Antidepressant discontinuation syndrome

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Antidepressant discontinuation syndrome
Other names: Antidepressant withdrawal syndrome[1]
SymptomsFlu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes[2]
Usual onsetWithin 3 days[2]
DurationFew weeks to months[3][4]
CausesStopping of an antidepressant medication[2][3]
Diagnostic methodBased on symptoms[2]
Differential diagnosisAnxiety, mania, stroke[2]
PreventionGradual dose reduction[2]
Frequency20-50%(with sudden stopping)[3][4]

Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication that was taken continuously for at least one month.[5] The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety.[2][3][4] The problem usually begins within three days and may last for several months.[2][4] Rarely psychosis may occur.[2]

A discontinuation syndrome can occur after stopping any antidepressant including selective serotonin re-uptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs).[2][3] The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life.[2] The underlying reason for its occurrence is unclear.[2] The diagnosis is based on the symptoms.[2]

Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering.[2][4][6] Treatment may include restarting the medication and slowly decreasing the dose.[2] People may also be switched to the long acting antidepressant fluoxetine which can then be gradually decreased.[6]

Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.[2][3][4] The condition is generally not serious,[2] though about half of people with symptoms describe them as severe.[4] Some restart antidepressants due to the severity of the symptoms.[4]

Signs and symptoms

People with antidepressant discontinuation syndrome have been on an antidepressant for at least four weeks and have recently stopped taking the medication, whether abruptly, after a fast taper, or each time the medication is reduced on a slow taper.[2] Commonly reported symptoms include flu-like symptoms (nausea, vomiting, diarrhea, headaches, sweating) and sleep disturbances (insomnia, nightmares, constant sleepiness). Sensory and movement disturbances have also been reported, including imbalance, tremors, vertigo, dizziness, and electric-shock-like experiences in the brain, often described by people who have them as "brain zaps". Mood disturbances such as dysphoria, anxiety, or agitation are also reported, as are cognitive disturbances such as confusion and hyperarousal.

In cases associated with sudden discontinuation of MAO inhibitors, acute psychosis has been observed.[2][7][8] Over fifty symptoms have been reported.[9]

A 2009 Advisory Committee to the FDA found that online anecdotal reports of discontinuation syndrome related to duloxetine included severe symptoms and exceeded prevalence of both paroxetine and venlafaxine reports by over 250% (although acknowledged this may have been influenced by duloxetine being a much newer drug).[10] It also found that the safety information provided by the manufacturer not only neglected important information about managing discontinuation syndrome, but also explicitly advised against opening capsules, a practice required to gradually taper dosage.[10]


Most cases of discontinuation syndrome may last between one and four weeks and resolve on their own.[2] Occasionally symptoms can last up to one year.[3] They typically resolve within a day of restoring the medication.[11] Paroxetine and venlafaxine seem to be particularly difficult to discontinue, and prolonged withdrawal syndrome (post-acute-withdrawal syndrome, or PAWS) lasting over 18 months has been reported with paroxetine.[12][13][14]


The underlying reason for its occurrence is unclear,[2] though the syndrome appears similar to withdrawal from other psychotropic drugs such as benzodiazepines.[1]

Prevention and treatment

In some cases, withdrawal symptoms may be prevented by taking medication as directed, and when discontinuing, doing so gradually, although symptoms may appear while tapering. When discontinuing an antidepressant with a short half-life, switching to a drug with a longer half-life (e.g. fluoxetine or citalopram) and then tapering, and eventually discontinuing, from that drug can decrease the severity of symptoms.[7]

Treatment is dependent on the severity of the discontinuation reaction and whether or not further antidepressant treatment is warranted. In cases where further antidepressant treatment is prescribed, then the only option suggested may be restarting the antidepressant. If antidepressants are no longer required, treatment depends on symptom severity. If symptoms of discontinuation are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously, or by switching to a drug with a longer half life, (such as Prozac), and then tapering and discontinuing that drug.[12] In severe cases, hospitalization may be required.[2]

Pregnancy and newborns

Antidepressants, including SSRIs, can cross the placenta and have the potential to affect the fetus and newborn, including an increased chance of miscarriage, presenting a dilemma for pregnant women to decide whether to continue to take antidepressants at all, or if they do, considering if tapering and discontinuing during pregnancy could have a protective effect for the newborn.[15]

Postnatal adaptation syndrome (PNAS) (originally called "neonatal behavioral syndrome", "poor neonatal adaptation syndrome", or "neonatal withdrawal syndrome") was first noticed in 1973 in newborns of mothers taking antidepressants; symptoms in the infant include irritability, rapid breathing, hypothermia, and blood sugar problems. The symptoms usually develop from birth to days after delivery and usually resolve within days or weeks of delivery.[15]

Culture and history

Antidepressant discontinuation symptoms were first reported with imipramine, the first tricyclic antidepressant (TCA), in the late 1950s, and each new class of antidepressants has brought reports of similar conditions, including monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs. As of 2001, at least 21 different antidepressants, covering all the major classes, were known to cause discontinuation syndromes.[12] The problem has been poorly studied, and most of the literature has been case reports or small clinical studies; incidence is hard to determine and controversial.[12]

With the explosion of use and interest in SSRIs in the late 1980s and early 1990s, focused especially on Prozac, interest grew as well in discontinuation syndromes.[16] Some of the symptoms emerged from discussion boards where people with depression discussed their experiences with the disease and their medications; "brain zaps" or "brain shivers" was one symptom that emerged via these websites.[17][18]

Heightened media attention and continuing public concerns led to the formation of an expert group on the safety of selective serotonin reuptake inhibitors in England, to evaluate all the research available prior to 2004.[19]: iv  The group determined that the incidence of discontinuation symptoms are between 5% and 49%, depending on the particular SSRI, the length of time on the medicine and abrupt versus gradual cessation.[19]: 126–136 

With the lack of a definition based on consensus criteria for the syndrome, a panel met in Phoenix, Arizona in 1997 to form a draft definition,[20] which other groups continued to refine.[21][22]

In the late 1990s, some investigators thought that the fact that symptoms emerged when antidepressants were discontinued might mean that antidepressants were causing addiction, and some used the term "withdrawal syndrome" to describe the symptoms. While people taking antidepressants do not commonly exhibit drug-seeking behavior, stopping antidepressants leads to similar symptoms as found in drug withdrawal from benzodiazapines, and other psychotropic drugs.[23][24] As such, some researchers advocate the term withdrawal over discontinuation, to communicate the similar physiological dependence and negative outcomes.[1] Due to pressure from pharmaceutical companies who make anti-depressants, the term "withdrawal syndrome" is no longer used by drug makers, and thus, most doctors, due to concerns that they may be compared to other drugs more commonly associated with withdrawal.[2]

2013 class action lawsuit

In 2013, a proposed class action lawsuit, Jennifer L Saavedra v. Eli Lilly and Company,[25] was brought against Eli Lilly claiming that the Cymbalta label omitted important information about "brain zaps" and other symptoms upon cessation.[26] Eli Lilly moved for dismissal per the "learned intermediary doctrine" as the doctors prescribing the drug were warned of the potential problems and are an intermediary medical judgment between Lilly and patients; in December 2013 Lilly's motion to dismiss was denied.[27]


The mechanisms of antidepressant withdrawal syndrome have not yet been conclusively identified.[2][8] The leading hypothesis is that after the antidepressant is discontinued, there is a temporary, but in some cases, long-lasting, deficiency in the brain of one or more essential neurotransmitters that regulate mood, such as serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid, and since neurotransmitters are an interrelated system, dysregulation of one affects the others.[2][28]

See also


  1. 1.0 1.1 1.2 "[112] Antidepressant Withdrawal Syndrome | Therapeutics Initiative". Therapeutics Initiative. 23 July 2018. Archived from the original on 3 August 2018. Retrieved 3 August 2018.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 Warner, CH; Bobo, W; Warner, C; Reid, S; Rachal, J (1 August 2006). "Antidepressant discontinuation syndrome". American Family Physician. 74 (3): 449–56. PMID 16913164.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Gabriel, M; Sharma, V (29 May 2017). "Antidepressant discontinuation syndrome". Canadian Medical Association Journal. 189 (21): E747. doi:10.1503/cmaj.160991. PMC 5449237. PMID 28554948.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Davies, J; Read, J (4 September 2018). "A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based?". Addictive Behaviors. 97: 111–121. doi:10.1016/j.addbeh.2018.08.027. PMID 30292574.
  5. Diagnostic and statistical manual of mental disorders : DSM-5 (5th ed.). American Psychiatric Association. 2013. pp. 712–714. ISBN 9780890425541.
  6. 6.0 6.1 Wilson, E; Lader, M (December 2015). "A review of the management of antidepressant discontinuation symptoms". Therapeutic Advances in Psychopharmacology. 5 (6): 357–68. doi:10.1177/2045125315612334. PMC 4722507. PMID 26834969.
  7. 7.0 7.1 Haddad, Peter M.; Anderson, Ian M. (October 2007). "Recognising and managing antidepressant discontinuation symptoms". Advances in Psychiatric Treatment. 13 (6): 447–57. doi:10.1192/apt.bp.105.001966.
  8. 8.0 8.1 Renoir T (2013). "Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved". Front Pharmacol. 4: 45. doi:10.3389/fphar.2013.00045. PMC 3627130. PMID 23596418.
  9. Haddad PM, Dursun SM (2008). "Neurological complications of psychiatric drugs: clinical features and management". Hum Psychopharmacol. 23 (Suppl 1): 15–26. doi:10.1002/hup.918. PMID 18098217.
  10. 10.0 10.1 "Cymbalta (Duloxetine) Discontinuation Syndrome: Issues of Scope, Severity, Duration & Management" (PDF). U.S. Food and Drug Administration (FDA). 9 June 2009. Archived (PDF) from the original on 9 May 2017. Retrieved 17 October 2016.
  11. Haddad, Peter M.; Anderson, Ian M. (1 November 2007). "Recognising and managing antidepressant discontinuation symptoms". Advances in Psychiatric Treatment. 13 (6): 447–457. doi:10.1192/apt.bp.105.001966. ISSN 2056-4678.
  12. 12.0 12.1 12.2 12.3 Haddad, Peter M. (March 2001). "Antidepressant discontinuation syndromes". Drug Safety. 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722.
  13. Tamam, L.; Ozpoyraz, N. (January–February 2002). "Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Review". Advances in Therapy. 19 (1): 17–26. doi:10.1007/BF02850015. PMID 12008858.
  14. Gartlehner, Gerald; Hansen, Richard A.; Morgan, Laura C.; et al. (December 2011). "Results". Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review (Report). Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality. Archived from the original on 2021-08-27. Retrieved 2017-08-30.
  15. 15.0 15.1 Byatt N, Deligiannidis KM, Freeman MP (Feb 2013). "Antidepressant use in pregnancy: a critical review focused on risks and controversies". Acta Psychiatr Scand. 127 (2): 94–114. doi:10.1111/acps.12042. PMC 4006272. PMID 23240634.
  16. Stutz, Bruce (2007-05-06). "Self-Nonmedication". New York Times. Archived from the original on 2019-05-20. Retrieved 2010-05-24.
  17. Christmas, M.B. (2005). "'Brain shivers': from chat room to clinic". Psychiatric Bulletin. 29 (6): 219–21. doi:10.1192/pb.29.6.219.
  18. Aronson, J. (8 October 2005). "Bottled lightning". BMJ. 331 (7520): 824. doi:10.1136/bmj.331.7520.824. PMC 1246084.
  19. 19.0 19.1 Expert Group on the Safety of Selective Serotonin Reuptake Inhibitors (SSRIs) (December 2004). Weller, Ian V.D. (ed.). "Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants" (PDF). Medicines and Healthcare Products Regulatory Agency. Archived (PDF) from the original on 28 February 2008. Retrieved 1 August 2014.
  20. Schatzberg, A.F.; Haddad, P.; Kaplan, E.M.; Lejoyeux, M.; Rosenbaum, J.F.; Young, A.H.; Zajecka, J. (1997). "Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Discontinuation Consensus panel". J Clin Psychiatry. 5u (7): 5–10. PMID 9219487.
  21. Black, K.; Shea, C.; Dursun, S.; Kutcher, S. (2000). "Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria". J Psychiatry Neurosci. 25 (3): 255–61. PMC 1407715. PMID 10863885.
  22. World Health Organization (2003). WHO Expert Committee on Drug Dependence – Thirty-third Report / WHO Technical Report Series 915 (Report). World Health Organization. Archived from the original on 2013-10-29. Retrieved 2013-06-14.
  23. Nielsen, M.; Hanse, E.H.; Gøtzsche, P.C. (2012). "What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors". Addiction. 105 (5): 900–8. doi:10.1111/j.1360-0443.2011.03686.x. PMID 21992148.
  24. Fava, G.A.; Gatti, A; Belaise, C.; et al. (2015). "Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review". Psychother Psychosom. 84 (2): 72–81. doi:10.1159/000370338. PMID 25721705.
  25. Justia. Jennifer L Saavedra v. Eli Lilly and Company Archived 2018-11-21 at the Wayback Machine Archived 2018-11-21 at the Wayback Machine
  26. Overley, Jeff (January 29, 2013). "Lilly Fights Cymbalta 'Brain Zaps' Suit, Saying It Warned Docs". Law360. Archived from the original on 29 January 2019. Retrieved 3 August 2014.
  27. Rebecca Tushnet for Rebecca Tushnet's 43(B)log December 09, 2013 Learned intermediary doctrine doesn't bar claim at pleading stage Archived 2018-12-03 at the Wayback Machine Archived 2018-12-03 at the Wayback Machine
  28. Damsa, C.; Bumb, A.; Bianchi-Demicheli, F.; et al. (August 2004). ""Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review". J Clin Psychiatry. 65 (8): 1064–8. doi:10.4088/JCP.v65n0806. PMID 15323590.

External links

  • ICD-10: Y49.0 Tricyclic and tetracyclic antidepressants
    Y49.1 Monoamine-oxidase-inhibitor antidepressants
    Y49.2 Other and unspecified antidepressants