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Amoxapine
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) have failed to control the depression.[1] Thus, it is indicated for treatment-resistant depression after the first and second-line medication has 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] Research (in mice) has revealed that amoxapine also decreases the production of amyloid-beta chains in Alzheimer disease by acting on the serotonin-6 (HTR-6, 5-HT-6) receptor.[4] In various studies, amoxapine also reduced the incidence of diarrhea in patients undergoing chemotherapy, specifically with irinotecan.[5][6] Additionally, research showed this drug to improve the prognosis of neuropathic pain.[7]
Mechanism of Action
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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 a minimal effect on serotonin receptors, asides from the serotonin-6 receptor (HTR-6, 5-HT-6).[2][4] Amoxapine has a minimal impact 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 reduce the incidence of diarrhea in patients after administering irinotecan chemotherapy.[2][6] The research revealed that these metabolites decreased tumor growth in such individuals.[6] Research has shown the half-life of the active metabolite, 8-hydroxyamoxapine, 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]
Amoxapine is administered orally, starting at 100 mg, with the potential to titrate the dosage up to 300 mg.[11][12] The normal therapeutic dose for depression is 200 to 300 mg orally, generally at bedtime.[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]
The most common side effects of amoxapine therapy include but are not limited to insomnia, palpitations, tachycardia, hypotension, and constipation.[14][15][2] Researchers found that amoxapine induces hypomanic states in patients with underlying bipolar disorder.[14] Amoxapine also induces noradrenaline contraction of the urethra in guinea pigs and rats in various laboratory studies, resulting in increased urethral resistance.[16][17] The drug also correlated with some incidences of painful ejaculations relieved by the administration of tamsulosin.[18] Furthermore, tricyclic antidepressants, such as amoxapine, are associated with an 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 with a history of 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 QTc interval.[22]
The primary mechanism of action of amoxapine is through inhibition of presynaptic reuptake of norepinephrine; patients should not take it alongside other antidepressants or drugs which impart similar effects, such as MAO inhibitors. Patients should not take the drug within 14 days of other antidepressants, allowing time for the previous antidepressant to leave the system entirely before initiating amoxapine or any other TCA.
Furthermore, due to the QTc prolongation effect of the drug, patients with increased QTc intervals or acute myocardial infarction should not be prescribed this medication to avoid exacerbating their symptoms.[22] Tricyclic antidepressants are also contraindicated in patients with a history of epilepsy or seizures, and the recommendation is, instead, to utilize SSRIs or SNRIs in such patients, as research has shown amoxapine to slightly increase the risk of seizures.[20] Additionally, as the drug is metabolized in the liver, patients with liver disease should not be prescribed amoxapine.
Amoxapine carries an FDA black box warning regarding suicidality risk in patients under 24 years of age and patients 65 and older.[23]
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 require monitoring in patients above 65 years of age.[24]
Toxicity
The primary 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 by extension, amoxapine overdose. The primary concern in cases of TCA overdose is to secure respiration and provide cardiovascular support. research has shown sodium bicarbonate to decrease the incidence of QRS widening in some cases.[25] This treatment requires strict monitoring of the sodium plasma concentrations, as there is a possibility of hypernatremia in patients receiving sodium bicarbonate. In most cases, however, if there is no 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 removing the drug from the system.
Enhancing Healthcare Team Outcomes
As TCAs are third-line drugs for depression, patients' demographics either receiving amoxapine or are under consideration for commencing the drugs are generally presenting with 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, they must have a cohesive interprofessional 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.[26]
Therapy with amoxapine and other antidepressant medications is best with an interprofessional healthcare team that oversees all aspects of the patient's case. This team includes physicians, who will prescribe and make other decisions regarding the regimen, specialists, who will dig more deeply and specialize in the condition treated, specialty-trained nursing staff, who can monitor care, verify patient adherence, and assist with monitoring, and pharmacists, who will perform medication reconciliation and verify dosing. All the interprofessional team members need to collaborate and have open communication to ensure optimal care and outcomes. [Level 5]
References
Cugurra F. [Drug therapy and affective disorders: state of the art]. La Clinica terapeutica. 1995 Oct:146(10):577-85 [PubMed PMID: 8590559]
Kinney JL, Evans RL Jr. Evaluation of amoxapine. Clinical pharmacy. 1982 Sep-Oct:1(5):417-24 [PubMed PMID: 6764165]
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:42(8):318-21 [PubMed PMID: 7019201]
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 10:7(1):4983. doi: 10.1038/s41598-017-04144-3. Epub 2017 Jul 10 [PubMed PMID: 28694424]
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:17(7):957-65. doi: 10.1177/1087057112444927. Epub 2012 Apr 24 [PubMed PMID: 22535688]
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 1:20(13):3521-30. doi: 10.1158/1078-0432.CCR-14-0395. Epub 2014 Apr 29 [PubMed PMID: 24780296]
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. 2013:65(6):1611-21 [PubMed PMID: 24553009]
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 12:61(24):908-11 [PubMed PMID: 7046092]
Kapoor R, Peyear TA, Koeppe RE 2nd, Andersen OS. Antidepressants are modifiers of lipid bilayer properties. The Journal of general physiology. 2019 Mar 4:151(3):342-356. doi: 10.1085/jgp.201812263. Epub 2019 Feb 22 [PubMed PMID: 30796095]
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:230(1):94-102 [PubMed PMID: 6086881]
Ban TA, Fujimori M, Petrie WM, Ragheb M, Wilson WH. Systematic studies with amoxapine, a new antidepressant. International pharmacopsychiatry. 1982:17(1):18-27 [PubMed PMID: 7045016]
Level 1 (high-level) evidenceBan TA, Wilson WH, McEvoy JP. Amoxapine: a review of literature. International pharmacopsychiatry. 1980:15(3):166-70 [PubMed PMID: 7016801]
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:30(12):2236-44 [PubMed PMID: 15956984]
Level 2 (mid-level) evidenceAono 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. 1981:35(2):115-21 [PubMed PMID: 7026396]
Hekimian LJ, Weise CC, Friedhoff AJ. Onset of action of amoxapine and doxepin in outpatients with "mixed anxiety/depression". The Journal of clinical psychiatry. 1983 Jul:44(7):248-52 [PubMed PMID: 6863224]
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 & physiology. 2019 May:46(5):444-455. doi: 10.1111/1440-1681.13072. Epub 2019 Mar 7 [PubMed PMID: 30737814]
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. 2019:103(3-4):189-201. doi: 10.1159/000495616. Epub 2019 Jan 29 [PubMed PMID: 30695779]
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:12(4):337-41 [PubMed PMID: 12126873]
Johannessen Landmark C, Henning O, Johannessen SI. Proconvulsant effects of antidepressants - What is the current evidence? Epilepsy & behavior : E&B. 2016 Aug:61():287-291. doi: 10.1016/j.yebeh.2016.01.029. Epub 2016 Feb 24 [PubMed PMID: 26926001]
Górska N, Słupski J, Cubała WJ, Wiglusz MS, Gałuszko-Węgielnik M. Antidepressants in epilepsy. Neurologia i neurochirurgia polska. 2018 Nov-Dec:52(6):657-661. doi: 10.1016/j.pjnns.2018.07.005. Epub 2018 Aug 11 [PubMed PMID: 30131174]
Farzam K, Sabir S, O'Rourke MC. Antihistamines. StatPearls. 2023 Jan:(): [PubMed PMID: 30844215]
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:381(5):385-400. doi: 10.1007/s00210-010-0496-7. Epub 2010 Mar 13 [PubMed PMID: 20229012]
Revet A, Montastruc F, Roussin A, Raynaud JP, Lapeyre-Mestre M, Nguyen TTH. Antidepressants and movement disorders: a postmarketing study in the world pharmacovigilance database. BMC psychiatry. 2020 Jun 16:20(1):308. doi: 10.1186/s12888-020-02711-z. Epub 2020 Jun 16 [PubMed PMID: 32546134]
Rochoy M, Zakhem-Stachera C, Béné J, Berkhout C, Gautier S, Réseau français des Centres Régionaux de Pharmacovigilance. [Antidepressive agents and hyponatremia: A literature review and a case/non-case study in the French Pharmacovigilance database]. Therapie. 2018 Oct:73(5):389-398. doi: 10.1016/j.therap.2018.02.006. Epub 2018 Mar 1 [PubMed PMID: 29773358]
Level 3 (low-level) evidenceKassim 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 19:10(6):e2840. doi: 10.7759/cureus.2840. Epub 2018 Jun 19 [PubMed PMID: 30430045]
Level 3 (low-level) evidenceBuckley NA, McManus PR. Can the fatal toxicity of antidepressant drugs be predicted with pharmacological and toxicological data? Drug safety. 1998 May:18(5):369-81 [PubMed PMID: 9589848]
Matsuoka M, Imai T, Iwabuchi S, Kinoshita K. Successful Treatment of Amoxapine-Induced Intractable Seizures With Intravenous Lipid Emulsion. The Journal of emergency medicine. 2023 Jan:64(1):62-66. doi: 10.1016/j.jemermed.2022.10.016. Epub 2022 Nov 28 [PubMed PMID: 36450616]