Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylatedmetabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximately 10 to 20 years after most of the other TCAs were introduced in the United States.[5]
Medical uses
Amoxapine is used in the treatment of major depressive disorder. Compared to other antidepressants it is believed to have a faster onset of action, with therapeutic effects seen within four to seven days.[6][7] In excess of 80% of patients that do respond to amoxapine are reported to respond within two weeks of the beginning of treatment.[8] It also has properties similar to those of the atypical antipsychotics,[9][10][11] and may behave as one[12][13] and may be used in the treatment of schizophrenia off-label. Despite its apparent lack of extrapyramidal side effects in patients with schizophrenia it has been found to exacerbate motor symptoms in patients with Parkinson's disease and psychosis.[14]
Contraindications
As with all FDA-approved antidepressants it carries a black-box warning about the potential of an increase in suicidal thoughts or behaviour in children, adolescents and young adults under the age of 25.[3] Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations.[3] Its use is also recommended against in the following disease states:[3]
Severe cardiovascular disorders (potential of cardiotoxic adverse effects such as QT interval prolongation)
Its use in breastfeeding mothers not recommended as it is excreted in breast milk and the concentration found in breast milk is approximately a quarter that of the maternal serum level.[6][15]
Side effects
Adverse effects by incidence:[3][16] Note: Serious (that is, those that can either result in permanent injury or are irreversible or are potentially life-threatening) are written in bold text.
Very common (>10% incidence) adverse effects include:
Oedema. An abnormal accumulation of fluids in the tissues of the body leading to swelling.
Prolactin levels increased. Prolactin is a hormone that regulates the generation of breast milk. Prolactin elevation is not as significant as with risperidone or haloperidol.
Agranulocytosis a drop in white blood cell counts. The white blood cells are the cells of the immune system that fight off foreign invaders. Hence agranulocytosis leaves an individual open to life-threatening infections.
Leukopaenia the same as agranulocytosis but less severe.
Neuroleptic malignant syndrome (a potentially fatal reaction to antidopaminergic agents, most often antipsychotics. It is characterised by hyperthermia, diarrhoea, tachycardia, mental status changes [e.g. confusion], rigidity, extrapyramidal side effects)
Tardive dyskinesia a most often irreversible neurologic reaction to antidopaminergic treatment, characterised by involuntary movements of facial muscles, tongue, lips, and other muscles. It develops most often only after prolonged (months, years or even decades) exposure to antidopaminergics.
Thrombocytopenia a significant drop in platelet count that leaves one open to life-threatening bleeds.
Eosinophilia an elevated level of the eosinophils of the body. Eosinophils are the type of immune cell that's job is to fight off parasitic invaders.
Jaundice yellowing of the skin, eyes and mucous membranes due to an impaired ability of the body to clear the by product of haem breakdown, bilirubin, most often the result of liver damage as it is the liver's responsibility to clear bilirubin.
It is considered particularly toxic in overdose,[19] with a high rate of renal failure (which usually takes 2–5 days), rhabdomyolysis, coma, seizures and even status epilepticus.[18] Some believe it to be less cardiotoxic than other TCAs in overdose, although reports of cardiotoxic overdoses have been made.[6][16]
- t1/2 is the elimination half life of the compound.
- tmax is the time to peak plasma levels after oral administration of amoxapine.
- CSS is the steady state plasma concentration.
- protein binding is the extent of plasma protein binding.
- Vd is the volume of distribution of the compound.
Society and culture
Brand names
Brand names for amoxapine include (where † denotes discontinued brands):[6][40]
^Ban TA, Fujimori M, Petrie WM, Ragheb M, Wilson WH (1982). "Systematic studies with amoxapine, a new antidepressant". International Pharmacopsychiatry. 17 (1): 18–27. doi:10.1159/000468553. PMID7045016.
^ abCohen BM, Harris PQ, Altesman RI, Cole JO (September 1982). "Amoxapine: neuroleptic as well as antidepressant?". The American Journal of Psychiatry. 139 (9): 1165–1167. doi:10.1176/ajp.139.9.1165. PMID6126130.
^Kapur S, Cho R, Jones C, McKay G, Zipursky RB (May 1999). "Is amoxapine an atypical antipsychotic? Positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy". Biological Psychiatry. 45 (9): 1217–1220. doi:10.1016/S0006-3223(98)00204-2. PMID10331115. S2CID21407817.
^Wadenberg MG, Sills TL, Fletcher PJ, Kapur S (April 2000). "Antipsychoticlike effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats". Biological Psychiatry. 47 (7): 670–676. doi:10.1016/S0006-3223(99)00267-X. PMID10745061. S2CID27619436.
^Chaudhry IB, Husain N, Khan S, Badshah S, Deakin B, Kapur S (December 2007). "Amoxapine as an antipsychotic: comparative study versus haloperidol". Journal of Clinical Psychopharmacology. 27 (6): 575–581. doi:10.1097/jcp.0b013e31815a4424. PMID18004123. S2CID45880666.
^Sa DS, Kapur S, Lang AE (July–August 2001). "Amoxapine shows an antipsychotic effect but worsens motor function in patients with Parkinson's disease and psychosis". Clinical Neuropharmacology. 24 (4): 242–244. doi:10.1097/00002826-200107000-00010. PMID11479398.
^Gelenberg AJ, Cooper DS, Doller JC, Maloof F (October 1979). "Galactorrhea and hyperprolactinemia associated with amoxapine therapy. Report of a case". JAMA. 242 (17): 1900–1901. doi:10.1001/jama.1979.03300170046029. PMID573343.
^Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
^ abcdTatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2–3): 249–258. doi:10.1016/s0014-2999(97)01393-9. PMID9537821.
^ abcdeRoth BL, Craigo SC, Choudhary MS, Uluer A, Monsma FJ, Shen Y, et al. (March 1994). "Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors". The Journal of Pharmacology and Experimental Therapeutics. 268 (3): 1403–1410. PMID7908055.
^Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, et al. (January 1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". Journal of Neurochemistry. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID8522988. S2CID35874409.
^ abcdefghijRichelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics. 230 (1): 94–102. PMID6086881.
^ abcBurstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, et al. (December 2005). "Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist". The Journal of Pharmacology and Experimental Therapeutics. 315 (3): 1278–1287. doi:10.1124/jpet.105.092155. PMID16135699. S2CID2247093.
^ abcAppl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (February 2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn-Schmiedeberg's Archives of Pharmacology. 385 (2): 145–170. doi:10.1007/s00210-011-0704-0. PMID22033803. S2CID253747520.
^ abPälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J (August 1996). "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology. 126 (3): 234–240. doi:10.1007/BF02246453. PMID8876023. S2CID24889381.
^ abcGozlan H, Saddiki-Traki F, Merahi N, Laguzzi R, Hamon M (December 1991). "[Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats]". L'Encéphale (in French). 17 Spec No 3: 415–422. PMID1666997.
^ abcWei HB, Niu XY (1990). "[Comparison of the affinities of amoxapine and loxapine for various receptors in rat brain and the receptor down-regulation after chronic administration]". Yao Xue Xue Bao = Acta Pharmaceutica Sinica (in Chinese). 25 (12): 881–885. PMID1966571.
^Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R (September 2005). "Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist". The Journal of Pharmacology and Experimental Therapeutics. 314 (3): 1310–1321. doi:10.1124/jpet.105.087965. PMID15947036. S2CID24248896.
^Onali P, Dedoni S, Olianas MC (January 2010). "Direct agonist activity of tricyclic antidepressants at distinct opioid receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics. 332 (1): 255–265. doi:10.1124/jpet.109.159939. PMID19828880. S2CID18893305.
^Midha KK, Hubbard JW, McKay G, Rawson MJ, Hsia D (September 1999). "The role of metabolites in a bioequivalence study II: amoxapine, 7-hydroxyamoxapine, and 8-hydroxyamoxapine". International Journal of Clinical Pharmacology and Therapeutics. 37 (9): 428–438. PMID10507241.
^Calvo B, García MJ, Pedraz JL, Mariño EL, Domínguez-Gil A (April 1985). "Pharmacokinetics of amoxapine and its active metabolites". International Journal of Clinical Pharmacology, Therapy, and Toxicology. 23 (4): 180–185. PMID3997304.
^Takeuchi H, Yokota S, Shimada S, Ohtani Y, Miura S, Kubo H (April 1993). "Pharmacokinetics of amoxapine and its active metabolites in healthy subjects". Current Therapeutic Research. 53 (4): 427–434. doi:10.1016/S0011-393X(05)80202-4.