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 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 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 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- 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 (Effexor),6 mirtazap- of the term “withdrawal” to describe discon- ine (Remeron),7 (Desyrel),8 and tinuation symptoms; however, antidepressant (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

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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 (Prozac) and 26 SSRI.15 This deficiency is compounded by of 52 patients (50 percent) given 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) , dopamine, and g-amino- than with paroxetine (66 percent) or 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 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

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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 fluoxetine.13,16,17,19,22 In recent years, slow-, (Celexa) 10 to 60 35 No extended-, or controlled-release formulations (Lexapro) 10 to 30 27 to 32 No of venlafaxine (Effexor XR), paroxetine (Paxil Fluoxetine (Prozac) 20 to 80 84 to 144 Yes CR), and fluoxetine (Prozac Weekly) have Paroxetine (Paxil) 10 to 60 21 No become available. Although there are limited Paroxetine CR (Paxil CR) 12.5 to 62.5 15 to 20 No data concerning weekly fluoxetine, antidepres- Sertraline (Zoloft) 50 to 200 26 Yes sant discontinuation syndrome reactions have Atypical antidepressant been reported with controlled-release parox- (Wellbutrin) 75 to 450 12 to 30 Yes 14,23 etine and extended-release venlafaxine. Buproprion SR 100 to 400 12 to 30 Yes (Wellbutrin SR) Clinical Manifestations Buproprion XL 150 to 450 12 to 30 Yes and Pathophysiology (Wellbutrin XL) clinical manifestations Duloxetine (Cymbalta)* 40 to 60 11 to 16 Yes Antidepressant discontinuation syndrome (Remeron) 15 to 45 20 to 40 No involves a large number of psychological Trazodone (Desyrel) 50 to 400 7.1 Yes and physiological signs and symptoms. Case Venlafaxine (Effexor) 75 to 450 3 to 13 Yes reports, audits of adverse drug reaction Venlafaxine XR 75 to 450 3 to 13 Yes databases, and clinical trials report certain (Effexor XR) characteristic symptoms. These symptoms Monoamine oxidase inhibitors depend on the class of antidepressant used (Nardil) 15 to 90 1.2 Yes 2,13,16,17,19,22,24,25 (Table 2). In a recent retro- Tricyclic antidepressant* 13 spective chart review of patients on anti- 25 to 300 9 to 25 Yes depressants and two small, prospective, (Anafranil) 25 to 250 22 to 84 No 16,24 randomized controlled trials, patients’ (Norpramin) 25 to 300 14.3 to 24.7 No SSRIs were replaced with placebo for five (Sinequan) 25 to 300 11 to 23 No days or their antidepressant medication was (Tofranil) 25 to 300 10 to 16 Yes abruptly discontinued. All noted that the (Pamelor) 25 to 150 18.2 to 35 No most common symptoms of SSRI withdrawal were dizziness, gastrointestinal upset, leth- *Dosages listed are for treatment of depression. argy or anxiety/hyperarousal, dysphoria, Information from references 20 and 21. sleep problems, and headache.13,16,24

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(Table 4).26 However, neither set of crite- Table 2 ria25,26 has been formally validated. Signs and Symptoms of Antidepressant Multiple case reports demonstrate that Discontinuation Syndrome antidepressant discontinuation syndrome associated with tricyclic antidepressants Atypical Tricyclic closely mimics that of the SSRIs.3,4 However, SSRI antidepressant antidepressant MAOI signs of parkinsonism and profound prob- General lems with balance appear to be especially Flu-like symptoms + + + — characteristic of antidepressant discontinu- Headache + + + + ation syndrome caused by tricyclic anti- 3,4 Lethargy + + + — depressant discontinuation. Additionally, Gastrointestinal case reports have noted that the antidepres- Abdominal cramping + — + — sant discontinuation syndrome associated Abdominal pain + — + — with MAOIs may involve more serious symp- Appetite disturbance + + + — tomatology such as aggressiveness, agitation, Diarrhea + + — catatonia, severe cognitive impairment, or Nausea/vomiting + + + — myoclonus and psychotic symptoms and Sleep may require more intensive management.4,5 Insomnia + + + + Nightmares + + + + onset and course Balance Discontinuation symptoms typically appear Ataxia + — + — within three days of stopping antidepres- Dizziness + + + — sant medication or initiating a medication Lightheadedness + — + — taper, though it has been reported that reac- Vertigo + + + — tions may occur within hours of the first Sensory missed dose.9 Untreated symptoms are usu- Blurred vision + — — — ally mild and resolve spontaneously in one “Electric shock” + + — — 19 sensations to two weeks. In rare but more serious Numbness + — — — cases involving psychosis, catatonia, or severe Paresthesia + + — — cognitive impairment, immediate psychiatric Movement consultation may be required. Akathisia + + + — Myoclonic jerks — — — + Diagnostic Considerations Parkinsonism + — + — maintain a high index of suspicion Tremor + — + — Any uncomfortable symptoms reported by Affective patients receiving antidepressants should Aggression/irritability + — — + prompt close questioning for missed doses, Agitation + — + + unreported downward adjustments in dos- Anxiety + + + — age, or outright medication discontinuation. Low mood + + + + Psychosis differentiation from relapse Catatonia — — — + The symptoms of antidepressant discontinu- Delirium — — — + ation syndrome that are associated with most Delusions — — — + antidepressants share features of major depres- Hallucinations — — — + sion, including dysphoria, appetite changes,

NOTE: Symptom categories listed by rate of incidence. sleep problems, cognitive problems, and SSRI = selective serotonin reuptake inhibitor; MAOI = monoamine oxidase inhibitor; fatigue. By focusing on symptoms that dis- + = occur in withdrawal from this medication; — = do not occur in withdrawal from tinguish antidepressant discontinuation syn- this medication. drome from depressive illness relapse (e.g., Information from references 2, 13, 16, 17, 19, 22, 24, and 25. dizziness, “electric shock” sensations, “rush- ing” sensations in the head, headache, and

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nausea) and observing for rapid (i.e., within a few days) reversal of symptoms after restarting Table 3 the antidepressant or complete resolution of Proposed Diagnostic Criteria for SSRI symptoms in one to two weeks (highly unchar- Discontinuation Syndrome acteristic of a depressive relapse), a definitive diagnosis is fairly easy to make.19,27 Depressive relapses or recurrences typically occur after at least two to three weeks or longer after cessa- tion of medication and are most often marked by gradual worsening of depression, insomnia, The rightsholder did not and psychomotor symptoms.28 grant rights to reproduce differentiation from other conditions this item in electronic Irritability, sleeplessness, and anxiety or agi- media. For the missing tation in a patient taking antidepressants item, see the original print may appropriately raise suspicion of an anti- version of this publication. depressant-associated bipolar manic episode that must be distinguished from antidepres- sant discontinuation syndrome. The devel- opment of these symptoms should prompt close questioning about medication adher- ence, as previously mentioned. If such symp- toms appear shortly after discontinuation or during dose reduction, rapid symptom resolution after restoring the antidepressant medication will lead to the correct diagnosis. Antidepressant discontinuation syndrome also may be misdiagnosed as severe con- Table 4 FINISH Mnemonic for Recognition ditions including stroke, other neurologic of Antidepressant Discontinuation conditions, infectious diseases, and adverse Syndrome effects of other medications the patient is taking.29 Antidepressant discontinuation Flu-like symptoms syndrome has been reported when switching Fatigue from one antidepressant agent to another.30 Lethargy When the new agent has different pharma- General malaise cologic mechanism reactions than the first Muscle aches/headaches agent, antidepressant discontinuation syn- Diarrhea drome may be misinterpreted as intolerable Insomnia side effects from the new medication.29 Nausea Imbalance Prevention and Management Gait instability Dizziness/lightheadedness use of antidepressants Vertigo For optimal treatment of most psychiat- Sensory disturbances ric conditions, and especially anxiety and Paresthesia depressive disorders, psychosocial interven- “Electric shock” sensations tions should be recommended along with or Visual disturbance considered as alternatives to pharmacologic Hyperarousal Anxiety therapies. The all-too-common practice of Agitation “short-term” prescriptions for off-label, non–mental health reasons (e.g., irritable Information from reference 26. bowel syndrome, weight loss, headaches,

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insomnia) has been associated with early discontinuing medication antidepressant discontinuation and may Although there are no clinical trials com- increase the risk of antidepressant discon- paring abrupt discontinuation with tapered tinuation syndrome.31 discontinuation of antidepressants, tapering is recommended by experts, based on the patients at risk OF discontinuation suspected pathophysiology of antidepres- Patients may be tempted to discontinue their sant discontinuation syndrome.33 Patients antidepressant medication after they begin should be forewarned of the possibility of to feel better, a practice that invites both antidepressant discontinuation syndrome if early relapse of illness and antidepressant antidepressants are discontinued, and that discontinuation syndrome. Women may dis- supervised tapering of medication over six continue antidepressant use after discover- to eight weeks may be required to minimize ing that they are pregnant. Ideally, patients discontinuation symptoms. Several RCTs should be counseled regarding the risks of have shown that with abrupt cessation of illness relapse, the importance of treating antidepressants, symptoms can begin within symptoms to remission, the need for contin- days.16,17,22 It may be possible to discon- uation and (where appropriate) maintenance tinue medication more quickly if doses are pharmacotherapy, and the need for gradual low; discontinuation may take longer (three discontinuation of medications before dis- months or more) after maintenance therapy. continuing care.27,32 It may be possible to stop fluoxetine therapy without tapering. There are no clear, vali- dated tapering recommendations. However, Table 5 Table 527 offers one expert’s recommenda- Gradual Taper Rates for Antidepressants tions for tapering rates.

Drug Recommended taper rate management

Monoamine oxidase inhibitor If antidepressant discontinuation syndrome Phenelzine (Nardil) Reduction of 15 mg per day every two occurs and other serious causes of these weeks or 10 percent per week symptoms have been ruled out, the physi- cian should begin by providing reassurance Tricyclic antidepressant Gradually, up to three months to the patient that the condition is reversible, Selective serotonin reuptake inhibitor is not serious or life threatening, and will Fluoxetine (Prozac) Gradual taper generally unnecessary run its course within one to two weeks. The Paroxetine (Paxil) Reduction of 10 mg per day every five to physician should then consider restarting the seven days with a final dosage of 5 to 10 mg per day before discontinuation* antidepressant medication with a slow dose Sertraline (Zoloft) Reduction of 50 mg per day every five to taper or providing support if the patient seven days with a final dosage of 25 to desires not to restart the antidepressant. 50 mg per day before discontinuation Severe symptoms should resolve in fewer Atypical antidepressant than three days, and often within 24 hours. If Venlafaxine (Effexor) Reduction of 25 mg day every five to the antidepressant discontinuation syndrome seven days with a final dosage of 25 to occurs during a tapering of the antidepres- 50 mg per day before discontinuation* sant, consider restarting at the original dose Venlafaxine XR (Effexor XR) Reduction of 37.5 to 75 mg per day every and then taper at a slower rate. In cases where week with a final dosage of 37.5 mg per slow tapering is poorly tolerated, a medicine day before discontinuation* with a longer half-life such as fluoxetine may

NOTE: These recommendations are expert opinion only. be substituted for the shorter half-life agent.

*—Slower taper may be needed. generic drugs and substitutions Adapted with permission from Shelton RC. Steps following attainment of remission: discontinuation of antidepressant therapy. Primary Care Companion J Clin Psychiatry Not all formulations of the same drug are 2001;3:172. bioequivalent. Generic drugs are allowed up to a 20 percent difference. This may result

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in an unintended sudden reduction in drug JAMES RACHAL, MAJ, USAF, MC, is the chief of psychiatry concentration if a patient’s medication is at Ehrling Berquist Air Force Hospital at Offutt Air Force Base in Omaha, Neb. Dr. Rachal received his medical switched to a generic or alternative brand. degree from the University of Cincinnati (Ohio) and is a graduate of the National Capital Consortium Family tricyclic antidepressants Practice-Psychiatry Residency Program at Walter Reed Army Medical Center and Malcolm Grow Air Force Medical Antidepressant discontinuation syndrome Center. He is currently serving in the U.S. Air Force. symptoms caused by tricyclic antidepressants that suggest cholinergic rebound (e.g., parkin- Address correspondence to Christopher Warner, M.D., 373 Steeple Chase Lane, Richmond Hill, GA 31324 (e- sonism and other problems with movement) mail: [email protected]). Reprints are may respond to short-term use of anticholin- not available from the authors. ergic agents such as atropine (Atropisol) or Author disclosure: Nothing to disclose. benztropine (Cogentin). This should be con- sidered especially for patients who are opposed to restarting their tricyclic antidepressant.34 REFERENCES 1. Rothschild AJ. Selective serotonin reuptake inhibitor- The opinions and assertions contained herein are the pri- induced sexual dysfunction: efficacy of a drug holiday. vate views of the authors and are not to be construed as Am J Psychiatry 1995;152:1514-6. official or as reflecting the views of the U.S. Department 2. Dilsaver SC, Greden FJ. Antidepressant withdrawal of Defense, the U.S. Army Medical Department, or the phenomena. Biol Psychiatry 1984;19:237-56. U.S. Army or U.S. Air Force Services at large. 3. Thompson C. Discontinuation of antidepressant ther- apy: emerging complications and their relevance. J Clin The Authors Psychiatry 1998;59:541-8. 4. Garner EM, Kelly MW, Thompson DF. Tricyclic anti- CHRISTOPHER H. WARNER, MAJ, MC, USA, is the division depressant withdrawal syndrome. Ann Pharmacother psychiatrist for the 3rd Infantry Division in the U.S. Army 1993;27:1068-72. and a staff family physician at Winn Army Community 5. Curtin F, Berney P, Kaufmann C. dis- Hospital at Fort Stewart, Ga. Dr. Warner is a graduate of continuation syndrome predominantly presenting the National Capital Consortium Family Practice-Psychiatry with influenza-like symptoms. J Psychopharmacol Residency Program at Walter Reed Army Medical Center, 2002;16:271-2. Washington, D.C., and Malcolm Grow Air Force Medical 6. Agelink MW, Zitzelsberger A, Klisser E. Withdrawal Center, Andrews Air Force Base, Md. He received his medi- syndrome after discontinuation of venlafaxine. Am J cal degree from the Uniformed Services University of the Psychiatry 1997;154:1473-4. Health Sciences, Bethesda, Md. 7. Berigan TR. Mirtazapine-associated withdrawal symp- WILLIAM BOBO, LCDR, MC, USN, is assistant professor in toms: a case report. Prim Care Companion J Clin Psy- chiatry 2001;3:143. the department of psychiatry at the Uniformed Services University of the Health Sciences, Bethesda, Md. He is 8. Peabody CA. Trazodone withdrawal and formication. J also the assistant program director of the National Capital Clin Psychiatry 1987;48:385. Consortium Family Practice-Psychiatry Residency Program 9. Cymbalta [package insert]. Indianapolis, Ind.: Eli Lilly at Walter Reed Army Medical Center, Washington, D.C. Dr. Pharmaceuticals; 2004. Accessed online October 19, Bobo received his medical degree from the University of 2005, at: http://pi.lilly.com/us/cymbalta-pi.pdf. Missouri-Columbia School of Medicine and completed his 10. Barr LC, Goodman WK, Price LH. Physical symptoms psychiatry residency training at Walter Reed Army Medical associated with paroxetine discontinuation. Am J Psy- Center. He is currently serving in the U.S. Navy. chiatry 1994;151:289. 11. Koopowitz LF, Berk M. Paroxetine induced withdrawal CAROLYNN WARNER, MAJ, MC, USA, is a staff fam- effects. Hum Psychophramacol 1995;10:147-8. ily physician at Winn Army Community Hospital, Fort 12. Lejoyeux M, Rodiere-Rein C, Ades J. Withdrawal syn- Stewart. Dr. Warner is a graduate of the National Capital drome from antidepressive drugs. Report of 5 cases [in Consortium Family Practice Residency Program at Malcolm French]. Encephale 1992;18:251-5. Grow Air Force Medical Center, Andrews Air Force Base, 13. Coupland NJ, Bell CJ, Potokar JP. Serotonin reup- and received her medical degree from the University of take inhibitor withdrawal. J Clin Psychopharmacol Maryland School of Medicine in Baltimore. She is currently 1996;16:356-62. serving in the U.S. Army. 14. Paxil CR [product monograph]. GlaxoSmithKline; 2005. SARA REID, CPT, USAF, MC, is a family physician at Bolling Accessed online October 19, 2005, at: http://us.gsk. Air Force Base in Washington, D.C. Dr. Reid received her com/products/assets/us_paxilcr.pdf. medical degree from the Uniformed Services University of 15. Lane RM. Withdrawal symptoms after discontinuation the Health Sciences and completed her family practice res- of selective serotonin reuptake inhibitors (SSRIs). J Sero- idency at the National Capital Consortium Family Practice tonin Res 1996; 3/2:75-83. Residency Program at Malcolm Grow Air Force Medical 16. Bogetto F, Bellino S, Revello RB, Patria L. Discontinua- Center. She is currently serving in the U.S. Air Force. tion syndrome in dysthymic patients treated with selec-

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tive serotonin reuptake inhibitors: a clinical investiga- 26. Berber MJ. FINISH: remembering the discontinuation tion. CNS Drugs 2002;16:273-83. syndrome. Flu-like symptoms, Insomnia, Nausea, Imbal- 17. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. ance, Sensory disturbances, and Hyperarousal (anxiety/ Selective serotonin reuptake inhibitor discontinuation agitation). J Clin Psychiatry 1998;59:255. syndrome: a randomized clinical trial. Biol Psychiatry 27. Shelton RC. Steps following attainment of remission: 1998;44:77-87. discontinuation of antidepressant therapy. Primary Care 18. Oehrberg S, Christiansen PE, Behnke K, Borup AL, Sev- Companion J Clin Psychiatry 2001;3:168-74. erin B, Soegaard J, et al. Paroxetine in the treatment of 28 . Rosenbaum JF, Zajecka J. Clinical management of panic disorder. A randomised, double-blind, placebo- antidepressant discontinuation. J Clin Psychiatry controlled study. Br J Psychiatry 1995;167:374-9. 1997;58(suppl 7):37-40. 19. Haddad P. Newer antidepressants and the discontinua- 29. Haddad PM, Qureshi M. Misdiagnosis of antidepres- tion syndrome. J Clin Psychiatry 1997;58(suppl 7):17-21. sant discontinuation symptoms. Acta Psychiatr Scand 20. Gury C, Cousin F. Pharmacokinetics of SSRI antidepres- 2000;102:466-7. sants: half-life and clinical applicability. Encephale 30. Phillips SD. A possible paroxetine withdrawal syndrome 1999;25:470-6. [letter]. Am J Psychiatry 1995;152:645-6. 21. Physicians’ Desk Reference. 59th ed. Montvale, N.J.: 31. Pomerantz JM, Finkelstein SN, Berndt ER, Poret AW, Thomson PDR, 2005: 731, 1269, 1282, 1585, 1592, Walker LE, Alber RC, et al. Prescriber intent, off-label 1655, 1659, 1663, 1873, 1925-6, 2213, 2458, 2578, usage, and early discontinuation of antidepressants: a 2681, 3220, 3296, 3321, 3326, 3430. retrospective physician survey and data analysis. J Clin 22. Judge R, Parry MG, Quail D, Jacobson JG. Discon- Psychiatry 2004;65:395-404. tinuation symptoms: comparison of brief interruption 32. Bull SA, Hu XH, Hunkeler EM, Lee JY, Ming EE, Mark- in fluoxetine and paroxetine treatment. Int Clin Psycho- son LE, et al. Discontinuation of use and switching of pharmacol 2002;17:217-25. antidepressants: influence of patient-physician com- 23. Gutierrez MA, Stimmel GL, Aiso JY. Venlafaxine: a 2003 munication. JAMA 2002;288:1403-9. update. Clin Ther 2003;25:2138-54. 33. British National Formulary. Antidepressant drugs. 24. Michelson D, Fava M, Amsterdam J, Apter J, Londborg Accessed January 31, 2006, at: http://www.bnf.org/ P, Tamura R, et al. Interruption of selective serotonin bnf/bnf/50/noframes/3294.htm (password required). reuptake inhibitor treatment. Double-blind, placebo- 34. Wolfe RM. Antidepressant withdrawal reactions controlled trial. Br J Psychiatry 2000;176:363-8. [published correction appears in Am Fam Physician 25. Black K, Shea C, Dursun S, Kutcher S. Selective sero- 1998;57:646]. Am Fam Physician 1997;56: 455-62. tonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatry Neurosci 2000;25:255-61.

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