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Background: Antidepressants can cause tolerance, dependence, and withdrawal syndromes, often understated by the term “antidepressant discontinuation syndrome.” While they do not induce craving or compulsive use, brain adaptations to these drugs can make them hard to stop, especially after long-term use. Despite growing evidence of withdrawal risks, antidepressant prescriptions and long-term use continue to increase globally. The potential duration and severity of debilitating withdrawal symptoms, including akathisia, suicidality, and protracted withdrawal, have been minimized. This is partly due to commercially sponsored guidelines that relied on short-term clinical trial data. Aims: Therapeutics Letter 156 updates evidence on antidepressant withdrawal syndrome, highlighting the potential for severe and prolonged symptoms. It encourages re-evaluation of prescribing practices, particularly in primary care, and suggests requirements for informed consent before patients start an antidepressant. Therapeutics Letter 156 also aims to distinguish withdrawal from relapse of an underlying mental illness. This topic will be explored further in Therapeutics Letter 157, which will examine deprescribing strategies in more detail, including “hyperbolic tapering.” Recommendations: Prescribers should ensure patients provide fully informed consent before starting antidepressants,explicitly discussing the risks of tolerance, dependence, and potentially severe, prolonged, or even irreversible withdrawal symptoms. This includes warning about new-onset suicidality and chronic akathisia. Informed consent should be documented formally, ideally using consent forms tailored to the prescriber’s practice. Patients should also be informed about the challenges of tapering, including the current lack of suitable drug formulations, and potential difficulties in finding experienced clinical support if withdrawal problems are severe.