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Antidepressant Discontinuation Syndrome

Lecture Handout

 D. McAuley, Pharm.D.  [December 6, 2008] Detroit VA Medical Center

New mandates:  The Mental Health clinic completed a Healthcare Failure mode and effects analysis on the above topic and the following tasks have been assigned to pharmacy: (1) Educate pharmacy staff regarding antidepressant withdrawal syndrome - December 2008.   (2)  Pharmacy staff to educate patients on withdrawal syndrome and document when meds are dispensed beginning 1/2/09   (3) Place a withdrawal syndrome warning label on all antidepressant medication containers beginning 1/2/09.

HFMEA:  proactive risk mgmt methodology that focuses on prevention and correction. It attempts to transform risk management from a reactive process to a proactive one.   Identify potential process failures before they occur!  Proactive process  (focuses on prevention) . Its not a reactive process like Root Cause Analysis


I listed below, some of the IMPORTANT reasons why a pharmacist should be familiar with this syndrome:
-
Abrupt discontinuation of an antidepressant may result in significant discomfort for the patient.
-On rare occasions, the effects may be severe enough to require hospitalization.

-Failure to recognize the syndrome may result in medical and psychiatric misdiagnosis. This syndrome can mimic stroke, other neurologic conditions, infectious diseases, or adverse effects of other medications the patient may be taking.

Which antidepressants are we concerned with?

All approved antidepressant agents have had case reports or warnings from their manufacturers of such reactions occurring in response to either abrupt discontinuation or medication tapering. [SSRIs, TCAs, MAOIs, atypical agents].


Antidepressant discontinuation syndrome is more likely to occur with an antidepressant that has a __________ half-life.

Another important consideration is:


Duration of treatment
:   Reactions are rare among individuals who have received less than _____________ weeks of antidepressant treatment.

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.  One study: 9 percent given fluoxetine (Prozac) and 50 percent given paroxetine (Paxil) reported discontinuation symptoms, with a mean onset of two days and mean duration of five days.  Shorter half-life = greater risk.   Another study: fluoxetine (14 percent) than with paroxetine (66 percent) or sertraline (Zoloft) (60 percent).  Study showed no significant added risk associated with age, sex, or diagnosis.

Potential causes
(1) Abrupt discontinuation by the patient [Drug was not working?  Patient experienced side effects?  Feeling better?]
(2) Switching antidepressants.
(3) Generic drug substitutions (FDA’s 80 - 125% rule). Substitution may result in an unintended sudden reduction in drug concentration.

(4) Missed doses (compliance)
(5) Unreported downward adjustments in dosage

Symptoms depend on the class of antidepressant used.

SSRIs:  Most common à most commonly prescribed class.  Symptoms may include dizziness, gastrointestinal upset (nausea), lethargy or  anxiety/hyperarousal, dysphoria, sleep problems, and headache.   [FINISH mnemonic (Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal). 

Facilitates rapid recognition of the syndrome ||  hyperarousal:  a state of increased psychological and physiological tension.  Example of a common sensory disturbance: electric shock sensations. Become familiar with the constellation of symptoms.

TCAs: Symptoms of antidepressant discontinuation syndrome closely mimics that of the SSRIs. However, signs of parkinsonism and profound problems with balance may appear.

MAOIs: Discontinuation syndrome associated with MAOIs may involve more serious symptomatology such as aggressiveness, agitation, catatonia, severe cognitive impairment, or myoclonic jerks and psychotic symptoms and may require more intensive management.

Other:   Bupropion:  discontinuation symptoms are uncommon.   Venlafaxine:  Abrupt discontinuation may cause dizziness, flu-like symptoms, and anxiety. These symptoms may be more severe than those produced by SSRI discontinuation.

Onset:  Discontinuation symptoms typically appear within three days, but in some cases may appear within hours of the first missed dose.  Symptoms can also occur when initiating a medication taper.

Course:  Untreated symptoms are usually mild and resolve spontaneously in one to three weeks. In rare but more serious cases involving psychosis, catatonia, or severe cognitive impairment, immediate psychiatric consultation may be required.
(Note: symptoms are rapidly extinguished with reinstitution of antidepressant medication.)

Pathophysiology:  

- No definitive pathophysiologic explanation for antidepressant discontinuation syndrome.

- Long-term use of reuptake inhibitors à down-regulation of postsynaptic receptors.  [Downregulation: An decrease in the number of receptors on the surface of target cells, making the cells less sensitive to a hormone or another agent.]

- There is speculation concerning the possibility of a temporary deficiency of synaptic serotonin with abrupt withdrawal of an SSRI.  This deficiency is compounded by the fact that down-regulated receptors will remain in their relatively hypoactive state for days to weeks.

- Because tricyclic antidepressants and MAOIs are also serotonergically active, the same mechanism is implicated for their respective antidepressant discontinuation syndromes; however, tricyclic antidepressants also affect the cholinergic system, so rapid discontinuation may cause signs of parkinsonism and problems with balance. Because MAOIs cause changes in the alpha2-adrenergic and dopaminergic receptors, their discontinuation may cause agitation and psychosis.

Counseling:

Educating patients about discontinuation symptoms can help prevent them from abruptly stopping antidepressants and may help reduce anxiety should adverse discontinuation effects occur.    [ See sample patient handout below:]

Antidepressant Discontinuation Syndrome: What You Should Know
What is antidepressant discontinuation syndrome?

If you suddenly stop taking your antidepressant medicine, you may feel like you have the flu. You also might have trouble sleeping, have an upset stomach, have shock-like sensations in the arms and hands, feel dizzy, or feel nervous. This is called antidepressant discontinuation syndrome. It is not dangerous or life threatening and usually goes away within one week.

Which antidepressants can cause this problem?

You are more likely to have a problem if you stop taking some brands, like paroxetine (brand: Paxil) and sertraline (brand: Zoloft), but you can get symptoms from stopping any antidepressant medicine.

What can I do if I have antidepressant discontinuation syndrome?

If you stopped your medicine without talking to your doctor or if you missed a dose, then you can just start taking your medicine again. If you stopped your medicine on purpose, talk to your doctor about why you stopped. If you and your doctor have decided you should slowly take less medicine until you stop, or if you are out of medicine, talk to your doctor right away about increasing your dose or restarting your medicine.

How do I keep this from happening again?

Take your medicine exactly like your doctor tells you to. If you want to stop taking your medicine, talk to your doctor first. Not being able to stop all at once does not mean that you are addicted to your medicine.

Source:  http://www.familydoctor.org/.

Discontinuing medication:  

- When stopping antidepressant treatment, antidepressants should be tapered; the antidepressant dose should be reduced by 25 percent per week so as to minimize the occurrence of discontinuation side effects.

- There are no clear, validated tapering recommendations.

- It may be possible to discontinue medication more quickly if doses are low; discontinuation may take longer (three months or more) after maintenance therapy.

- It may be possible to stop fluoxetine therapy without tapering.

- If the antidepressant discontinuation syndrome occurs during a tapering of the antidepressant, consider restarting at the original dose and then taper at a slower rate. In cases where slow tapering is poorly tolerated, a medicine with a longer half-life such as fluoxetine may be substituted for the shorter half-life agent.

Management

- Provide reassurance to the patient that the condition is reversible, is not serious or life threatening, and will run its course within one to two weeks.

- Consider restarting the antidepressant medication with a slow dose taper or providing support if the patient desires not to restart the antidepressant.

- Severe symptoms should resolve in fewer than three days, and often within 24 hours.

- Tricyclic antidepressants:   Antidepressant discontinuation syndrome symptoms caused by tricyclic antidepressants that suggest cholinergic rebound (e.g., parkinsonism and other problems with movement) may respond to short-term use of anticholinergic agents such as atropine or benztropine. This should be considered especially for patients who are opposed to restarting their tricyclic antidepressant.

References:

1)  Birnbaum  R, Hirsch M.  Antidepressant medication in adults: Switching and discontinuing medication. UpToDate®. 2008;16(3). http://www.uptodate.com/ . Accessed: 12/5/2008.

2)  Blier P, Tremblay P. Physiologic mechanism underlying the antidepressant discontinuation syndrome. J Clin Psychiatry. 2006;67(suppl 4):8-13.

3)  Robinson DS. Antidepressant Discontinuation Syndrome. Primary Psychiatry. 2006;13(10):23-24.

4)  Rosenbaum JF, Fava M , Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87.

Appendix

--------------------------------------------------------------------------------------
1]  Signs and Symptoms of Antidepressant Discontinuation Syndrome
2]  Side effects of antidepressant medications
3]  Pharmacokinetic properties of antidepressants.

4]  Switching antidepressant medications – cross tapering.
5]  Gradual taper rates for antidepressants.

Signs and Symptoms of Antidepressant Discontinuation Syndrome

 

SSRI

Atypical antidepressant

Tricyclic antidepressant

MAOI

General

       

Flu-like symptoms

+

+

+

-

Headache

+

+

+

+

Lethargy

+

+

+

-

Gastrointestinal

       

Abdominal cramping

+

-

+

-

Abdominal pain

+

-

+

-

Appetite disturbance

+

+

+

-

Diarrhea

+

 

+

-

Nausea/vomiting

+

+

+

-

Sleep

       

Insomnia

+

+

+

+

Nightmares

+

+

+

+

Balance

       

Ataxia

+

-

+

-

Dizziness

+

+

+

-

Lightheadedness

+

-

+

-

Vertigo

+

+

+

-

Sensory

       

Blurred vision

+

-

-

-

"Electric shock" sensations

+

+

-

-

Numbness

+

-

-

-

Paresthesia

+

+

-

-

Movement

       

Akathisia

+

+

+

-

Myoclonic jerks

-

-

-

+

Parkinsonism

+

-

+

-

Tremor

+

-

+

-

Affective

       

Aggression/irritability

+

-

-

+

Agitation

+

-

+

+

Anxiety

+

+

+

-

Low mood

+

+

+

+

Psychosis

       

Catatonia

-

-

-

+

Delirium

-

-

-

+

Delusions

-

-

-

+

Hallucinations

-

-

-

+


NOTE: Symptom categories listed by rate of incidence.  +  = occur in withdrawal from this medication;   -  = do not occur in withdrawal from this medication.
Source:  Warner CH, et al. Antidepressant Discontinuation Syndrome. Am Fam Physician 2006;74:449-56, 457.

Side effects of antidepressant medications

Drug

Anticholinergic

Drowsiness

Insomnia/ agitation

OH

Cardiac arrhythmia

GI distress

Weight gain*

Tricyclics and tetracyclics

Amitriptyline

4+

4+

0

4+

3+

0

4+

Amoxapine

2+

2+

2+

2+

3+

0

1+

Clomipramine

3+

3+

4+

2+

2+

3+

3+

Desipramine

1+

1+

1+

2+

2+

0

1+

Doxepin

3+

4+

0

2+

2+

0

3+

Imipramine

3+

3+

1+

4+

3+

1+

3+

Maprotiline

2+

4+

0

0

1+

0

2+

Nortriptyline

1+

1+

0

2+

2+

0

1+

Protriptyline

2+

1+

1+

2+

2+

0

0

Selective serotonin reuptake inhibitors

Citalopram

0

0

1+

0

0

3+

0

Escitalopram

0

0

1+

0

0

3+

0

Fluoxetine

0

0

2+

0

0

3+

0

Fluvoxamine

0

1+

1+

0

0

3+

0

Paroxetine

1+

1+

1+

0

0

3+

0

Paroxetine CR

1+

1+

1+

0

0

1+

0

Sertraline

0

0

2+

0

0

3+

0

Monoamine oxidase inhibitors

Isocarboxid

1+

1+

2+

2+

0

1+

1+

Phenelzine

1+

2+

1+

3+

0

1+

2+

Selegiline

1+

0

1+

1+

0

0

0

Tranylcypromine

1+

1+

2+

2+

0

1+

1+

Atypicals:

Dopamine-norepinephrine reuptake inhibitors

Bupropion

0

0

2+

0

1+

1+

0

Bupropion SR

0

0

1+

0

1+

1+

0

Bupropion XL

0

0

1+

0

1+

1+

0

Serotonin-norepinephrine reuptake inhibitors

Duloxetine

0

0

2+

0

0

3+

0

Venlafaxine

0

0

2+

0

0

3+

0

Venlafaxine XR

0

0

2+

0

0

1+

0

Serotonin modulators

Nefazodone [bullet]

1+

2+

0

1+

0

2+

0

Trazodone

0

4+

0

1+

1+

1+

1+

Noradrenergic and specific serotonergic antidepressant

Mirtazapine

1+

4+

0

0

0

0

4+

SWITCHING ANTIDEPRESSANT MEDICATIONS1

Cross-tapering — For many drug switches, cross-tapering is the best technique to assure that the patient's depression is not unmasked from rapid drug withdrawal, while minimizing the risk of drug-drug interactions. In a cross-taper, the dose of the current antidepressant is gradually reduced, over a one to two week period or longer, while the dose of the antidepressant being initiated is gradually increased to therapeutic range over the same time period.

[Gradually decrease dose of current antidep, while slowly increasing the dose of the new antidepressant]

Action / Concerns

Approach

Switching between SSRIs

Immediate.

"Switching between SSRIs — This is generally the simplest antidepressant switch. Selective serotonin reuptake inhibitors (SSRIs) overlap in their mechanism of action, and the new SSRI will usually prevent discontinuation symptoms that may occur when the first SSRI is stopped. Substituting a new SSRI at the relatively equivalent dose of the former SSRI is typically well-tolerated, though starting the new SSRI at a lower dose may also be considered since patients occasionally have idiosyncratic side effects to particular SSRIs."

Approximate dose equivalents of antidepressants

Fluoxetine 20 mg

Paroxetine 20 mg

Sertraline 50-75 mg  (50mg)

Citalopram 20 mg

Escitalopram 5-10 mg

Fluvoxamine 100 mg

Venlafaxine 75 mg

Switching from SSRI to TCA

2D6 concerns

"Switching from SSRI to TCA — The most common method used to switch from an SSRI to a tricyclic antidepressant (TCA) is a cross-taper (see "Cross-tapering" above). It is important to remember that fluoxetine and paroxetine are strong inhibitors of the p450 enzyme 2D6 (sertraline, citalopram, and escitalopram are significantly milder inhibitors). This enzyme is involved in the metabolism of many TCAs and inhibition will cause an increased TCA blood level (in some cases, several-fold higher), which can result in toxicity. Because of this, TCAs should be started at low doses when cross-tapering with an SSRI, particularly with fluoxetine and paroxetine; TCA blood levels can be checked during this period for added safety. Inhibition of p450 2D6 will be present to some degree until the SSRI is completely cleared; most SSRIs are cleared in approximately five days, but fluoxetine persists in the system for up to five weeks due to its long half-life. Completely tapering off the SSRI prior to starting a TCA can prevent this issue of drug-enzyme interaction, but is often impractical because of the risk of exacerbating the patient's psychiatric condition."

Switching from SSRI to venlafaxine or duloxetine

2D6 concerns

"SSRI to venlafaxine or duloxetine — Since both venlafaxine and duloxetine both have strong serotonergic properties, switching immediately from most SSRIs to the equivalent dose of venlafaxine (show table 1) or duloxetine is typically well-tolerated. If starting from a high dose of an SSRI, a cross-taper may be preferable (see "Cross-tapering" above). However, caution is needed in switching from fluoxetine or paroxetine, because venlafaxine and duloxetine are metabolized by p450 2D6 (see discussion above) and it is prudent to start them at low doses. Since fluoxetine has a very long half-life, 2D6 inhibition may be present up to five weeks after discontinuation."

Switching from Venlafaxine or duloxetine to antidepressants other than MAOIs

Long cross-taper (2 – 3 weeks)

"Venlafaxine or duloxetine to antidepressants other than MAOIs — Venlafaxine is associated with uncomfortable discontinuation symptoms upon cessation. Switching to an antidepressant that shares some neurotransmitter effects (such as an SSRI) may mitigate these symptoms to a degree, but does not do so consistently. Because of this, we recommend cross-tapering venlafaxine with the new antidepressant over a two to three week period"

Switching between venlafaxine and duloxetine

Immediate

"Switching between venlafaxine and duloxetine — These medications share many properties. At low doses (less than 150 mg of venlafaxine or less than 60 mg of duloxetine), immediately switching from one medication to another is usually well-tolerated. At higher doses, a cross-taper may be preferred."

Switching to or from mirtazapine

Cross-taper

Switching to or from mirtazapine — A cross-taper is recommended in switching between mirtazapine and SSRIs, TCAs, venlafaxine, or duloxetine

Switching to Bupropion or from antidepressants other than MAOIs

Cross-taper

"Bupropion to or from antidepressants other than MAOIs — Bupropion does not have significant serotonergic properties, so would not be expected to mitigate discontinuation symptoms that result from discontinuing medications that are strongly serotonergic. Therefore, when switching from an SSRI, a TCA, venlafaxine, duloxetine, or mirtazapine to bupropion, we recommend cross-tapering off the former medication over a one to two week period (two to three weeks for venlafaxine and duloxetine)"

Switching to or from MAOIs

Two week washout period

"Switching to or from MAOIs — Since the combination of MAOIs and other antidepressants can result in severe toxicity (eg, hypertensive crisis, serotonin syndrome), it is recommended that two weeks elapse between discontinuing an MAOI and starting a different antidepressant.   Two weeks should also elapse between discontinuing a TCA, SSRI (other than fluoxetine), venlafaxine, duloxetine, or mirtazapine and starting an MAOI. Because of fluoxetine's long half-life, five weeks should elapse between discontinuing fluoxetine and starting an MAOI.   When switching between MAOIs we recommend that two weeks elapse between discontinuing the first MAOI and starting the second."

1.     Birnbaum  R, Hirsch M.  Antidepressant medication in adults: Switching and discontinuing medication. UpToDate®. 2008;16(3). http://www.uptodate.com/ . Accessed: 12/5/2008.

Gradual Taper Rates for Antidepressants


Drug


Recommended taper rate

Monoamine oxidase inhibitor

Phenelzine (Nardil)

Reduction of 15 mg per day every two weeks or 10 percent per week

Tricyclic antidepressants

Gradually, up to three months

 

Selective serotonin reuptake inhibitor

Fluoxetine (Prozac)

Gradual taper generally unnecessary

Paroxetine (Paxil)

Reduction of 10 mg per day every five to seven days with a final dosage of 5 to 10 mg per day before discontinuation*

Sertraline (Zoloft)

Reduction of 50 mg per day every five to seven days with a final dosage of 25 to 50 mg per day before discontinuation

Atypical antidepressant

Venlafaxine (Effexor)

Reduction of 25 mg day every five to seven days with a final dosage of 25 to 50 mg per day before discontinuation*

Venlafaxine XR (Effexor XR)

Reduction of 37.5 to 75 mg per day every week with a final dosage of 37.5 mg per day before discontinuation*


NOTE: These recommendations are expert opinion only.
*-Slower taper may be needed.

Adapted with permission from Shelton RC. Steps following attainment of remission: discontinuation of antidepressant therapy. Primary Care Companion J Clin Psychiatry 2001;3:172.

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