New insights on the antidepressant discontinuation syndrome.

Abstract

Antidepressants are at best 50–55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology. The relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to “design-out” a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome.