RESEARCH MONOGRAPH · KDC-MN-223
Amoxapine
Amoxapine (Asendin) is a hybrid drug: chemically it is a derivative of the antipsychotic loxapine, and pharmacologically it does both jobs at once, blocking the norepinephrine pump like a tricyclic antidepressant and blocking dopamine D2 receptors like an antipsychotic. That dual action made it briefly attractive in the early 1980s for depressed patients with psychotic features. The downside is that it carries the entire side-effect package of antipsychotics, including risk of tardive dyskinesia (a movement disorder that can become permanent) and neuroleptic malignant syndrome (a rare but life-threatening reaction). Those risks have largely pushed it out of routine use in favor of separate SSRI and antipsychotic combinations. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Tricyclic antidepressant with antipsychotic-like activity
A 2-chloro-loxapine derivative TCA with substantial D2 antagonism; an antidepressant with antipsychotic-class side effects including extrapyramidal symptoms.
Abstract
Amoxapine (2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine; CAS 14028-44-5; molecular formula C17H16ClN3O; molecular weight 313.78) is a dibenzoxazepine TCA developed at Lederle as a derivative of the antipsychotic loxapine, approved by the FDA in 1980 under the trade name Asendin. NET Ki approximately 16 nM, SERT Ki approximately 58 nM; the compound retains the dibenzoxazepine scaffold of loxapine which confers D2 antagonism (Ki approximately 100 nM) atypical for an antidepressant. Active metabolite 7-hydroxyamoxapine has even more potent D2 antagonism. The dopaminergic activity produces extrapyramidal side effects (akathisia, tardive dyskinesia, parkinsonism) and rare neuroleptic malignant syndrome at clinical doses, distinguishing amoxapine from other TCAs and complicating its safety profile. Plasma half-life is 8 to 30 hours. Approved for major depressive disorder; effective in psychotic depression where D2 antagonism is therapeutic, but the antipsychotic-class adverse events have limited mainstream use. Used as a reference compound for combined monoaminergic and dopaminergic antagonist pharmacology.
Mechanism of action
NET inhibition combined with D2 antagonism; active metabolite is a more potent D2 antagonist. Pharmacology resembles a hybrid TCA-antipsychotic.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- Greenblatt DJ, et al. Amoxapine: clinical pharmacology and therapeutic application. J Clin Psychopharmacol 1981.
- Kapur S, et al. Antidepressant amoxapine occupies dopamine D2 receptors. Neuropsychopharmacology 1999.
- Kuhn KU, et al. Amoxapine in psychotic depression. Pharmacopsychiatry 1991.
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The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.