Amoxapine


Article Author:
Sayeda Abbas


Article Editor:
Raman Marwaha


Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
5/16/2019 11:56:13 AM

Indications

Amoxapine is FDA approved drug belonging to the class of second-generation tricyclic dibenzoxazepine antidepressants.[1][2] It is generally reserved for second or third line treatment after selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) has failed to control the depression.[1] Thus, it is indicated for treatment-resistant depression, after the first and second line medication have failed to improve symptoms.

Indications for this medication also include use in cases of depression with other psychiatric issues, such as anxiety, agitation, psychosis as well as neurotic or recurrent depression.[2] Amoxapine may either be taken as a single oral tablet daily or divided into two daily doses.[3] Amoxapine was also found to decrease the production of amyloid- beta chains in Alzheimer disease by acting of the serotonin-6 (HTR-6) receptor.[4] In various studies, amoxapine was also found to decrease the incidence of diarrhea in patients undergoing chemotherapy, specifically with irinotecan.[5][6] This drug was also found to improve the prognosis of neuropathic pain.[7]

Mechanism of Action

Amoxapine is a second-generation tricyclic dibenzoxazepine antidepressant; therefore it works primarily by inhibiting the reuptake of norephedrine in the neuronal synapses.[2][8][9] It appears to have the minimal effect of serotonin receptors, asides from the serotonin-6 receptor (HTR-6).[2][4] Amoxapine has also been found to have a minimal effect on the histamine H1 receptor.[10]

Amoxapine is primarily metabolized into two active metabolites by the liver through aromatic hydroxylation. The active metabolites are 7-hydroxyamoxapine and 8-hydroxyamoxapine, which were found to reduce the incidence of diarrhea in patients after the administration of irinotecan chemotherapy.[2][6] These metabolites were also found to decrease tumor growth in such individuals.[6] The half-life of the active metabolite, 8-hydroxy amoxapine, is found to be 30 hours, while the half-life of the drug itself is 8 hours.[2] The primary method of excretion of the drug from the body is through the urine, with a small portion eliminated in the feces.[2]

Administration

Amoxapine is administered orally, starting at 100mg, with the potential to titrate the dosage up to 300mg.[11][12][13][2] The drug can be administered as one dose daily, or divided into two tablets daily.[3] However, due to the long half-life of the active metabolites of the drug, it was found to be more beneficial to have one single dose compared to two divided doses.[11] The antidepressant effects of amoxapine are observable in as little as seven days.[8]

Adverse Effects

The most common side effects of amoxapine therapy include, but are not limited to insomnia, palpitations, tachycardia, hypotension, and constipation.[14][15][2] Amoxapine was also found to induce hypomanic states in patients with underlying bipolar disorder.[14] Amoxapine was found to induce noradrenaline contraction of the urethra in guinea pigs and rats in various laboratory studies, resulting in increased urethral resistance.[16][17] The drug was also found to have certain incidences of painful ejaculations, relieved by the administration of tamsulosin.[18] Furthermore, tricyclic antidepressants, such as amoxapine, are associated with increased risk of seizures in patients with epilepsy and the elderly population.[19][20] it is recommended to use selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients suffering from epilepsy and seizures.

Also, since amoxapine imparts, although minimal, effects on the histamine H1 receptor, antihistamine side effects must be taken into account, especially in the elderly population consisting of patients above the age of 65. These effects include sedation, insomnia, dry mouth, delirium and Parkinsonism symptoms.[21] It was also found, in a few patient cases, to prolong the QT interval.[22]

Contraindications

The primary mechanism of action of amoxapine is through inhibition of presynaptic reuptake of norepinephrine; it should not be taken alongside other antidepressant or drugs which impart similar effects, such as MAO inhibitors. The drug should not be taken within 14 days of other antidepressants. TIme should be given for the previous antidepressant to leave the system entirely before initiating amoxapine, or any other TCA.

Furthermore, due to the QT prolongation effect of the drug, patients with increased QT intervals or acute myocardial infarction should not be prescribed this medication to avoid any exacerbation of their symptoms.[22] Tricyclic antidepressants are also contraindicated in patients suffering from epilepsy or seizures, and it is recommended, instead, of utilizing SSRIs or SNRIs in such patients, as it has been shown to slightly increase the risk of seizures.[20] Additionally, as the drug gets metabolized in the liver, patients with liver disease should not be prescribed amoxapine.

Monitoring

Patients taking amoxapine should be monitored for resolution or reduction of symptoms, withdrawal symptoms from abrupt discontinuation, weight and BMI, blood pressure, blood glucose, worsening of depression, suicidality, or unusual behavior at the initiation of therapy or when changing the dose. An electrocardiogram (ECG) is also necessary for older adults and patients with preexisting cardiac disease or hyperthyroidism. There is an increased risk of hyponatremia in the elderly population; therefore electrolytes should be monitored in patients above 65 years of age.[23]

Toxicity

The major concern for TCA toxicity is serotonin syndrome, especially if combining the medication with another antidepressant, such as an SSRI or SNRI. The characteristics of serotonin syndrome are hyperthermia, hypertension, muscle rigidity, and delirium. 

There is no specific antidote for TCA, and therefore amoxapine, overdose. The major concern in cases of TCA overdose is to secure respiration and to provide cardiovascular support. Sodium bicarbonate has been shown to decrease the incidence of QRS widening in some cases.[24] This treatment requires strict monitoring of the sodium levels, as there is a possibility of hypernatremia in patients receiving sodium bicarbonate. In most cases, however, if there is not an immediate change of electrolytes, the recommended steps are to closely monitor the patient in the intensive care unit for any cardiac abnormalities and provide adequate hydration to aid in the removal of the drug from the system.

Enhancing Healthcare Team Outcomes

As TCAs are a third line drug for depression, the demographics of patients either receiving amoxapine or are under consideration for commencing the drugs are generally suffering from recurring or reactive depression; this means that other forms of medication and treatment have failed to control the symptoms. As such, these patients are at a higher risk of self-harming and suicidal behavior. Therefore, it is imperative that they have a cohesive team involved in their treatment, including frequent coordination between their primary physician, their psychiatrist and/or counselors to ensure proper compliance with medication regimen and response to treatment. During every office visit, they must undergo evaluation for suicidal ideations, plans or inclinations. Overdose and proper precautions should commence in case patients are at any risk to themselves or others.[25]

Therapy with amoxapine and other antidepressant medications is best done with an interprofessional healthcare team oversees all aspects of the patient's case. This team includes physicians, specialists, specialty-trained nursing staff, and pharmacists, all collaborating to ensure optimal care and outcomes. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Amoxapine - Questions

Take a quiz of the questions on this article.

Take Quiz
A 72-year-old patient presents to the clinic for worsening depression. His depression has been stable on venlafaxine for the last ten years. His wife of 40 years passed away six months ago, and he is still experiencing sadness and frequent tearfulness. He reports that he is sleeping 3 to 5 hours a night and awakening frequently. He states that his clothes have been starting to fit loosely and he does not have an appetite. He has had thoughts of harming himself. However, he has no plan of action. He states that he often sees his wife exiting his room when he wakes up, but when he goes to follow her, she disappears. He sometimes hears her voice although he cannot make out what she is saying. His vital signs are normal. It is decided to start treatment with amoxapine. This course of treatment increases this patients risk of which of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Amoxapine - References

References

Proconvulsant effects of antidepressants - What is the current evidence?, Johannessen Landmark C,Henning O,Johannessen SI,, Epilepsy & behavior : E&B, 2016 Aug     [PubMed]
Górska N,Słupski J,Cubała WJ,Wiglusz MS,Gałuszko-Węgielnik M, Antidepressants in epilepsy. Neurologia i neurochirurgia polska. 2018 Nov - Dec;     [PubMed]
Cugurra F, [Drug therapy and affective disorders: state of the art]. La Clinica terapeutica. 1995 Oct;     [PubMed]
Kinney JL,Evans RL Jr, Evaluation of amoxapine. Clinical pharmacy. 1982 Sep-Oct;     [PubMed]
Ragheb M,Wilson WH,Ban TA,Brannen JO, Amoxapine: once versus divided daily doses in neurotic and endogenous depression. The Journal of clinical psychiatry. 1981 Aug;     [PubMed]
Li X,Wang Q,Hu T,Wang Y,Zhao J,Lu J,Pei G, A tricyclic antidepressant, amoxapine, reduces amyloid-β generation through multiple serotonin receptor 6-mediated targets. Scientific reports. 2017 Jul 10;     [PubMed]
Obara K,Imanaka S,Fukuhara H,Yamaki F,Matsuo K,Yoshio T,Tanaka Y, Evaluation of the potentiating effects of antidepressants on the contractile response to noradrenaline in guinea pig urethra smooth muscles. Clinical and experimental pharmacology     [PubMed]
Obara K,Michino M,Ito M,Ao L,Sawada A,Yamaki F,Matsuo K,Yoshio T,Tanaka Y, Evaluation of Antidepressant Effects on Recovery of Electrical Field Stimulation-Induced Contractions that have been Suppressed by Clonidine in Isolated Rat Vas Deferens. Pharmacology. 2019;     [PubMed]
Ahmad S,Hughes MA,Yeh LA,Scott JE, Potential repurposing of known drugs as potent bacterial β-glucuronidase inhibitors. Journal of biomolecular screening. 2012 Aug;     [PubMed]
Demyttenaere K,Huygens R, Painful ejaculation and urinary hesitancy in association with antidepressant therapy: relief with tamsulosin. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2002 Aug;     [PubMed]
Kong R,Liu T,Zhu X,Ahmad S,Williams AL,Phan AT,Zhao H,Scott JE,Yeh LA,Wong ST, Old drug new use--amoxapine and its metabolites as potent bacterial β-glucuronidase inhibitors for alleviating cancer drug toxicity. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014 Jul 1;     [PubMed]
Ban TA,Fujimori M,Petrie WM,Ragheb M,Wilson WH, Systematic studies with amoxapine, a new antidepressant. International pharmacopsychiatry. 1982;     [PubMed]
Aono T,Kaneko M,Numata Y,Takahashi Y,Yamamoto T,Kumashiro H, Effects of amoxapine, a new antidepressant, on pseudoneurotic schizophrenia. Folia psychiatrica et neurologica japonica. 1981;     [PubMed]
Kapoor R,Peyear TA,Koeppe RE 2nd,Andersen OS, Antidepressants are modifiers of lipid bilayer properties. The Journal of general physiology. 2019 Mar 4;     [PubMed]
Hekimian LJ,Weise CC,Friedhoff AJ, Onset of action of amoxapine and doxepin in outpatients with     [PubMed]
Mika J,Zychowska M,Makuch W,Rojewska E,Przewlocka B, Neuronal and immunological basis of action of antidepressants in chronic pain - clinical and experimental studies. Pharmacological reports : PR. 2013;     [PubMed]
Rochoy M,Zakhem-Stachera C,Béné J,Berkhout C,Gautier S, [Antidepressive agents and hyponatremia: A literature review and a case/non-case study in the French Pharmacovigilance database]. Therapie. 2018 Oct;     [PubMed]
van Wyk EM,Louw DA, Amoxapine in the treatment of depression. A clinical evaluation in ambulant patients. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. 1982 Jun 12;     [PubMed]
Ban TA,Wilson WH,McEvoy JP, Amoxapine: a review of literature. International pharmacopsychiatry. 1980;     [PubMed]
Apiquian R,Fresan A,Ulloa RE,de la Fuente-Sandoval C,Herrera-Estrella M,Vazquez A,Nicolini H,Kapur S, Amoxapine as an atypical antipsychotic: a comparative study vs risperidone. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2005 Dec;     [PubMed]
Buckley NA,McManus PR, Can the fatal toxicity of antidepressant drugs be predicted with pharmacological and toxicological data? Drug safety. 1998 May;     [PubMed]
Richelson E,Nelson A, Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. The Journal of pharmacology and experimental therapeutics. 1984 Jul;     [PubMed]
Farzam K,O'Rourke MC, Antihistamines 2019 Jan;     [PubMed]
Obers S,Staudacher I,Ficker E,Dennis A,Koschny R,Erdal H,Bloehs R,Kisselbach J,Karle CA,Schweizer PA,Katus HA,Thomas D, Multiple mechanisms of hERG liability: K current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine. Naunyn-Schmiedeberg's archives of pharmacology. 2010 May;     [PubMed]
Kassim T,Mahfood Haddad T,Rakhra A,Kabach A,Qurie A,Selim M,Nayfeh AS,Aly A,Holmberg MJ, A Case of Amitriptyline-induced Myocarditis. Cureus. 2018 Jun 19;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pharmacy-Technician (PTCB). The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pharmacy-Technician (PTCB), it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pharmacy-Technician (PTCB), you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pharmacy-Technician (PTCB). When it is time for the Pharmacy-Technician (PTCB) board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pharmacy-Technician (PTCB).