Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database

To our knowledge, this pharmacovigilance study provides the first real-world data estimating the magnitude of reporting withdrawal syndrome for antidepressants compared to other drugs. Disproportionality analyses yielded significant associations for most antidepressants currently on the market, including TCAs, SSRIs and SNRIs. The extent of reporting for duloxetine, paroxetine, venlafaxine and desvenlafaxine did not differ from buprenorphine; thus, supporting a clinical and epidemiological impact of withdrawal syndrome by these antidepressants. These estimates provide the first large body of real-world evidence, suggesting that SNRIs and SSRIs and also TCAs could be associated with a higher risk of withdrawal syndrome, compared to all other drugs [4, 5, 10, 14].

Our a priori developed set of specific criteria to clinically prioritise disproportionality signals is extremely important for a clinically useful interpretation of these findings, as already suggested by other authors [36]. Based on these criteria, paroxetine, desvenlafaxine, duloxetine and venlafaxine emerged as strongest clinical priorities for withdrawal syndrome, clomipramine, sertraline, citalopram, imipramine and vilazodone as moderate, whereas the ranking for the rest of the antidepressants was weak. One possible explanation for the differential reporting observed for different antidepressants may be related to their half-life [10, 14]. Individuals discontinuing shorter half-life antidepressants may be more likely to report withdrawal syndrome than those discontinuing antidepressants with longer half-lives, confirming the findings of Quilichini and colleagues [14]. Indeed, in our analysis, antidepressants with the strongest safety signals were those with the shortest half-life, such as paroxetine, duloxetine, venlafaxine and desvenlafaxine. In line with our findings, previous clinical trials, case reports on individual antidepressants, and two pharmacovigilance studies suggested that paroxetine may have a strong potential for withdrawal syndrome [4, 5, 13, 42], and, among TCAs, clomipramine [42]. Previous findings additionally suggested that, among the SNRIs, venlafaxine may have the highest risk [4]. Our data, by contrast, indicated that duloxetine may carry a higher risk than venlafaxine. This is clinically relevant, considering that duloxetine is frequently prescribed for a wide variety of indications, including medical conditions such as chronic pain, functional medical disorders, and menopausal symptoms [43, 44].

Further, we found a higher reporting of withdrawal syndrome with SSRIs and other antidepressants compared to buprenorphine, a drug known for causing withdrawal syndrome [34]. Although the hypothesis that antidepressants may carry a potential risk for withdrawal syndrome that is similar to addictive drugs is not new [45], we are not aware of any direct comparison between antidepressants and opioids. It must be noted that the overall disproportionality signal found for antidepressants altogether was mainly explained by the four antidepressants that showed a significant disproportionality of withdrawal syndrome compared to buprenorphine, i.e., paroxetine, duloxetine, venlafaxine and desvenlafaxine (RORs of 4.6, 4.16, 2.98, and 2.89, respectively). This result boosts concerns on these antidepressants and on how much their related withdrawal syndrome has been underestimated [10, 34].

The most common symptoms of withdrawal syndrome included dizziness, nausea, paraesthesia, headache, feeling abnormal, anxiety, suicidal ideation, insomnia and depression. Around two-thirds of cases were reported for females and the mean age was around 40 years, in line with that previously found by another pharmacovigilance study [14]. The mean duration of the syndrome was around six days in non-serious reactions and 24 days in serious reactions. Possibly, two distinct clinical forms of withdrawal syndrome may therefore exist, one form showing mild symptoms for a few days only [46], and another showing symptoms over several weeks, with associated severe impairments [47, 48]. Individuals more likely to experience severe forms of antidepressant-related withdrawal syndrome include adolescents and younger adults, men, people treated for more than two years with antidepressants, and with psychotropic comedications. Different aspects could explain these results. First, persons taking other psychotropic drugs may possibly suffer from mental health comorbidities, and may therefore be more at risk of serious reactions and drug-drug interactions, as previously pointed out for other psychotropic drugs [20]. Second, regarding treatment duration, it has been suggested that long-term treatment with antidepressants can induce long-term modifications to neuronal receptors, resulting in more severe withdrawal symptoms [9, 10]. The highlighted clinical and demographic characteristics may explain the huge variability in the prevalence estimates found in observational retrospective studies [2].

When interpreting the findings of this study some limitations need to be considered. Apart from the traditional limitations of pharmacovigilance research (inability to infer causality, quality of information, and lack of denominators, which does not allow to calculate incidence rates), disproportionality in spontaneous reporting databases may increase after a safety alert or when concerns are raised in the literature. In our analyses, this phenomenon, known as notoriety bias [49], cannot be excluded, as antidepressants with the highest disproportionality were also those with the highest absolute number of reports. Specifically, the attention recently received by these antidepressants may have inflated the number of reports and the RORs, as also found by a recent work by Chiappini et al [13, 20]. By contrast, antidepressants recently introduced in the market with lower RORs or no disproportionality, such as esketamine and agomelatine, had a very low number of cases. This may explain why less strong disproportionality, or no signal was reported for some short half-life antidepressants, such as fluvoxamine, milnacipran, reboxetine, mianserin, esketamine and agomelatine. Moreover, although the accuracy of our original scoring system cannot be determined, we used well-established criteria comprising qualitative and disproportionality analyses, and we adopted a conservative approach in the selection of thresholds (e.g., two points only if more than 2/3 of the cases were not affected by confounders; no point if lower limit of the 95% CI of ROR was ≤ 10), which include the robustness of findings across disproportionality analyses. This approach supports the potential role of the scoring system as a prioritisation tool of withdrawal syndrome in pharmacovigilance. Another limitation regards the nature of some reported symptoms of withdrawal syndrome, such as depression, anxiety, insomnia, and suicidal ideation. It could be argued that such affective symptoms might overlap with symptoms of relapse of depression or anxiety, making it extremely challenging for clinicians to distinguish between them. This is indeed a clinically difficult differential diagnosis [2, 47, 50]. However, considering that the mean reported duration of withdrawal syndrome was 6 days after antidepressant discontinuation for non-serious reactions and 24 for serious reactions, it is unlikely that a relapse would occur over such a short period of time [3]. Finally, another important limitation is the lack of information regarding the modality of antidepressant discontinuation (if abruptly discontinued or tapered, and whether over a short or long period of time). Thus, whether antidepressant slow tapering could mitigate antidepressant-related withdrawal syndrome could not have been addressed by the present analysis [6, 51].

Despite these limitations, pharmacovigilance assessments represent an essential and reliable opportunity to monitor drug safety [23], especially in an area where expert opinions and small clinical studies predominate over attempts of collecting large samples of epidemiological and clinical real-world data [12]. This study provided additional evidence to a recently published pharmacovigilance study [14], as we compared the reporting of withdrawal syndrome for antidepressants to other drugs, and we performed intra-class comparisons among antidepressants, identified subgroup of patients susceptible to severe reactions, and described the symptoms that are more commonly reported along with withdrawal syndrome. Our findings have, therefore, several implications for clinicians, patients, policy-makers and researchers.

Clinical Implications

First, when balancing potential benefits and risks for each individual patient, the risk of withdrawal syndrome should not be underestimated, as used to happen with other drugs, such as opioids and benzodiazepines [52]. Second, when discontinuing antidepressants, clinicians should acknowledge the potential occurrence of withdrawal syndrome and recognise the corresponding symptoms, informing patients about this possibility and about any potential management strategies, instead of mainly focusing on the relapse risk [12]. Third, extra caution is needed in specific subgroups of patients. Adolescents, younger adults, and male patients who discontinued long-term antidepressant treatment or who were prescribed with a high-risk antidepressant, or with polypharmacy, showing symptoms for longer than one week, must be carefully followed up, as these patients may suffer from more serious withdrawal reactions with potentially severe consequences. Evidence-based clinical guidelines, such as NICE (National Institute for Health and Care Excellence) guidelines, or WHO reports, currently mention a generical risk of withdrawal symptoms for antidepressants discontinuation and especially for venlafaxine and paroxetine [53, 54]. Although our findings might suffer the limitations of disproportionality analyses, and they need further confirmation, we suggest that recommendations could be updated, giving emphasis to our proposed ranking, which suggests clinically important differences between individual antidepressants. Moreover, these findings may be of value to better describe the type of symptoms that usually characterise this syndrome, and to detail specific risk factors and subgroups of patients with high risk of severe reactions [53].

Research Implications

This work provides methodological directions for future studies aiming to improve current understanding of antidepressant-related withdrawal syndrome, including its clinical features, as well as its pharmacodynamic and pharmacokinetic correlates.

Specifically, our findings on differential risks for different subgroups of patients could be of essential help for stratifying future observational studies based on the subgroup characteristics. Specifically, we argue that future prevalence, cohort or case-control studies should stratify the study population based on sex, age, type of antidepressant, duration of treatment, to better estimate the prevalence of withdrawal syndrome in these subgroups of patients that exist in the real world, reducing the previously found high variability. Furthermore, further research should investigate possible explanations for the higher risk of severe withdrawal symptoms in men and younger individuals.

Second, our findings provide directions for future RCTs, that should investigate strategies to mitigate the symptoms, such as slow tapering, stratifying the participants considering the differential risk of withdrawal syndrome of each single antidepressant.

Finally, the risk/benefits balance of long-term treatment or ‘maintenance’ antidepressant treatment should be reassessed [47, 55].

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