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Antidepressant Discontinuation Syndrome CHRISTOPHER H Antidepressant Discontinuation Syndrome CHRISTOPHER H. WARNER, MAJ, MC, USA, Winn Army Community Hospital, Fort Stewart, Georgia WILLIAM BOBO, LCDR, MC, USN, Uniformed Services University of the Health Sciences, Bethesda, Maryland CAROLYNN WARNER, MAJ, MC, USA, Winn Army Community Hospital, Fort Stewart, Georgia SARA REID, CPT, USAF, MC, Bolling Air Force Base, Washington, D.C. JAMES RACHAL, MAJ, USAF, MC, Ehrling Berquist Air Force Hospital, Offutt Air Force Base, Omaha, Nebraska Antidepressant discontinuation syndrome occurs in approximately 20 percent of patients after abrupt discontinuation of an antidepressant medication that was taken for at least six weeks. Typical symptoms of antidepressant discontinuation syndrome include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal. These symptoms usu- ally are mild, last one to two weeks, and are rapidly extinguished with reinstitution of antide- pressant medication. Antidepressant discontinuation syndrome is more likely with a longer duration of treatment and a shorter half-life of the treatment drug. A high index of suspicion should be maintained for the emergence of discontinuation symptoms, which should prompt close questioning regarding accidental or purposeful self-discontinuation of medication. Before antidepressants are prescribed, patient education should include warnings about the potential problems associated with abrupt discontinuation. Education about this common and likely underrecognized clinical phenomenon will help prevent future episodes and minimize the risk of misdiagnosis. (Am Fam Physician 2006;74:449-56, 457. Copyright © 2006 American Academy of Family Physicians.) Patient information: nterruption of treatment with an anti- severe enough to require hospitalization10-12; A handout on antidepres- depressant medication is sometimes (2) failure to recognize antidepressant dis- sant discontinuation syndrome, written by the associated with an antidepressant dis- continuation syndrome may result in medi- authors of this article, is continuation syndrome; in early reports cal and psychiatric misdiagnosis, potentially provided on page 457. I it was referred to as a “withdrawal reaction.”1 exposing patients to unnecessary diagnostic Symptoms of antidepressant discontinuation investigations or potentially risky medical syndrome can include flu-like symptoms, interventions; (3) patients may be unwilling insomnia, nausea, imbalance, sensory distur- to use psychotropic medications in the future, bances, and hyperarousal. All approved anti- thereby increasing their vulnerability to future depressant agents have had case reports or relapses of depressive or anxiety disorders. warnings from their manufacturers of such reactions occurring in response to either Pathophysiology abrupt discontinuation or medication taper- Although several hypotheses exist, the defini- ing.2 These medications include selective tive pathophysiologic explanation for antide- serotonin reuptake inhibitors (SSRIs),3 tri- pressant discontinuation syndrome remains cyclic antidepressants,4 monoamine oxidase unknown. Early reports of antidepressant inhibitors (MAOIs),5 and atypical agents discontinuation syndrome made heavy use such as venlafaxine (Effexor),6 mirtazap- of the term “withdrawal” to describe discon- ine (Remeron),7 trazodone (Desyrel),8 and tinuation symptoms; however, antidepressant duloxetine (Cymbalta).9 medications are not believed to be habit form- The importance of understanding and rec- ing and are not associated with drug-seeking ognizing antidepressant discontinuation syn- behavior.13 Long-term use of SSRIs increases drome is threefold: (1) though typically mild, synaptic levels of serotonin through blockade antidepressant discontinuation syndrome of the serotonin reuptake pump, resulting in symptoms are associated with significant dis- down-regulation of postsynaptic receptors.14 comfort, work absenteeism, other psychoso- There is speculation concerning the pos- cial problems, and may on rare occasions be sibility of a temporary deficiency of synaptic Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2006 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Antidepressant Discontinuation Syndrome SORT: KEY RECOMMENDATIONs fOR PRACTICE Evidence Clinical recommendation rating References Maintain a high index of suspicion for antidepressant C 19 discontinuation syndrome. Be alert to times when patients may need guidance on C 27,32 discontinuing an antidepressant or when they are likely to discontinue an antidepressant on their own. Be sure to differentiate antidepressant discontinuation syndrome C 19,27,28 from relapse of depression and other psychiatric and medical conditions. Gradually discontinue medication using one of the suggested C 16,17,21,22,27,28 tapering regimens (Table 5). A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 363 or http://www.aafp.org/afpsort.xml. serotonin with abrupt withdrawal of an (9 percent) given fluoxetine (Prozac) and 26 SSRI.15 This deficiency is compounded by of 52 patients (50 percent) given paroxetine the fact that down-regulated receptors will (Paxil) reported discontinuation symptoms, remain in their relatively hypoactive state with a mean onset of two days and mean dura- for days to weeks.15 This is believed to result tion of five days. A randomized controlled in antidepressant discontinuation syndrome trial17 (RCT) comparing three SSRIs found a directly or indirectly via downstream effects lower incidence of antidepressant discontinu- on other neurotransmitter systems (e.g., ation syndrome with fluoxetine (14 percent) norepinephrine, dopamine, and g-amino- than with paroxetine (66 percent) or sertraline butyric acid) implicated in depressive and (Zoloft) (60 percent). This study was limited anxiety disorders.15 by its open-label design and was sponsored by Because tricyclic antidepressants and the manufacturer of fluoxetine. In addition, MAOIs also are serotonergically active, the a retrospective chart review13 of 350 patients same mechanism is implicated for their using SSRIs showed no significant added risk respective antidepressant discontinuation associated with age, sex, or diagnosis. syndromes; however, tricyclic antidepres- Perhaps the best evidence comes from sants also affect the cholinergic system, an RCT18 that found mild to moderate anti- so rapid discontinuation may cause signs depressant discontinuation symptoms in of parkinsonism and problems with bal- 35 percent of patients given paroxetine and ance. Because MAOIs cause changes in the 14 percent given placebo who were abruptly alpha2-adrenergic and dopaminergic recep- withdrawn from treatment after 12 weeks. tors, their discontinuation may cause agita- The difference of approximately 20 percent tion and psychosis. between active treatment and placebo for one of the drugs most commonly associated Epidemiology and Risk Factors with antidepressant discontinuation syn- Because of the varied clinical presentation, drome may provide an upper boundary for transient nature, and lack of pathognomonic the probability of the condition.18 clinical features, there are relatively few data on incidence, prevalence, and other estimates DURATION OF TREATMENT of burden associated with antidepressant Although unconfirmed by prospective clini- discontinuation syndrome. One observa- cal trials, case reports of antidepressant dis- tional study16 found that four of 45 patients continuation syndrome reactions are rare 450 American Family Physician www.aafp.org/afp Volume 74, Number 3 ◆ August 1, 2006 Antidepressant Discontinuation Syndrome among individuals who have received less Antidepressant discontinuation syn- than six to eight weeks of antidepressant drome is most often seen in the primary treatment.19 This generalization applies to care office in association with SSRI discon- antidepressant discontinuation syndrome tinuation, because SSRIs are the most com- that occurs in the settings of both abrupt and monly prescribed class of antidepressant gradual antidepressant discontinuation. Such medications. In 2000, a systematic review25 a time frame may be required to allow the of 46 case reports of SSRI discontinuation synaptic changes that occur during long-term proposed the diagnostic criteria listed in pharmacologic antidepressant treatment. Table 3.25 The FINISH mnemonic (Flu- like symptoms, Insomnia, Nausea, Imbal- PHARMACOLOGIC prOFILE ance, Sensory disturbances, Hyperarousal) For SSRIs, a relatively homogenous drug was created to facilitate rapid recognition class, differences among the pharmacokinetic properties such as elimination half-life and metabolism may be the most clinically rele- TABLE 1 Pharmacologic Properties of Selected Antidepressants vant (Table 1).20,21 Specifically, antidepressant discontinuation syndrome is more common in patients discontinuing agents with rela- Dosage range Half-life Active Drug (mg per day) (hours) metabolite? tively short half-lives, such as paroxetine, than in those with longer half-lives, such as Selective serotonin reuptake inhibitor fluoxetine.13,16,17,19,22 In recent years, slow-,
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