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9/8/2019 10:15:26 PM


Doxepin is a tricyclic antidepressant that was FDA approved in 1969 to treat major depressive disorder. Doxepin was primarily approved to treat depression; however, it can also target multiple receptors and has proven beneficial in the treatment of other disorders. Doxepin displays antagonist effects on alpha-adrenergic, muscarinic, and histaminic receptors. With such a wide variety of receptors to block, oral formulations of doxepin have been FDA approved to treat insomnia and anxiety, and topical formulations have been approved to manage skin pruritus.[1][2][3][4] 

In literature and research studies, doxepin has proven to be an effective analgesic in the treatment of 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. 

Mechanism of Action

Depression is thought 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.[9][10]


Antidepressants are commercially available in the form of oral tablets, capsules, and solutions. Oral administration is the most common method used by the population and comes in two dosages, 3 mg, and 6mg. Oral capsules come in dosages of 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg. Oral solutions come in doses of 10 mg/mL. Other forms available include topical creams (5%) and transdermal patches. Topical creams of doxepin act as a local anesthetic in the management of pain and have been useful in the treatment of urethral irritation and dysuria.[11][12][13] 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]

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. 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.[16][17][18]

Doxepin blocks alpha-adrenergic receptors and should be carefully monitored in those with cardiovascular disorders because it can cause orthostatic hypotension.[19]

Lastly, doxepin blocks muscarinic receptors and produces anticholinergic side effects such as dry mouth, constipation, dizziness, lightheadedness, tachycardia, and prolonged QT interval.[20][21][22]

Patients prescribed an antidepressant such as doxepin require careful observation due to the black box warning that states a possible increase in suicidality.[23]


Physicians are required to get a thorough medical history as well as 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.[24][25] 

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.[26][27] 

Lastly, doxepin has a poor safety profile in postpartum lactating mothers and is contraindicated in breastfeeding due to its sedative and respiratory depressive effects.[28][29]

Patients with hypersensitivity should also avoid doxepin.


Therapeutic drug monitoring is a valuable guide used to measure the concentration of a medication and its break down 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.[30] Drug monitoring is useful in medications that have 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 such as antidepressants because it has provided a more reliable index of target drug concentration compared to its 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.[31] Side effects occurred more often when the serum levels were above the therapeutic range.[32] Although there is no definite recommendation, therapeutic drug monitoring of doxepin requires more research to maximize its effectiveness and benefits.


Tricyclic antidepressants are one of the most frequently ingested substances used for self-poison in an attempt to commit suicide. The case fatality index is a tool used to measure ratios and compare toxic levels of drugs to one another.[33] 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.[34][35] 

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.[36] 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 and developed cardiac arrest and was persistently hypotensive.[37] 

Doxepin can also cause neurological effects such as coma, grand mal seizures, and respiratory depression.[10][38][39][40]

Treatment options that are beneficial in patients with doxepin intoxication include sodium bicarbonate, hemodialysis/hemoperfusion, and in some cases, supportive therapy.[41][42]

Enhancing Healthcare Team Outcomes

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. To accurately diagnose, treat, and manage patients with psychiatric disorders, a team approach is necessary to provide the best care quality to patients.

Studies have shown that an individual’s belief about their mental illness can significantly influence their treatment plan and medication adherence.[43] Using a team approach which includes physicians, nurses, therapists, pharmacists, and the patient will help shape an individual’s belief about their illness and will hopefully decrease the number of patients who are left untreated and resort to suicide.

Nursing can coordinate between therapist, pharmacist, and the physician. The pharmacist can watch for drug interactions, verify dosing, and consult if treatment is not successful, recommending other medication options, notably a pharmacist with psychiatric certification. A psychiatric health specialty nurse will have significant contact with the patient and can monitor for 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 V]

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Doxepin - Questions

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A 16-year-old female presents to her primary care provider complaining of difficulty concentrating and problems with her sleep over the past month. She states that she has lost 5 lbs in the last month due to a lack of appetite. She also mentions that she has lost interest and no longer enjoys attending gymnastics practice. Due to her symptoms, the patient expresses that she feels like her life is worthless and that she should drop out of school due to her poor performance in her classes. Which of the following medications will help treat this patient's symptoms?

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A 50-year-old female is seen in the clinic complaining of difficulty sleeping. Low dose doxepin is prescribed to help with her symptoms. After a few weeks, the patient returns to the clinic complaining of constipation, urinary retention, flushing, and dry mouth. What receptor does doxepin antagonize that leads to the production of these symptoms?

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A 65-year-old male with a history of mood disorder is found unconscious on his living room floor with an empty bottle of medications next to him. His wife makes resuscitation efforts, but the patient remains unconscious. Minutes after, the wife witnesses the patient’s body shaking and foaming from his mouth. She immediately calls 911, and when he is transferred to the emergency department. They perform an EKG and notice cardiac arrhythmias. Based on his overdose symptoms, which class of medications did the patient overdose on, and what antidote helps reverse his arrhythmia?

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A 74-year-old diabetic male presents to the emergency department for left-sided chest pain. His past medical history is significant for type 2 diabetes, major depressive disorder, and congestive heart failure. A bedside EKG is performed and shows a left bundle branch block. The patient takes doxepin for his depression. Which of the following is the next best step in the management of this patient?

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A 25-year-old female is brought to the emergency department with agitation, confusion, tremors, diarrhea, increased body temperature, and flushing. She has a history of major depressive disorder. She was recently prescribed a month’s supply of an antidepressant but ran out of her medication. Due to scheduling issues, the patient was unable to get a new prescription and took unknown pills from her grandmother’s medicine cabinet. Which of the following combination of medications is most likely to cause this presentation?

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Doxepin - References


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