Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management

Haddad, Peter M.

doi:10.2165/00002018-200124030-00003

Cited by 214Treatment of Major DepressionPharmacovigilance and Adverse Drug ReactionsElectroconvulsive Therapy Studies

Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management

Haddad, Peter M.·2001·Drug Safety

DOI 10.2165/00002018-200124030-00003

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Abstract

Discontinuation symptoms are recognised with tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and miscellaneous antidepressants. A wide variety of symptoms have been described, differing somewhat between antidepressant classes, and several symptom clusters or discontinuation syndromes appear to exist. A common feature is onset within a few days of stopping the antidepressant or, less commonly, reducing the dosage. Discontinuation syndromes are clinically relevant as they are common, can cause significant morbidity, can be misdiagnosed leading to inappropriate treatment and can adversely effect future antidepressant compliance. Preventative strategies include tapering antidepressants prior to stoppage and educating patients and healthcare professionals to ensure that antidepressants are taken consistently and not stopped abruptly. Most reactions are mild and short-lived and require no treatment other than patient reassurance. Severe cases can be treated symptomatically or the antidepressant can be reinstated before being gradually withdrawn. Reinstatement usually leads to symptom resolution within 24 hours. Some individuals require very conservative tapering schedules to prevent the re-emergence of symptoms. With SSRIs and venlafaxine another strategy to consider is switching to fluoxetine, which may suppress the discontinuation symptoms, but which has little tendency to cause such symptoms itself. Neonatal discontinuation symptoms can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and doctor must take this into consideration when making prescribing decisions. Discontinuation symptoms have received little systematic study with the result that most of the recommendations made here are based on anecdotal data or expert opinion. Research is needed to provide a firm evidence base for future recommendations.

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Gradual discontinuation can reduce both rebound insomnia and rebound anxiety.
“In addition, it has been suggested that gradual discontinuation can reduce both rebound insomnia [84, 85] and rebound anxiety [1].”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [84]
Antidepressant withdrawal syndrome is more common and severe than earlier presumed, affecting roughly 30-50% of those who attempt to stop their treatment.
“It is now suspected that antidepressant withdrawal syndrome is more common and severe than earlier presumed, affecting roughly 30–50% of those who attempt to stop their treatment.12,13,23,24”
From Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum (2020) · cites this paper as [24]
With new-generation antidepressants, it has been widely observed that risk of withdrawal emerges after the drugs have been taken for 1 to 2 months.
“With new-generation antidepressants, it has been widely observed that risk of withdrawal emerges after the drugs have been taken for 1 to 2 months.24,39”
From Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum (2020) · cites this paper as [24]
There is increasing evidence for postwithdrawal disorders with SSRI long-term use.
“We now have increasing evidence for postwithdrawal disorders with SSRI long-term use [6,15,16,26,37] .”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]
Persistent postwithdrawal disorders have been described with different classes of CNS drugs (e.g. protracted insomnia for alcohol and benzodiazepine withdrawal and major depression/dysphoria for cocaine and amphetamine withdrawal), and even more so with specific drugs (e.g. quetiapine and paroxetine) within a drug class.
“Persistent postwithdrawal disorders have been described with different classes of CNS drugs (e.g.protracted insomnia for alcohol and benzodiazepine withdrawal [10,36] and major depression/dysphoria for cocaine and amphetamine withdrawal [10,23] ), and even more so with specific drugs (e.g.quetiapine and paroxetine) within a drug class [6,15,16,33] .”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]

Data from controlled trials, case reports, and online patient reports show that paroxetine is most likely to be associated with new withdrawal symptoms, and fluoxetine the least.
“Data from controlled trials [15,20,29] , case reports [16] , and online patient reports [26] show that paroxetine is most likely to be associated with new withdrawal symptoms, and fluoxetine the least.”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]
Rebound anxiety and rebound panic were reported with abrupt benzodiazepine discontinuation.
“Rebound anxiety [2,14] and rebound panic [15] were then reported with abrupt benzodiazepine discontinuation [9] .”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]
According to most studies, even with gradual tapering, withdrawal symptoms still occur.
“According to most studies [1,15,16,20,29] , even with gradual tapering, withdrawal symptoms still occur.”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]
Postwithdrawal disorders may resemble rebound symptoms being more severe than the original symptoms, but these disorders persist at least 6 weeks in contrast to rebound symptoms.
“They may resemble rebound symptoms being more severe than the original symptoms, but these disorders persist at least 6 weeks in contrast to rebound symptoms and [6,15,16,26,37] .”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]
Paroxetine carries a high risk of disabling withdrawal.
“Given the evidence for the high risk of disabling withdrawal with paroxetine”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]
The high risk of disabling withdrawal with paroxetine is thought to be related to noradrenergic and cholinergic supersensitivity.
“thought to be related to noradrenergic and cholinergic supersensitivity [15,35]”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]
Persistent postwithdrawal panic disorder has been shown to occur following withdrawal of paroxetine, and paroxetine has also been associated with other postwithdrawal disorders.
“Persistent postwithdrawal panic disorder [15,38] has been shown to occur following withdrawal of paroxetine, and paroxetine has also been associated with other postwithdrawal disorders [6,15,16] .”
From New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal (2015) · cites this paper as [15]

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Adverse Effects of Atypical Antipsychotics
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Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale
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Discontinuation Syndrome in Dysthymic Patients Treated with Selective Serotonin Reuptake Inhibitors: A Clinical Investigation
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Pharmacotherapy of Mood Disorders
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Use of psychopharmacological agents for functional gastrointestinal disorders.
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Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum
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What I have learnt from helping thousands of people taper off antidepressants and other psychotropic medications
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The pharmacological management of depression
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Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database
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Depression and Erectile Dysfunction
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New insights on the antidepressant discontinuation syndrome
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Drug-Induced Insomnia and Excessive Sleepiness
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The Marketization of Depression: The Prescribing of SSRI Antidepressants to Women *
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Antidepressant withdrawal – the tide is finally turning
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The Use of Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors in Women Who Are Breastfeeding
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Drug-Induced Insomnia and Excessive Sleepiness
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Sertraline inhibits increases in body fat and carbohydrate dysregulation in adult female cynomolgus monkeys
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The Use of a Cholinesterase Inhibitor Review Committee in Long-Term Care
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Executive Agency for Health and Consumers
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An Open-label Study of Duloxetine for the Treatment of Major Depressive Disorder
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Immediate Switching of Antidepressant Therapy: Results from a Clinical Trial of Duloxetine
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The Prescription of Benzodiazepines for Panic Disorder
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INTRODUCTION
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Rebound effect of drugs: fatal risk of conventional treatment and pharmacological basis of homeopathic treatment
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Venlafaxine in the treatment of anxiety disorders
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Odorants: a tool to provide nonpharmacological intervention to reduce anxiety during normal and pathological aging
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Authors: Haddad, P. M.
Corresponding author: Haddad, Peter M.
ORCID: Haddad, Peter M.
Venue: Drug Safety
Publisher: Springer Science and Business Media LLC
Published: 2001
Volume: 24
Issue: 3
Pages: 183-197
ISSN: 0114-5916 (ISSN-L)
DOI: 10.2165/00002018-200124030-00003
OpenAlex: W1593032895
Cited by: 214
References: 99
Citations by year: 2026: 7 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 10 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 7 · 2015: 10 · 2014: 7 · 2013: 24 · 2012: 4
FWCI: 1.13
Type: journal article
Language: en
Open access: closed
Locations: Drug Safety (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (submittedVersion)
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: antidepressant discontinuation syndrome, antidepressant withdrawal symptoms, selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, antidepressant tapering, fluoxetine, venlafaxine, breastfeeding
MeSH terms: Animals, Antidepressive Agents, Antidepressive Agents, Tricyclic, Humans, Monoamine Oxidase Inhibitors, Patient Compliance, Substance Withdrawal Syndrome, Syndrome, Selective Serotonin Reuptake Inhibitors

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