Continuing Education Activity

Amoxapine is classified as a second-generation tricyclic dibenzoxazepine antidepressant approved by the U.S. Food and Drug Administration (FDA). This medication is typically prescribed for managing treatment-resistant or persistent depression. Amoxapine is indicated for use in cases of depression accompanied by other psychiatric issues such as anxiety, agitation, psychosis, neurosis, or recurrent depression. The objective of this activity is to familiarize medical practitioners with the appropriate usage of amoxapine and its dosing guidelines, administration, monitoring instructions, and the adverse effects associated with this drug. This activity also highlights the critical roles of a unified interprofessional team in the treatment of patients using amoxapine for their depression.

Objectives:

• Identify appropriate patient candidates for amoxapine therapy, considering their clinical history, comorbid psychiatric conditions, and resistance to previous treatments.

• Differentiate amoxapine from other antidepressants, understanding its unique mechanisms of action, adverse effect profile, and potential interactions with other medications.

• Screen patients for contraindications, allergies, and potential risk factors associated with amoxapine use, such as seizure disorders or cardiac issues.

• Collaborate with other healthcare professionals, such as psychiatrists, toxicologists, and pharmacists, to ensure coordinated and comprehensive care for patients receiving amoxapine.

Indications

FDA-Approved Indications

Amoxapine is classified as a second-generation tricyclic dibenzoxazepine antidepressant approved by the U.S. Food and Drug Administration (FDA). This medication is typically used as a second- or third-line treatment option when selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) have failed to control depression. Thus, amoxapine is indicated for managing treatment-resistant depression when the first- and second-line medications have proven ineffective in alleviating symptoms. Amoxapine is indicated for use in cases of depression accompanied by other psychiatric issues such as anxiety, agitation, psychosis, neurosis, or recurrent depression.[1][2]

Off-Label Uses

Research conducted in mice has shown that amoxapine can reduce the production of amyloid-beta chains associated with Alzheimer disease by targeting the serotonin-6 (HTR-6, 5-HT-6) receptor.[3] Multiple studies have shown that amoxapine can reduce the incidence of diarrhea in patients undergoing chemotherapy, particularly when used in conjunction with irinotecan.[4][5] Furthermore, research has highlighted amoxapine's effectiveness in the management of neuropathic pain.[6]

Mechanism of Action

Amoxapine, a second-generation tricyclic dibenzoxazepine antidepressant, primarily functions by inhibiting the reuptake of norepinephrine in neuronal synapses. The drug exhibits minimal effect on the histamine H1 receptor and serotonin receptors, except for the serotonin-6 receptor (HTR-6, 5-HT-6).[7][8][9] Furthermore, amoxapine also acts as a dopamine (DA) receptor antagonist, specifically targeting D2 and D4 receptors.[10]

Pharmacokinetics

Absorption: Amoxapine is rapidly absorbed in the body after oral administration. The time to peak plasma concentration for amoxapine is approximately 90 minutes.

Distribution: Amoxapine exhibits a high plasma protein binding of approximately 90%.

Metabolism: Amoxapine undergoes hepatic metabolism primarily via the CYP2D6 enzyme, leading to the formation of 2 active metabolites—7-hydroxy-amoxapine and 8-hydroxy-amoxapine. These active metabolites have been shown to reduce the incidence of diarrhea in patients after administering irinotecan chemotherapy. Research findings demonstrated that these metabolites effectively reduced tumor growth in patients.[5][11]

Elimination: Research indicates that the active metabolite, 8-hydroxy-amoxapine, has a half-life of 30 hours, whereas the drug has a half-life of 8 hours. The primary route of drug elimination from the body is through urine, with a minor fraction excreted in the feces.[2]

Administration

Available Dosage Forms and Strengths

Amoxapine is available in oral tablet formulations, with strengths of 25 mg, 50 mg, 100 mg, and 150 mg doses.

Adult Dosage

Amoxapine is typically administered orally at a starting dose of 100 mg, with the option to increase the dosage up to a maximum of 300 mg. The normal therapeutic dose for depression is between 200 and 300 mg, usually taken orally at bedtime.[12][13][14] Amoxapine can be administered daily to patients either as a single dose or 2 equally divided doses.[15] However, due to the prolonged half-life of the active drug metabolites, a single daily dose of amoxapine is often preferred over divided doses for more effective treatment. Antidepressant benefits from amoxapine may become noticeable within just 7 days, and more than 80% of patients experience significant improvement within 2 weeks.[7] The maximum recommended dosage of amoxapine for outpatient settings is 400 mg daily, whereas, for hospitalized patients with no history of seizures, it is 600 mg daily.

Maintenance Dosage

The recommended maintenance dose for amoxapine is the minimum effective dose needed to maintain remission. If symptoms reappear, the dosage should be increased to the previous level until they are under control. Notably, it is recommended to take a single dose of ≤300 mg at bedtime for maintenance therapy.

Specific Patient Populations

Hepatic impairment: The product labeling does not specify dosage adjustments for hepatic impairment. However, it is advisable to exercise caution when administering amoxapine to these patients, considering its liver-dependent metabolism.[11]

Renal impairment: The product labeling does not contain specific guidance on dosage adjustments for renal impairment. Thus, it is crucial to exercise caution when prescribing amoxapine to patients with renal impairment, as its primary elimination route is through the kidneys.

Pregnancy considerations: Amoxapine was previously classified by the FDA as a pregnancy category C drug. Studies on animals revealed fetotoxic effects, including intrauterine death, decreased birth weight, and stillbirth, occurring at oral doses 3 to 10 times higher than the human dose. There is limited availability of well-controlled studies involving pregnant women. Consequently, amoxapine use during pregnancy should be approached cautiously. Decisions regarding medication use in pregnant women should be made judiciously, taking into account a careful assessment of the potential benefits and risks to the fetus.[16]

Breastfeeding considerations: Limited published data exist on amoxapine use during breastfeeding. Cases of galactorrhea have been observed in non-breastfeeding women using amoxapine. When nursing a newborn or preterm infant, it is advisable to explore alternative agents, such as sertraline, due to its more established safety profile in this context.[17]

Pediatric patients: Amoxapine lacks FDA approval for use in pediatric patients.

Older patients: Clinical studies of amoxapine in individuals 65 and older did not establish whether they exhibit different responses compared to younger subjects. As amoxapine is metabolized by the liver and excreted by the kidney, healthcare providers should exercise caution when prescribing the medication to older patients, considering potential hepatic and renal impairments. According to the American Geriatrics Society (AGS) Beers Criteria, amoxapine is noted for its potent anticholinergic properties. Therefore, its use should be considered only after a meticulous risk-benefit assessment.[18]

Adverse Effects

The common adverse effects of amoxapine therapy include, but are not limited to, insomnia, palpitations, tachycardia, hypotension, and constipation.[19][20][2] Furthermore, research has indicated that amoxapine may trigger hypomanic states in individuals with underlying bipolar disorder.[19] Amoxapine has been observed to induce noradrenaline-mediated contraction of the urethra in guinea pigs and rats in various laboratory studies, leading to elevated urethral resistance.[21][22] In addition, the drug has been associated with instances of painful ejaculations relieved by the administration of tamsulosin.[23] Notably, tricyclic antidepressants (TCAs), including amoxapine, are correlated with an increased risk of seizures, especially in older patients and those with epilepsy.[24][25] Therefore, it is recommended to use SSRIs or SNRIs in patients with a history of epilepsy and seizures.

Amoxapine's anticholinergic properties can result in adverse effects such as sedation, dry mouth, delirium, and drug-induced Parkinsonism, particularly among older patients.[26] In a few cases, amoxapine has been associated with QTc interval prolongation.[27] Notably, as amoxapine may lead to urinary retention, it is important to exercise caution when prescribing the drug for patients with bladder outlet obstruction.[28]

Drug-Drug Interactions

• Amoxapine has the potential to enhance central nervous system depression caused by barbiturates and alcohol. Therefore, concurrent use of the drug with barbiturates and alcohol should be avoided.[29]

• In a subset of the Caucasian population who are poor metabolizers with reduced CYP2D6 activity, TCAs, such as amoxapine, have increased plasma concentrations.

• Dose reduction may be necessary when TCAs, such as amoxapine, are combined with CYP2D6-inhibiting drugs, including quinidine, cimetidine, phenothiazines, propafenone, and flecainide.[30]

• All SSRIs exhibit varying degrees of CYP2D6 inhibition. Therefore, clinicians should exercise caution when combining TCAs with SSRIs or making transitions between these 2 classes of medications. In addition, when switching from fluoxetine to amoxapine, a substantial time interval is necessary due to the extended half-life of fluoxetine, which is at least 5 weeks. This precaution helps prevent potential interactions and ensures the safe use of medications.[31]

Contraindications

Amoxapine is contraindicated in patients with a known hypersensitivity to dibenzoxazepine compounds. The primary mechanism of action of amoxapine involves inhibiting the presynaptic reuptake of norepinephrine. Therefore, patients are advised against taking amoxapine concurrently with other antidepressants or medications, such as monoamine oxidase inhibitors (MAOIs), that produce similar effects. Patients should avoid taking the drug within a 14-day window of taking other antidepressants. This period allows the prior antidepressant to be eliminated from the system before initiating amoxapine or any other TCA. Furthermore, due to amoxapine's potential for QTc prolongation, it is not prescribed to patients with extended QTc intervals or those experiencing acute myocardial infarction, as it may worsen their symptoms.[27]

Box Warning

Amoxapine has an FDA black box warning for increased suicidality risk in individuals aged 24 and younger and aged 65 and older. Amoxapine is not recommended for the treatment of pediatric depression.[32]

Warnings and Precautions

Although amoxapine is effective for certain conditions, it demands vigilant consideration of particular concerns to mitigate potential risks and adhere to essential safety measures associated with its usage.

Extrapyramidal adverse effects: Amoxapine's ability to block dopamine receptors increases the risk of experiencing extrapyramidal adverse effects and tardive dyskinesia.

Angle-closure glaucoma: Amoxapine's potential for inducing pupillary dilation is a crucial concern, especially for patients with anatomically narrow angles, as it heightens the risk of angle-closure glaucoma.

Seizures: TCAs are also contraindicated in patients with a history of epilepsy or seizures. Instead, individuals who are at risk of seizures should consider taking SSRIs or SNRIs instead of amoxapine, as research indicates that amoxapine may slightly increase the risk of seizures.[25]

Hepatic impairment: As amoxapine is metabolized in the liver, it is imperative to exercise extreme caution when prescribing this medication to patients with hepatic impairment or active liver disease.[11]

Electroconvulsive therapy: The concurrent administration of amoxapine and electroshock therapy may heighten the associated risks of electroconvulsive therapy. 

Neuroleptic malignant syndrome (NMS): NMS can arise as a result of antipsychotic drugs, including amoxapine. Clinical manifestations of NMS encompass hyperpyrexia, muscle rigidity, altered mental status, and signs of autonomic instability, such as irregular pulse or labile blood pressure, diaphoresis, and cardiac dysrhythmias. The management of NMS entails the immediate discontinuation of causative medications, including amoxapine, along with vigilant medical supervision and the prompt implementation of supportive care measures.[33][34]

Bipolar disorder: The initial manifestation of bipolar disorder can often resemble a major depressive episode. However, a concern prevails that using antidepressant monotherapy, such as amoxapine, can trigger a manic episode in individuals with a predisposition to bipolar disorder. Therefore, it is essential to conduct a thorough assessment of the patient's personal and family history of bipolar disorder and suicide before initiating antidepressant treatment.[35][36]

Monitoring

Patients taking amoxapine should undergo regular monitoring for resolution or reduction of symptoms, withdrawal symptoms from abrupt discontinuation, changes in body weight and BMI, blood pressure and blood glucose levels, worsening of depression, the emergence of suicidal thoughts, or unusual behavior at the onset of therapy or during dose adjustments. Older individuals and those with preexisting cardiac disease or hyperthyroidism should undergo a 12-lead electrocardiogram as part of their evaluation. As the older population faces an elevated risk of hyponatremia, necessitating electrolyte monitoring in patients 65 and older is important.[37] Clinicians can monitor patient responses using validated questionnaires such as the patient health questionnaire (PHQ-9) and the Hamilton Rating Scale for Depression. Furthermore, it is crucial to remain vigilant for signs of suicidal ideation.[38][39]

Toxicity

Signs and Symptoms of Overdose

The primary concern for TCA toxicity is the potential development of serotonin syndrome, particularly when the medication is combined with other antidepressants such as SSRIs or SNRIs. Serotonin syndrome is characterized by symptoms such as hyperthermia, hypertension, muscle rigidity, and delirium. 

Management of Overdose

In case of TCA or amoxapine overdose, there is no particular antidote available. The primary concern in cases of TCA overdose is ensuring proper respiration and delivering cardiovascular support to patients. Research has demonstrated that, in certain instances, sodium bicarbonate can reduce the incidence of QRS widening.[40] This treatment requires vigilant monitoring of sodium plasma concentrations, as there is a possibility of hypernatremia in patients receiving sodium bicarbonate. However, in the absence of immediate electrolyte changes, the standard protocol involves close monitoring of the patient in the intensive care unit to detect any cardiac abnormalities and ensure adequate hydration to facilitate drug elimination from the system. Analysis of U.S. Poison Control Center data from 2000 to 2014 reveals that amoxapine toxicity may lead to severe complications, including cardiac arrest, renal failure, and intractable seizures.[41] 

In a recent case report, intractable seizures were observed following an amoxapine overdose resulting from a suicide attempt involving the consumption of 3 g of the drug. Despite the administration of intravenous diazepam, levetiracetam, and phenobarbital, the seizures remained uncontrolled. However, the seizures ceased just within 2 minutes of initiating intravenous lipid emulsion (ILE). Although a seizure recurrence occurred 30 minutes after the initial ILE treatment, these seizures were effectively managed through the re-administration of ILE. Therefore, ILE should be considered as a potential intervention for managing severe amoxapine overdose.[42] The prevailing mechanism of lipid emulsion treatment as adjunctive therapy in cases of drug toxicity is based on the hypothesis of lipid shuttling. ILE administration establishes a substantial lipid compartment that efficiently absorbs highly lipid-soluble drugs such as amoxapine, aiding in their removal from the system.[43]

Enhancing Healthcare Team Outcomes

As TCAs, such as amoxapine, are typically reserved as third-line treatments for depression, patients who receive them or are being considered for their use typically exhibit recurrent or reactive depression. This suggests that other medication and treatment approaches have proven ineffective in managing the symptoms of these patients. Consequently, these patients are at an elevated risk of engaging in self-harming and suicidal behaviors. To address these concerns effectively, it is imperative to assemble a cohesive interprofessional healthcare team to oversee their treatment. This team should encompass regular coordination between the patient's primary physician, psychiatrist, and counselors, ensuring adherence to the medication regimen and monitoring the response to treatment. At every office visit, comprehensive assessments for suicidal ideations, plans, or tendencies should be conducted. Appropriate overdose precautions should be initiated if there is any indication that patients pose a risk to themselves or others.[44]

Treatment with amoxapine and other antidepressant medications is most effective when managed by an interprofessional healthcare team responsible for all aspects of the patient's case. This team comprises physicians who prescribe and make regimen-related decisions, specialists who provide in-depth condition-specific expertise, specialized nursing staff who oversee care, ensure patient adherence, and assist with monitoring patient symptoms, and pharmacists who conduct medication reconciliation and dosage verification. A retrospective analysis of data from hospitalized patients with poisoning indicates significant reductions in hospitalization duration, healthcare costs, and mortality rates when medical toxicologists actively participate in patient care.[45] All interprofessional team members, including clinicians (MD, DO, NP, and PA), nurses, specialists, toxicologists, and pharmacists, should collaborate and maintain open communication to ensure optimal care and outcomes related to amoxapine therapy.