INTRODUCTION — When patients fail to respond to a particular antidepressant, or exhibit side effects, and a trial of another antidepressant is indicated, the clinician must be familiar with the pharmacology of the drug that is being discontinued, the potential for drug-drug interactions, and the time to onset of effectiveness of the new medication. Similarly, when antidepressants are being discontinued after a therapeutic course, care must be taken to avoid precipitating an antidepressant withdrawal syndrome. These issues are addressed in this topic. Indications for switching or stopping antidepressants, general information about the treatment of depression and individual medications, and the prognosis of depression are discussed separately.
SWITCHING ANTIDEPRESSANT MEDICATION — There are several issues to consider when switching a patient from one antidepressant to another, to avoid drug toxicity or re-emergence of depression symptoms.
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.
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.
Switching from SSRI to TCA — The most common method used to switch from an SSRI to a tricyclic antidepressant (TCA) is a cross-taper. 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.
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 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.
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.
Less is known about discontinuation symptoms with
duloxetine ; since it shares many characteristics with
venlafaxine , it is prudent to also employ this manner of cross-taper when switching to a new antidepressant. Duloxetine is an inhibitor of the liver enzyme p450 2D6, so may increase the blood levels of medications that rely on this enzyme for their metabolism.
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.
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).
Bupropion itself is not frequently associated with discontinuation symptoms. Bupropion can usually be tapered off over the course of one week while initiating a new antidepressant medication at its typical dosing schedule. Bupropion is an inhibitor of the liver enzyme p450 2D6, so may increase the blood levels of medications that rely on this enzyme for their metabolism. Of note, bupropion is also metabolized by the liver enzyme p450 2D6; antidepressants that inhibit p450 2D6, such as
paroxetine ,
fluoxetine , and
fluvoxamine , may increase the blood level of bupropion, potentially increasing the risk of bupropion-induced seizure. Because of this, it is prudent to avoid prescribing high-dose bupropion concomitantly with paroxetine, fluoxetine, or fluvoxamine.
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.
DISCONTINUATION OF ANTIDEPRESSANTS — Most antidepressants have been associated with adverse effects when abruptly discontinued. Symptoms may be prevented if patients are informed when initiating medication about risks associated with abrupt discontinuation [
1 ]. While discontinuation symptoms are usually mild and self-limited, this is not always the case and complexity can arise when discontinuation symptoms persist and become difficult to distinguish from the underlying depression.
When antidepressants are discontinued, it is common practice to taper them over two to four weeks to minimize symptoms associated with abrupt discontinuation. However, data conflict on the effectiveness of slow medication tapers. A randomized trial with 28 patients compared tapering over three days with tapering over two weeks, and found no difference in discontinuation and depressive symptoms [
2 ]. By contrast, an observational study of 224 patients found that the median time to recurrence of depression in euthymic patients who discontinued their antidepressant over one to seven days was significantly shorter compared with patients who discontinued their antidepressant over 14 or more days (3.2 versus 7.6 months) [
3 ]. Both studies found that antidepressants with a short half-life (eg,
paroxetine or
venlafaxine ) were associated with significantly more discontinuation and depressive symptoms.
Selective serotonin reuptake inhibitors — A constellation of discontinuation effects, sometimes referred to as a "discontinuation syndrome," has been best characterized with abrupt cessation of SSRIs. The constellation of symptoms, which typically occurs within days of abrupt cessation of an SSRI, may include dizziness, nausea, fatigue, muscle aches, chills, anxiety, and irritability [
1,4,5 ]. Although these symptoms are not dangerous and usually dissipate over one to two weeks, they can be quite distressing and uncomfortable.
While discontinuation symptoms can occur with any SSRI, different SSRIs have different likelihoods of producing symptoms with abrupt discontinuation, perhaps related to differences in half-life; symptoms are mild with
fluoxetine (long half-life) [
6 ] and can be particularly severe with
paroxetine . Blinded trials have shown the following:
These data suggest that
fluoxetine causes the least discontinuation symptoms, and
paroxetine causes the most discontinuation symptoms. A study of physician-initiated reports of adverse drug reactions included 430 cases of withdrawal reactions from paroxetine; analysis of 71 patients who were not treated for the withdrawal syndrome from paroxetine found that the mean time to recovery was 11 days [
12 ].
Clinical experience suggests that discontinuation symptoms associated with SSRI withdrawal can be reduced by a slow tapering of the drug. An observational study found that patients who tapered their medication reported fewer adverse effects than patients who stopped medication abruptly [
5 ]. However, a small trial (n = 28) found no difference in symptoms between patients randomly assigned to taper their SSRI over 3 days or over 14 days [
2]. These results need to be confirmed in a larger trial.
Patients who have difficulty tapering off of
paroxetine may benefit from being switched to an equivalent dose of
fluoxetine (
table 1 ); the fluoxetine can then be tapered off, typically without discontinuation effects.
In addition, patients who suffer a discontinuation syndrome after an SSRI has been stopped can be acutely treated by starting
fluoxetine 10 to 20 mg per day. Once the withdrawal symptoms have abated and the patient has been stabilized on fluoxetine 10 mg per day for one to two weeks, the drug can be discontinued. For patients who have difficulty discontinuing fluoxetine 10 mg per day, a liquid formulation is available for administering a dose less than 10 mg per day.
Venlafaxine — Abrupt discontinuation of
venlafaxine commonly causes discontinuation symptoms, including dizziness, flu-like symptoms, and anxiety [
4,13,14 ]. These symptoms may be more severe than those produced by SSRI discontinuation.
Heterocyclics and MAOIs — In contrast to the distressing, yet typically benign discontinuation symptoms described above, abrupt discontinuation of heterocyclic antidepressants and MAOIs can cause severe and potentially dangerous discontinuation syndromes.
- Abrupt discontinuation of heterocyclic antidepressants can cause irritability, agitation, sleep disturbance, flu-like symptoms and, rarely, cardiac arrhythmia [ 15 ].
- Abrupt cessation of MAOIs can cause delirium, agitation, myoclonic jerks, and insomnia [ 15-17 ].
Other antidepressants
- There have been anecdotal reports of discontinuation effects from abrupt cessation of nefazodone and mirtazapine , but these effects are not well characterized [ 18,19 ].
- In controlled trials, discontinuation symptoms with duloxetine were more common than with placebo [ 20 ].
- Discontinuation symptoms from bupropion are uncommon.
Recommendations — Educating patients about discontinuation symptoms can help prevent them from abruptly stopping antidepressants and may help reduce anxiety should adverse discontinuation effects occur.
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. Among SSRIs,
fluoxetine probably causes the least discontinuation symptoms.
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SUMMARY AND RECOMMENDATIONS
Switching between antidepressants
- For many drug switches, cross-tapering is the best technique. 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 new antidepressant is gradually increased to therapeutic range over the same time period. (See 'Cross-tapering' above.)
- To switch between selective serotonin reuptake inhibitors (SSRIs), we generally substitute the new SSRI at the relatively equivalent dose of the discontinued SSRI ( table 1 ). A reasonable alternative is to start the new SSRI at a lower dose because patients may have idiosyncratic side effects to particular SSRIs. (See 'Switching between SSRIs' above.)
- To switch from an SSRI to a tricyclic antidepressant (TCA), we generally use cross-tapering. The TCA is started at a low dose to avoid toxicity that can result from the SSRI inhibiting the hepatic enzyme that metabolizes TCAs. Serum TCA concentrations can be checked during this period for added safety. Inhibition of the hepatic enzyme occurs 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. (See 'Switching from SSRI to TCA' above.)
- To switch from an SSRI to the strongly serotonergic drugs venlafaxine or duloxetine , we generally switch immediately to the equivalent dose of venlafaxine ( table 1 ) or duloxetine. (See 'SSRI to venlafaxine or duloxetine' above.)
- To switch from venlafaxine or duloxetine to antidepressants other than MAOIs, we generally use cross-tapering over a two to three week period. Duloxetine inhibits the liver enzyme that metabolizes some antidepressants and may thus increase their serum concentrations. (See 'Venlafaxine or duloxetine to antidepressants other than MAOIs' above.)
- To switch between venlafaxine and duloxetine at low doses (<150 mg of venlafaxine and <60 mg of duloxetine), we generally switch immediately, and at higher doses use cross-tapering. (See 'Switching between venlafaxine and duloxetine' above.)
- To switch between mirtazapine and SSRIs, TCAs, venlafaxine , or duloxetine , we generally use cross-tapering. (See 'Switching to or from mirtazapine' above.)
- To switch between bupropion and antidepressants other than MAOIs, we generally use cross-tapering over a one to two week period (two to three weeks for venlafaxine and duloxetine ). Bupropion inhibits the liver enzyme that metabolizes some antidepressants and may thus increase their serum concentrations. In addition, bupropion is metabolized by the same enzyme, and antidepressants that inhibit it, such as paroxetine ,fluoxetine , and fluvoxamine , may increase the serum concentration of bupropion, potentially increasing the risk of bupropion-induced seizure. (See 'Bupropion to or from antidepressants other than MAOIs' above.)
- The combination of monoamine oxidase inhibitors (MAOIs) and other antidepressants can result in severe toxicity (eg, hypertensive crisis or serotonin syndrome). Thus, we wait two weeks between discontinuing an MAOI and starting a different antidepressant. In addition, two weeks should also elapse between discontinuing a TCA, SSRI (other than fluoxetine ), venlafaxine , duloxetine , or mirtazapine and starting an MAOI. Due to the long half-life of fluoxetine, five weeks should elapse between discontinuing fluoxetine and starting an MAOI. When switching between MAOIs, we allow two weeks to elapse between discontinuing the first MAOI and starting the second. (See 'Switching to or from MAOIs' above.)
Discontinuation of antidepressants
- Most antidepressants have been associated with adverse effects when abruptly discontinued. Educating patients about discontinuation symptoms can help prevent them from abruptly stopping antidepressants and reduce anxiety should adverse discontinuation effects occur. (See'Discontinuation of antidepressants' above.)
- When antidepressants are discontinued, we typically taper them over two to four weeks to minimize symptoms associated with abrupt discontinuation. (See 'Recommendations' above.)
