Incidence of Antidepressant Withdrawal Symptoms

A 2019 systematic review identified 14 relevant studies from which to calculate the incidence of antidepressant withdrawal symptoms [5]. The incidence rates ranged from 27 to 86%, with a median of 55% and a weighted average of 56.4% [5]. Restricting the analysis only to double-blind randomised controlled trials (RCTs) from this review, the incidence of withdrawal syndrome was 53.9% (six RCTs, 731 participants) [Table 1] (where the majority of studies used an increase in discontinuation emergent signs and symptoms [DESS] [41] of ≥ 4 to define a withdrawal syndrome).

Table 1 Incidence of withdrawal in double-blind RCTs captured in Davies and Read [5]

A potential limitation of this review was that, in addition to RCTs and observational studies, it included three online surveys; critics point out it is possible that surveys may capture a skewed sample of patients motivated to answer the survey because of their experience with more severe withdrawal symptoms than average, and withdrawal symptoms were reported by patients rather than using objective withdrawal questionnaires [4, 14]. However, the weighted average incidence of withdrawal symptoms was similar in the six RCTs (53.9%) to the five observational studies (52.5%) and the three online surveys (57.1%) [5]. Restricting analysis to studies of SSRIs, the most widely used class of antidepressants, discontinuation syndromes occurred with a median rate of 53.6%, and a weighted average of 50.5% [5]. The double-blind, placebo-controlled, staggered discontinuation studies are the most reliable of the studies conducted and are highlighted in Table 1.

Nocebo/Psychosomatic Effects

Another limitation to the Davies and Read review is reporting of single-arm frequencies, that is, withdrawal effects from stopping antidepressants are not compared to withdrawal effects from stopping placebo or continuing antidepressants as a control. Some have suggested that withdrawal symptoms may be a psychosomatic response rather than genuine physiological symptoms [4]. These authors have hypothesised that patients have negative expectations of the consequence of stopping their antidepressants, leading to nocebo withdrawal effects (the opposite of the placebo effect) [4]. The presence of antidepressant withdrawal symptoms in both animals [16] and neonates of antidepressant-using mothers [42] suggests that the process is primarily physiological rather than psychosomatic. Randomised controlled trials conducted to detect withdrawal symptoms used double-blind placebo-controlled designs so that the patient and doctor were unaware whether the patient was receiving a continuation of their antidepressant or identical placebo pills for several days [41, 43]. This design minimises the role of psychological expectation or nocebo effects and therefore suggests that withdrawal effects are physiological consequences of stopping the medication [41]. In one carefully conducted study, the average number of new symptoms recorded on the DESS scale was 5.7 (standard deviation 6.96) for sertraline patients and 7.8 (standard deviation 8.55) for paroxetine-treated patients, suggesting a large number of symptoms, including physical symptoms (such as dizziness, and headache) with onset at the same time, and resolution upon re-commencing the antidepressants (unbeknownst to the participants) consistent with a physiological syndrome [41]. Furthermore, cessation of fluoxetine (whose half-life of 7–15 days makes withdrawal symptoms unlikely in the 5–8 days of the study) produced a non-significant increase of 0.2 symptoms, serving as a useful negative control group [41].

The rate of such nocebo withdrawal effects has been explored in six double-blind RCTs in two ways: either by cessation of placebo or continuation of antidepressants unbeknownst to the patient. These six studies were reviewed previously [44] and results are presented in Table 2 [44]. Excluding the outlier of 75% (defined as experiencing any symptom of withdrawal) [45] yields a weighted average of nocebo withdrawal effects of 11.8%. A limitation to this analysis is that the severity of withdrawal effects is not measured in these studies, and it is not clear that ‘dizziness’ or ‘nausea’ reported in the nocebo group is the same as such symptoms in the withdrawal group (there are case reports of such symptoms being severe enough to prompt an investigation of stroke) [46]. Furthermore, withdrawal effects from placebo show no relationship with duration of treatment, in the same way that withdrawal from paroxetine does, with marked divergence over time (Fig. 2, with Fisher’s exact tests showing significant differences between the two groups after 2 months [p = 0.005], 3 months [p < 0.001] and more than 4 months of treatment [p < 0.001]) [47]. Therefore, as with all health symptoms, there may be a psychological component to withdrawal effects but this is likely to be minor. For example, the data in Fig. 2 appear to be consistent with a ceiling value similar to that calculated above for nocebo withdrawal. Adjusting the reported single-arm frequencies for antidepressant withdrawal for the rate of withdrawal in the ‘nocebo’ condition yields an incidence of 42.1% (53.9–11.8%) for antidepressants in double-blind RCTs and 38.7% (50.5–11.8%) for trials looking specifically at SSRIs [44].

Table 2 Summary of studies that have estimated the role of nocebo effects in the incidence of withdrawal syndromeFig. 2

Relationship between duration of treatment (before stopping) and proportion of patients who experienced withdrawal effects on stopping either paroxetine or placebo (overall trend p value <0.001) [47]. Significance for Fisher exact tests for by-month group comparisons. *p < 0.05; **p < 0.01; ***p < 0.001

Severity of Antidepressant Withdrawal Symptoms

The severity of the withdrawal syndrome from SSRIs varies widely, with a range from mild short-lasting cases that can be managed with education and reassurance, to severe cases that cause significant disruptions to normal functioning [5, 10]. This variability presumably relates to differing degrees of neurobiological adaptation to antidepressants amongst individuals. In its severe form, the SSRI withdrawal syndrome has been reported to be associated with ataxia leading to falls, electric shock sensations that impair walking and driving [10], and urgent consultations at emergency departments [46, 48], in published case studies. The discontinuation period is also associated with a 60% relative increase in suicide attempts, compared with previous users of antidepressants [11]. It is improbable that these suicide attempts arose as a consequence of relapse, as relapse is generally thought to be delayed in onset for more than 2 weeks after stopping antidepressants [49].

The systematic review also identified five studies that evaluated the severity of withdrawal effects [5], with nearly half of participants who had experienced withdrawal effects choosing the most extreme option in the scale offered to them to describe the severity of those effects [5]. For example, in response to a question ‘How severely do you feel withdrawal has affected your life?’ on a scale of 0–10 given to 580 people who had attempted withdrawal from antidepressants, mostly SSRIs, 43% (249) of participants chose 10, the highest level of the scale [50]. As above, it is possible that the online survey method employed by four of these studies may be biased by patients with more negative experiences; however, it is notable that somewhat more than half of the participants surveyed in these studies had used antidepressants for more than 3 years [51], similar to the wider English population (where about half of antidepressant users have been taking them for more than 2 years) [2]. However, the self-selected nature of this population of respondents limits the ability to extrapolate to the wider population of people taking antidepressants.

The remaining study, conducted by Pfizer, found that 34.3% of patients treated with sertraline for 8 weeks experienced moderately severe symptoms (as rated by an investigator on a global assessment), 23.9% of them experienced a mild withdrawal reaction, while 23.9% reported a minimal reaction [52]. For venlafaxine, after only 8 weeks of use, 38.7% of patients were rated by study researchers as experiencing moderately severe withdrawal symptoms, with 3.2% as ‘severe’ and 1.6% as ‘very severe’ [52]. As a longer duration of treatment appears to be associated with a greater incidence and severity of withdrawal symptoms (see below) [47, 51], patients who are taking antidepressants for longer than 8 weeks are more likely to experience more severe withdrawal symptoms.

Other double-blind staggered RCTs of discontinuation of antidepressants do not measure the severity of withdrawal per se but the mean number of symptoms recorded on the DESS, for each antidepressant provides a proxy measure of severity, albeit imperfect, because a patient could have many minimal symptoms or one very severe symptom-aspects that would not be captured by such a method. Nevertheless, as shown in Table 3, withdrawal symptoms from paroxetine are numerically greater than for citalopram and sertraline, which are in turn numerically greater than fluoxetine (albeit measured only over short periods of time), consistent with their risk of withdrawal (see below).

Table 3 Incidence of withdrawal and measure of severity (by numerical count of DESS or investigator global assessment) for specific antidepressants in double-blind randomised controlled trials captured in Davies and Read [5]Duration of Withdrawal Symptoms

There is significant evidence that withdrawal symptoms can last for weeks, months or even years in some cases [13, 50], but a weighted average of the ten studies included in the recent systematic review was not possible, owing to methodological heterogeneity [5]. One study examining reports from doctors to the Medicines and Healthcare products Regulatory Agency in the UK described a duration of withdrawal symptoms from 1 to 52 days, with an average of 10.5 days, although this is likely to represent an underestimate as a number of patients taking paroxetine had to be re-started on the drug because their withdrawal symptoms were too severe [53]. A Royal College of Psychiatrists online survey found that for the 512 users who experienced withdrawal, the symptoms lasted for up to 6 weeks, and a quarter of the group reported anxiety lasting more than 12 weeks [5]. This is consistent with an earlier study that found withdrawal symptoms lasted at least 6 weeks in 40% of people [45]. In another online study of 580 people who had withdrawn from antidepressant medication, 86.7% responded that the syndrome had lasted at least 2 months, 58.6% at least 1 year and 16.2% for more than 3 years [50], although this study may have surveyed a population with a more severe experience of withdrawal than average. Other studies also report longer durations of withdrawal symptoms, in at least some cases, symptoms can persist for years [13, 50, 54]. It is difficult to establish to what extent these very long-lasting syndromes represent outliers, as it is not possible to establish that these are representative populations of antidepressant users, but withdrawal symptoms likely persist significantly longer than the 1-week or 2-week periods that have been previously ascribed to them, albeit in an unknown proportion of patients [55].

Determinants of Antidepressant Withdrawal Symptoms

As adaptations to the presence of the drug are thought to underlie withdrawal symptoms, a longer duration of use and a higher dosage would be expected to contribute to the degree of adaptation and thus to the incidence, severity and duration of withdrawal symptoms. Drugs with shorter half-lives may induce more severe withdrawal effects with an earlier onset than those drugs with longer half-lives because the mis-match between what the brain has accommodated to and what is provided is greater (Fig. 1). Alternatively, different antidepressants may cause greater effects on the brain, perhaps related to their different receptor targets and binding properties. Individual physiological differences [10, 27] may also affect the degree of adaptation to the drug and thus the risk of withdrawal symptoms. We explore evidence for all of these determinants.

Effect of Duration of Use on Incidence, Severity and Duration of Withdrawal Symptoms

Although the primary data are not publicly available, the CSM was granted access to unpublished manufacturer’s data for antidepressant withdrawal effects for a variety of antidepressants [47]. The Committee was provided with all clinical trial data (placebo-controlled or active-controlled studies) from which the manufacturers had evaluated the incidence and severity of withdrawal effects (calculated according to the manner that they had been evaluated in the trials) and their relationship to duration of use and tapering.

Duration of use of paroxetine was found to be related to the incidence of withdrawal symptoms on stopping, when adult clinical trial data were obtained from the manufacturer (Fig. 2) [47]. Although there was not enough information for the CSM to make a determination of the role of duration of treatment in citalopram withdrawal effects, there was some indication that a longer duration of treatment with escitalopram increased the risk of a withdrawal reaction [47]. There was limited evidence of an effect related to the duration of use for fluoxetine, fluvoxamine (although there was confusion between adverse effects that led to a drop out from trials and adverse effects arising from the withdrawal process itself), mirtazapine (pooled analyses not appropriate to evaluate this question) or sertraline. Venlafaxine demonstrated some evidence of a duration of treatment effect: 14% of patients after 8 weeks of treatment experienced dizziness, while this rose to 29% after 24 weeks of treatment [47].

Although no RCTs examined the severity of withdrawal symptoms in association with treatment duration (rather, they only counted the number of symptoms), online surveys of patients did so [56, 57]. Although these surveys may have captured skewed samples, the line of best fit suggests a clear gradient between the duration of use and severity (as well as the incidence) of withdrawal syndrome (Fig. 3) [57]. These surveys included patients who stopped taking various antidepressants including paroxetine, venlafaxine, citalopram, fluoxetine, escitalopram, sertraline and tricyclic antidepressants [57]. Duration of antidepressant use is likely to lead to greater physiological adaptations increasing the risk and severity of withdrawal symptoms [57]. The relationship between duration of use and the risk of withdrawal effects also appears to have a second-order relationship (the gradient between the risk of withdrawal effects become less steep over time) perhaps consistent with ceiling effects for adaptation.

Fig. 3

Relationship between duration of treatment and severity and duration of withdrawal symptoms from surveys of antidepressant users and observational studies. The relationship between duration of treatment of antidepressants and incidence of moderate or severe withdrawal symptoms. Graph is derived from data in Read et al. [57]

Effect of Dose on Withdrawal Symptoms

The CSM also examined the relationship between the dose of medication and the risk of withdrawal, and though it was not explicit about the nature of these studies, the implication is that these data were derived from studies mostly abruptly stopping the medications [47]. Although it is difficult to make comparisons between such studies analysed by the CSM, and other studies that looked at dose-dependent effects [58] because such data are susceptible to the ecological fallacy, there is evidence of dose-dependent effects within individual trials (Table 4). There was a higher incidence of withdrawal effects for higher dosages of paroxetine in the analysis by the CSM [47], although the effect reached a threshold at 20 mg (Table 4), probably because of the hyperbolic relationship between antidepressant dosage and effect on its target receptors [59,60,61,62]. There was a more pronounced dose-dependent relationship for venlafaxine withdrawal effects (Table 4) [47], with an increased incidence at higher dosages possibly related to greater noradrenergic effects at these dosages [63, 64]. Fluvoxamine and mirtazapine did not demonstrate clear dose-dependent effects; however, the CSM cautioned that the pooled analysis applied may not have been appropriate to detect these effects [47]. Overall, dosage does appear to have some relationship to the risk of withdrawal symptoms (where higher doses were associated with an increased risk of withdrawal), but its influence may not be as strong as the duration of use, perhaps because higher dosages have only small additional pharmacological effects over minimum clinically employed dosages because of the hyperbolic shape of their dose-response curves [60, 62, 65,66,67].

Table 4 Relationship between dosage of antidepressants and incidence of withdrawal effectsEffect of Drug Type on Withdrawal Symptoms

It has been suggested that the risk of withdrawal symptoms varies between different antidepressants. This could be due to differing half-lives, with drugs with shorter half-lives being eliminated more quickly and therefore producing more precipitous drops in inputs ‘expected’ by the system (Fig. 1) [15]. This is supported by the finding that percentage reductions in plasma concentrations of fluoxetine, sertraline and paroxetine, following cessation, showed a significant correlation with the appearance of withdrawal symptoms [68]. Cessation of paroxetine for several days causes withdrawal symptoms in 66–100% of patients [41, 43], cessation of sertraline in 59–60% of patients [41, 43] and fluoxetine in 14–77% of patients [41, 43], (double-blind RCTs examining drugs are summarised in Table 3). In surveys, which may include a self-selected population, these differences among common SSRIs are roughly preserved: 69, 62 and 44% of patients stopping paroxetine, sertraline, and fluoxetine, respectively, report withdrawal symptoms [5].

However, withdrawal symptoms following the cessation of fluoxetine, the SSRI with the longest half-life (7–15 days for its active metabolite, nor-fluoxetine), has been observed to occur with a delay of onset of 4–6 weeks after discontinuation in one study [45], and 2 weeks after discontinuation in another [