Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression
Abstract
BACKGROUND: Treatment-resistant depression (TRD) is a long-term, disabling illness. We report on the characteristics and outcomes of a large cohort of patients with a level of treatment resistance that is very substantial and who were treated for 2 years with standard care. METHOD: This 2-year prospective, multicenter, observational study (patients enrolled from January 2001 through July 2004) tracked the outcomes of 124 patients with treatment-resistant, nonpsychotic major depressive disorder (N = 109) or bipolar depressed phase disorder (N = 15) who received treatment as usual (TAU) (i.e., any therapeutic regimen agreed to by patients and psychiatrists, including medications, electroconvulsive therapy [ECT], and psychotherapy). Treatments could be adjusted, started, and stopped as necessary. The primary outcome, treatment response, was defined a priori as > or = 50% improvement from baseline as measured by the 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR-30). Remission was defined as an IDS-SR-30 score of < or = 14. The Medical Outcomes Study (MOS) 36-item Short Form Health Survey (SF-36) was used to monitor quality-of-life changes. RESULTS: The 12- and 24-month IDS-SR-30 response rates were 11.6% (13/112) and 18.4% (19/103), respectively. Of the 13 responders at 12 months, only 5 were responders at 24 months. The 12- and 24-month IDS-SR-30 remission rates were 3.6% (4/112) and 7.8% (8/103), respectively. Only 1 of the 4 12-month remitters was also a remitter at 24 months. The SF-36 indicated globally poor quality of life in this sample. CONCLUSIONS: Despite the wide range of treatment options available for depression, the response rates, remission rates, and quality-of-life results in this study show that most patients with a substantial degree of treatment resistance continue to have significant symptomatology and functional disability when receiving TAU.
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Another study reported that in patients with treatment-resistant depression, the lifetime risk of suicide attempts is assessed to be close to 30%.
“Another study 33 reported that in TRD patients, the life-time risk of suicide attempts is assessed to be close to 30%.”
From Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression (2020) · cites this paper as [33]
Remission rates are lower in treatment-resistant depression, which is associated with a higher risk of recurrence, substance abuse, and suicidal behavior.
“These remission rates are lower in treatment-resistant depression (TRD) [5] which is associated with a higher risk of recurrence, substance abuse, and suicidal behavior [6,7].”
From The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review (2018) · cites this paper as [5]
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“This is of major importance for the clinical routine, where patients with TRD often remain misdiagnosed and subsequently undertreated (Fava and Davidson 1996; Schlaepfer et al. 2012), remaining under significant functional disability (Dunner et al. 2006; Amital et al. 2013; Kraus et al. 2017).”
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Self-citationSomatic Treatments for Mood Disorders
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“In a naturalistic outcome, Dunner et al (2006) found a response rate of 11% (13/112) in 12 months and 18% (19/103) in 24 months.”
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“INTRODUCTION Treatment-resistant major depression (TRMD) is a severe form of major depressive disorder (MDD) in which patients fail to respond to multiple standard antidepressant treatments (1, 2).”
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“There is, however, indirect evidence to suggest that the placebo response rates are significantly lower in subjects with TRD as compared to those with uncomplicated MDD (Dunner et al., 2006; Fournier et al., 2010).”
ResultDurability of antidepressant response to vagus nerve stimulation (VNS)
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“In these latter studies, both response (27%–53%) and remission (15%–33%) rates over 12 months were significantly higher in patients who received VNS treatment in addition to medications compared with what was reported in another study with similar patients who received only medications (12% response and 4% remission)…”
Administration of ketamine for unipolar and bipolar depression
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“Moreover, despite a wide array of effective pharmaceutical, physical and psychological antidepressant treatments, TRD patients continue to suffer from significant symptoms and functional disability (Dunner et al. 2006; Amital et al. 2013).”
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“Table I summarizes most defi nitions of TRD available in the literature (22-27).”
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“4 In the few last years iVNS has also been tested on several comorbid diseases: depression (Rush et al., 2000; Sackeim et al., 2001; Krahl et al., 2004; George et al., 2005; Nahas et al., 2005; Dunner et al., 2006; Bajbouj et al., 2010; Aaronson et al., 2013), migraine”
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“…TRD patients are tracked over two years with treatment according to the current standard of care (i.e., “treatment as usual” such as medications with augmentation strategies, psychotherapy, electroconvulsive therapy), over 65% do not respond at anytime, while 81% do not remit (Dunner et al, 2006).”
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“The same is true with regard to the maintenance of response over an additional year with close to 65–77% of patients in the VNS plus TAU group maintaining their response [144] as compared to 38% of patients receiving TAU alone [145].”
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“Despite this, studies with long-term follow-up of patients with TRD are scarce and do not include risk factor analyses of adverse outcomes such as death or suicide (Dunner et al., 2006; Fekadu et al., 2009).”
BackgroundComparison and Selection of Current Implantable Anti-Epileptic Devices
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Self-citationUpdate on deep brain stimulation for neuropsychiatric disorders
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“Similar to non-TRMD MDD, women outnumbered men by 2–1, consistent with other TRMD studies (16, 17, 23, 26, 27).”
BackgroundResultInfluentialFitzgerald, P. B., Segrave, R. A., Richardson, K. E., Knox, L., Herring, S. E., Daskalakis, Z. J., & Bittar, R. G. (2018) · Brain stimulation · doi:10.1016/j.brs.2018.04.013 · Cited by 54 · see citing works
Vagus nerve stimulation: An update on a novel treatment for treatment-resistant depression
Kamel, L. Y., Xiong, W., Gott, B. M., Kumar, A., & Conway, C. R. (2022) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2022.120171 · Cited by 59 · see citing works
Akhtar, H., Bukhari, F., Nazir, M., Anwar, M. N., & Shahzad, A. (2016) · Neuroscience Bulletin · doi:10.1007/s12264-015-0009-2 · Cited by 58 · see citing works
Berlim, M. T., den Eynde, F. V., Tovar-Perdomo, S., Chachamovich, E., Zangen, A., & Turecki, G. (2014) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2014.925141 · Cited by 51 · see citing works
“There is a growing consensus in the literature that studies aiming at comprehensively measuring the benefi ts of treatments for MDD should also assess broader domains such as, for example, QOL (Kennedy et al. 2001; Demyttenaere et al. 2003; Papakostas et al. 2004).”
InfluentialRoss, E. L., & Soeteman, D. I. (2020) · Psychiatric Services · doi:10.1176/appi.ps.201900625 · Cited by 51 · see citing works
“We chose this time horizon to ensure adequate time for longer-term costs and benefits to accrue without requiring excess extrapolation beyond available outcomes data (4, 15, 16); we varied the time horizon between 2 and 10 years in sensitivity analysis.”
MethodMismatch negativity in treatment-resistant depression and borderline personality disorder
He, W., Chai, H., Zheng, L., Yu, W., Chen, W., Jian-ming, L., Chen, W., & Wang, W. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2009.12.021 · Cited by 49 · see citing works
Olfson, M., Amos, T. B., Benson, C., McRae, J., & Marcus, S. C. (2018) · Journal of Managed Care & Specialty Pharmacy · doi:10.18553/jmcp.2018.24.3.226 · Cited by 48 · see citing works
Solvason, H. B., Husain, M. M., Fitzgerald, P. B., Rosenquist, P., McCall, W. V., Kimball, J. N., Gilmer, W. S., Demitrack, M. A., & Lisanby, S. H. (2013) · Brain stimulation · doi:10.1016/j.brs.2013.10.008 · Cited by 48 · see citing works
“This impairment is most notable in how patients perceive their emotional wellbeing, social functioning, vitality, and mental health [12].”
BackgroundPersonalised depression forecasting using mobile sensor data and ecological momentary assessment
Kathan, A., Harrer, M., Küster, L., Triantafyllopoulos, A., He, X., Milling, M., Gerczuk, M., Yan, T., Rajamani, S. T., Heber, E., et al. (2022) · Frontiers in Digital Health · doi:10.3389/fdgth.2022.964582 · Cited by 47 · see citing works
“They are associated with a vast array of negative consequences for the individual and society, including increased disability (5), loss of quality of life (6, 7), suicidality (8, 9), excess mortality (10, 11), as well as large economic costs (12, 13).”
BackgroundCathomas, F., Bevilacqua, L., Ramakrishnan, A., Kronman, H., Costi, S., Schneider, M., Chan, K. L., Li, L., Nestler, E. J., Shen, L., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-021-01712-0 · Cited by 45 · see citing works
The Emerging Use of Technology for the Treatment of Depression and Other Neuropsychiatric Disorders
Howland, R. H., Shutt, L. S., Berman, S., Spotts, C., & Denko, T. (2011) · Annals of Clinical Psychiatry · doi:10.1177/104012371102300108 · Cited by 46 · see citing works
“These 2 clinical research efforts should provide more definitive data about the safety and efficacy of DBS for TRD.”
InfluentialMatsunaga, M., Okamoto, Y., Suzuki, S.-I., Kinoshita, A., Yoshimura, S., Yoshino, A., Kunisato, Y., & Yamawaki, S. (2010) · BMC Psychiatry · doi:10.1186/1471-244x-10-22 · Cited by 47 · see citing works
“[8], but these scores in our study showed sustained improvement, especially for the mental components (MCS), after CBT treatment and one year later.”
BackgroundMethodInfluentialBerlim, M. T., McGirr, A., Beaulieu, M.-M., & Turecki, G. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.10.011 · Cited by 46 · see citing works
“, 2006), andgrowingevidence suggests that TRD is associated with very high levels of morbidity, chronicity, relapse and societal costs (Dunner et al., 2006; Greden, 2001).”
BackgroundVergunst, F. K., Fekadu, A., Wooderson, S. C., Tunnard, C. S., Rane, L. J., Markopoulou, K., & Cleare, A. J. (2013) · Psychiatry Research · doi:10.1016/j.psychres.2013.03.022 · Cited by 45 · see citing works
“They are more likely to experience comorbid physical and mental health problems, to suffer significant short-term (Dunner et al., 2006) and longer-term (Kennedy and Paykel, 2004) social impairment, and are more likely to attempt suicide (Kornstein et al., 2000; Dunner et al., 2006).”
BackgroundBaune, B. T. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_19 · Cited by 46 · see citing works
“In a study examining the effect of ubiquitin-specific processing protease 8 (USP8) in luteolin-treated microglia, it was found that luteolin inhibits microglial inflammation by enhancing USP8 protein production and USP8 might represent a novel mechanism for the treatment of neuroinflammation and neurodegeneration [68].”
BackgroundJanicak, P. G., Dünner, D. L., Aaronson, S. T., Carpenter, L. L., Boyadjis, T. A., Brock, D. G., Cook, I. A., Lanocha, K. I., Solvason, H. B., Bonneh‐Barkay, D., et al. (2013) · CNS Spectrums · doi:10.1017/s1092852913000357 · Cited by 42 · see citing works
“Despite a variety of treatment options available for depression, recent studies find that pharmacoresistant patients continue to experience symptomatic and functional disability.(31,46) This study explored the effect of an acute trial of TMS on health-related QOL outcomes in patients with treatment-resistant depressio…”
Self-citationRooney, W., Schuklenk, U., & van de Vathorst, S. (2018) · Health Care Analysis · doi:10.1007/s10728-017-0344-8 · Cited by 44 · see citing works
Understanding treatment-resistant depression using “omics” techniques: A systematic review
Amasi-Hartoonian, N., Pariante, C. M., Cattaneo, A., & Sforzini, L. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.09.011 · Cited by 43 · see citing works
Espadaler, J., Tuson, M., López-Ibor, J. M., Lopez-Ibor, F., & López‐Ibor, M. I. (2016) · CNS Spectrums · doi:10.1017/s1092852915000711 · Cited by 42 · see citing works
Quality of life across domains among individuals with treatment-resistant depression
Lex, H., Ginsburg, Y., Sitzmann, A. F., Grayhack, C., Maixner, D. F., & Mickey, B. J. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.09.062 · Cited by 40 · see citing works
“Do the SF-36 and WHOQOL-BREF measure the same constructs?”
MethodInfluentialBrenner, P., Brandt, L., Li, G., DiBernardo, A., Bodén, R., & Reutfors, J. (2019) · Addiction · doi:10.1111/add.14596 · Cited by 42 · see citing works
“The results in this study should be considered in the light of findings not only on the negative consequences of TRD on various social and health outcomes [26,44,45], but also on the detrimental impact of the ‘dual diagnosis’ of depression and SUD.”
BackgroundMultiple-therapy-resistant major depressive disorder: a clinically important concept
McAllister-Williams, R. H., Christmas, D. M. B., Cleare, A. J., Currie, A., Gledhill, J., Insole, L., Malizia, A. L., McGeever, M., Morriss, R., Robinson, L. J., et al. (2018) · British Journal of Psychiatry · doi:10.1192/bjp.2017.33 · Cited by 40 · see citing works
Corticolimbic balance shift of regional glucose metabolism in depressed patients treated with ECT
Suwa, T., Namiki, C., Takaya, S., Oshita, A., Ishizu, K., Fukuyama, H., Suga, H., & Murai, T. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.11.040 · Cited by 39 · see citing works
“, 2001) and in bipolar disorder (BD) (Dunner et al., 2006).”
BackgroundConway, C. R., Chibnall, J. T., Gangwani, S., Mintun, M. A., Price, J. L., Hershey, T. G., Giuffra, L. A., Bucholz, R. D., Christensen, J. J., & Sheline, Y. I. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.02.007 · Cited by 41 · see citing works
“, any antidepressant treatment) have shown poor response rates (~12%) (Dunner et al., 2006; George et al., 2005).”
BackgroundWhy Do You Need to Move Beyond First-Line Therapy for Major Depression?
Culpepper, L. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.9104su1c.01 · Cited by 38 · see citing works
“Reprinted with permission from Dunner et al.(16) Scores below 50 are considered below average.”
MethodNovel targets for antidepressant therapies
Holtzheimer, P. E., & Nemeroff, C. B. (2008) · Current Psychiatry Reports · doi:10.1007/s11920-008-0075-5 · Cited by 37 · see citing works
“Also, the maintenance of response with VNS plus TAU [73] appears to be greater than that seen with TAU alone [ 74 ], although this has not been studied in a randomized, controlled fashion.”
MethodHowland, R. H. (2009) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s5453 · Cited by 38 · see citing works
Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial.
Aaronson, S., van der Vaart, A. D., Miller, T. M., LaPratt, J., Swartz, K., Shoultz, A., Lauterbach, M., Suppes, T., & Sackeim, H. (2025) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20231063 · Cited by 34 · see citing works
Lee, Y.-J., Lee, G.-W., Seo, W. S., Koo, B., Kim, H.-G., & Cheon, E. (2019) · Journal of Korean Medical Science · doi:10.3346/jkms.2019.34.e287 · Cited by 33 · see citing works
Significantly decreased mRNA levels of BDNF and MEK1 genes in treatment-resistant depression
Hong, W., Fan, J.-B. B., Yuan, C., Zhang, C., Hu, Y., Peng, D.-H., Wang, Y., Huang, J., Li, Z.-Z., Yu, S.-Y., et al. (2014) · NeuroReport · doi:10.1097/wnr.0000000000000165 · Cited by 34 · see citing works
Neurostimulation for depression in epilepsy
Conway, C. R., Anita, U., & Schachter, S. C. (2018) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2018.06.007 · Cited by 34 · see citing works
Yang, C., Bosker, F. J., Li, J., & Schoevers, R. A. (2018) · BMC Psychiatry · doi:10.1186/s12888-018-1845-1 · Cited by 34 · see citing works
Havlik, J. L., Wahid, S., Teopiz, K. M., McIntyre, R. S., Krystal, J. H., & Rhee, T. G. (2024) · Current Psychiatry Reports · doi:10.1007/s11920-024-01494-4 · Cited by 33 · see citing works
“…that depression severity (measured with the MADRS) decreased through the 4-week induction (IND) phase and maintained levels through the 48-week optimization/maintenance (OP/MAINT) phase (mean [SD] change from base-line of respective phase to endpoint, IND, −16.4 [8.76]; OP/ MAINT, 0.3 [8.12]).”
Influential
- Authors
- Dunner, D. L., Rush, A. J., Russell, J. M., Burke, M., Woodard, S., Wingard, P., & Allen, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Eli Lilly (United States) (US)
- University of Kansas (US)
- IQVIA (United States) (US)
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2006-05-15
- Volume
- 67
- Issue
- 05
- Pages
- 688-695
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W1978161441
- Cited by
- 234
- References
- 0
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 14 · 2023: 10 · 2022: 23 · 2021: 11 · 2020: 13 · 2019: 14 · 2018: 22 · 2017: 11 · 2016: 10 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 13
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
- Keywords
- treatment-resistant depression, major depressive disorder, bipolar depression, treatment response, remission, quality of life, functional disability, long-term outcomes, usual care, electroconvulsive therapy, psychotherapy, antidepressant treatment
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Antidepressive Agents, Bipolar Disorder, Major Depressive Disorder, Depressive Disorder, Drug Resistance, Electroconvulsive Therapy, Health Status, Humans, Longitudinal Studies, Middle Aged, Personality Inventory, Prospective Studies, Psychiatric Status Rating Scales, Psychotherapy, Psychotropic Drugs, Quality of Life, Surveys and Questionnaires, Recurrence, Cohort Studies, Treatment Outcome
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