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.

Regaining control over opioid use? The potential application of auricular transcutaneous vagus nerve stimulation to improve opioid treatment in China

“…98 Further, given that atVNS has been approved for the treatment of pharmacoresistant depression, 43 it might be better suited for OUD than standard pharmacotherapy such as antidepressants, which are often accompanied by side-effects or withdrawal and rebound phenomena when discontinued. 99 More importantly, a systemic review revealed that MMT does not only show a very limited effectivity, but even detrimental effects in restoring normal cognitive control functioning, which is crucial to regain control over opioid intake. 9 Indeed MMT patients, compared to abstinent heroin users or non-user healthy controls, displayed reduced psychomotor speed and impairments in working memory, planning and response inhibition.…”

“…Indeed, mixing benzodiazepine, a drug prescribed to treat opiate withdrawal symptoms, with MMT can be lethal because of respiratory depression 98 . Further, given that atVNS has been approved for the treatment of pharmacoresistant depression, 43 it might be better suited for OUD than standard pharmacotherapy such as antidepressants, which are often accompanied by side‐effects or withdrawal and rebound phenomena when discontinued 99 . More importantly, a systemic review revealed that MMT does not only show a very limited effectivity, but even detrimental effects in restoring normal cognitive control functioning, which is crucial to regain control over opioid intake 9 .…”