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Cited by 1,002Treatment of Major DepressionAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesMental Health Treatment and Access

Medication Augmentation after the Failure of SSRIs for Depression

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Trivedi, Madhukar H., Fava, Maurizio, Wisniewski, Stephen R., Thase, Michael E., Quitkin, Frederick, Warden, Diane, Ritz, Louise, Nierenberg, Andrew A. +5 more·2006·New England Journal of Medicine
DOI 10.1056/nejmoa052964
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Abstract

BACKGROUND: Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. METHODS: We randomly assigned 565 adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy (mean final dose, 55 mg per day) to receive sustained-release bupropion (at a dose of up to 400 mg per day) as augmentation and 286 to receive buspirone (at a dose of up to 60 mg per day) as augmentation. The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of this study; scores were obtained over the telephone by raters blinded to treatment assignment. The 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR-16) was used to determine the secondary outcomes of remission (defined as a score of less than 6 at the end of this study) and response (a reduction in baseline scores of 50 percent or more). RESULTS: The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission (29.7 percent and 30.1 percent, respectively), QIDS-SR-16 remission (39.0 percent and 32.9 percent), and QIDS-SR-16 response (31.8 percent and 26.9 percent). Sustained-release bupropion, however, was associated with a greater reduction (from baseline to the end of this study) in QIDS-SR-16 scores than was buspirone (25.3 percent vs. 17.1 percent, P<0.04), a lower QIDS-SR-16 score at the end of this study (8.0 vs. 9.1, P<0.02), and a lower dropout rate due to intolerance (12.5 percent vs. 20.6 percent, P<0.009). CONCLUSIONS: Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events. (ClinicalTrials.gov number, NCT00021528.).

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  • TRD is associated with prolonged mental and physical dysfunction, increased healthcare spending, worse clinical outcomes, and a higher risk of suicide.

    “Overall, Treatment Resistant Depression (TRD) is associated with several comorbid features, including prolonged mental and physical dysfunction, increased healthcare spending, worse clinical outcomes, and a higher risk of suicide [4,6,7,8,9].”

    From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [4]

  • Diminishing returns demonstrated in the STAR*D trial underscore the need for novel treatment avenues targeting the pathophysiological source of treatment resistance.

    “Diminishing returns demonstrated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial underscore the need for novel treatment avenues targeting the pathophysiological source of treatment resistance [4].”

    From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [4]

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Research works printed but not linked: 14

  1. Depression Guideline Panel. Depres- sion in primary care. Vol. 2. Treatment of major depression. Clinical practice guide- line, number 5. Rockville, Md.: Agency for Health Care Policy and Research, April 1993. (AHCPR publication no. 93-0551.)
  2. Greden JF. Recurrent depression -its overwhelming burden. In: Greden JF, ed. Treatment of recurrent depression. Review of psychiatry. Vol. 20. No. 5. Washington, D.C.: American Psychiatric Publishing, 2001:1-18.
  3. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Proj- ect: report of the Texas Consensus Con- ference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychia- try 1999;60:142-56.
  4. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the se- quenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am 2003;26:457-94.
  5. Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psycho- som (in press).
  6. Rush AJ, Fava M, Wisniewski SR, et al. Sequenced treatment alternatives to re- lieve depression (STAR*D): rationale and design. Control Clin Trials 2004;25:119- 42. 1. 2. 3. 4. 5.
  7. Trivedi MH, Rush AJ, Crismon ML, et al. Clinical results for patients with major depressive disorder in the Texas Medica- tion Algorithm Project. Arch Gen Psychi- atry 2004;61:669-80.
  8. Rush AJ, Trivedi MH. Strategies and tactics in the treatment of depression. In: Evans DL, Charney DS, eds. The physician's guide to depression and bi-polar disorders. New York: McGraw-Hill, 2005:1-8.
  9. Joffe RT, Singer W, Levitt AJ, MacDon- ald C. A placebo-controlled comparison of lithium and triiodothyronine augmen- tation of tricyclic antidepressants in uni- polar refractory depression. Arch Gen Psy- chiatry 1993;50:387-93.
  10. Thase ME, Rush AJ. Treatment-resis- tant depression. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: fourth genera- tion of progress. New York: Raven Press, 1995:1081-97.
  11. Lavori PW, Rush AJ, Wisniewski SR, et al. Strengthening clinical effectiveness trials: equipoise-stratified randomization. Biol Psychiatry 2001;50:792-801.
  12. Redrobe JP, Bourin M. Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test. Psycho- pharmacology (Berl) 1998;138:198-206. 7. 8. 9. 10. 11. 12.
  13. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalo- pram for depression using measurement- based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28-40.
  14. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of De- pressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry 2003;54:573-83. [Erratum, Biol Psychiatry 2003;54:585.

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Authors
Trivedi, M. H., Fava, M., Wisniewski, S. R., Thase, M. E., Quitkin, F., Warden, D., Ritz, L., Nierenberg, A. A., Lebowitz, B. D., Biggs, M. M., Luther, J. F., Shores-Wilson, K., & Rush, A. J.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • University of Pittsburgh (US)
  • New York State Psychiatric Institute (US)
  • National Institute of Mental Health (US)
  • Massachusetts General Hospital (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2006-03-23
Volume
354
Issue
12
Pages
1243-1252
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa052964
OpenAlex
W1985193354
Cited by
1,002
References
3
Citations by year
2026: 12 · 2025: 25 · 2024: 28 · 2023: 26 · 2022: 22 · 2021: 38 · 2020: 39 · 2019: 36 · 2018: 52 · 2017: 49 · 2016: 45 · 2015: 59 · 2014: 52 · 2013: 52 · 2012: 61
FWCI
57.48
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Health and Human Services
  • Abbott Laboratories
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Bayer
  • GlaxoSmithKline
  • Sanofi
  • Pharmavite
  • University of Texas Southwestern Medical Center
  • H. Lundbeck A/S
  • National Institutes of Health (n01mh90003-26-0-0, N01MH90003)
  • National Institute of Mental Health (N01‐MH‐90003)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
Keywords
depression, antidepressant augmentation, selective serotonin reuptake inhibitors, citalopram, bupropion, buspirone, treatment-resistant depression, remission, drug intolerance, adverse events, outpatients, Hamilton Depression Rating Scale, cost-effectiveness, antidepressant side effects
MeSH terms
Adult, Buspirone, Delayed-Action Preparations, Depressive Disorder, Major, Major Depressive Disorder, Drug Administration Schedule, Drug Therapy, Combination, Female, Humans, Male, Remission Induction, Citalopram, Logistic Models, Bupropion, Treatment Failure, Serotonin Receptor Agonists, Selective Serotonin Reuptake Inhibitors, Dopamine Uptake Inhibitors

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