Doxepin


Article Author:
Anasheh Almasi


Article Editor:
Carlos Meza


Editors In Chief:
Sherri Murrell


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/8/2019 10:15:26 PM

Indications

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]

Administration

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]

Contraindications

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.

Monitoring

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.

Toxicity

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

References

Feighner JP, Mechanism of action of antidepressant medications. The Journal of clinical psychiatry. 1999;     [PubMed]
Sheffler ZM,Abdijadid S, Antidepressants 2019 Jan;     [PubMed]
Sandig AG,Campmany AC,Campos FF,Villena MJ,Naveros BC, Transdermal delivery of imipramine and doxepin from newly oil-in-water nanoemulsions for an analgesic and anti-allodynic activity: development, characterization and in vivo evaluation. Colloids and surfaces. B, Biointerfaces. 2013 Mar 1;     [PubMed]
Leppert W,Malec-Milewska M,Zajaczkowska R,Wordliczek J, Transdermal and Topical Drug Administration in the Treatment of Pain. Molecules (Basel, Switzerland). 2018 Mar 17;     [PubMed]
Owen RT, Selective histamine H(1) antagonism: a novel approach to insomnia using low-dose doxepin. Drugs of today (Barcelona, Spain : 1998). 2009 Apr;     [PubMed]
Wu J,Chang F,Zu H, Efficacy and safety evaluation of citalopram and doxepin on sleep quality in comorbid insomnia and anxiety disorders. Experimental and therapeutic medicine. 2015 Oct;     [PubMed]
Kouwenhoven TA,van de Kerkhof PCM,Kamsteeg M, Use of oral antidepressants in patients with chronic pruritus: A systematic review. Journal of the American Academy of Dermatology. 2017 Dec;     [PubMed]
Eschler DC,Klein PA, An evidence-based review of the efficacy of topical antihistamines in the relief of pruritus. Journal of drugs in dermatology : JDD. 2010 Aug;     [PubMed]
Yeung WF,Chung KF,Yung KP,Ng TH, Doxepin for insomnia: a systematic review of randomized placebo-controlled trials. Sleep medicine reviews. 2015 Feb;     [PubMed]
Punay NC,Couch JR, Antidepressants in the treatment of migraine headache. Current pain and headache reports. 2003 Feb;     [PubMed]
Wörz R,Berlin J, [Treatment of chronic pain syndromes with antidepressants.]. Schmerz (Berlin, Germany). 1989 Mar;     [PubMed]
Casale R,Symeonidou Z,Bartolo M, Topical Treatments for Localized Neuropathic Pain. Current pain and headache reports. 2017 Mar;     [PubMed]
Hershey LA,Bednarczyk EM, Treatment of headache in the elderly. Current treatment options in neurology. 2013 Feb;     [PubMed]
Vande Griend JP,Anderson SL, Histamine-1 receptor antagonism for treatment of insomnia. Journal of the American Pharmacists Association : JAPhA. 2012;     [PubMed]
Sep-Kowalikowa B,Prokopowicz A,Pankiewicz P, [Weight gain during antidepressant therapy]. Psychiatria polska. 1992 Jan-Apr;     [PubMed]
Baker B,Dorian P,Sandor P,Shapiro C,Schell C,Mitchell J,Irvine MJ, Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder. Journal of clinical psychopharmacology. 1997 Feb;     [PubMed]
Feighner J,Hendrickson G,Miller L,Stern W, Double-blind comparison of doxepin versus bupropion in outpatients with a major depressive disorder. Journal of clinical psychopharmacology. 1986 Feb;     [PubMed]
Feighner JP,Cohn JB, Double-blind comparative trials of fluoxetine and doxepin in geriatric patients with major depressive disorder. The Journal of clinical psychiatry. 1985 Mar;     [PubMed]
Roose SP,Dalack GW,Glassman AH,Woodring S,Walsh BT,Giardina EG, Is doxepin a safer tricyclic for the heart? The Journal of clinical psychiatry. 1991 Aug;     [PubMed]
Kołodziej M,Majewska M,Krajewska A,Szponar J, [Prolonged toxic coma and anisocoria secondary to doxepin, lorazepam and phenobarbital poisoning--case study]. Przeglad lekarski. 2012;     [PubMed]
Hawton K,Bergen H,Simkin S,Cooper J,Waters K,Gunnell D,Kapur N, Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. The British journal of psychiatry : the journal of mental science. 2010 May;     [PubMed]
Henry JA, A fatal toxicity index for antidepressant poisoning. Acta psychiatrica Scandinavica. Supplementum. 1989;     [PubMed]
White N,Litovitz T,Clancy C, Suicidal antidepressant overdoses: a comparative analysis by antidepressant type. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2008 Dec;     [PubMed]
Brennan FJ, Electrophysiologic effects of imipramine and doxepin on normal and depressed cardiac Purkinje fibers. The American journal of cardiology. 1980 Oct;     [PubMed]
Giardina EG,Cooper TB,Suckow R,Saroff AL, Cardiovascular effects of doxepin in cardiac patients with ventricular arrhythmias. Clinical pharmacology and therapeutics. 1987 Jul;     [PubMed]
Frank RD,Kierdorf HP, Is there a role for hemoperfusion/hemodialysis as a treatment option in severe tricyclic antidepressant intoxication? The International journal of artificial organs. 2000 Sep;     [PubMed]
Diltoer MW,Poelmans LW,Hubloue I,Spapen HD,Maes V,Huyghens LP, Combined intoxication with a tricyclic antidepressive agent and a neuroleptic. European journal of emergency medicine : official journal of the European Society for Emergency Medicine. 1996 Mar;     [PubMed]
Sakka SG,Kuethe F,Demme U,Hüttemann E, [Intoxication with a tricyclic antidepressant]. Der Anaesthesist. 2007 Jun;     [PubMed]
Degner D,Grohmann R,Kropp S,Rüther E,Bender S,Engel RR,Schmidt LG, Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry. 2004 Mar;     [PubMed]
Starkey IR,Lawson AA, Poisoning with tricyclic and related antidepressants--a ten-year review. The Quarterly journal of medicine. 1980 Winter;     [PubMed]
McCleane G, Topical application of the tricyclic antidepressant doxepin can reduce dysuria and frequency. Scandinavian journal of urology and nephrology. 2004;     [PubMed]
Drug interactions with selective serotonin reuptake inhibitors, especially with other psychotropics. Prescrire international. 2001 Feb;     [PubMed]
Isbister GK,Buckley NA,Whyte IM, Serotonin toxicity: a practical approach to diagnosis and treatment. The Medical journal of Australia. 2007 Sep 17;     [PubMed]
Glassman AH,Bigger JT Jr, Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review. Archives of general psychiatry. 1981 Jul;     [PubMed]
Rodriguez de la Torre B,Dreher J,Malevany I,Bagli M,Kolbinger M,Omran H,Lüderitz B,Rao ML, Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients. Therapeutic drug monitoring. 2001 Aug;     [PubMed]
Uguz F, A New Safety Scoring System for the Use of Psychotropic Drugs During Lactation. American journal of therapeutics. 2019 Apr 1;     [PubMed]
Lanza di Scalea T,Wisner KL, Antidepressant medication use during breastfeeding. Clinical obstetrics and gynecology. 2009 Sep;     [PubMed]
Gimeno A,Calpena AC,Sanz R,Mallandrich M,Peraire C,Clares B, Transbuccal delivery of doxepin: studies on permeation and histological investigation. International journal of pharmaceutics. 2014 Dec 30;     [PubMed]
Fiaturi N,Greenblatt DJ, Therapeutic Drug Monitoring of Antidepressants. Handbook of experimental pharmacology. 2018 Sep 8;     [PubMed]
Leucht S,Steimer W,Kreuz S,Abraham D,Orsulak PJ,Kissling W, Doxepin plasma concentrations: is there really a therapeutic range? Journal of clinical psychopharmacology. 2001 Aug;     [PubMed]
Müller MJ,Dragicevic A,Fric M,Gaertner I,Grasmäder K,Härtter S,Hermann E,Kuss HJ,Laux G,Oehl W,Rao ML,Rollmann N,Weigmann H,Weber-Labonte M,Hiemke C, Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical conditions? Pharmacopsychiatry. 2003 May;     [PubMed]
Brown C,Battista DR,Bruehlman R,Sereika SS,Thase ME,Dunbar-Jacob J, Beliefs about antidepressant medications in primary care patients: relationship to self-reported adherence. Medical care. 2005 Dec;     [PubMed]
Isacsson G,Rich CL, Antidepressant drugs and the risk of suicide in children and adolescents. Paediatric drugs. 2014 Apr;     [PubMed]

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