amoxapine

General Information

Amoxapine (brand Asendin; generics) is an older antidepressant indicated for the relief of symptoms of depression, including depression with anxiety or agitation (label).

A key differentiator is clinically meaningful dopamine receptor blocking activity. This can produce extrapyramidal symptoms (EPS) and is associated with a warning about Tardive dyskinesia—a profile that overlaps with antipsychotic monitoring concerns (label).

Because of anticholinergic burden, orthostasis, seizure risk at higher doses, and the possibility of movement disorders, amoxapine is generally used selectively rather than as a first-line depression option (clinical).

Label pharmacokinetics report a parent half-life of ~8 hours and a major metabolite (8-hydroxy-amoxapine) with a longer ~30-hour half-life, which can extend both benefits and adverse effects (label).

The compare view, amoxapine evidence feed, and amoxapine print page support counseling and documentation when a tricyclic-like antidepressant is being weighed in the context of psychosis risk or prior antipsychotic exposure.

Amoxapine is used infrequently in modern practice because safer options exist for most patients. When it is selected, monitoring focuses on movement disorders (EPS/TD), seizure risk at higher doses, and typical tricyclic-like tolerability issues (orthostasis and anticholinergic effects).

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Amoxapine inhibits norepinephrine and serotonin uptake and has dopamine receptor blocking activity; the dopamine-blocking component explains its uncommon antidepressant association with EPS and tardive dyskinesia (label/mechanism).

Antagonism at histamine H1, muscarinic, and α1-adrenergic receptors contributes to sedation, constipation/urinary retention, and Orthostatic hypotension (class effects).

• Tricyclic-like antidepressant with dopamine-blocking activity (EPS/TD risk).

Metabolism and Pharmacokinetics

• Rapidly absorbed; label describes peak blood levels around 90 minutes after ingestion (label).
• Extensively metabolized. Parent half-life is ~8 hours; major metabolite 8-hydroxy-amoxapine has a biologic half-life of ~30 hours (label).
• Metabolites are excreted in urine in conjugated form as glucuronides (label).

Dosing and Administration

• Label dosing is individualized. A common initiation is 50 mg two or three times daily with gradual increases based on response and tolerability (label).
• Some patients transition to 100 mg two or three times daily; labeling notes that if 300 mg/day is ineffective after 2 weeks, higher doses may be required in select patients (label).
• Label allows single-bedtime dosing when total daily dose does not exceed 300 mg; higher doses are divided (label).
• Hospitalized, treatment-refractory patients without seizure history may require higher doses (up to 600 mg/day in labeling), with close monitoring for seizures, orthostasis, and movement disorders (label/clinical).
• Gradual tapering is commonly used when discontinuing after longer courses to reduce withdrawal symptoms and to distinguish withdrawal from relapse (clinical).

Monitoring & Labs

• Movement-disorder screening for EPS (rigidity, tremor, akathisia) and abnormal movements concerning for tardive dyskinesia, especially during titration and at higher doses (label/clinical).
• Seizure risk review (history, co-medications) and reassessment when dose escalation is considered (label/clinical).
• Orthostatic vitals, falls risk, and anticholinergic burden (bowel and bladder symptoms, cognition), especially in older adults (clinical).
• ECG planning in patients with cardiac history, older age, electrolyte disturbance risk, or multiple QT-active drugs (clinical).
• Suicidality and mood switching surveillance early in treatment and after dose changes (label/clinical).

Monitoring for amoxapine blends antidepressant follow-up with antipsychotic-like movement-disorder screening because of dopamine-blocking activity.

Adverse Effects

Interactions

• MAOIs are contraindicated; washout periods are used to reduce risk of severe reactions (label).
• Additive CNS depression can occur with alcohol, benzodiazepines, opioids, and other sedatives; functional safety is a common review topic (label/clinical).
• CYP2D6 inhibition (fluoxetine, paroxetine, quinidine) can increase exposure of tricyclic-like antidepressants; medication reconciliation is commonly used to anticipate toxicity risk (clinical).
• Other anticholinergic medications (some antipsychotics, antihistamines) can compound constipation, urinary retention, and delirium risk (clinical).

Other Useful Information

• Amoxapine is generally positioned after SSRIs/SNRIs in depression guidelines because safer alternatives exist for most patients (APA/CANMAT/clinical).
• If abnormal movements, rigidity, restlessness, or Akathisia emerge, clinicians commonly reassess the medication choice and consider switching to a non–dopamine-blocking antidepressant (label/clinical).
• When depressive symptoms occur in bipolar disorder, antidepressants are commonly paired with a mood stabilizer and monitored for mood switching; see the bipolar disorder hub for longitudinal care pathways.
• For older adults, medication review that reduces additive anticholinergic and sedative burden is often higher yield than adding multiple “side-effect” medications (clinical).

References

1. Amoxapine tablets prescribing information — DailyMed (2024)
2. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
3. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)
4. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018)