemoperfusion, and in some cases, supportive therapy.[42][43]

Enhancing Healthcare Team Outcomes

The major depressive disorder affects more than 17.3 million Americans in the U.S.; 75% of individuals who suffer from mental disorders remain untreated, and about 1 million people commit suicide. Therefore, an interprofessional team approach is necessary to provide the best quality care to patients to accurately diagnose, treat, and manage patients with psychiatric disorders.

Studies have shown that individuals' beliefs about their mental illness can significantly influence their treatment plan and medication adherence.[44] Using an interprofessional team approach that includes clinicians, mid-level practitioners, nurses, therapists, pharmacists, and the patient will help shape an individual's belief about their illness and hopefully decrease the number of patients left untreated and resort to suicide or misusing other drugs.

Nursing can coordinate between the therapist, pharmacist, and the clinician. The pharmacist can watch for drug interactions, verify dosing, and consult if treatment is unsuccessful, recommending other medication options, notably a pharmacist with psychiatric certification. A mental health specialty nurse will have significant contact with the patient and monitor medication side effects, informing the doctor of any concerns.

Doxepin has been used to treat major depressive disorder since 1969; however, patients should receive education about medication compliance, side effects, toxicity, and possible interactions with other medications. Patients should be encouraged to follow up and communicate with their primary care provider, pharmacist, psychiatrist, and therapist if they experience any changes or feel like their medication is not beneficial. The interprofessional approach to depression and doxepin therapy increases the odds of successful treatment for these patients. [Level 5]