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

Abstract

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.

Fig. 1 a.

Illustration of the suggested shift in monoaminergic signaling underlying withdrawal and rebound effects. Please note that antidepressants with a short half-life are expected to cause more severe dysregulation (i. e., deficient monoaminergic signaling) and thus more severe cognitive deficits upon their discontinuation. b. Illustration of the antidepressant drug types and the different neurotransmitters that they affect. The first generation of antidepressants (TCAs and MAOIs) affects a broad spectrum of neurotransmitters, whereas the second generation of antidepressants (SSRIs and SNRIs) has a more selective effect. The targeted neurotransmitters also determine the range of cognitive deficits that are likely to develop as a result of withdrawal and rebound effects triggered by drug discontinuation.