Skip to main content

Predicting relapse after antidepressant withdrawal – a systematic review

  • I. M. Berwian (a1) (a2), H. Walter (a3), E. Seifritz (a1) and Q. J. M. Huys (a1) (a2)

A substantial proportion of the burden of depression arises from its recurrent nature. The risk of relapse after antidepressant medication (ADM) discontinuation is high but not uniform. Predictors of individual relapse risk after antidepressant discontinuation could help to guide treatment and mitigate the long-term course of depression. We conducted a systematic literature search in PubMed to identify relapse predictors using the search terms ‘(depress* OR MDD*) AND (relapse* OR recurren*) AND (predict* OR risk) AND (discontinu* OR withdraw* OR maintenance OR maintain or continu*) AND (antidepress* OR medication OR drug)’ for published studies until November 2014. Studies investigating predictors of relapse in patients aged between 18 and 65 years with a main diagnosis of major depressive disorder (MDD), who remitted from a depressive episode while treated with ADM and were followed up for at least 6 months to assess relapse after part of the sample discontinued their ADM, were included in the review. Although relevant information is present in many studies, only 13 studies based on nine separate samples investigated predictors for relapse after ADM discontinuation. There are multiple promising predictors, including markers of true treatment response and the number of prior episodes. However, the existing evidence is weak and there are no established, validated markers of individual relapse risk after antidepressant cessation. There is little evidence to guide discontinuation decisions in an individualized manner beyond overall recurrence risk. Thus, there is a pressing need to investigate neurobiological markers of individual relapse risk, focusing on treatment discontinuation.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Predicting relapse after antidepressant withdrawal – a systematic review
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Predicting relapse after antidepressant withdrawal – a systematic review
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Predicting relapse after antidepressant withdrawal – a systematic review
      Available formats
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (, which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author
*Address for correspondence: I. M. Berwian, Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Wilfriedstrasse 6, 8032 Zürich, Switzerland. (Email:
Hide All
American Psychiatric Association (2000). Diagnostic and Statistical Manual Text Revision (DSM-IV-TR) . American Psychiatric Association: Washington, DC.
Andrews PW, Kornstein SG, Halberstadt LJ, Gardner CO, Neale MC (2011). Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression. Frontiers in Psychology 2, 159.
Baldessarini RJ, Lau WK, Sim J, Sum MY, Sim K (2015). Duration of initial antidepressant treatment and subsequent relapse of major depression. Journal of Clinical Psychopharmacology 35, 7576.
Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller H-J (2013). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World Journal of Biological Psychiatry 14, 334385.
Berlanga C, Heinze G, Torres M, Apiquián R, Caballero A (1999). Personality and clinical predictors of recurrence of depression. Psychiatric Services 50, 376380.
Burcusa SL, Iacono WG (2007). Risk for recurrence in depression. Clinical Psychology Review 27, 959985.
Chekroud AM, Zotti RJ, Shehzad Z, Gueorguieva R, Johnson MK, Trivedi MH, Cannon TD, Krystal JH, Corlett PR (2016). Cross-trial prediction of treatment outcome in depression: a machine learning approach. Lancet Psychiatry 3, 243250.
Dunlop BW, Holland P, Bao W, Ninan PT, Keller MB (2012). Recovery and subsequent recurrence in patients with recurrent major depressive disorder. Journal of Psychiatric Research 46, 708715.
El-Mallakh PRS, Briscoe B (2012). Studies of long-term use of antidepressants. CNS Drugs 26, 97109.
Farb NAS, Anderson AK, Bloch RT, Segal ZV (2011). Mood-linked responses in medial prefrontal cortex predict relapse in patients with recurrent unipolar depression. Biological Psychiatry 70, 366372.
Fava M, Wiltse C, Walker D, Brecht S, Chen A, Perahia D (2009). Predictors of relapse in a study of duloxetine treatment in patients with major depressive disorder. Journal of Affective Disorders 113, 263271.
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ, Weissman MM (1991). Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Archives of General Psychiatry 48, 851855.
Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM (2003). Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 361, 653661.
Glue P, Donovan MR, Kolluri S, Emir B (2010). Meta-analysis of relapse prevention antidepressant trials in depressive disorders. Australian and New Zealand Journal of Psychiatry 44, 697705.
Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman ATF (2010). Prevalence and predictors of recurrence of major depressive disorder in the adult population. Acta Psychiatrica Scandinavica 122, 184191.
Hochstrasser B, Isaksen PM, Koponen H, Lauritzen L, Mahnert FA, Rouillon F, Wade AG, Andersen M, Pedersen SF, Swart JCGD, Nil R (2001). Prophylactic effect of citalopram in unipolar, recurrent depression. British Journal of Psychiatry 178, 304310.
Hollon SD, DeRubeis RJ, Shelton RC, Amsterdam JD, Salomon RM, O'Reardon JP, Lovett ML, Young PR, Haman KL, Freeman BB, Gallop R (2005). Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Archives of General Psychiatry 62, 417422.
Hunot VM, Horne R, Leese MN, Churchill RC (2007). A cohort study of adherence to antidepressants in primary care: the influence of antidepressant concerns and treatment preferences. Primary Care Companion to the Journal of Clinical Psychiatry 9, 9199.
Huys QJM, Moutoussis M, Williams J (2011). Are computational models of any use to psychiatry? Neural Networks 24, 544551.
Iovieno N, van Nieuwenhuizen A, Clain A, Baer L, Nierenberg AA (2011). Residual symptoms after remission of major depressive disorder with fluoxetine and risk of relapse. Depression and Anxiety 28, 137144.
Joliat MJ, Schmidt ME, Fava M, Zhang S, Michelson D, Trapp NJ, Miner CM (2004). Long-term treatment outcomes of depression with associated anxiety: efficacy of continuation treatment with fluoxetine. Journal of Clinical Psychiatry 65, 373378.
Kaymaz N, van Os J, Loonen AJM, Nolen WA (2008). Evidence that patients with single versus recurrent depressive episodes are differentially sensitive to treatment discontinuation: a meta-analysis of placebo-controlled randomized trials. Journal of Clinical Psychiatry 69, 14231436.
Keller MB, Kocsis JH, Thase ME, Gelenberg AJ, Rush AJ, Koran L, Schatzberg A, Russell J, Hirschfeld R, Klein D, Mccullough JP, Fawcett JA, Kornstein S, Lavange L, Harrison W (1998). Maintenance phase efficacy of sertraline for chronic depression: a randomized controlled trial. Journal of the American Medical Association 280, 16651672.
Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, Friedman ES, Gelenberg AJ, Kocsis JH, Dunner DL, Hirschfeld RMA, Rothschild AJ, Ferguson JM, Schatzberg AF, Zajecka JM, Pedersen RD, Yan B, Ahmed S, Musgnung J, Ninan PT (2007). The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) study: outcomes from the 2-year and combined maintenance phases. Journal of Clinical Psychiatry 68, 12461256.
Kendler KS, Thornton LM, Gardner CO (2000). Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “Kindling” hypothesis. American Journal of Psychiatry 157, 12431251.
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS; National comorbidity survey Replication (2003). The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Journal of the American Medical Association 289, 30953105.
Khan A, Bhat A, Kolts R, Thase ME, Brown W (2010). Why has the antidepressant–placebo difference in antidepressant clinical trials diminished over the past three decades? CNS Neuroscience and Therapeutics 16, 217226.
Kornstein SG, Pedersen RD, Holland PJ, Nemeroff CB, Rothschild AJ, Thase ME, Trivedi MH, Ninan PT, Keller MB (2014). Influence of sex and menopausal status on response, remission, and recurrence in patients with recurrent major depressive disorder treated with venlafaxine extended release or fluoxetine: analysis of data from the PREVENT study. Journal of Clinical Psychiatry 75, 6268.
Lythe KE, Moll J, Gethin JA, Workman CI, Green S, Lambon Ralph MA, Deakin JF, Zahn R, (2015). Self-blame–selective hyperconnectivity between anterior temporal and subgenual cortices and prediction of recurrent depressive episodes. JAMA Psychiatry 72, 11191126.
McGrath PJ, Stewart JW, Petkova E, Quitkin FM, Amsterdam JD, Fawcett J, Reimherr FW, Rosenbaum JF, Beasley CM (2000). Predictors of relapse during fluoxetine continuation or maintenance treatment of major depression. Journal of Clinical Psychiatry 61, 518524.
McGrath PJ, Stewart JW, Quitkin FM, Chen Y, Alpert JE, Nierenberg AA, Fava M, Cheng J, Petkova E (2006). Predictors of relapse in a prospective study of fluoxetine treatment of major depression. American Journal of Psychiatry 163, 15421548.
Monroe SM, Harkness KL (2005). Life stress, the ‘Kindling’ hypothesis, and the recurrence of depression: considerations from a life stress perspective. Psychological Review 112, 417445.
Monroe SM, Harkness KL (2011). Recurrence in major depression: a conceptual analysis. Psychological Review 118, 655674.
Montague PR, Dolan RJ, Friston KJ, Dayan P (2012). Computational psychiatry. Trends in Cognitive Sciences 16, 7280.
National Collaborating Centre for Mental Health (UK) (2010). Depression: The Treatment and Management of Depression in Adults (Updated Edition) . National Institute for Health and Clinical Excellence: Guidance. British Psychological Society: Leicester, UK.
Nierenberg AA, Husain MM, Trivedi MH, Fava M, Warden D, Wisniewski SR, Miyahara S, Rush AJ (2010). Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychological Medicine 40, 4150.
Nierenberg AA, Quitkin FM, Kremer C, Keller MB, Thase ME (2004). Placebo-controlled continuation treatment with mirtazapine: acute pattern of response predicts relapse. Neuropsychopharmacology 29, 10121018.
Olfson M, Marcus SC, Tedeschi M, Wan GJ (2006). Continuity of antidepressant treatment for adults with depression in the United States. American Journal of Psychiatry 163, 101108.
Palmer DM (2015). Biomarkers for antidepressant selection: iSPOT-D Study. Current Behavioral Neuroscience Reports 2, 137145.
Perahia DG, Gilaberte I, Wang F, Wiltse CG, Huckins SA, Clemens JW, Montgomery SA, Montejo AL, Detke MJ (2006). Duloxetine in the prevention of relapse of major depressive disorder. British Journal of Psychiatry 188, 346353.
Quitkin FM, Rabkin JD, Markowitz JM, Stewart JW, McGrath PJ, Harrison W (1987). Use of pattern analysis to identify true drug response: a replication. Archives of General Psychiatry 44, 259264.
Rothschild AJ, Dunlop BW, Dunner DL, Friedman ES, Gelenberg A, Holland P, Kocsis JH, Kornstein SG, Shelton R, Trivedi MH, Zajecka JM, Goldstein C, Thase ME, Pedersen R, Keller MB (2009). Assessing rates and predictors of tachyphylaxis during the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) Study. Psychopharmacology Bulletin 42, 520.
Rouillon F, Berdeaux G, Bisserbe JC, Warner B, Mesbah M, Smadja C, Chwalow J (2000). Prevention of recurrent depressive episodes with milnacipran: consequences on quality of life. Journal of Affective Disorders 58, 171180.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry 163, 19051917.
Schmidt ME, Fava M, Robinson JM, Judge R (2000). The efficacy and safety of a new enteric-coated formulation of fluoxetine given once weekly during the continuation treatment of major depressive disorder. Journal of Clinical Psychiatry 61, 851857.
Sim K, Lau WK, Sim J, Sum MY, Baldessarini RJ (2015). Prevention of relapse and recurrence in adults with major depressive disorder: systematic review and meta-analyses of controlled trials. International Journal of Neuropsychopharmacology 19, pyv076.
Stewart JW, Quitkin FM, McGrath PJ, Amsterdam J, Fava M, Fawcett J, Reimherr F, Rosenbaum J, Beasley C, Roback P (1998). 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 55, 334343.
Szegedi A, Jansen WT, Van Willigenburg APP, Van Der Meulen E, Stassen HH, Thase ME (2009). Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. Journal of Clinical Psychiatry 70, 344353.
Thase ME, Nierenberg AA, Keller MB, Panagides J; Relapse Prevention Study Group (2001). Efficacy of mirtazapine for prevention of depressive relapse: a placebo-controlled double-blind trial of recently remitted high-risk patients. Journal of Clinical Psychiatry 62, 782788.
Trinh N-HT, Shyu I, McGrath PJ, Clain A, Baer L, Fava M, Yeung A (2011). Examining the role of race and ethnicity in relapse rates of major depressive disorder. Comprehensive Psychiatry 52, 151155.
Viguera AC, Baldessarini RJ, Friedberg J (1998). Discontinuing antidepressant treatment in major depression. Harvard Review of Psychiatry 5, 293306.
Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T (2013). Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382, 15751586.
Wolfers T, Buitelaar JK, Beckmann CF, Franke B, Marquand AF (2015). From estimating activation locality to predicting disorder: a review of pattern recognition for neuroimaging-based psychiatric diagnostics. Neuroscience and Biobehavioral Reviews 57, 328349.
Yang H, Chuzi S, Sinicropi-Yao L, Johnson D, Chen Y, Clain A, Baer L, McGrath PJ, Stewart JW, Fava M, Papakostas GI (2009). Type of residual symptom and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine. European Archives of Psychiatry and Clinical Neuroscience 260, 145150.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 28
Total number of PDF views: 448 *
Loading metrics...

Abstract views

Total abstract views: 680 *
Loading metrics...

* Views captured on Cambridge Core between 27th October 2016 - 18th November 2017. This data will be updated every 24 hours.