Stopping long-term antidepressants in people with depression or anxiety

Review question

We aimed to find out if it is effective and safe to stop antidepressants for people with depression or anxiety who have been taking them for six months or longer.

We compared different approaches for stopping long-term antidepressants versus continuation. We looked at benefits (e.g. successful discontinuation rate) and harms, such as return of the depressive or anxiety episode (relapse), side effects, and withdrawal symptoms (i.e. symptoms people experience when stopping an antidepressant).

Background

Antidepressants are widely used for depression and anxiety. Guidelines recommend that an antidepressant should be continued for at least six months after people start to feel better, and for at least two years if they have had two or more periods of depression. Many people take antidepressants for much longer, and as they can cause unpleasant side effects, long-term use puts people at risk of harm that may outweigh the benefits.

Study characteristics

Our search up until January 2020 found 33 studies, which included 4995 adult participants. Most people in these studies had recurrent depression (two or more episodes of depression before stopping antidepressants), and most were recruited from specialist mental healthcare services. In 13 studies, the antidepressant was stopped abruptly; in 18 studies, the antidepressant was stopped gradually over several weeks ("tapering"); in four studies, psychological therapy support was also offered; and in one study, stopping was prompted by a letter to the GP with guidance on tapering. Most tapering schemes lasted four weeks or less.

Key results

We found very low-certainty evidence suggesting that abrupt stopping may lead to higher risk of relapse and there was insufficient evidence of its effect on occurrence of side effects compared to continuation of the antidepressant.

We found very low-certainty evidence suggesting that "tapering" over a few weeks may lead to higher risk of a return and again may have little or no effect on side effects compared to continuation.

We found evidence of very low to low certainty to suggest that stopping the antidepressant in combination with providing preventive cognitive therapy (PCT), or MBCT, was possible for 40% to 75% of participants in the group tapering the antidepressant and may show no difference in effects on relapse.

We found low-certainty evidence suggesting that a prompt letter and guidance on tapering sent to the GP may have no effect on the number of people who stop their antidepressant.

We were unable to draw conclusions about withdrawal symptoms after abrupt or gradual stopping of an antidepressant, as this generally was not assessed.

None of the studies used very slow tapering schemes beyond a few weeks, tapered liquid forms of antidepressants, or used tapering strips (to allow tapering with very low doses).

None of the identified studies investigated stopping combined with providing supportive therapy such as online support or self-help therapy.

Certainty of evidence

Overall, the certainty of evidence was low to very low. This means we have limited or little confidence in the results, and new research is likely to change our conclusions. The main reasons for this assessment of evidence certainty were that trials did not distinguish between symptoms of relapse of depression and symptoms of withdrawal. Also, most studies used no tapering or very "rapid" tapering schedules (four weeks or less), and nearly all studies included people with recurrent depression (more than two episodes).

Conclusions

We found few studies that examined stopping long-term antidepressants. We are uncertain if the approaches for stopping long-term antidepressants studied to date are effective and safe in people with recurrent depression. People should discuss with their doctor when they want to stop their antidepressant.

Future studies should include people in primary care with only one or no earlier episodes of depression, older people, and people taking antidepressants for anxiety. Studies should taper antidepressants slowly while taking care to distinguish withdrawal symptoms from relapse.

Authors' conclusions: 

Currently, relatively few studies have focused on approaches to discontinuation of long-term antidepressants. We cannot make any firm conclusions about effects and safety of the approaches studied to date. The true effect and safety are likely to be substantially different from the data presented due to assessment of relapse of depression that is confounded by withdrawal symptoms. All other outcomes are confounded with withdrawal symptoms. Most tapering regimens were limited to four weeks or less. In the studies with rapid tapering schemes the risk of withdrawal symptoms may be similar to studies using abrupt discontinuation which may influence the effectiveness of the interventions. Nearly all data come from people with recurrent depression.  

There is an urgent need for trials that adequately address withdrawal confounding bias, and carefully distinguish relapse from withdrawal symptoms. Future studies should report key outcomes such as successful discontinuation rate and should include populations with one or no prior depression episodes in primary care, older people, and people taking antidepressants for anxiety and use tapering schemes longer than 4 weeks.

Read the full abstract...
Background: 

Depression and anxiety are the most frequent indication for which antidepressants are prescribed. Long-term antidepressant use is driving much of the internationally observed rise in antidepressant consumption. Surveys of antidepressant users suggest that 30% to 50% of long-term antidepressant prescriptions had no evidence-based indication. Unnecessary use of antidepressants puts people at risk of adverse events. However, high-certainty evidence is lacking regarding the effectiveness and safety of approaches to discontinuing long-term antidepressants.

Objectives: 

To assess the effectiveness and safety of approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults.

Search strategy: 

We searched all databases for randomised controlled trials (RCTs) until January 2020.

Selection criteria: 

We included RCTs comparing approaches to discontinuation with continuation of antidepressants (or usual care) for people with depression or anxiety who are prescribed antidepressants for at least six months. Interventions included discontinuation alone (abrupt or taper), discontinuation with psychological therapy support, and discontinuation with minimal intervention. Primary outcomes were successful discontinuation rate, relapse (as defined by authors of the original study), withdrawal symptoms, and adverse events. Secondary outcomes were depressive symptoms, anxiety symptoms, quality of life, social and occupational functioning, and severity of illness.

Data collection and analysis: 

We used standard methodological procedures as expected by Cochrane.

Main results: 

We included 33 studies involving 4995 participants. Nearly all studies were conducted in a specialist mental healthcare service and included participants with recurrent depression (i.e. two or more episodes of depression prior to discontinuation). All included trials were at high risk of bias. The main limitation of the review is bias due to confounding withdrawal symptoms with symptoms of relapse of depression. Withdrawal symptoms (such as low mood, dizziness) may have an effect on almost every outcome including adverse events, quality of life, social functioning, and severity of illness.

Abrupt discontinuation

Thirteen studies reported abrupt discontinuation of antidepressant.

Very low-certainty evidence suggests that abrupt discontinuation without psychological support may increase risk of relapse (hazard ratio (HR) 2.09, 95% confidence interval (CI) 1.59 to 2.74; 1373 participants, 10 studies) and there is insufficient evidence of its effect on adverse events (odds ratio (OR) 1.11, 95% CI 0.62 to 1.99; 1012 participants, 7 studies; I² = 37%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of abrupt discontinuation on withdrawal symptoms (1 study) is very uncertain.

None of these studies included successful discontinuation rate as a primary endpoint.

Discontinuation by "taper"

Eighteen studies examined discontinuation by "tapering" (one week or longer). Most tapering regimens lasted four weeks or less.

Very low-certainty evidence suggests that "tapered" discontinuation may lead to higher risk of relapse (HR 2.97, 95% CI 2.24 to 3.93; 1546 participants, 13 studies) with no or little difference in adverse events (OR 1.06, 95% CI 0.82 to 1.38; 1479 participants, 7 studies; I² = 0%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of discontinuation on withdrawal symptoms (1 study) is very uncertain.

Discontinuation with psychological support

Four studies reported discontinuation with psychological support. Very low-certainty evidence suggests that initiation of preventive cognitive therapy (PCT), or MBCT, combined with "tapering" may result in successful discontinuation rates of 40% to 75% in the discontinuation group (690 participants, 3 studies). Data from control groups in these studies were requested but are not yet available.

Low-certainty evidence suggests that discontinuation combined with psychological intervention may result in no or little effect on relapse (HR 0.89, 95% CI 0.66 to 1.19; 690 participants, 3 studies) compared to continuation of antidepressants. Withdrawal symptoms were not measured. Pooling data on adverse events was not possible due to insufficient information (3 studies).

Discontinuation with minimal intervention

Low-certainty evidence from one study suggests that a letter to the general practitioner (GP) to review antidepressant treatment may result in no or little effect on successful discontinuation rate compared to usual care (6% versus 8%; 146 participants, 1 study) or on relapse (relapse rate 26% vs 13%; 146 participants, 1 study). No data on withdrawal symptoms nor adverse events were provided.

None of the studies used low-intensity psychological interventions such as online support or a changed pharmaceutical formulation that allows tapering with low doses over several months. Insufficient data were available for the majority of people taking antidepressants in the community (i.e. those with only one or no prior episode of depression), for people aged 65 years and older, and for people taking antidepressants for anxiety.

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