There have been significant developments in the understanding of antidepressant withdrawal in recent years. Before this period, for many years guidelines reported that antidepressant discontinuation symptoms are 'mild and self-limiting', for example, by NICE 1 in the UK. In the USA, the depression guidelines from the APA, published in 2010, still suggest 'discontinuation-emergent symptoms … typically resolve without specific treatments over 1-2 weeks'. 2 The APA guidelines do identify that 'some patients do experience more protracted discontinuation syndromes, particularly those treated with paroxetine'. 2
In a systematic analysis of worldwide clinical practice guidelines for depression withdrawal symptoms were mostly described as mild, brief and self-limiting, and severe in a minority of cases. 3 Estimates of the duration and incidence were included in only a quarter of guidelines and the values given were in all cases lower than those reported in systematic review. 3 This systematic analysis concluded that clinical practice guidelines from most countries provide scarce and inadequate information on antidepressant withdrawal symptoms and only limited guidance for distinguishing withdrawal symptoms from symptoms of relapse. 3
In recent years there has been more widespread recognition in some countries that withdrawal symptoms from antidepressants are common, can be severe and may be long-lasting, over months or years. 1, 4, 5 RCPsych in the UK issued a position statement emphasising that 'There should be greater recognition of the potential in some people for severe and long-lasting withdrawal symptoms', 6 and a corresponding update to the NICE guidelines highlighted '[antidepressant withdrawal] symptoms lasting much longer (sometimes months or more) and being more severe for some patients'. 1
There has been perhaps less obvious acknowledgement of this change in characterisation of withdrawal in other countries, including the USA. 7 There are some exceptions. The Therapeutics Initiative (TI) in Canada, which produces guidance on medications independent from drug company sponsorship, based at the University of British Columbia, points out that for antidepressants 'severe and prolonged withdrawal symptoms have been reported lasting weeks to months'. 8 The TI guidance also recognises that 'antidepressants should be added to the list of drugs associated with tolerance, dependence and a withdrawal syndrome' and that withdrawal symptoms occur in at least one-third of patients who stop. 4 TI also points out that patients must be informed of the possibility of withdrawal symptoms before starting an antidepressant, drawing a comparison to opioid treatment: 'the requirements for informed consent are analogous to recommendations before initiating long-term opioid therapy'. 8 RCPsych and NICE in the UK both recommend that providing information on withdrawal symptoms from stopping antidepressants should be a part of informed consent when an antidepressant is being considered. 6
Patients often report that withdrawal symptoms from antidepressants are under-recognised, or minimised by clinicians, 9, 10, 11 probably as a result of official guidance minimising the frequency and severity of antidepressant withdrawal symptoms. 3 One consequence of this has been that many patients are forced to seek help outside the medical system from peer support websites 11 or social media sites, including private Facebook groups. 10
Withdrawal symptoms can be somewhat different from those of depression and anxiety but there are important similarities. 12 Withdrawal should now be carefully considered by clinicians as an important differential diagnosis whenever antidepressant doses are reduced or missed - especially given that patients commonly report that their withdrawal symptoms from antidepressants are mis-diagnosed as relapse. 10, 12 A quarter of clinical practice guidelines around the world highlight the risk of mis-diagnosing antidepressant withdrawal symptoms as a relapse of the underlying condition. 3 The TI underlines the risk of mis-diagnosing withdrawal symptoms as a return of a mental health condition by pointing out that on stopping antidepressants 'depressive symptoms or increased suicidality may represent withdrawal or re-emergence of the original condition'. 8 Patients report that the lack of understanding or recognition of withdrawal symptoms by clinicians compounds the problems that arise on stopping antidepressants and adds unnecessary distress. 9
The term 'dependence' has recently come to be used interchangeably with 'addiction' (to mean uncontrolled drug-seeking behaviour). Inevitably this has led to some unfortunate confusion. 13 This choice of language was made in DSM-III-R because the term 'addiction' was thought to be pejorative while the word 'dependence' was thought more neutral. 13 However, the original usage of the word 'dependence' referred to 'physiological adaptation that occurs when medications acting on the central nervous system are ingested with rebound when the medication is abruptly discontinued'. 13 The National Institute on Drug Abuse (NIDA) in the USA states 'Dependence means that when a person stops using a drug, their body goes through “withdrawal”: a group of physical and mental symptoms that can range from mild (if the drug is caffeine) to life-threatening … Many people who take a prescription medicine every day over a long period of time can become dependent; when they go off the drug, they need to do it gradually, to avoid withdrawal discomfort. But people who are dependent on a drug or medicine are not necessarily addicted.' 14 In addition, Goodman and Gilman's textbook of pharmacology points out 'The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence.' 15
All major classes of antidepressants SSRIs, SNRIs, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), noradrenaline and specific serotonergic antidepressants (NaSSAs)) can be associated with withdrawal symptoms on cessation or dose reduction. These symptoms occur in a substantial proportion of patients, most likely as a result of physical dependence (a normal neurobiological response to drugs that act on the central nervous system) in these patients. 13, 16, 17, 18, 19, 20 Physical dependence on antidepressants arises because the body and brain undergo adaptations to the presence of a drug, countering its effect in order to maintain homeostasis. 13, 21, 22 The only evidence necessary for a state of physical dependence to be diagnosed is the appearance of withdrawal symptoms on reducing or stopping the drug. 15 It is also clear that the vast majority of antidepressants - with the possible exceptions of tranylcypromine and amineptine - do not cause addiction, as they do not induce compulsion, craving and other symptoms of addiction. 23, 24
Some patients may be uninterested in academic distinctions between dependence and addiction and more interested in the reality that they cannot stop their antidepressants because of unpleasant withdrawal effects. They may therefore describe them colloquially as 'addictive', 25, 26 though antidepressants do not fit the strict definition of this. Some patients may also not be happy being described as 'dependent' on antidepressants (which they may still associate with the concept of addiction), and in this case, it may be better to talk in terms of 'neuroadaptation' or 'adaptation'.
The term 'discontinuation symptom' was promoted by drug manufacturers to minimise patient concerns regarding their product and to prevent association with the idea of addiction. 27, 28 There is now widespread recognition that this euphemism is misleading and that its use minimises the potential adverse consequences of stopping antidepressants. 28, 29, 30 The more pharmacologically accurate term is 'withdrawal symptoms', now adopted by RCPsych, 6, 28 the British Medical Association 28 and NICE in the UK. 1, 31 In Canada, the TI has updated its language as well: 'The effects of stopping any antidepressant should be more precisely termed “withdrawal syndrome” instead of “antidepressant discontinuation syndrome”.' 8 There has been limited official acknowledgement of this in the USA.