1. Drug Discontinuation Syndrome Sarah Quick, PharmD 2015 IPA Spring Meeting April 15, 2015

2. Disclosure I have no relevant financial or nonfinancial relationships or conflicts of interest to disclose.

3. Learning Objectives  Define drug discontinuation syndrome.  Identify psychiatric medications that have been associated with discontinuation syndrome.  Recall signs of discontinuation syndrome for the associated classes.  Discuss appropriate treatment and prevention strategies for discontinuation syndrome.

4. Discontinuation Syndrome Mixture of psychological and physiological symptoms from abrupt discontinuation of medication Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456.

5. Discontinuation versus Withdrawal  Non-habit forming medications  No drug-seeking behavior Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456. Haddad PM. Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management. Drug Safety 2001; 24: 189-197

6. Rebound Symptoms  Beta-blockers  Nitrates  Diuretics  Centrally acting antihypertensives  Sympathomimetics  Dopaminergic agents Haddad PM. Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management. Drug Safety 2001; 24: 189-197

7. Discontinuation Syndrome  Selective Serotonin Releasing Inhibitors (SSRIs)  Serotonin-Norepinephrine Releasing Inhibitor (SNRIs)  Tricyclic Antidepressants (TCAs)  Monoamine Oxidase Inhibitors (MAOIs) Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456.

8. Depression in the US In 2009–2012, 7.6% of Americans aged 12 and over had depression (moderate or severe depressive symptoms in the past 2 weeks). CDC: Depression in the U.S Household Population, 2009-2012

9. Depression in the US About one in 10 Americans aged 12 and over takes anti-depressant medication. CDC: Antidepressant Use in Persons Aged 12 and Over: United States, 2005-2008

10. Background Physicians may be unaware that patients may experience discontinuation syndrome Lamoure J. Discontinuation syndrome: relapse vs. withdrawal. Can J Diagnosis 2006;23(9):95-8

11. Clinical Importance  Avoid negative impact on patients’ quality of life ◦Work absenteeism ◦Psychosocial problems ◦Complications leading to hospitalization  Avoid misdiagnosis ◦Unnecessary medical treatment ◦Unnecessary testing  Promote appropriate treatment for the future ◦Avoid misconception that antidepressants are addictive Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456. Haddad PM. Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management. Drug Safety 2001; 24: 189-197.

12. Mechanism for Discontinuation Syndrome  Long-term use increases synaptic levels of serotonin  Down-regulation of postsynaptic receptors  Downstream effect of other neurotransmitter ◦Norepinephrine ◦Dopamine ◦Glutamate  Also affect on cholinergic system Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456.

13. Harvey BH, Slabbert FN. New Insights on the Antidepressant Discontinuation Syndrome. Hum Psychopharmacol Clin Exp. 2014; 29: 503-516

14. Signs and Symptoms SSRIs ◦Dizziness ◦GI upset ◦Lethargy ◦Anxiety/hyperarousal ◦Dysphoria ◦Sleep problems ◦Headache FINISH ◦Flu-like symptoms ◦Insomnia ◦Nausea ◦Imbalance ◦Sensory disturbances ◦Hyperarousal Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456.

15. Signs and Symptoms SNRIsTCAs MAOIs Similar to SSRIs Occasional auditory and visual hallucinations Similar to SSRIs Signs of Parkinson's Profound balance problems Delirium Panic attacks Aggressiveness Agitation Catatonia Severe cognitive impairment Myoclonus and psychotic symptoms Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456. Haddad PM. Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management. Drug Safety 2001; 24: 189-197

16. DESS Checklist  Discontinuation-Emergent Signs and Symptoms  Patients asked about symptoms in the past seven days ◦New symptom ◦Old symptom, but worse ◦Old symptom, but improved ◦Old symptom, but unchanged or symptom not present Rosenbaum JF, Fava M, Hood SL, Ascroft RC, Krebs WB. Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Randomized Clinical Trial. Biol Psychiatry 1998; 44: 77-87

17. Comparison of SSRIs  Study Design ◦Four week study ◦Open label, randomized, double-blind, placebo-substitution period ◦242 patients  Primary objective ◦Compare the mean number of discontinuation-emergent events following a treatment interruption  Secondary objectives ◦Compare specific reported ADRs ◦Assess stability of antidepressant response following the brief interruption Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87

18. Comparison of SSRIs  Increase in DESS was significant in sertraline and paroxetine treated groups  Non-significant in fluoxetine treated group Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87

19. Comparing Specific ADRs FluoxetineParoxetineSertraline Reported by > 10% of patients Headache (16%)Dizziness (29%) Nausea (29%) Insomnia (19%) Headache (17%) Abnormal dreams (16%) Nervousness (16%) Asthenia (11%) Diarrhea (11%) Dizziness (18%) Headache (18%) Nervousness (18%) Nausea (11%) Rosenbaum JF, Fava M, H oog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87

20. Comparing Antidepressant Response Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87 Mean scores for the 28-item Hamilton Depression Rating Scale (HDRS 28 ) Mean scores for the Montgomery-Asberg Depression Rating Scale (MADRS)

21. Onset and Course  Within three days of stopping medication ◦Usually not more than one week  Untreated symptoms resolve in one to two weeks ◦Mean duration was five days  Symptoms resolve in 24 hours if previous dose resumed Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456 Haddad PM, Anderson IM. Recognising and managing antidepressant discontinuation symptoms. Adv Psychiatr Treat. 2007; 13: 447-457

22. Drug Properties  Half-life ◦Shorter half-life is higher risk for discontinuation syndrome  Active metabolites  Route of metabolism ◦Medications ◦Genetic variations Harvey BH, Slabbert FN. New Insights on the Antidepressant Discontinuation Syndrome. Hum Psychopharmacol Clin Exp. 2014; 29: 503-516

23. Drug Properties MedicationHalf-lifeActive MetaboliteMedicationHalf-lifeActive Metabolite SSRIsMISC Paroxetine33 hrsNTrazodone7-10 hrsY Sertraline26 hrsYMirtazapine26-37 hrsY Escitalopram27-54 hrsNSNRIs Citalopram35 hrsNVenlafaxine5 hrsY Fluoxetine4-5 daysYDuloxetine8-17 hrsY TCAsMAOI Amitriptyline9-25 hrsYPhenelzine12 hrsY Nortriptyline18-33 hrsNTranylcypromine2.5 hrsY Ogle NR, Akkerman, SR. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults. J Pharm Pract 2013 26:389-396 Harvey BH, Slabbert FN. New Insights on the Antidepressant Discontinuation Syndrome. Hum Psychopharmacol Clin Exp. 2014; 29: 503-516

24. Assessment Question #1 Which property of paroxetine makes it more likely to cause discontinuation syndrome? A. Anticholinergic effects B. Short half-life C. Active metabolite D. Usual requirement for higher doses

25. Differential  Discontinuation Syndrome versus Relapse ◦Symptoms ◦Restarting medication ◦Timing of symptoms ◦Resolution of symptoms  Misdiagnosis ◦Another psychiatric illness ◦Neurologic diagnosis ◦Intolerance to new prescription Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456.

26. Risk Assessment  Treatment duration ◦Longer than eight weeks of treatment is more common with discontinuation syndrome  Medication being stopped  Medication difference ◦If changing agents  Compliance ◦Patients self-discontinue medication when they start to feel better Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456

27. Reasons for Abrupt Discontinuation  Patient driven ◦Stigma associated with mental illness ◦Feeling better  Troubling side effects  Pregnancy Harvey BH, Slabbert FN. New Insights on the Antidepressant Discontinuation Syndrome. Hum Psychopharmacol Clin Exp. 2014; 29: 503-516

28. Assessment Question #2 What factors should be considered when assessing disease recurrence versus discontinuation syndrome? A. Medication dose that was stopped B. Time since medication was discontinued C. Reported symptoms D. Time when symptoms start

29. Strategies for Prevention  Avoid use for short-term therapy  Off label uses ◦IBS ◦Weight loss ◦Headaches ◦Insomnia  Assess appropriateness for taper Harvey BH, Slabbert FN. New Insights on the Antidepressant Discontinuation Syndrome. Hum Psychopharmacol Clin Exp. 2014; 29: 503-516

30. Discontinuation Syndrome Treatment  Determine ultimate intention ◦Non-compliant patient still needing treatment ◦Patient wishes to permanently discontinue medication  Assess symptom severity ◦Requirement for abrupt discontinuation ◦Symptomatic management ◦Restart medication Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456 Haddad PM. Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management. Drug Safety 2001; 24: 189-1970

31. Discontinuation Syndrome Treatment  Education about symptoms  Symptom management  Cognitive behavior therapy  Taper ◦Longer taper ◦Use medication with longer half-life  Restart Medication Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456 Haddad PM. Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management. Drug Safety 2001; 24: 189-197

32. Tapering Schedule Warner CH, Bobo W, Warner C, Reid S, Rachal, J. Antidepressant Discontinuation Syndrome. Am Fam Physician. 2006; 74: 449-456

33. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults  Review of available literature and resources  Generally acceptable to reduce dose by 25% per week  Higher risk patients slower taper ◦Reduce dose by 25% per month Ogle NR, Akkerman, SR. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults. J Pharm Pract 2013 26:389-396

34. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults ClassMedicationRecommendation SSRIParoxetine Reduce by 25% weekly 5-10 mg every 5-7 days to final dose of 25-50 mg Sertraline Reduce by 25% weekly 50 mg every 5-7 days to final dose of 25-50 mg Fluvoxamine Reduce gradually over at least 1-2 weeks 5-10 mg every 5-7 days to final dose of 25-50 mg CitalopramReduce by 25% weekly EscitalopramReduce gradually over at least 1-2 weeks Fluoxetine Not usually required If dose is > 40 mg/d may reduce gradually over 2 weeks Ogle NR, Akkerman, SR. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults. J Pharm Pract 2013 26:389-396

35. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults ClassMedicationRecommendation SNRIsDuloxetine Reduce gradually over at least 1-2 weeks 50% decrease per week Venlafaxine Reduce by 25% weekly 75 mg reduction every 4 days to final dose 25-50 mg 25 mg every 5-7 days to final dose 25-50 mg Venlafaxine XR37.5-75 mg decrease weekly to final dose 37.5 mg DesvenlafaxineLittle information- may extend to 50 mg every 48 hours Ogle NR, Akkerman, SR. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults. J Pharm Pract 2013 26:389-396

36. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults ClassMedicationRecommendation MAOIsPhenelzine Reduce by 25% weekly Reduce by 15 mg every 2 weeks Reduce by 10% weekly Tranylcypromine Reduce by 25% weekly Reduce by 10 mg every 2 weeks Reduce by 10% weekly Ogle NR, Akkerman, SR. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults. J Pharm Pract 2013 26:389-396

37. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults ClassMedicationRecommendation TCAs Reduce by 25% weekly MISCNefazodone No information- symptoms are rare Trazodone Reduce by 25% weekly Vilazodone No information Bupropion Reduce gradually over 1 week Mirtazapine Reduce by 25% weekly Ogle NR, Akkerman, SR. Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults. J Pharm Pract 2013 26:389-396

38. Switching Agents  Pharmacodynamics profile ◦Abrupt switch ◦Start-taper  Wash-out period needed ◦MAOIs ◦Fluoxetine and TCAs  Interacting medications Haddad PM. Antidepressant Discontinuation Syndromes: Clinical Relevance, Prevention and Management. Drug Safety 2001; 24: 189-197 Haddad PM, Anderson IM. Recognising and managing antidepressant discontinuation symptoms. Adv Psychiatr Treat. 2007; 13: 447-457

39. Patient Case JR is a 38 year old male with chronic depression PMH: none Current medication ◦Sertraline 50 mg PO daily Patient has trouble remembering appointments and is a frequent no-show. When he came to his last appointment he reported worsening depression symptoms and his HDRS 28 has increased from 7 to 13. (Information from the pharmacy- he is one to two weeks late each month refilling prescriptions) Physician wants to increase patient’s dose to sertraline 75 mg PO daily

40. Patient Case AS is a 57 year old female with major depressive illness following the death of her spouse one year ago PMH: HTN, HLD Current medication ◦Sertraline 50 mg PO daily AS underwent treatment of depression including counselling Spoke with her doctor about discontinuing her sertraline but continuing the counselling ◦She stopped her sertraline last Thursday Tuesday she presents with headache and dizziness for past three days

41. Patient Case Both of these patients have signs of discontinuation syndrome  How are they different? ◦Should they be treated differently?  What strategies would you recommend for treatment in each case?

42. Application  Be aware of symptoms  Use information available to assess compliance  Ask questions about medication changes  Know when to intervene with physician and an appropriate recommendation to make  Provide education

43. Questions ?

44. Drug Discontinuation Syndrome Sarah Quick, PharmD 2015 IPA Spring Meeting April 15, 2015