Antidepressant Discontinuation Syndromes: Common, Under-Recognised and Not Always

Drug Ther Perspect 17(20):12-15, 2001. © 2001 Adis International Limited

Antidepressants have varying potentials to cause discontinuation syndromes. Symptoms begin within a few days of stopping or reducing the dosage of the drug and are usually mild and short-lived. However, in some patients, antidepressant discontinuation symptoms can produce significant morbidity, be incorrectly attributed to other causes, and lead to subsequent lack of compliance with antidepressant therapy. The best approach to the problem is prevention, which involves educating patients and healthcare professionals about discontinuation symptoms and ensuring that antidepressants are tapered before they are stopped. When symptoms do occur, reassurance is usually sufficient; in some patients, however, there may be a need for symptomatic treatment, temporary reinstatement of the antidepressant (followed by careful tapering), or a switch to fluoxetine (which has a low potential for discontinuation symptoms). More research into this common and clinically relevant syndrome is required so that evidence-based recommendations can be developed.

So far, at least 21 different antidepressants have been reported to cause discontinuation symptoms (table 1). All major classes of antidepressants have been implicated.^[1]

Discontinuation syndromes vary considerably with respect to symptom type, grouping and severity. General features associated with discontinuation syndromes involving different classes of antidepressants are as follows:

• in patients stopping selective serotonin reuptake inhibitors (SSRIs), the most common discontinuation syndrome involves 6 main symptom groups (table 2). Both physical and psychological symptoms may be experienced; the most commonly reported symptoms are dizziness, nausea, lethargy and headache^[2]

• as with SSRIs, tricyclic antidepressant (TCA)-associated discontinuation syndromes also include both physical and psychological symptoms but are much less likely to be associated with sensory abnormalities and problems with equilibrium (table 2). Hypomania, akathisia, parkinsonism, cardiac arrhythmias, panic attacks and delirium have been reported on rare occasions in patients discontinuing TCAs^[1]

• stoppage of venlafaxine can result in an SSRI-like discontinuation syndrome^[1]

• monoamine oxidase inhibitor (MAOI) discontinuation syndromes, particularly those involving tranylcypromine, can result in psychotic confusion, worsening of depressive symptoms, hypomania and generalised seizures.^[1]

Common clinical features of antidepressant discontinuation syndromes include the following:

• antecedent antidepressant discontinuation or (less commonly) dosage reduction

• appropriate onset, i.e. usually within a few days of discontinuing or reducing the dose of an antidepressant

• adequate duration of treatment. Antidepressant discontinuation symptoms are rare in patients who have been treated for less than 5 weeks

• short duration (between 1 day and 3 weeks) if left untreated

• rapid reversibility (within 24 hours) on recommencement of the withdrawn drug.^[1]

It is important to note, however, that while most antidepressant discontinuation reactions are mild and transient, others may persist for up to 3 months and/or be associated with substantial morbidity.^[1]

Discontinuation symptom rates in patients taking older antidepressants can be high, as evidenced by reports of 100% with imipramine, 80% with amitriptyline, 33% with clomipramine and 32% with phenelzine.^[1] Abrupt discontinuation of treatment with newer agents such as sertraline,^[3] paroxetine,^[3,4] and venlafaxine^[5] also results in spontaneously reported discontinuation symptoms in at least 1 out of 3 patients. Even higher rates have been documented when patients are specifically asked about symptoms, with one study finding evidence of discontinuation syndromes in 2 out of 3 patients treated with paroxetine and sertraline.^[6]

...Except in Patients Taking Fluoxetine

Presumably because of the long half-lives of the parent drug (2 to 4 days) and its active metabolite norfluoxetine (7 to 15 days), fluoxetine appears to be much less likely to be associated with discontinuation symptoms than SSRIs such as paroxetine and sertraline.^[1,7] When spontaneous adverse drug reaction reports in the UK (up to March 1993) were analysed, the rate of discontinuation reactions per 1000 prescriptions was 100 times lower with fluoxetine than with paroxetine (0.002 vs 0.3 per 1000, respectively) [see fig. 1].^[8] Furthermore, in a double-blind placebo-controlled 'treatment interruption' study, discontinuation of fluoxetine for 5 to 8 days was found to produce fewer adverse events than discontinuation of sertraline or paroxetine for a similar length of time (p </= 0.001).^[6]

Unexpected physical or psychological symptoms in a patient who has recently stopped taking an antidepressant point to an antidepressant discontinuation syndrome. The diagnosis also becomes clearer when direct questioning reveals noncompliance with therapy in patients currently on an antidepressant prescription.^[1]

...And Prevents the Pitfalls of Misdiagnosis

Antidepressant discontinuation symptoms can be misinterpreted as:^[1]

• recurrence of depression in a patient who stops his/her antidepressant therapy following remission of the original illness

• evidence that an antidepressant is ineffective in a patient who fails to comply with his/her therapy

• adverse effects of a new antidepressant following switching from 1 antidepressant to another.

In all of these cases, subsequent decisions about investigation, referral and treatment are likely to be inappropriate, may lead to a waste of resources, and can contribute to an incorrect and more negative prognosis.^[1]

Figure 1. Data from an analysis of UK spontaneous adverse reaction (ADR) reports of selective serotonin reuptake inhibitors (to March 1993) showing the number of discontinuation reactions per 1000 prescriptions.^[8]

It is not uncommon for patients to miss antidepressant doses for several days. Such discontinuations would be expected to produce symptoms, which can develop within hours of missing a single dose of some agents. A compliance problem can then arise if the patient links his/her symptoms to the antidepressant without understanding the mechanism for development of symptoms, and particularly when the patient considers these symptoms to be evidence of 'addiction' to the antidepressant. In this way, discontinuation symptoms can result from, and cause, poor compliance.^[1]

Various case reports have shown that discontinuation symptoms can be suppressed by re-introduction of the antidepressant, with subsequent tapering preventing their re-emergence. Such findings support the conventional recommendation that discontinuation of antidepressants should be tapered as a matter of routine.^[1]

...But is More an Art Than a Science

Unfortunately, there are no controlled data demonstrating the effectiveness of tapering in general or of any tapering regimen in particular. According to the British National Formulary, antidepressants administered for 8 weeks or more should be reduced over a 4-week period.^[9] Other authorities suggest reducing treatment dosage by one-quarter every 4 to 6 weeks after maintenance treatment. Another approach with SSRIs is to halve the dose and administer the drug on alternate days.^[1]

A number of specific factors will also influence tapering strategies. These include:

• the antidepressant used. Fluoxetine, for example, rarely causes discontinuation symptoms^[6,8] and accordingly may not need to be tapered as a matter of routine.^[6,8,10] Paroxetine^[6,8] and venlafaxine,^[5] in contrast, are much more likely to be associated with discontinuation symptoms and should therefore be tapered. Careful tapering is also required when stopping MAOIs, which can cause very severe discontinuation symptoms^[1]

• duration of therapy. Discontinuation symptoms are more likely in patients who have received more prolonged periods of therapy. Indeed, there is probably no need for tapering in patients who have received antidepressants for short periods^[1]

• previous history of discontinuation symptoms. Patients who have previously experienced discontinuation symptoms may require very gradual tapering.^[1]

Fluoxetine May Help

Anecdotal reports suggest that fluoxetine, at least in some cases, can suppress discontinuation symptoms associated with other SSRIs and venlafaxine. When successful in this regard, fluoxetine can then generally be stopped without re-emergence of symptoms.^[1]

Switching Therapies is a Special Case

The importance of establishing effective antidepressant therapy overrides concerns about possible discontinuation symptoms in patients who require a switch of antidepressant therapy because of lack of efficacy. In such cases, rapid tapering or even abrupt switching is often justifiable, although the potential for discontinuation symptoms must be borne in mind. Other factors to consider when switching antidepressants include the possibility of drug interactions and the need for an appropriate wash-out period.^[1]

Education of Both Patients and Doctors Needed

Current evidence suggests that substantial proportions of general practitioners, psychiatrists and pharmacists are unfamiliar with antidepressant discontinuation syndromes. In addition, patients are generally unaware that antidepressants are not addictive, that abrupt stoppage of antidepressants (because of noncompliance or when starting drug holidays to reduce adverse effects) can cause discontinuation symptoms, and that tapering of antidepressants is recommended to avoid such symptoms.^[1]

Patients with discontinuation symptoms who remain depressed (e.g. treatment noncompliers) and those who are at high risk of relapse/recurrence should be recommenced on their antidepressant. In other cases, the severity of the discontinuation syndrome should determine treatment. Most patients will have mild reactions and need to be reassured only. Symptoms of moderate severity may require symptomatic treatment (e.g. short course benzodiazepines for insomnia). Severe or treatment-refractory symptoms may require recommencement of the antidepressant and subsequent careful tapering. Antipsychotics and hospital admission may also be required in patients who develop severe mania, confusion or psychotic symptoms.^[1]

Maternal use of antidepressants during pregnancy can result in a neonatal discontinuation syndrome characterised by symptoms such as irritability, respiratory difficulty and poor feeding. Tapering or discontinuing antidepressants prior to delivery may therefore be beneficial for the neonate, but also introduces the risk of depressive relapse in the mother. Neonates born to mothers on antidepressant therapy should be monitored for discontinuation symptoms over the first week of life.^[1]

...Or Even as a Result of Breast Feeding

All antidepressants studied have been shown to be present in breast milk and therefore have the potential to cause toxic effects in breast fed infants. Furthermore, a possible case of neonatal discontinuation reaction following abrupt discontinuation of sertraline by a nursing mother has been reported.^[11] Whether the possibility of antidepressant neonatal toxicity and/or discontinuation symptoms outweighs the benefits of breast feeding for mother and infant is a decision which can be made only on a case by case basis.

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