Amoxapine

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.{{cite journal | vauthors = Ban TA, Fujimori M, Petrie WM, Ragheb M, Wilson WH | title = Systematic studies with amoxapine, a new antidepressant | journal = International Pharmacopsychiatry | volume = 17 | issue = 1 | pages = 18–27 | year = 1982 | pmid = 7045016 | doi = 10.1159/000468553 }} In excess of 80% of patients that do respond to amoxapine are reported to respond within two weeks of the beginning of treatment.Product Information: Asendin(R), amoxapine tablets. Physicians' Desk Reference (electronic version), MICROMEDEX, Inc, Englewood, CO, USA, 1999. It also has properties similar to those of the atypical antipsychotics,{{cite journal | vauthors = Cohen BM, Harris PQ, Altesman RI, Cole JO | title = Amoxapine: neuroleptic as well as antidepressant? | journal = The American Journal of Psychiatry | volume = 139 | issue = 9 | pages = 1165–1167 | date = September 1982 | pmid = 6126130 | doi = 10.1176/ajp.139.9.1165 }}{{cite journal | vauthors = Kapur S, Cho R, Jones C, McKay G, Zipursky RB | title = Is amoxapine an atypical antipsychotic? Positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy | journal = Biological Psychiatry | volume = 45 | issue = 9 | pages = 1217–1220 | date = May 1999 | pmid = 10331115 | doi = 10.1016/S0006-3223(98)00204-2 | s2cid = 21407817 }}{{cite journal | vauthors = Wadenberg MG, Sills TL, Fletcher PJ, Kapur S | title = Antipsychoticlike effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats | journal = Biological Psychiatry | volume = 47 | issue = 7 | pages = 670–676 | date = April 2000 | pmid = 10745061 | doi = 10.1016/S0006-3223(99)00267-X | s2cid = 27619436 }} and may behave as one{{cite journal | vauthors = Apiquian R, Fresan A, Ulloa RE, de la Fuente-Sandoval C, Herrera-Estrella M, Vazquez A, Nicolini H, Kapur S | display-authors = 6 | title = Amoxapine as an atypical antipsychotic: a comparative study vs risperidone | journal = Neuropsychopharmacology | volume = 30 | issue = 12 | pages = 2236–2244 | date = December 2005 | pmid = 15956984 | doi = 10.1038/sj.npp.1300796 | doi-access = free }}{{cite journal | vauthors = Chaudhry IB, Husain N, Khan S, Badshah S, Deakin B, Kapur S | title = Amoxapine as an antipsychotic: comparative study versus haloperidol | journal = Journal of Clinical Psychopharmacology | volume = 27 | issue = 6 | pages = 575–581 | date = December 2007 | pmid = 18004123 | doi = 10.1097/jcp.0b013e31815a4424 | s2cid = 45880666 }} and thus 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 worsen motor function in a study of three patients with Parkinson's disease and psychosis.{{cite journal | vauthors = Sa DS, Kapur S, Lang AE | title = Amoxapine shows an antipsychotic effect but worsens motor function in patients with Parkinson's disease and psychosis | journal = Clinical Neuropharmacology | volume = 24 | issue = 4 | pages = 242–244 | date = July–August 2001 | pmid = 11479398 | doi = 10.1097/00002826-200107000-00010 }}

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. Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations. Its use is also recommended against in the following disease states:

• Severe cardiovascular disorders (potential of cardiotoxic adverse effects such as QT interval prolongation)
• Uncorrected narrow angle glaucoma
• Acute recovery post-myocardial infarction

Its use is also advised against in individuals concurrently on monoamine oxidase inhibitors or if they have been on one in the past 14 days and in individuals on drugs that are known to prolong the QT interval (e.g. ondansetron, citalopram, pimozide, sertindole, ziprasidone, haloperidol, chlorpromazine, thioridazine, etc.).

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.{{cite journal | vauthors = Gelenberg AJ, Cooper DS, Doller JC, Maloof F | title = Galactorrhea and hyperprolactinemia associated with amoxapine therapy. Report of a case | journal = JAMA | volume = 242 | issue = 17 | pages = 1900–1901 | date = October 1979 | pmid = 573343 | doi = 10.1001/jama.1979.03300170046029 }}

Adverse effects by incidence:{{cite web|title=AMOXAPINE TABLET [WATSON LABORATORIES, INC.]|work=DailyMed|publisher=Watson Laboratories, Inc.|date=July 2010|access-date=26 November 2013|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a16297df-3158-48db-85e5-5cd506885556}}

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:

• Constipation
• Dry mouth
• Sedation

Common (1–10% incidence) adverse effects include:

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• Anxiety
• Ataxia
• Blurred vision
• Confusion
• Dizziness
• Headache
• Fatigue
• Nausea
• Nervousness/restlessness
• Excessive appetite
• Rash
• Increased perspiration (sweating)
• Tremor
• Palpitations
• Nightmares
• Excitement
• Weakness
• ECG changes

{{div col end}}

• 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.

Uncommon/Rare (<1% incidence) adverse effects include:

{{div col|colwidth=30em}}

• Diarrhoea
• Flatulence
• Hypertension (high blood pressure)
• Hypotension (low blood pressure)
• Syncope (fainting)
• Tachycardia (high heart rate)
• Menstrual irregularity
• Disturbance of accommodation
• Mydriasis (pupil dilation)
• Orthostatic hypotension (a drop in blood pressure that occurs upon standing up)
• Seizure
• Urinary retention (being unable to pass urine)
• Urticaria (hives)
• Vomiting
• Nasal congestion
• Photosensitization
• Hypomania (a dangerously elated/irritable mood)
• Tingling
• Paresthesias of the extremities
• Tinnitus
• Disorientation
• Numbness
• Incoordination
• Disturbed concentration
• Epigastric distress
• Peculiar taste in the mouth
• Increased or decreased libido
• Impotence (difficulty achieving an erection)
• Painful ejaculation
• Lacrimation (crying without an emotional cause)
• Weight gain
• Altered liver function
• Breast enlargement
• Drug fever
• Pruritus (itchiness)

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• Vasculitis a disorder where blood vessels are destroyed by inflammation. Can be life-threatening if it affects the right blood vessels.
• Galactorrhoea (lactation that is not associated with pregnancy or breast feeding)
• Delayed micturition (that is, delays in urination from when a conscious effort to urinate is made)
• Hyperthermia (elevation of body temperature; its seriousness depends on the extent of the hyperthermia)
• Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) this is basically when the body's level of the hormone, antidiuretic hormone, which regulates the conservation of water and the restriction of blood vessels, is elevated. This is potentially fatal as it can cause electrolyte abnormalities including hyponatraemia (low blood sodium), hypokalaemia (low blood potassium) and hypocalcaemia (low blood calcium) which can be life-threatening.
• 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.
• Extrapyramidal side effects. Motor symptoms such as tremor, parkinsonism, involuntary movements, reduced ability to move one's voluntary muscles, etc.

Unknown incidence or relationship to drug treatment adverse effects include:

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• Paralytic ileus (paralysed bowel)
• Atrial arrhythmias including atrial fibrillation
• Myocardial infarction (heart attack)
• Stroke
• Heart block
• Hallucinations
• Purpura
• Petechiae
• Parotid swelling
• Changes in blood glucose levels
• Pancreatitis swelling of the pancreas
• Hepatitis swelling of the liver
• Urinary frequency
• Testicular swelling
• Anorexia (weight loss)
• Alopecia (hair loss)

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• 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 tends to produce less anticholinergic effects, sedation and weight gain than some of the earlier TCAs (e.g. amitriptyline, clomipramine, doxepin, imipramine, trimipramine).{{cite web|title=Side effects of antidepressant medications|work=UpToDate|publisher=Wolters Kluwer Health|access-date=26 November 2013|url=http://www.uptodate.com/contents/image?imageKey=PC%2F62488&source=image_view&view=print&topicKey=PSYCH/85816&source=see_link&elapsedTimeMs=2}} It may also be less cardiotoxic than its predecessors.{{cite book | isbn = 978-0-7020-4293-5 | title = Clinical Pharmacy and Therapeutics | year = 2007 | orig-year = 1994 | publisher = Churchill Livingstone Elsevier | location = Edinburgh | edition = 4th |editor1=Walker, R |editor2=Whittlesea, C }}

{{Main|Tricyclic antidepressant overdose}}

It is considered particularly toxic in overdose,{{cite journal | vauthors = White N, Litovitz T, Clancy C | title = Suicidal antidepressant overdoses: a comparative analysis by antidepressant type | journal = Journal of Medical Toxicology | volume = 4 | issue = 4 | pages = 238–250 | date = December 2008 | pmid = 19031375 | pmc = 3550116 | doi = 10.1007/BF03161207 }} with a high rate of renal failure (which usually takes 2–5 days), rhabdomyolysis, coma, seizures and even status epilepticus. Some believe it to be less cardiotoxic than other TCAs in overdose, although reports of cardiotoxic overdoses have been made.{{cite book|title=Amoxapine|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|location=London, UK|date=30 January 2013|access-date=26 November 2013|url=https://www.medicinescomplete.com/mc/martindale/current/2503-q.htm}}

{{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}}

Amoxapine possesses a wide array of pharmacological effects. It is a moderate and strong reuptake inhibitor of serotonin and norepinephrine, respectively, and binds to the 5-HT_2A,{{cite journal | vauthors = Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J | title = Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor | journal = Psychopharmacology | volume = 126 | issue = 3 | pages = 234–240 | date = August 1996 | pmid = 8876023 | doi = 10.1007/BF02246453 | s2cid = 24889381 }} 5-HT_2B,{{cite journal | vauthors = Glusa E, Pertz HH | title = Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT(2B) receptors | journal = British Journal of Pharmacology | volume = 130 | issue = 3 | pages = 692–698 | date = June 2000 | pmid = 10821800 | pmc = 1572101 | doi = 10.1038/sj.bjp.0703341 }} 5-HT_2C, 5-HT₃,{{cite journal | vauthors = Gozlan H, Saddiki-Traki F, Merahi N, Laguzzi R, Hamon M | title = [Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats] | language = fr | journal = L'Encéphale | volume = 17 Spec No 3 | pages = 415–422 | date = December 1991 | pmid = 1666997 }} 5-HT₆, 5-HT₇, D₂, α₁-adrenergic, D₃, D₄, and H₁ receptors with varying but significant affinity, where it acts as an antagonist (or inverse agonist depending on the receptor in question) at all sites. It has weak but negligible affinity for the dopamine transporter and the 5-HT_1A, 5-HT_1B, D₁,{{cite journal | vauthors = Wei HB, Niu XY | title = [Comparison of the affinities of amoxapine and loxapine for various receptors in rat brain and the receptor down-regulation after chronic administration] | language = zh | journal = Yao Xue Xue Bao = Acta Pharmaceutica Sinica | volume = 25 | issue = 12 | pages = 881–885 | year = 1990 | pmid = 1966571 }} α₂-adrenergic, H₄,{{cite journal | vauthors = Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 314 | issue = 3 | pages = 1310–1321 | date = September 2005 | pmid = 15947036 | doi = 10.1124/jpet.105.087965 | s2cid = 24248896 }} mACh, and GABA_A receptors, and no affinity for the β-adrenergic receptors or the allosteric benzodiazepine site on the GABA_A receptor. Amoxapine is also a weak GlyT2 blocker,{{cite book| vauthors = Sitte H, Freissmuth M |title=Neurotransmitter Transporters|url=https://books.google.com/books?id=CeZDAAAAQBAJ&pg=PA472|date=2 August 2006|publisher=Springer Science & Business Media|isbn=978-3-540-29784-0|pages=472–}} as well as a weak (K_i = 2.5 μM, EC₅₀ = 0.98 μM) δ-opioid receptor partial agonist.{{cite journal | vauthors = Onali P, Dedoni S, Olianas MC | title = Direct agonist activity of tricyclic antidepressants at distinct opioid receptor subtypes | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 332 | issue = 1 | pages = 255–265 | date = January 2010 | pmid = 19828880 | doi = 10.1124/jpet.109.159939 | s2cid = 18893305 }}

7-Hydroxyamoxapine, a major active metabolite of amoxapine, is a more potent dopamine receptor antagonist and contributes to its neuroleptic efficacy, whereas 8-Hydroxyamoxapine is a norepinephrine reuptake inhibitor but a stronger serotonin reuptake inhibitor and helps to balance amoxapine's ratio of serotonin to norepinephrine transporter blockade.{{cite journal | vauthors = Midha KK, Hubbard JW, McKay G, Rawson MJ, Hsia D | title = The role of metabolites in a bioequivalence study II: amoxapine, 7-hydroxyamoxapine, and 8-hydroxyamoxapine | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 37 | issue = 9 | pages = 428–438 | date = September 1999 | pmid = 10507241 }}

Amoxapine is metabolised into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine.

Where:

• t_1/2 is the elimination half life of the compound.
• t_max is the time to peak plasma levels after oral administration of amoxapine.
• C_SS is the steady state plasma concentration.
• protein binding is the extent of plasma protein binding.
• V_d is the volume of distribution of the compound.

Brand names for amoxapine include (where † denotes discontinued brands):{{cite web|title=Amoxapine -Drugs.com|publisher=Drugs.com|year=2013|access-date=26 November 2013|url=https://www.drugs.com/international/amoxapine.html}}

• Adisen (KR)
• Amolife (IN)
• Amoxan (JP)
• Asendin† (previously marketed in CA, NZ, US)
• Asendis† (previously marketed in IE, UK)
• Défanyl (FR)
• Demolox (DK†, IN, ES†)
• Oxamine (IN)
• Oxcap (IN)

• Loxapine

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