Antidepressant Discontinuation Syndrome

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Depression is a highly prevalent, severely debilitating mental disorder that affects nearly 5% of the global population, and has a high risk of relapse. Commonly used to treat depression, antidepressant drugs are currently the most prescribed class of CNS medications globally.

However, overt side-effects markedly complicate antidepressant pharmacotherapy. For example, digestive and sleep disorders, headache, anxiety, and metabolic and reproductive dysfunctions are frequently associated with antidepressant treatment. In addition to such well-reported side effects of antidepressants, their discontinuation is also a growing health concern.

Antidepressant discontinuation syndrome (ADS) is a condition that can occur following the interruption, dose reduction, or discontinuation of antidepressant drugs. It is currently reported for all major antidepressants, often lasting for days or weeks, and even months. Patient groups at most risk of ADS include females, patients with affective disorders, patients taking higher doses or longer courses of antidepressants, those who reduced treatment more abruptly, and the elderly.

In general, ADS symptomology is complex and consists of several body-oriented and mental symptoms. The first cluster includes imbalance, vertigo, paresthesias, fatigue, headache, nausea, tremor, weight gain, diarrhea, and visual disturbances. Mental ADS symptoms include anxiety, low mood, insomnia, irritability, impaired cognition, anhedonia, mania, and psychosis. In many clinical signs, ADS resembles a classical drug withdrawal syndrome, commonly seen after discontinuation of drugs of abuse such as opioids. However, the two syndromes differ pathogenetically since the molecular mechanism of discontinuation form opioids and from antidepressant is connected with different neurotransmitter systems. ADS is not connected directly with the reinforcing system of the brain and antidepressants do not seem to cause addiction.

Nowadays preventing ADS is based on minimizing health risks associated with discontinuation of antidepressants. Hence, most of the therapeutic strategies involve well-planned tapering by gradually decreasing antidepressant dose based on the half-life of specific antidepressants or switching to other, better-tolerated medication.

Unfortunately, our ability to understand causes, drug interactions, as well as the role of genetic and environment modulation of ADS, remains limited since clinical literature is sparse, thereby necessitating the development of animal (experimental) models of ADS. While animal models are an indispensable tool in translational biological psychiatry research, they have been only recently applied to ADS.

Recent rodent studies examining commonly used antidepressants (e.g., fluoxetine, citalopram, sertraline and paroxetine) note altered serotonin and other monoamines of the brain. Complementing rodent models, primates more closely relate to humans and have multiple genetic polymorphisms, making them suitable for studying long-term antidepressant action. Moreover, preclinical ADS studies can also include non-mammalian models and even invertebrates. For instance, an aquatic teleost species, zebrafish (Danio rerio) is rapidly gaining popularity in neuropharmacology and toxicology, also showing overt drug withdrawal-like responses and sensitivity to antidepressants.

The final goal of research on animal models and neurotransmitter systems is the new targets for drug therapy. New potential drugs can help decrease the negative effects of ADS or even eliminate them. Interestingly, some novel antidepressants have fewer or no ADS-like effects. For example, agomelatine is not known to cause ADS, likely due to high selectivity to melatonin receptors, which regulate circadian rhythms. It is, therefore, possible that new classes of drugs will be found while analyzing all the molecular and genetic alterations which happen on the brain during therapy and after its discontinuation. Thus, developing new models of ADS can create productive momentum to investigate this disorder in detail, as part of bigger clinical and translational efforts to improve our understanding of affective/mood disorders and their therapy.

These findings are described in the article entitled Understanding antidepressant discontinuation syndrome (ADS) through preclinical experimental models, recently published in the European Journal of Pharmacology. This work was conducted by Konstantin N. Zabegalov, Tatiana O. Kolesnikova, and Sergey L. Khatsko from the Ural Federal University, Andrey D. Volgin, Oleg A. Yakovlev, Darya A. Meshalkina, Konstantin A. Demin, and Raul R. Gainetdinov from St. Petersburg State University, Tamara G. Amstislavskaya from Novosibirsk State University, Polina A. Alekseeva from Almazov National Medical Research Centre, Ashton J. Friend and Allan V. Kalueff from Southwest University (China), and Wandong Bao from Southwest University.

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1 Comment

  • “Discontinuation” syndrome?? Try *withdrawal*!! That is a G-rated, dumbing down of an obvious phenomenon to shield pharmaceutical companies and doctors from ire and liability because no one will admit that antidepressants are in fact ADDICTIVE and that many patients do not stand a chance of successfully quitting these drugs without serious consequences!

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