Classics in Chemical Neuroscience: Amitriptyline.

Amitriptyline was the second tricyclic antidepressant to appear on the market for major depressive disorder under the brand name Elavil in 1961. Since its emergence, amitriptyline has been an effective therapeutic in various disease states and disorders but has also been a concerning source of cardiotoxicity. Amitriptyline inhibits serotonin and norepinephrine reuptake as well as produces off-target activity at histaminergic, muscarinic, and various other receptors. Its role as a modulator of monoamines helped further establish the monoamine theory to understand various mood disorders, paving the way for the now more common selective serotonin/norepinephrine reuptake inhibitors. In this review, we will discuss amitriptyline's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, and its history and importance in therapy to present amitriptyline as a true classic in chemical neuroscience.