Prevention of Recurrence After Recovery From a Major Depressive Episode | Depressive Disorders | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral TherapyPhase 2 of a 2-Phase Randomized Clinical Trial

Educational Objective
To determine the effects of combining cognitive behavioral therapy (CBT) with antidepressant medication (ADM) on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with major depressive disorder (MDD).
1 Credit CME
Key Points

Question  What are the effects of combining cognitive behavioral therapy with antidepressant medications on the prevention of depressive recurrence when antidepressant medications are withdrawn or maintained after recovery in patients with major depressive disorder?

Findings  In this phase 2 randomized clinical trial of 292 adult patients with major depressive disorder who recovered from a chronic or recurrent major depressive episode, withdrawal of antidepressant medication treatment was associated with higher rates of recurrence compared with maintenance of antidepressant medication treatment regardless of whether patients achieved recovery with or without acute cognitive behavioral therapy treatment.

Meaning  Maintenance of antidepressant medication treatment was associated with a reduced risk of depressive recurrence, but previous treatment with cognitive behavioral therapy was not; whether cognitive behavioral therapy has a similar protective effect or whether adding antidepressant medications to cognitive behavioral therapy treatment interferes with any such protective effect remains unclear.

Abstract

Importance  Antidepressant medication (ADM) maintenance treatment is associated with the prevention of depressive recurrence in patients with major depressive disorder (MDD), but whether cognitive behavioral therapy (CBT) treatment is associated with recurrence prevention remains unclear.

Objective  To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD.

Design, Setting, and Participants  A total of 292 adult outpatients with chronic or recurrent MDD who participated in the second phase of a 2-phase trial. Participants had recovered in the first phase of the trial receiving ADM, either alone or in combination with CBT. The trial was conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance of or withdrawal from ADM and were followed up for 3 years. The first and last patients entered phase 2 in August 2003 and October 2009, respectively. The last patient completed phase 2 in August 2012. Data were analyzed from December 2013 to December 2018.

Interventions  Maintenance of or withdrawal from treatment with ADM.

Main Outcomes and Measures  Recurrence of an MDD episode using longitudinal interval follow-up evaluations; sustained recovery across both phases.

Results  A total of 292 participants (171 women, 121 men; mean [SD] age 45.1 [12.9] years) were included in analyses of depressive recurrence. Maintenance ADM yielded lower rates of recurrence compared with ADM withdrawal regardless of whether patients had achieved recovery in phase 1 with ADM alone (48.5% vs 74.8%; z = −3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or ADM plus CBT (48.5% vs 76.7%; z = −3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Sustained recovery rates differed as a function of phase 2 condition, with maintenance ADM superior to ADM withdrawal (z = 2.90; P = .004; OR, 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). Phase 1 condition was not associated with differential rates of sustained recovery (ADM alone vs ADM plus CBT; z = 0.22; P = .83; OR, 1.08; 95% CI, 0.52-2.11; NNT, 26.0; 95% CI, number needed to harm 3.2 to NNT 2.8), nor was there a significant interaction of phase 1 condition and phase 2 condition (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88).

Conclusions and Relevance  Maintenance ADM treatment, but not previous exposure to CBT, was associated with reduced rates of depressive recurrence. In previous studies, when CBT has been provided without ADM, CBT has shown a preventive effect on depressive relapse. Whether CBT also has a preventive effect on depressive recurrence, or if adding ADM interferes with any such preventive effect, remains unclear.

Trial Registration  ClinicalTrial.gov identifier: NCT00057577

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: September 12, 2019.

Published Online: December 4, 2019. doi:10.1001/jamapsychiatry.2019.3900

Correction: This article was corrected on January 29, 2020, to fix errors in the curves of Figure 2 and to revise the subtitle and Abstract, as well as titles and captions to Figures 2 and 3.

Corresponding Author: Robert J. DeRubeis, PhD, Department of Psychology, University of Pennsylvania, 425 S University Ave, Philadelphia, PA 19104 (derubeis@psych.upenn.edu).

Author Contributions: Drs DeRubeis and Hollon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: DeRubeis, Zajecka, Shelton, Amsterdam, Fawcett, Hollon.

Acquisition, analysis, or interpretation of data: DeRubeis, Shelton, Amsterdam, Fawcett, Xu, Young, Gallop, Hollon.

Drafting of the manuscript: DeRubeis, Zajecka, Xu, Gallop.

Critical revision of the manuscript for important intellectual content: DeRubeis, Zajecka, Shelton, Amsterdam, Fawcett, Xu, Young, Hollon.

Statistical analysis: DeRubeis, Xu, Gallop.

Obtained funding: DeRubeis, Amsterdam, Fawcett, Hollon.

Administrative, technical, or material support: Zajecka, Shelton, Amsterdam, Fawcett, Xu, Young, Hollon.

Supervision: DeRubeis, Amsterdam, Fawcett, Young, Hollon.

Conflict of Interest Disclosures: Dr DeRubeis reported receiving grants from the National Institute of Mental Health during the conduct of the study. Dr Zajecka reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Actavis Generics, Alkermes, Allergan, AstraZeneca, Axsome Therapeutics, the Cheryl T. Herman Foundation, Cyberonics, ElMindA, Forest Pharmaceuticals, Hoffman-La Roche, Janssen Pharmaceuticals, Johnson & Johnson, Lundbeck, Naurex, Neuralstem, Novartis, Otsuka, Sage Therapeutics, Taisho, and Takeda outside the submitted work. Dr Shelton reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Avanir Pharmaceuticals, Intra-cellular Therapies, Myriad Genetics, NeuroRx, Novartis, Otsuka, the Patient-Centered Outcomes Research Institute, Sage Therapeutics, and Genomind; grants and personal fees from Acadia Pharmaceuticals, Allergan, Cerecor, Janssen Pharmaceuticals, and Takeda; and personal fees from Lundbeck outside the submitted work. Dr Fawcett reported receiving grants from the National Institute of Mental Health during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by grants MH60713 and MH01697 (K02) (Dr Hollon), MH60998 (Dr DeRubeis), and MH060768 (Drs Fawcett and Zajecka) from the National Institute of Mental Health. Wyeth Pharmaceuticals provided venlafaxine, and Pfizer provided sertraline for the clinical trial.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: Brent Freeman, BA, and Bernadette Kooi, MS, of the University of Pennsylvania; Debra Klbecka, RN, and Matthew Marasco, BA, of Rush University; and Margaret L. Lovett, MEd, of Vanderbilt University served as the study coordinators. Giampaolo Gallo, MD, Moira Molloy, MSN, Bobbie Posmontier, PhD, Nancy Rutherford, MSN, Irene Soeller, CRNP, Jeffrey Staab, MD, and Jay D. Amsterdam, MD, of the University of Pennsylvania; Jagannath Devulapally, MD, Corey Goldstein, MD, Ian Mackey, MD, William Miles, MD, Raj Tummale, MD, and John Zajecka, MD, of Rush University; and Virginia Gardner, MSN, Jennifer Scroggie, MSN, Sandra Seidel, MSN, and Vatsal Thakkar, MD, of Vanderbilt University served as study pharmacotherapists. Julie Jacobs, PhD, Cory P. Newman, PhD, and Rita Ryan, PhD, of the University of Pennsylvania; David C. Clark, PhD, Kristen Flynn, PhD, John Larson, MD, Patricia Meaden, PhD, Chad Owen, PsyD, and Paula R. Young, PhD, of Rush University; and Laurel L. Brown, PhD, Kirsten Haman, PhD, Karl N. Jannasch, PhD, Sandra Seidel, MSN, and Dorothy D. Tucker, PhD, of Vanderbilt University served as the cognitive therapists. Kirsten L. Haman, PhD, oversaw the training of the clinical interviewers. All of the aforementioned contributors were reimbursed for their participation. William T. McKinney, MD, of Northwestern University (emeritus); Irene Elkin, PhD, of the University of Chicago (emerita); Robert Gibbons, PhD, and Mark Siegler, MD, of the University of Chicago; and Burt Jensen of the Federal Bureau of Investigation (retired) served on the independent data safety monitoring board and received honoraria for their participation. DatStat developed the data entry and patient management system used to conduct the study. Paul W. Andrews, PhD, of McMaster University and Lois A. Gelfand, PhD, of the University of Pennsylvania provided helpful comments on an earlier draft of this article.

Additional Information: Drs DeRubeis, Fawcett, and Hollon were the principal investigators; Drs Amsterdam, Zajecka, and Shelton were the coprincipal investigators. Drs DeRubeis, Hollon, and Young oversaw the implementation of computed tomography at the University of Pennsylvania, Vanderbilt University, and Rush University, respectively. Dr Fawcett oversaw the implementation of pharmacotherapy across the study; Drs Amsterdam, Zajecka, and Shelton supervised the implementation of pharmacotherapy at the respective sites.

References
1.
Cuijpers  P, Berking  M, Andersson  G, Quigley  L, Kleiboer  A, Dobson  KS.  A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments.  Can J Psychiatry. 2013;58(7):376-385. doi:10.1177/070674371305800702PubMedGoogle Scholar
2.
de Maat  SM, Dekker  J, Schoevers  RA, de Jonghe  F.  Relative efficacy of psychotherapy and combined therapy in the treatment of depression: a meta-analysis.  Eur Psychiatry. 2007;22(1):1-8. doi:10.1016/j.eurpsy.2006.10.008PubMedGoogle Scholar
3.
Cuijpers  P, van Straten  A, Warmerdam  L, Andersson  G.  Psychotherapy versus the combination of psychotherapy and pharmacotherapy in the treatment of depression: a meta-analysis.  Depress Anxiety. 2009;26(3):279-288. doi:10.1002/da.20519PubMedGoogle Scholar
4.
Cuijpers  P, Sijbrandij  M, Koole  SL, Andersson  G, Beekman  AT, Reynolds  CF  III.  Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis.  World Psychiatry. 2014;13(1):56-67. doi:10.1002/wps.20089PubMedGoogle Scholar
5.
Glue  P, Donovan  MR, Kolluri  S, Emir  B.  Meta-analysis of relapse prevention antidepressant trials in depressive disorders.  Aust N Z J Psychiatry. 2010;44(8):697-705. doi:10.3109/00048671003705441PubMedGoogle Scholar
6.
Reid  S, Barbui  C.  Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants.  BMJ. 2010;340:c1468. doi:10.1136/bmj.c1468PubMedGoogle Scholar
7.
Cuijpers  P, Hollon  SD, van Straten  A, Bockting  C, Berking  M, Andersson  G.  Does cognitive behaviour therapy have an enduring effect that is superior to keeping patients on continuation pharmacotherapy? a meta-analysis.  BMJ Open. 2013;3(4):e002542. doi:10.1136/bmjopen-2012-002542PubMedGoogle Scholar
8.
Hollon  SD, DeRubeis  RJ, Fawcett  J,  et al.  Effect of cognitive therapy with antidepressant medications vs antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial  [retracted in JAMA Psychiatry. 2016;73(6):639-640].  JAMA Psychiatry. 2014;71(10):1157-1164. doi:10.1001/jamapsychiatry.2014.1054PubMedGoogle Scholar
9.
Hollon  SD, DeRubeis  RJ, Shelton  RC,  et al.  Prevention of relapse following cognitive therapy vs medications in moderate to severe depression.  Arch Gen Psychiatry. 2005;62(4):417-422. doi:10.1001/archpsyc.62.4.417PubMedGoogle Scholar
10.
Fournier  JC, DeRubeis  RJ, Shelton  RC, Gallop  R, Amsterdam  JD, Hollon  SD.  Antidepressant medications v. cognitive therapy in people with depression with or without personality disorder.  Br J Psychiatry. 2008;192(2):124-129. doi:10.1192/bjp.bp.107.037234PubMedGoogle Scholar
11.
Wei  LJ, Lachin  JM.  Properties of the urn randomization in clinical trials.  Control Clin Trials. 1988;9(4):345-364. doi:10.1016/0197-2456(88)90048-7PubMedGoogle Scholar
12.
Klein  DF.  Preventing hung juries about therapy studies.  J Consult Clin Psychol. 1996;64(1):81-87. doi:10.1037/0022-006X.64.1.81PubMedGoogle Scholar
13.
Therneau  TM, Crowson  CS, Atkinson  EJ. Adjusted survival curves. https://cran.r-project.org/web/packages/survival/vignettes/adjcurve.pdf. Published January 2015. Accessed May 7, 2019.
14.
Therneau  TM. Survival analysis in S version 2.38. https://CRAN.R-project.org/package=survival. Published 2015. Accessed May 7, 2019.
15.
Altman  DG.  Confidence intervals for the number needed to treat.  BMJ. 1998;317(7168):1309-1312. doi:10.1136/bmj.318.7200.1764cPubMedGoogle Scholar
16.
Dobson  KS, Hollon  SD, Dimidjian  S,  et al.  Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression.  J Consult Clin Psychol. 2008;76(3):468-477. doi:10.1037/0022-006X.76.3.468PubMedGoogle Scholar
17.
Evans  MD, Hollon  SD, DeRubeis  RJ,  et al.  Differential relapse following cognitive therapy and pharmacotherapy for depression.  Arch Gen Psychiatry. 1992;49(10):802-808. doi:10.1001/archpsyc.1992.01820100046009PubMedGoogle Scholar
18.
Blackburn  IM, Eunson  KM, Bishop  S.  A two-year naturalistic follow-up of depressed patients treated with cognitive therapy, pharmacotherapy and a combination of both.  J Affect Disord. 1986;10(1):67-75. doi:10.1016/0165-0327(86)90050-9PubMedGoogle Scholar
19.
Simons  AD, Murphy  GE, Levine  JL, Wetzel  RD.  Cognitive therapy and pharmacotherapy for depression: sustained improvement over one year.  Arch Gen Psychiatry. 1986;43(1):43-48. doi:10.1001/archpsyc.1986.01800010045006PubMedGoogle Scholar
20.
Otto  MW, McHugh  RK, Kantak  KM.  Combined pharmacotherapy and cognitive-behavioral therapy for anxiety disorders: medication effects, glucocorticoids, and attenuated treatment outcomes.  Clin Psychol (New York). 2010;17(2):91-103. doi:10.1111/j.1468-2850.2010.01198.xPubMedGoogle Scholar
21.
Rosen  CS, Greenbaum  MA, Schnurr  PP, Holmes  TH, Brennan  PL, Friedman  MJ.  Do benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress disorder?  J Clin Psychiatry. 2013;74(12):1241-1248. doi:10.4088/JCP.13m08592PubMedGoogle Scholar
22.
Barlow  DH, Gorman  JM, Shear  MK, Woods  SW.  Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial.  JAMA. 2000;283(19):2529-2536. doi:10.1001/jama.283.19.2529PubMedGoogle Scholar
23.
Fava  GA, Ruini  C, Rafanelli  C, Finos  L, Conti  S, Grandi  S.  Six-year outcome of cognitive behavior therapy for prevention of recurrent depression.  Am J Psychiatry. 2004;161(10):1872-1876. doi:10.1176/ajp.161.10.1872PubMedGoogle Scholar
24.
Segal  ZV, Bieling  P, Young  T,  et al.  Antidepressant monotherapy vs sequential pharmacotherapy and mindfulness-based cognitive therapy, or placebo, for relapse prophylaxis in recurrent depression.  Arch Gen Psychiatry. 2010;67(12):1256-1264. doi:10.1001/archgenpsychiatry.2010.168PubMedGoogle Scholar
25.
Teasdale  JD, Segal  ZV, Williams  JM, Ridgeway  VA, Soulsby  JM, Lau  MA.  Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy.  J Consult Clin Psychol. 2000;68(4):615-623. doi:10.1037/0022-006X.68.4.615PubMedGoogle Scholar
26.
March  J, Kraemer  HC, Trivedi  M,  et al.  What have we learned about trial design from NIMH-funded pragmatic trials?  Neuropsychopharmacology. 2010;35(13):2491-2501. doi:10.1038/npp.2010.115PubMedGoogle Scholar
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close