Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review
Open accessAbstract
Background: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation. Methods: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: “duloxetine” OR “venlafaxine” OR “desvenlafaxine” OR “milnacipran” OR “levomilnacipran” OR “SNRI” OR “second generation antidepressant” OR “serotonin norepinephrine reuptake inhibitor” AND “discontinuation” OR “withdrawal” OR “rebound.” Only published trials in the English language were included. Results: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well. Conclusions: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.
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Fava et al. published the first systematic review on SNRIs.
“and a few years later, Fava et al. [6] published the first systematic review on SNRIs.”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [6]
The Introduction (p. 1) says that, to the authors’ knowledge, no English-language systematic review had covered the clinical aspects of SNRI discontinuation. The Results (p. 2) confirm that this paper is such a review. The citing sentence omits those limits and calls it the first systematic review on SNRIs generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAntidepressants have been associated with withdrawal symptoms since 1960 for TCAs and MAOs, and since the 1990s for SSRIs and SNRIs.
“Antidepressants have been associated with withdrawal symptoms since 1960 for TCAs and MAOs (Nilsen 2012), and since the 1990s for SSRIs and SNRIs (Fava 2015; Fava 2018b).”
From Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults (2021) · cites this paper as Fava 2018b
New withdrawal symptoms may occur after discontinuation of SNRIs (venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran).
“A systematic review of the literature [6] indicated that new withdrawal symptoms may occur also after discontinuation of SNRIs (i.e., venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran).”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [6]
Discontinuation of antidepressant medications such as SSRIs, duloxetine, and venlafaxine represents a major clinical challenge.
“Discontinuation of antidepressant medications such as selective serotonin reuptake inhibitors, duloxetine and venlafaxine represents a major clinical challenge 99,100 .”
From The pursuit of euthymia (2020) · cites this paper as [100]
Discontinuation symptoms were found to occur after gradual tapering.
“Even though discontinuation symptoms were mostly reported after abrupt discontinuation, they were found to occur after gradual tapering [5, 6]”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [6]
SNRI withdrawal symptoms typically appear within a few days from drug discontinuation and last a few weeks.
“They typically appear within a few days from drug discontinuation and last a few weeks.”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [6]
Withdrawal syndromes after decrease or discontinuation of antidepressants may be associated with additional clinical manifestations, including modifications of the illness course such as switching to mania or other forms of excessive behavioral activations, loss of clinical effects, and refractoriness to treatment.
“Withdrawal syndromes after decrease or discontinuation of antidepressants may be associated with additional clinical manifestations. They include modifications of the illness course, such as switching to mania or other forms of excessive behavioral activations [24], but also loss of clinical effects and refractoriness to treatment; they have been reported with SSRI and SNRI [5, 6, 27].”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [6]
The prevalence of new withdrawal symptoms varies among different drugs but was highest after the discontinuation of venlafaxine (rates of withdrawal from controlled trials and open trials range from 23 to 78%) and lowest after the discontinuation of levomilnacipran (rates range from 9 to 10%).
“The prevalence of new withdrawal symptoms vary among the different drugs but was highest after the discontinuation of venlafaxine (rates of withdrawal from controlled trials and open trials rage from 23 to 78%) and lowest after the discontinuation of levomilnacipran (rates of withdrawal from controlled trials and open trials rage from 9 to 10%) [6].”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [6]
Stopping antidepressants commonly causes withdrawal symptoms, which can be severe and long-lasting.
“Recent systematic reviews of withdrawal symptoms from antidepressants have drawn attention to the fact that withdrawal symptoms are more common, more severe and longer-lasting than previously supposed,5,7,8”
Three recent systematic reviews indicated that the NICE and US guideline estimates of withdrawal duration are gross underestimates.
“Three recent systematic reviews have, however, indicated that these are gross underestimates.21–23”
From A survey of UK general practitioners about depression, antidepressants and withdrawal: implementing the 2019 Public Health England report (2020) · cites this paper as [23]
Users of antidepressants, especially SSRIs and SNRIs, often experience difficulties coming off medication.
“there is consensus that users of antidepressants and especially of SSRIs (Selective serotonin reuptake inhibitors) and SNRIs (Serotonin and norepinephrine reuptake inhibitors) often experience difficulties coming off medication.1,2”
From Successful use of tapering strips for hyperbolic reduction of antidepressant dose: a cohort study (2021) · cites this paper as [2]
A possible driver of unnecessary long-term medication could be the propensity of antidepressants to cause physical dependence and withdrawal symptoms upon dose reduction or cessation discouraging discontinuation.
“A possible driver of unnecessary long-term medication could be the propensity of antidepressants to cause physical dependence (i.e., pharmacodynamic neurophysiological adaptations) and withdrawal symptoms upon dose reduction or cessation discouraging discontinuation.11–18”
From Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum (2020) · cites this paper as [14]
These symptoms are also frequent acute withdrawal symptoms.
“Moreover, these symptoms are also frequent acute withdrawal symptoms,11,13,14,28”
From Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum (2020) · cites this paper as [14]
The clinical phenomena of antidepressant discontinuation pertain to withdrawal syndromes and do not differ from those that occur with other psychotropic drugs.
“However, this position is no longer tenable in view of current evidence that indicates that the clinical phenomena pertain to withdrawal syndromes and do not differ from those that occur with other psychotropic drugs.”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [42]
Withdrawal symptoms following discontinuation of antidepressant treatment have been described with any type of AD, but particularly with SSRI, venlafaxine, and duloxetine.
“They have been described with any type of AD, but particularly with SSRI, venlafaxine, and duloxetine.”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [42]
Untreated withdrawal symptoms may be mild and resolve spontaneously in 1-3 weeks; in other cases they may persist for months or even years, leading to persistent post-withdrawal disorder.
“Untreated symptoms may be mild and resolve spontaneously in 1–3 weeks; in other cases they may persist for months or even years,40–45 leading to what has been defined as persistent post-withdrawal disorder.”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [42]
The withdrawal syndrome encompasses a broad range of somatic symptoms (e.g. headache, dizziness, flu-like symptoms, nausea).
“The withdrawal syndrome encompasses a broad range of somatic symptoms (e.g. headache, dizziness, flu-like symptoms, nausea).”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [42]
With both benzodiazepines and antidepressants, withdrawal reactions and post-withdrawal syndromes may ensue despite slow tapering.
“It would seem that, with both types of drugs, that withdrawal reactions and post-withdrawal syndromes may ensue, despite slow tapering.”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [42]
After their introduction, more pronounced problems occurred with most of the newer antidepressants.
“However, in due course after their introduction, more pronounced problems occurred with most of the newer antidepressants.40–46”
From May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance (2020) · cites this paper as [42]
Behavioral toxicity can be subtle and detected only by specific assessment, such as cognitive impairment with all psychotropic drugs or apathy with antidepressants.
“Other times, behavioral toxicity may entail subtle manifestations, which may be detected only with specific assessment strategies, such as with cognitive impairment associated with all psychotropic drugs [34] or with apathy related to the use of antidepressant drugs [35].”
From Iatrogenic Factors in Psychopathology (2019) · cites this paper as [35]
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- 2 Fava GA, Gatti A, Belaise C, Guidi J, Offidani E: Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom 2015; 84: 72-81.
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“In addition, the reference lists and citations of initially identified articles, including relevant systematic reviews and pivotal studies (e.g., Fava et al. , 2015, 2018), were manually searched to identify further original studies not captured by the electronic literature search.”
Conversations with clients about antidepressant withdrawal and discontinuation
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Do discontinuation symptoms predict depression relapse after antidepressant cessation?
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- Authors
- Fava, G. A., Benasi, G., Lucente, M., Offidani, E., Cosci, F., & Guidi, J.
- Affiliations
- University at Buffalo, State University of New York (US)
- University of Bologna (IT)
- Pennsylvania State University (US)
- University of Florence (IT)
- Venue
- Psychotherapy and Psychosomatics
- Publisher
- S. Karger AG
- Published
- 2018
- Volume
- 87
- Issue
- 4
- Pages
- 195-203
- ISSN
- 0033-3190 (ISSN-L)
- 1423-0348
- OpenAlex
- W2883393306
- Semantic Scholar
- 574fd1f66941838008917a45df3fbebd6b045fae
- Cited by
- 209
- References
- 76
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 37 · 2023: 19 · 2022: 28 · 2021: 21 · 2020: 33 · 2019: 28 · 2018: 6
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Psychotherapy and Psychosomatics (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- serotonin-norepinephrine reuptake inhibitors, drug discontinuation, withdrawal symptoms, antidepressant discontinuation, venlafaxine, duloxetine, desvenlafaxine, milnacipran, levomilnacipran, antidepressant tapering, rebound, mood and anxiety disorders
- MeSH terms
- Duloxetine Hydrochloride, Desvenlafaxine Succinate, Venlafaxine Hydrochloride, Humans, Substance Withdrawal Syndrome, Randomized Controlled Trials as Topic, Adrenergic Uptake Inhibitors, Mood Disorders
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