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Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults

Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults
Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults

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 METHODS: 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.

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.

1469-493X
Van Leeuwen, Ellen
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van Driel, Mieke L
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Horowitz, Mark A
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Kendrick, Tony
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Donald, Maria
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De Sutter, An Im
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Robertson, Lindsay
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Christiaens, Thierry
4994839c-3b12-4df6-b8cc-1522cb03caf5
Van Leeuwen, Ellen
c2de311a-3a69-4375-9039-11f28b593062
van Driel, Mieke L
daeac878-0204-4bd3-8b06-5389a10c1ab0
Horowitz, Mark A
93bf4bd6-60fe-4e5f-bb35-df95b7344c5c
Kendrick, Tony
c697a72c-c698-469d-8ac2-f00df40583e5
Donald, Maria
80987a94-860b-4b0b-bfee-c8c4f2bda962
De Sutter, An Im
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Robertson, Lindsay
a7bcb5ee-2fc5-4145-b0f4-6d85302041fc
Christiaens, Thierry
4994839c-3b12-4df6-b8cc-1522cb03caf5

Van Leeuwen, Ellen, van Driel, Mieke L, Horowitz, Mark A, Kendrick, Tony, Donald, Maria, De Sutter, An Im, Robertson, Lindsay and Christiaens, Thierry (2021) Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults. The Cochrane database of systematic reviews, 2021 (4), [CD013495]. (doi:10.1002/14651858.CD013495.pub2).

Record type: Article

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 METHODS: 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.

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.

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More information

Published date: 15 April 2021
Additional Information: Sources of support: External sources National Institute for Health Research (NIHR), UK Tony Kendrick: is lead researcher on a grant from the NIHR PGfAR programme for the REviewing long term anti‐Depressant Use by Careful monitoring in Everyday practice (REDUCE) programme to determine the feasibility, effectiveness, safety and cost‐effectiveness of Internet and telephone support for discontinuing inappropriate long‐term antidepressant use. TK is also an unpaid member of the national guideline committee updating the NICE clinical guideline on depression, 2015‐2021.

Identifiers

Local EPrints ID: 449122
URI: http://eprints.soton.ac.uk/id/eprint/449122
ISSN: 1469-493X
PURE UUID: bc94c509-10fb-401d-8d3b-bf634f5526c6
ORCID for Tony Kendrick: ORCID iD orcid.org/0000-0003-1618-9381

Catalogue record

Date deposited: 17 May 2021 16:34
Last modified: 28 Apr 2022 01:43

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Contributors

Author: Ellen Van Leeuwen
Author: Mieke L van Driel
Author: Mark A Horowitz
Author: Tony Kendrick ORCID iD
Author: Maria Donald
Author: An Im De Sutter
Author: Lindsay Robertson
Author: Thierry Christiaens

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