April 2000
Withdrawal reactions
Patients may be at risk if their antidepressant is stopped too quickly
BY LISA BURRY, BSC PHARM, AND NATALIE KENNIE, PHARMD
Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are widely used due to their efficacy and tolerability. However, one complication of antidepressant therapy that has been receiving increasing attention in the medical literature is the “antidepressant discontinuation reaction.”1 This reaction is distinguished by the appearance of characteristic physical and psychological symptoms after the antidepressant is discontinued or, in some cases, after the dose is reduced. This phenomenon has been reported with all classes of antidepressants, and has been well described in the medical literature.2-4
This article discusses the antidepressant discontinuation reaction, as it occurs with SSRIs, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). The discussion will focus particularly on the SSRIs, since most of the published literature involves this class, and SSRIs are being prescribed with increasing frequency.
When patients stop long-term therapy with antidepressants, discontinuation symptoms frequently occur. These symptoms range in severity from mild somatic distress and gastrointestinal intolerance, to serious cognitive impairment and catatonia that may require hospitalization. Pharmacists should be aware of this reaction and its associated symptoms so that they may educate patients and other healthcare professionals, and assist in reaction prevention and management.
CLINICAL PRESENTATION
The antidepressant discontinuation reaction is also referred to as the antidepressant withdrawal reaction or withdrawal syndrome, or the serotonin reuptake inhibitor discontinuation syndrome. It is a group of characteristic physical and psychological symptoms that begin shortly after abruptly stopping antidepressant therapy or, in some cases, after reducing the dose. Discontinuation reactions have been documented with all major classes of antidepressants. There are similarities and differences in symptom presentation among the various classes of antidepressants, as outlined in Table 1.
There are several characteristic features of this reaction:
- Onset occurs within days of abrupt antidepressant discontinuation or tapering. It is unusual for this reaction to occur later than one week after discontinuing therapy.
- Symptoms may occur with intermittent noncompliance.
- Symptoms are generally mild and self-limiting, but can be severe and disabling.
- Symptoms usually spontaneously resolve within two to three weeks.
- The reaction is more common with longer courses of therapy.
- Symptoms are rapidly reversed by reintroducing the original medication or an agent with similar pharmacologic activity.
The antidepressant discontinuation reaction has been well characterized by anecdotal case reports, case series and retrospective analyses.3,5,6 Recent reports have highlighted a number of withdrawal reactions with trazodone, as well as SSRIs such as paroxetine, fluvoxamine, sertraline and citalopram.1,3,7,8 Clomipramine and venlafaxine can be classified with the SSRIs, since they have many of the same characteristic discontinuation symptoms, likely due to their serotonin activity (see Table 1).3,5
Five key symptom groups have been identified in the antidepressant discontinuation reaction (see Table 1): gastrointestinal, flu-like, sleep disturbances, psychological and neurological.3,5 In addition, some unique symptoms have been reported with the discontinuation of SSRIs: disequilibrium (e.g., dizziness, vertigo, ataxia), sensory disturbances (e.g., paresthesia, sensations of electric shock), and aggressive and impulsive behaviours.3 Patients have described dizziness as “swimming,” feeling “spaced out” or “drunken-like,” usually exacerbated by slight movements.5,7 Sensory disturbances have been described as “tingles” or “electric shocks.”7 These sensory disturbances, which tend to be localized to the upper half of the body and face, are usually intense, distracting sensations that last a few moments.3,7,8
Discontinuation of TCAs or MAOIs also results in the five key symptom groups. However, in addition, TCAs have the unique ability to cause cardiac disturbances (e.g., tachycardia),3 while MAOI withdrawal can cause psychosis, delirium and hallucinations.3,6
The mnemonic “FINISH” has been suggested as a way to remember the six main symptoms that occur when patients discontinue antidepressant therapy:
Flu-like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbances
Hyperarousal
MECHANISM OF THE REACTION
Although a number of cases of antidepressant discontinuation reactions have been documented in the literature, the mechanism is not well understood. Several theories have been postulated to explain the reaction and the associated symptoms for each class of antidepressants (see Table 1).
In general, it is thought that neurotransmitter receptors affected by the antidepressant are upregulated, just as beta-blockers cause an upregulation of the beta receptors.1,3,8 For example, persistent serotonergic blockade with SSRIs leads to receptor upregulation (i.e., an increased number of receptors is made available); this results as the system attempts to counteract the receptor blockade and restore normal activity. If the antidepressant is abruptly withdrawn, this results in neurotransmitter “overdrive,” since more receptors will be available for stimulation by the neurotransmitter(s). Other theories postulate that the reaction is due to the biological or cognitive sensitivity of the individual patient.
ONSET AND DURATION
In most cases, symptoms usually begin within one to three days of abrupt discontinuation, irrespective of antidepressant class. However, there have been case reports suggesting that symptoms may occur as early as 12 to 24 hours with venlafaxine, paroxetine and TCAs.9 In contrast, the onset of withdrawal symptoms may be delayed one to three weeks after fluoxetine discontinuation.3 Symptoms have also been reported to occur during tapering or dosage reductions, and with intermittent noncompliance.1,3,7
Symptoms of the antidepressant discontinuation reaction are usually short-lived. Most symptoms disappear within two weeks, but occasionally last for several weeks.3,7 In a recent retrospective chart review of 171 patients in whom an SSRI was discontinued, symptoms persisted for a mean of 11.8 days after onset, and a maximum of 21 days.10
INCIDENCE OF DISCONTINUATION
REACTION WITH VARIOUS ANTIDEPRESSANTS
Most of the literature published regarding the risk of antidepressant discontinuation symptoms has focused on newer antidepressants such as the SSRIs and venlafaxine.
A retrospective case study attempted to determine which SSRI (including clomipramine) was most likely to cause the discontinuation reaction, by examining charts of outpatients who were treated with clomipramine or an SSRI.10 Of 352 patients, 171 (48.6%) discontinued treatment under medical supervision, and at least one new symptom (e.g., dizziness, paresthesia or nightmares) emerged in 21 patients (12%), despite a slow taper. It was found that symptoms occurred more frequently in those who were treated with clomipramine (30.8%), paroxetine (20%) or fluvoxamine (14%), compared to sertraline (2.2%) or fluoxetine (0%).
To date, there are only two case reports of withdrawal symptoms with citalopram. It is unclear whether this is due to a low potential to cause the reaction or the fact that the drug is new on the market.3,8 An evaluation of case reports and case series suggests that venlafaxine has the highest rate of SSRI discontinuation reactions, with an incidence of 30-40 per cent.5
Symptoms that result from abrupt or gradual discontinuation of TCAs have been well documented in the literature; however, the incidence of discontinuation reactions with specific TCAs has not yet been identified.11,12
RISK FACTORS
Currently, there is no method for predicting which patients will experience the antidepressant discontinuation reaction, or which patients will have moderate to severe symptoms. However, several factors have been identified that may increase the patient’s risk of experiencing the reaction:3,10,13
- prolonged administration of an antidepressant (e.g. > 5 weeks)
- high doses
- agents with short half-lives
- agents that do not have an active metabolite
- previous antidepressant discontinuation reaction
- patients with a history of noncompliance to antidepressant therapy
The incidence of the reaction has been well correlated with the antidepressant’s half-life, with a higher incidence in antidepressants with a shorter half-life.10 Thus, patients using drugs with short half-lives (e.g., venlafaxine, clomipramine, paroxetine) have a greater risk of experiencing the reaction than those taking fluoxetine.
DISCONTINUATION REACTION
vs. DISEASE RELAPSE
Symptoms of disease relapse can also occur when antidepressants are discontinued, and may resemble those of a discontinuation reaction. It is important to make this distinction, since mislabelling the symptoms as a relapse may lead to unnecessary long-term reinstatement of the antidepressant.1,14
Symptoms directly related to discontinuation of the antidepressant can be distinguished from a disease relapse by the onset and duration of symptoms, and the rapid relief of symptoms when the antidepressant is reintroduced.3,7,14 Antidepressant discontinuation symptoms typically appear within one to two days of abrupt discontinuation or dose reduction; they persist for seven to 14 days, and rapidly resolve by reinstating the antidepressant or one that is pharmacologically similar.3,7,14 In contrast, disease relapse has a much slower onset (i.e., two to three weeks after discontinuation), and it does not spontaneously disappear. However, in both disease relapse and discontinuation reactions, symptoms quickly disappear with reintroduction of the antidepressant.1,14
MANAGEMENT
There are no published controlled trials or treatment protocols to guide the management of the antidepressant discontinuation reaction. However, several authors have suggested possible treatment options based on symptom severity (see Figure 1).3,14 No intervention is required for mild symptoms, and patients should be reassured that symptoms are temporary.
For symptoms of moderate severity, the antidepressant can be reinstated and then slowly tapered (see Table 2). A pharmacologically similar antidepressant may be substituted, but to date this method is not considered reliable.3
Those with severe or intolerable symptoms may require adjunctive therapy. The use of adjunctive therapy has not been well documented, as most of the evidence of efficacy comes from case reports. Table 3 summarizes potential adjunctive agents that may help to control various discontinuation symptoms.
PREVENTION
Treatment guidelines for depression provide advice on diagnosis, starting and maintaining therapy, but have given little attention to discontinuing treatment. Little has been published on the methods of preventing the antidepressant discontinuation reaction,14 but several authors have suggested possible tapering schedules (see Table 2) that could minimize the risk of withdrawal symptoms.3,7,14
Typically, the antidepressant dosage can be decreased by 25 per cent every seven to 14 days, with the exception of fluoxetine, which has a long half-life and active metabolites that allows “self-tapering,” i.e., a gradual taper is not required.3,7 The rate of dosage taper generally depends upon factors such as the pharmacologic profile of the drug (e.g., half-life), current dose (higher doses require slower tapers), duration of treatment (longer duration requires slower taper), and the patient’s ability to tolerate adverse events (some patients are more sensitive to adverse effects).3,14
THE PHARMACIST’S ROLE
Pharmacists can play an important role in the prevention and identification of antidepressant discontinuation reactions. First, they have a key role in providing general information to patients regarding the possibility of a reaction and the various symptoms that can occur if their antidepressant is stopped abruptly. Patient counselling tips are summarized in Table 4. Pharmacists can also advocate for a slow taper of the antidepressant, if the patient is discontinuing therapy. They can play a supportive role in monitoring for symptoms of the discontinuation reaction, when tapering drug therapy or during periods of noncompliance with the medication. Possible management strategies can also be suggested for patients who experience symptoms upon discontinuation.
CONCLUSION
The antidepressant discontinuation reaction is an often-overlooked phenomenon in antidepressant pharmacotherapy. Pharmacists have an important role to play in preventing, recognizing and managing this reaction.
At the time of authorship Lisa Burry, BSc Pharm, was a PharmD candidate at the University of Toronto on clinical rotation with Natalie Kennie, PharmD, a primary care pharmacist at St. Michael’s Hospital Health Centre, Toronto.
REFERENCES
1. Thompson C. Discontinuation of antidepressant therapy: emerging complications and their relevance. J Clin Psychiatry 1998;59:541-8.
2. Haddad P, Lejoyeux M, Young A. Antidepressant discontinuation reactions are preventable and simple to treat. Br Med J 1998;316:1105-6.
3. Wolfe R. Antidepressant withdrawal reactions. Am Fam Phys 1997;56:455-62.
4. Donoghue J, Haddad P. Pharmacists lack knowledge of antidepressant discontinuation symptoms. J Clin Psychiatry 1999;60:124-5.
5. Haddad P. Newer antidepressants and the discontinuation syndrome. J Clin Psychiatry 1997;58 (suppl 7):17-21.
6. Lawrence J. Reactions to withdrawal of antidepressants, antiparkinsonian drugs, and lithium. Psychosomatics 1985;26:869-77.
7. Schatzberg AF, Haddad P, Kaplan EM, et al. Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. J Clin Psychiatry 1997;58(suppl 7):5-10.
8. Lejoyeux M, Ades J. Antidepressant discontinuation: a review of the literature. J Clin Psychiatry 1997;58(suppl 7):11-5.
9. Zajecka J, Tracey KA, Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. J Clin Psychiatry 1997;58:291-6.
10. Coupland NJ, Bell CJ, Potokar JP. Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol 1996;16:356-62.
11. Dilsaver S. Antidepressant withdrawal syndromes: phenomenology and pathophysiology. Acta Psychiatry Scand 1989;79:113-7.
12. Lazowick AL, Levin GM. Potential withdrawal syndrome associated with SSRI discontinuation. Ann Pharmacother 1995;29:1284-5.
13. Barr LC, Goodman WK, Price LH. Physical symptoms associated with paroxetine discontinuation. Am J Psychiatry 1994;151:289.
14. Rosenbaum JF, Zajecka J. Clinical management of antidepressant discontinuation. J Clin Psychiatry 1997;58(suppl 7):37-40.
15. Schatzberg AF, Haddad P, Kaplan EM. Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome. J Clin Psychiatry 1997;58(suppl 7):23-7.
16. Berber M. Remembering the discontinuation syndrome. J Clin Psychiatry 1998;59:255.
| TABLE 1: Characteristic Features of Antidepressant Discontinuation Reaction | ||||
| Drug | Proposed mechanism(s) | Onset | Duration | Clinical features |
| SSRIs venlafaxine clomipramineIncidence is variable: 2-40% |
1. decreased synaptic serotonin in the face of down-regulated serotonin receptors2. secondary effects of GABA, dopamine, NE
3. biologic & cognitive sensitivity 4. cholinergic rebound |
Variable as it depends upon the agent e.g., 1 day with venlafaxine vs. 2-3 weeks with fluoxetine |
7-14 days | Gastrointestinal (e.g., abdominal pain, anorexia, diarrhea, dry mouth, increased appetite, nausea, vomiting)Flu-like (e.g., chest discomfort, chills, fatigue, headache, malaise, myalgia, sweating, weakness)
Sleep (e.g., nightmares, insomnia) Psychiatric (e.g., anxiety, aggressiveness, confusion, depersonalization, hallucinations, low mood, hypomania, panic) Neurologic (e.g., akathisia, dizziness, vertigo, dyskinesia, dystonia, tremor, paresthesia, electric shock sensation, Lhermitte’s sign (electric shock in the spine due to neck flexion), “buzzing” of the head, migraine-like scotomas, tinnitus |
| TCAsReported incidence 20-80% | 1. Cholinergic overdrive2. Adrenergic overdrive | 1-3 days | 5-14 daysreports up to 21 days | Gastrointestinal (e.g., nausea, vomiting, diarrhea, dry mouth, abdominal pain)Flu-like (e.g., chills, fever, fatigue, headache & malaise)
Cardiovascular (e.g., bigeminy [two consecutive premature ventricular contractions], palpitations, tachycardia) Sleep (e.g., nightmares, insomnia) Psychiatric (e.g., anxiety, depersonalization, depression, hypomania, mania, panic) Neurologic (e.g., delirium, dizziness, dyskinesia, tremor) |
| TrazodoneIncidence unknown | Adrenergic rebound | 1-4 days | 4-5 days | Gastrointestinal(e.g., nausea, vomiting, anorexia, diarrhea, abdominal pain)Flu-like (e.g., headache, malaise, myalgia, sweating, fatigue)
Cardiovascular (e.g., palpitations, tachycardia) Neurologic (e.g., tremor, paresthesia) Sleep (e.g., nightmares, insomnia) Psychiatric (e.g., anxiety, auditory distortions, hypomania, mania, panic) |
| MAOIsIncidence unknown | Monoaminergic overdrive | 1-3 days | 7-14 days | Somatic (e.g., headache, weakness, shivering, orthostatic hypotension)Psychiatric (e.g., anxiety, agitation, hallucinations, irritability, paranoia, psychosis)
Neurologic (e.g., ataxia, catatonia, delirium, paresthesias) Sleep disturbances (e.g., excessive vivid dreams, nightmares, insomnia) |
| GABA = gamma aminobutyric acid MAOIs = monoamine oxidase inhibitors NE = norepinephrine SSRIs = selective serotonin reuptake inhibitors TCAs = tricyclic antidepressants |
||||
| TABLE 2:SUGGESTED TAPERING SCHEDULES FOR VARIOUS ANTIDEPRESSANTS 2,3,14 | |
| Antidepressant | Rate of taper |
|
25-50 mg/d every 5-7 days 25-50 mg/d every 5-7 days 10 mg/d every 5-7 days gradual taper is unnecessary |
| venlafaxine | 18.75-37.5 mg/d every 5-7 days |
| TCAs | Gradual taper of 25% per week over 4 weeks |
| MAOIs | Gradual taper of 25% per week over 4 weeks |
| MAOIs = monoamine oxidase inhibitors TCAs = tricyclic antidepressants |
|
| TABLE 3: ADJUNCTIVE THERAPIES FOR ANTIDEPRESSANTDISCONTINUATION REACTIONS1,3,14 | |
| Symptom | Treatment options |
| Cholinergic rebound (e.g., nausea, vomiting, sweating) from TCAs & trazodone | atropine 1 mg tid-qid benztropine 0.5-4 mg po prn trihexyphenidyl 1-4 mg tid-qid belladonna/phenobarbital, e.g., Donnatal ii tid-qid |
| Anxiety | benzodiazepines (e.g., lorazepam 0.5-1 mg q6h prn) |
| Dizziness | meclizine 12.5-25 mg q6h prn dimenhydrinate 25-50 mg q6h prn |
|
propranolol 10-20 mg tid-qid clonazepam 0.5-2 mg prn benztropine or trihexyphenidyl as above benztropine 1-2 mg IM or IV |
|
Admit to hospital Treat with standard modalities for the medical symptoms (e.g., IV fluids for dehydration, lithium & neuroleptics for mania) |
| IM = intramuscular IV = intravenous |
|
| TABLE 4: ANTIDEPRESSANT DISCONTINUATION: PATIENT COUNSELLING TIPS |
|