Drug Discontinuation Syndrome

S a rah Qu i c k , P h a rmD 2 0 1 5 I PA S p r ing M e et i ng A p r i l 1 5 , 2 0 1 5

Disclosure

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

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.

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.

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

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

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.

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

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

Background

Physicians may be unaware that patients may experience discontinuation syndrome

GENERAL PRACTITIONERS PSYCHIATRISTS Unaware 28% Aware 72% Unaware 70% Aware 30%

Lamoure J. Discontinuation syndrome: relapse vs. withdrawal. Can J Diagnosis 2006;23(9):95-8

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.

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.

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

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.

Signs and Symptoms

SNRIs TCAs 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

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

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

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

Comparing Specific ADRs

Fluoxetine Paroxetine Sertraline 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

Comparing Antidepressant Response

Mean scores for the 28-item Hamilton Depression Rating Scale (HDRS 28 ) Mean scores for the Montgomery-Asberg Depression Rating Scale (MADRS) 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

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

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

Drug Properties

Medication SSRIs

Paroxetine Sertraline Escitalopram Citalopram Fluoxetine

Half-life

33 hrs 26 hrs 27-54 hrs 35 hrs 4-5 days

Active Metabolite Medication

N Y N N Y

MISC

Trazodone Mirtazapine

SNRIs

Venlafaxine Duloxetine

Half-life

7-10 hrs 26-37 hrs 5 hrs 8-17 hrs

Active Metabolite

Y Y Y Y

TCAs MAOI

Amitriptyline 9-25 hrs Nortriptyline 18-33 hrs Y Phenelzine 12 hrs Y N Tranylcypromine 2.5 hrs Y 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

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

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.

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

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

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

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

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

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

Tapering Schedule

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

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

Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults

Class SSRI Medication

Paroxetine Sertraline Fluvoxamine Citalopram Escitalopram Fluoxetine • • • • • •

Recommendation

Reduce by 25% weekly 5-10 mg every 5-7 days to final dose of 25-50 mg Reduce by 25% weekly 50 mg every 5-7 days to final dose of 25-50 mg Reduce gradually over at least 1-2 weeks 5-10 mg every 5-7 days to final dose of 25-50 mg Reduce by 25% weekly Reduce gradually over at least 1-2 weeks • • 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

Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults

Class Medication

SNRIs Duloxetine Venlafaxine • • • • •

Recommendation

Reduce gradually over at least 1-2 weeks 50% decrease per week 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 XR 37.5-75 mg decrease weekly to final dose 37.5 mg Desvenlafaxine Little 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

Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults

Class Medication Recommendation MAOIs

Phenelzine • • • 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

Guidance for the Discontinuation or Switching of Antidepressant Therapies in Adults

Class TCAs MISC Medication

Nefazodone Trazodone Vilazodone Bupropion Mirtazapine • • • • • •

Recommendation

Reduce by 25% weekly No information- symptoms are rare Reduce by 25% weekly No information Reduce gradually over 1 week 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

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

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

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

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?

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

Questions

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Drug Discontinuation Syndrome

S a rah Qu i c k , P h a rmD 2 0 1 5 I PA S p r ing M e et i ng A p r i l 1 5 , 2 0 1 5