Transcript Drug Discontinuation Syndrome

Drug Discontinuation
Syndrome
S a rah Qu i c k , P h a rm D
2 0 1 5 I PA S p r ing Me et i ng
April 15, 2015
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
PSYCHIATRISTS
Unaware
28%
GENERAL PRACTITIONERS
Aware
30%
Aware
72%
Unaware
70%
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
• Similar to SSRIs
• Occasional
auditory and visual
hallucinations
• Similar to SSRIs
• Signs of Parkinson's
• Profound balance
problems
• Delirium
• Panic attacks
MAOIs
•
•
•
•
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
Reported by >
10% of patients
Fluoxetine
Headache (16%)
Paroxetine
Dizziness (29%)
Nausea (29%)
Insomnia (19%)
Headache (17%)
Abnormal dreams
(16%)
Nervousness
(16%)
Asthenia (11%)
Diarrhea (11%)
Sertraline
Dizziness (18%)
Headache (18%)
Nervousness
(18%)
Nausea (11%)
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 Antidepressant Response
Mean scores for the 28-item
Hamilton Depression Rating
Scale (HDRS28)
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
Active Metabolite Medication
33 hrs
N
26 hrs
Y
27-54 hrs
N
35 hrs
N
4-5 days
Y
TCAs
Amitriptyline 9-25 hrs
Nortriptyline 18-33 hrs
Y
N
MISC
Trazodone
Mirtazapine
SNRIs
Venlafaxine
Duloxetine
Half-life
Active Metabolite
7-10 hrs
Y
26-37 hrs
Y
5 hrs
Y
8-17 hrs
Y
MAOI
Phenelzine
12 hrs
Tranylcypromine 2.5 hrs
Y
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
Medication
Recommendation
SSRI
Paroxetine
• 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
Citalopram
Reduce by 25% weekly
Escitalopram
Reduce 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
Guidance for the Discontinuation or Switching
of Antidepressant Therapies in Adults
Class
Medication
SNRIs Duloxetine
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
Venlafaxine
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 HDRS28 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
?
Drug Discontinuation
Syndrome
S a rah Qu i c k , P h a rm D
2 0 1 5 I PA S p r ing Me et i ng
April 15, 2015