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Meta-Analysis
. 2021 Apr 15;4(4):CD013495.
doi: 10.1002/14651858.CD013495.pub2.

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

Ellen Van Leeuwen  1   2 , Mieke L van Driel  2   3 , Mark A Horowitz  4 , Tony Kendrick  5 , Maria Donald  3 , An Im De Sutter  2 , Lindsay Robertson  6   7 , Thierry Christiaens  1
Affiliations
Meta-Analysis

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

Ellen Van Leeuwen et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

Conflict of interest statement

EVL: none known.

MVD: none known.

MH: none known.

TK: 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.

MD: none known.

ADS: none known.

LR: none known.

TC: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1: Abrupt discontinuation versus continuation of antidepressants, Outcome 1: Relapse (as defined by study authors)
1.2
1.2. Analysis
Comparison 1: Abrupt discontinuation versus continuation of antidepressants, Outcome 2: Adverse events
1.3
1.3. Analysis
Comparison 1: Abrupt discontinuation versus continuation of antidepressants, Outcome 3: Depressive symptoms
1.4
1.4. Analysis
Comparison 1: Abrupt discontinuation versus continuation of antidepressants, Outcome 4: Severity of illness
2.1
2.1. Analysis
Comparison 2: Discontinuation by tapering versus continuation, Outcome 1: Relapse (as defined by study authors)
2.2
2.2. Analysis
Comparison 2: Discontinuation by tapering versus continuation, Outcome 2: Adverse events
2.3
2.3. Analysis
Comparison 2: Discontinuation by tapering versus continuation, Outcome 3: Depressive symptoms
2.4
2.4. Analysis
Comparison 2: Discontinuation by tapering versus continuation, Outcome 4: Anxiety symptoms
2.5
2.5. Analysis
Comparison 2: Discontinuation by tapering versus continuation, Outcome 5: Quality of life
2.6
2.6. Analysis
Comparison 2: Discontinuation by tapering versus continuation, Outcome 6: Social and occupational functioning
2.7
2.7. Analysis
Comparison 2: Discontinuation by tapering versus continuation, Outcome 7: Severity of illness
3.1
3.1. Analysis
Comparison 3: Discontinuation with high‐intensity psychological interventions versus continuation, Outcome 1: Relapse (as defined by study authors)
3.2
3.2. Analysis
Comparison 3: Discontinuation with high‐intensity psychological interventions versus continuation, Outcome 2: Depressive symptoms
3.3
3.3. Analysis
Comparison 3: Discontinuation with high‐intensity psychological interventions versus continuation, Outcome 3: Quality of life
4.1
4.1. Analysis
Comparison 4: Subgroup age, abrupt discontinuation versus continuation, Outcome 1: Relapse (HR)
5.1
5.1. Analysis
Comparison 5: Subgroup indication, tapering versus continuation, Outcome 1: Relapse (HR)
6.1
6.1. Analysis
Comparison 6: Subgroup type of antidepressant, tapering versus continuation, Outcome 1: Relapse
7.1
7.1. Analysis
Comparison 7: Subgroup duration of antidepressant, tapering versus continuation, Outcome 1: Relapse
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Dinan 2001 {published data only}
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    1. Fava M, Schmidt ME, Zhang S, Gonzales J, Raute NJ, Judge R. Treatment approaches to major depressive disorder relapse. Part 2: reinitiation of antidepressant treatment. Psychotherapy & Psychosomatics 2002;71(4):195-9. - PubMed
Ferguson 2007 {published data only}
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GlaxoSmithKline 1994 {published data only}
    1. GlaxoSmithKline. A Double-Blind, Placebo-Controlled Continuation of Study 29060/120 to Assess the Long Term Safety and Efficacy of Paroxetine in the Treatment of Panic Disorder and Its Role in the Prevention of Relapse/Recurrence. GSK - clinical study register; www.gsk-clinicalstudyregister.com. 1994.
GlaxoSmithKline 1999 {published data only}
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Glen 1984 {published data only}
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Godfrin 2010 {published data only}
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Goodwin 2009 {published data only}
    1. Goodwin GM, Emsley R, Rembry S, Rouillon F, Agomelatine Study Group. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry 2009;70(8):1128-37. - PubMed
Goodwin 2013 {published data only}
    1. Goodwin GM, Boyer P, Emsley R, Rouillon F, Bodinat C. Is it time to shift to better characterization of patients in trials assessing novel antidepressants? An example of two relapse prevention studies with agomelatine. International Clinical Psychopharmacology 2013;28(1):20-8. - PubMed
Gorwood 2007 {published data only}
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Harrison 1986 {published data only}
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Kamijima 2005 {published data only}
    1. Kamijima K, Kuboki T, Kumano H, Burt T, Cohen G, Arano I, et al. A placebo-controlled, randomized withdrawal study of sertraline for panic disorder in Japan. International Clinical Psychopharmacology 2005;20(5):265-73. - PubMed
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Klerman 1974 {published data only}
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Lepine 2004 {published data only}
    1. Lepine JP, Caillard V, Bisserbe JC, Troy S, Hotton JM, Boyer P. A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. American Journal of Psychiatry 2004;161(5):836-42. [PMID: ] - PubMed
Licht 2013 {published data only}
    1. Licht RW. Is it possible to evaluate true prophylactic efficacy of antidepressants in severely ill patients with recurrent depression? Lessons from a placebo-controlled trial. The Fifth Trial of the Danish University Antidepressant Group (DUAG-5). Journal of Affective Disorders 2013;148(2‐3):286-90. - PubMed
Liebowitz 1999 {published data only}
    1. Liebowitz MR, Heimberg RG, Schneier FR, Hope DA, Davies S, Holt CS, et al. Cognitive-behavioral group therapy versus phenelzine in social phobia: long term outcome. Depression and Anxiety 1999;10(3):89‐98. - PubMed
Liebowitz 2010 {published data only}
    1. Liebowitz M, Lam RW, Lepola U, Datto C, Sweitzer D, Eriksson H. Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Depression and Anxiety 2010;27(10):964-76. [PMID: ] - PubMed
Lustman 2006 {published data only}
    1. Lustman PJ, Clouse RE, Nix BD, Freedland KE, Rubin EH, McGill JB, et al. Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Archives of General Psychiatry 2006;63(5):521-9. - PubMed
Lyketsos 2011 {published data only}
    1. Lyketsos CG, Weiller E, Katona C, Gorwood P. Are old-old patients with major depression more likely to relapse than young-old patients during continuation treatment with escitalopram? BMC Geriatrics 2011;11:2. - PMC - PubMed
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    1. Markowitz JS, DeVane CL, Liston HL, Montgomery SA. An assessment of selective serotonin reuptake inhibitor discontinuation symptoms with citalopram. International Clinical Psychopharmacology 2000;15(6):329-33. - PubMed
McGrath 2006 {published data only}
    1. McGrath PJ, Stewart JW, Quitkin FM, Chen Y, Alpert JE, Nierenberg A, et al. Predictors of relapse in a prospective study of fluoxetine treatment of major depression. American Journal of Psychiatry 2006;163(9):1542-8. - PubMed
Michelson 1999 {published data only}
    1. Michelson D, Pollack M, Lydiard RB, Tamura R, Tepner R, Tollefson G. Continuing treatment of panic disorder after acute response: randomised, placebo-controlled trial with fluoxetine. British Journal of Psychiatry 1999;174:213-8. - PubMed
Montgomery 1993 {published data only}
    1. Montgomery SA, Rasmussen JG, Tanghoj P. A 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression. International Clinical Psychopharmacology 1993;8(3):181-8. [PMID: ] - PubMed
Montgomery 1993a {published data only}
    1. Montgomery SA, Dunbar G. Paroxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression. International Clinical Psychopharmacology 1993;8(3):189-95. - PubMed
Montgomery 2005 {published data only}
    1. Montgomery SA, Nil R, Durr-Pal N, Loft H, Boulenger JP. A 24-week randomized, double-blind, placebo-controlled study of escitalopram for the prevention of generalized social anxiety disorder. Journal of Clinical Psychiatry 2005;66(10):1270-8. - PubMed
NCT00878748 {published data only}
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OADIG 1993 {published data only}
    1. Old Age Depression Interest Group. How long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin. British Journal of Psychiatry 1993;162:175-82. [PMID: ] - PubMed
Rapoport 2010 {published data only}
    1. Rapoport MJ, Mitchell RA, McCullagh S, Herrmann N, Chan F, Kiss A, et al. A randomized controlled trial of antidepressant continuation for major depression following traumatic brain injury. Journal of Clinical Psychiatry 2010;71(9):1125-30. - PubMed
Reimherr 1998 {published data only}
    1. Reimherr FW, Amsterdam JD, Quitkin FM, Rosenbaum JF, Fava M, Zajecka J, et al. Optimal length of continuation therapy in depression: a prospective assessment during long-term fluoxetine treatment. American Journal of Psychiatry 1998;155:1247-53. - PubMed
Reynolds 1992 {published data only}
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Reynolds 1999 {published data only}
    1. Reynolds CF, Frank E, Perel JM, Imber SD, Cornes C, Mileer MD, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA 1999;281(1):39-45. - PubMed
Robinson 1991 {published data only}
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Sackeim 2001 {published data only}
    1. Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ, Pettinati HM, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA 2001;285(10):1299-307. [PMID: ] - PubMed
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    1. Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C. Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. Journal of Clinical Psychiatry 2012;73(7):1002-8. - PubMed
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    1. Stewart JW, Quitkin FM, McGrath PJ, Amsterdam J, Fava M, Fawcett J, et al. Use of pattern analysis to predict differential relapse of remitted patients with major depression during 1 year of treatment with fluoxetine or placebo. Archives of General Psychiatry 1998;55(4):334-43. - PubMed
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References to studies awaiting assessment

Mangin 2015 {published data only}
    1. Mangin D, Dowson C, Mulder R, Wells E, Toop L, Dowell T. The effectiveness of maintenanceSSRI treatment in primary care depression to prevent recurrence: multicentre double blinded placebo controlled RCT. In: Proceedings of the 2015 North American Primary Care Research Group (NAPCRG) 43rd Annual Meeting. 2015.
Molenaar 2016 {published data only}
    1. Molenaar NM, Brouwer ME, Bockting CL, Bonsel GJ, Veere CN, Torij HW, et al. Stop or go? Preventive cognitive therapy with guided tapering of antidepressants during pregnancy: study protocol of a pragmatic multicentre non-inferiority randomized controlled trial. BMC Psychiatry 2016;16:72. - PMC - PubMed

References to ongoing studies

Duffy 2019 {published data only}
    1. Duffy L, Bacon F, Clarke CS, Donkor Y, Freemantle N, Gilbody S, et al. A randomised controlled trial assessing the use of citalopram, sertraline, fluoxetine and mirtazapine in preventing relapse in primary care patients who are taking long-term maintenance antidepressants (ANTLER: ANTidepressants to prevent reLapse in dEpRession): study protocol for a randomised controlled trial. Trials 2019;20:319. - PMC - PubMed
ISRCTN12417565 {published data only}
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