Abstract
Jacobson recently highlighted many of the significant issues associated with the development of tolerance to antidepressants. He pointed out that there had been a hesitancy to apply the term ‘tolerance’ to antidepressants despite strong evidence suggesting this occurs, along with (frequently severe) withdrawal symptoms on cessation (indicating physiological dependence) in a significant proportion of people (Jacobson, 2021). Despite all this, for nearly three decades now psychiatry has used the term ‘discontinuation syndrome’ to describe the withdrawal symptoms often experienced by people who stop taking antidepressants (see Table 1). ‘Withdrawal’ refers to a syndrome that occurs when blood or tissue concentrations of a substance decline in an individual who had maintained prolonged use of the substance (American Psychiatric Association (APA), 2013). Importantly, withdrawal does not require the complete discontinuation (i.e. cessation) of the drug to occur (e.g. a person may experience withdrawal symptoms on dose reduction or prolonged duration between doses, particularly with drugs with shorter half-lives). Antidepressant withdrawal may therefore arise in the setting of any significant pharmacodynamic or pharmacokinetic change that affects drug serum levels. Withdrawal may also be prolonged and polymorphic and, as Jacobson points out, its presence may easily be confused with relapse, falsely vindicating the ‘prophylactic’ use of antidepressants. Given we readily apply the term withdrawal syndrome to other dependence-forming drugs (e.g. benzodiazepines and opiates), it is worth exploring why antidepressants got special treatment.
Symptoms associated with antidepressant withdrawal.
Source: Adapted from (Malhi, 2021)
The acronym ‘FINISH’ has been widely taught to provide a reminder of the main symptoms (F – flu-like symptoms; I – insomnia; N – nausea; I – imbalance; S – sensory disturbances; H – hyperarousal). Importantly, antidepressants with significant anticholinergic properties (e.g. tricyclics) may also demonstrate cholinergic rebound symptoms (e.g. headache, restlessness, nausea, vomiting, anxiety, insomnia, myalgias, diaphoresis, rhinorrhea, sialorrhea, diarrhoea).
The first mention of an antidepressant ‘discontinuation syndrome’ was in a paper published in 1993 regarding sudden cessation of fluvoxamine (Massabki and Abi-Jaoude, 2021). Alan Schatzberg next described it in a 1997 supplement to the Journal of Clinical Psychiatry that was based on a closed symposium, ‘SSRI Discontinuation Effects’ – both the supplement and the symposium were sponsored by Eli Lilly (Massabki and Abi-Jaoude, 2021). Following this, ‘discontinu-ation syndrome’ became common psychiatric parlance. But why the divergence from withdrawal? In an influential 2006 paper, Richard Shelton argued that people didn’t crave antidepressants on cessation, nor exhibit drug-seeking behaviours for them and therefore the ‘discontinuation syndrome [was] unrelated to addiction’ (and, by implication, unrelated to withdrawal) (Shelton, 2006). Ironically, in the same paper Shelton cited evidence that nearly 4 out of 5 lay people believe antidepressants are, in fact, addictive. Shelton went on to argue that given the amount of ‘misinformation in the popular media’ and the ‘negative connotations’ associated with the term withdrawal, its use should be avoided and ‘discontinuation syndrome’ used instead. But Shelton had conflated the ill-defined term addiction (generally, compulsive and habitual use of a substance despite negative consequences) with physiological dependence (a neuroadaptive state that leads to withdrawal symptoms upon reduction in blood or tissue concentration of a substance). A person need not be ‘addicted’ (however defined) to suffer withdrawal. It is noteworthy that Shelton also had ties to no fewer than 7 pharmaceutical companies and his paper was funded by Wyeth Pharmaceuticals (makers of venlafaxine – an antidepressant known to cause a severe withdrawal syndrome).
In a recent analysis, Massakabki and Abi-Jaoude concluded that attempts to define selective serotonin reuptake inhibitor (SSRI) with the term ‘discontinuation syndrome’ were not supported by evidence. They reported that SSRIs may indeed result in both physiological dependence and withdrawal and argued that acknowledging (and disclosing) this may help patients make more informed choices about using these drugs, as well as inform strategies for safe tapering where appropriate (Massabki and Abi-Jaoude, 2021).
It is encouraging that the Royal Australian and New Zealand College of Psychiatrists (RANZCP) new clinical practice guidelines (CPG) for mood disorders (Malhi et al., 2021) contain nearly two pages on antidepressant withdrawal including recommendations for medically supervised, individually tailored, slow tapering over an extended period of time (see Table 2). It is not clear, however, why the CPGs still use the term ‘discontinuation’ and misappropriated the neurological acronym DAWS (‘dopamine agonist withdrawal syndrome’) to mean ‘discontinuation and withdrawal symptoms’. Discontinuation refers to the physical act of not taking (or prescribing) the drug – it does not describe the consequent symptomatology.
RANZCP CPG for mood disorders 2020 – recommendations for withdrawal of antidepressants.
Source: Adapted from (Malhi, 2021)
CPG: clinical practice guidelines; RANZCP: Royal Australian and New Zealand College of Psychiatrists; CBR: consensus-based recommendation; AD: antidepressants; EBR: evidence-based recommendation; MAOI: monoamine oxidase inhibitor.
‘Discontinuation syndrome’ is a euphemism that appears to have evolved out of pressure from pharmaceutical companies to delineate their products from other dependence-forming drugs (e.g. benzodiazepines). Use of the term has been perpetuated by conflation of the term ‘addiction’ (with all its negative connotations) with ‘dependence’, and probably doctors’ fears of worrying patients about taking another dependence-forming drug. It is a misleading term that is not supported by evidence and minimises the potential adverse consequences of antidepressant withdrawal while ignoring the fact that withdrawal symptoms may occur without ‘discontinuing’ the drug. Time to discontinue the ‘discontinuation syndrome’ and talk antidepressant ‘withdrawal syndrome’.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship and/or publication of this article.
