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Harvey, 2014 New insights on antidepressant discontinuation syndrome

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This paper provides an argument about why withdrawal occurs, its effects and how their shiny new drug might shows us the way forward

Hum Psychopharmacol. 2014 Nov;29(6):503-16.
New insights on the antidepressant discontinuation syndrome.
Harvey BH, Slabbert FN.

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/25111000 Full text here

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.

Edited by Altostrata
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Link to full text added.


At the time, I felt Dr. Harvey was too optimistic about agomelatine:



February 5, 2015


Dr. Harvey —


I was curious to verify that agomelatine did not have withdrawal difficulties in general use. Every single one of the new antidepressants originally claimed they did not cause sexual side effects or withdrawal syndrome, and these claims have been inaccurate for every single one of them.


Unfortunately, I have found some anecdotal reports of withdrawal syndrome from Valdoxan, as I expected http://www.drugs.com/answers/hi-friends-hope-all-is-well-with-you-all-435468.html Also complaints of other typical antidepressant side effects.


A few weeks of mouse studies or even human studies are inadequate to delineate the frequency and intensity of adverse effects.







Agomelatine is not prescribed often, and is not approved in the US. We have few members who have taken it.


We do have a few cases of agomelatine withdrawal syndrome:




On the other hand:



Other reports of agomelatine withdrawal symptoms:




I wonder if agomelatine withdrawal syndrome is known in the Netherlands? Cinderella Therapeutics makes tapering strips for it.



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A systematic review of agomelatine-induced liver injury

Silka Dawn Freiesleben and Karolina Furczyk


"Agomelatine prescription at therapeutic doses does pose a risk of inducing liver injury, which is usually reversible. However, rare cases of severe and life-threatening hepatotoxicity have also occurred. "

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