CC BY-NC-ND 4.0 · Pharmacopsychiatry 2021; 54(06): 252-260
DOI: 10.1055/a-1520-4784

An Oppositional Tolerance Account for Potential Cognitive Deficits Caused by the Discontinuation of Antidepressant Drugs

Lorenza Colzato
1   Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany
2   Department of Cognitive Psychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr University Bochum, Bochum, Germany
3   Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China
Wenxin Zhang
3   Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China
Henrik Walter
4   Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Christian Beste
1   Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany
3   Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China
1   Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany
5   Biopsychology, Faculty of Psychology, TU Dresden, Dresden, Germany
› Author Affiliations
Funding: This work was supported by a research grant from 100 Talent Grant of the Province of Shandong, China, to LSC, WZ, and CB


Depression is the leading cause of disability worldwide, making antidepressant drugs the most used psychiatric drugs in the USA. Withdrawal effects and rebound symptoms frequently occur after the reduction and/or discontinuation of these drugs. Although these phenomena have been investigated with respect to the clinical symptomatology, no studies have systematically investigated the effects of withdrawal/rebound on general cognition. We present a novel framework based on the idea of allostatic adaptation, which allows to predict how different antidepressants likely impair different cognitive processes as a result of withdrawal and rebound effects. This framework relies on the assumptions that the type of cognitive impairments evoked by an antidepressant is determined by the targeted neurotransmitter systems, while the severity of deficits depends on its half-life. Our model predicts that the severity of detrimental cognitive withdrawal and rebound effects increases with a shorter half-life of the discontinued antidepressant drug. It further proposes drug-specific effects: antidepressants mainly targeting serotonin should primarily impair aversive and emotional processing, those targeting norepinephrine should impair the processing of alerting signals, those targeting dopamine should impair motivational processes and reward processing, and those targeting acetylcholine should impair spatial learning and memory. We hope that this framework will motivate further research to better understand and explain cognitive changes as a consequence of antidepressant discontinuation.

Publication History

Received: 15 January 2021
Received: 12 April 2021

Accepted: 26 May 2021

Article published online:
22 July 2021

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