Continuing Education Activity

Amoxapine is an FDA-approved drug belonging to the class of second-generation tricyclic dibenzoxazepine antidepressants. Generally, it is reserved for resistant or persistent depression. The goal of this activity is to familiarize practitioners with the proper usage of this drug and recognize the adverse effects of this medication. This activity also explores the roles of a cohesive interprofessional team in treating patients using amoxapine to treat their depression.

Objectives:

• Describe the indications of amoxapine in a patient suffering from depression or anxiety.
• Identify the mechanism of action of amoxapine and its active metabolites.
• Explain the correct methods for monitoring toxicity with amoxapine.
• Summarize the importance of antidepressant stewardship and how it affects refractory depression related to improving care coordination among the interprofessional team when initiating therapy.

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) 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

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]

Administration

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]

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] 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]

Contraindications

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]

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 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]