Antidepressant discontinuation syndrome

Not to be confused with Serotonin syndrome.
Antidepressant discontinuation syndrome
Classification and external resources
Specialty Toxicology, psychiatry

Antidepressant discontinuation syndrome is a condition that can occur following the interruption, dose reduction, or discontinuation of antidepressant drugs, including selective serotonin re-uptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs). The symptoms can include flu-like symptoms and disturbances in sleep, senses, movement, mood, and thinking. In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by reintroduction of the drug, which usually leads to resolution within one day.

Signs and symptoms

People with 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.[1] 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 sufferers 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.[1][2][3] Over fifty symptoms have been reported.[4]

Most cases of discontinuation syndrome last between one and four weeks, are relatively mild, and resolve on their own; in rare cases symptoms can be severe or extended.[1] Paroxetine (Paxil) and venlafaxine (Effexor) seem to be particularly difficult to discontinue and prolonged withdrawal syndrome lasting over 18 months have been reported with paroxetine.[5][6][7]

A 2009 Advisory Committee to the FDA found that online anecdotal reports of discontinuation syndrome related to duloxetine (Cymbalta) included severe symptoms and exceeded prevalence of both Paroxetine (Paxil) and venlafaxine (Effexor) reports by over 250% (although acknowledged this may have been influenced by duloxetine being a much newer drug).[8] 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.[8]

Prevention and treatment

Discontinuation syndrome can be prevented by taking medication as directed, and when discontinuing, doing so gradually. 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 discontinuing from that drug can decrease the likelihood and severity of symptoms.[2]

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 required then the only step required is restarting the antidepressant; this is usually the case following patient noncompliance with the drug. If antidepressants are no longer required, treatment depends on symptom severity. Mild reactions may only require reassurance. Moderate cases may require symptom management. If symptoms of discontinuation are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously.[5] In rare but severe cases, hospitalization may be required.[1]

Pregnancy and newborns

Antidepressants, including SSRIs, can cross the placenta and have the potential to affect the fetus and newborns, presenting a dilemma whether pregnant women should take antidepressants at all, and if they do, whether tapering them near the end of pregnancy could have a protective effect for the newborn.[9]

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.[9]

Research

Further information: Chemical synapse

The mechanisms of antidepressant withdrawal syndrome have not yet been conclusively identified.[1][3] The leading hypothesis is that after the antidepressant is discontinued, there is a temporary 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.[1][10]

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.[5] 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.[5]

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.[11] 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.[12][13]

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.[14]:page 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.[14](p126–136)

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,[15] which other groups continued to refine.[16][17]

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. Some addictive substances cause physiological dependence, so that drug withdrawal causes suffering. These theories were abandoned, since addiction leads to drug-seeking behavior, and people taking antidepressants do not exhibit drug-seeking behavior. The term "withdrawal syndrome" is no longer used with respect to antidepressants, to avoid confusion with problems that arise from dependence or addiction.[1]

2013 class action lawsuit

In 2013, a proposed class action lawsuit, Jennifer L Saavedra v. Eli Lilly and Company,[18] was brought against Eli Lilly claiming that the Cymbalta label omitted important information about "brain zaps" and other symptoms upon cessation.[19] 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.[20]

See also

References

  1. 1 2 3 4 5 6 7 Warner CH, Bobo W, Warner C, Reid S, Rachal J (August 2006). "Antidepressant discontinuation syndrome". Am Fam Physician. 74 (3): 449–56. PMID 16913164.
  2. 1 2 Haddad, P.M.; Anderson, I.M. (2007). "Recognising and managing antidepressant discontinuation symptoms". Advances in Psychiatric Treatment. 13 (6): 447–457. doi:10.1192/apt.bp.105.001966.
  3. 1 2 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 3627130Freely accessible. PMID 23596418.
  4. ↑ 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.
  5. 1 2 3 4 Haddad, P. (2001). "Antidepressant discontinuation syndromes". Drug Saf. 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722.
  6. ↑ 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. Retrieved 2012-11-28.
  7. ↑ Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review Comparative Effectiveness Reviews, No. 46. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Dec.
  8. 1 2 "Cymbalta (Duloxetine) Discontinuation Syndrome: Issues of Scope, Severity, Duration & Management" (PDF). U.S. Food and Drug Administration (FDA). 9 June 2009. Retrieved 17 October 2016.
  9. 1 2 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. PMID 23240634.
  10. ↑ 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.
  11. ↑ Stutz, Bruce (2007-05-06). "Self-Nonmedication". New York Times. Retrieved 2010-05-24.
  12. ↑ Christmas, M.B. (2005). "'Brain shivers': from chat room to clinic". Psychiatric Bulletin. 29 (6): 219–21. doi:10.1192/pb.29.6.219.
  13. ↑ Aronson, J. (8 October 2005). "Bottled lightning". BMJ. 331 (7520): 824. doi:10.1136/bmj.331.7520.824. PMC 1246084Freely accessible.
  14. 1 2 Expert Group on the Safety of Selective Serotonin Reuptake Inhibitors (SSRIs) (December 2004). Professor Ian V D Weller MD FRCP, ed. "Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants" (PDF). Medicines and Healthcare Products Regulatory Agency. Retrieved 1 August 2014.
  15. ↑ 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.
  16. ↑ 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 1407715Freely accessible. PMID 10863885.
  17. ↑ World Health Organization (2003). WHO Expert Committee on Drug Dependence – Thirty-third Report / WHO Technical Report Series 915 (Report). World Health Organization.
  18. ↑ Justia. Jennifer L Saavedra v. Eli Lilly and Company
  19. ↑ Overley, Jeff (January 29, 2013). "Lilly Fights Cymbalta 'Brain Zaps' Suit, Saying It Warned Docs". Law360. Retrieved 3 August 2014.
  20. ↑ Rebecca Tushnet for Rebecca Tushnet's 43(B)log December 09, 2013 Learned intermediary doctrine doesn't bar claim at pleading stage
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