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5/16/2019 11:56:13 AM


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]


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]


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.


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]


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]

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Amoxapine - Questions

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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?

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Amoxapine - References


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