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Clinical Factors Associated With Treatment Resistance in Major Depressive Disorder: Results From a European Multicenter Study
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OBJECTIVES: Very few studies have investigated clinical features associated with treatment-resistant depression (TRD) defined as failure of at least 2 consecutive antidepressant trials. The primary objective of this multicenter study was to identify specific clinical and demographic factors associated with TRD in a large sample of patients with major depressive episodes that failed to reach response or remission after at least 2 consecutive adequate antidepressant treatments. METHOD: A total of 702 patients with DSM-IV major depressive disorder, recruited from January 2000 to February 2004, were included in the analysis. Among them, 346 patients were considered as nonresistant. The remaining 356 patients were considered as resistant, with a 17-item Hamilton Rating Scale for Depression score remaining greater than or equal to 17 after 2 consecutive adequate antidepressant trials. Cox regression models were used to examine the association between individual clinical variables and TRD. RESULTS: Among the clinical features investigated, 11 variables were found to be associated with TRD. We found anxiety comorbidity (p < .001, odds ratio [OR] = 2.6), comorbid panic disorder (p < .001, OR = 3.2) and social phobia (p = .008, OR = 2.1), personality disorder (p = .049, OR = 1.7), suicidal risk (p = .001, OR = 2.2), severity (p = .001, OR = 1.7), melancholia (p = .018, OR = 1.5), a number of hospitalizations > 1 (p = .003, OR = 1.6), recurrent episodes (p = .009, OR = 1.5), early age at onset (p = .009, OR = 2.0), and nonresponse to the first antidepressant received lifetime (p = .019, OR = 1.6) to be the factors associated with TRD. CONCLUSIONS: Our findings provide a set of 11 relevant clinical variables associated with treatment resistance in major depressive disorder that can be explored at the clinical level. The statistical model used in this analysis allowed for a hierarchy of these variables (based on the OR) showing that comorbid anxiety disorder is the most powerful clinical factor associated with TRD.
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“This comorbidity pattern may also affect treatment outcomes, with pharmacotherapy studies indicating that comorbid SAD is associated with a poorer course of illness (Mulder, Joyce, Frampton, Luty, & Sullivan, 2006), treatment-resistant depression (Souery et al., 2007), and a greater number and earlier onset of depressive recurrences compared with patients without comorbid SAD (Holma, Holma, Melart”
From An Integrated, Acceptance-Based Behavioral Approach for Depression With Social Anxiety: Preliminary Results (2014) · cites this paper as Souery et al., 2007
In the citing paper
“Prevalence estimates of TRS, TRD, and treatment resistant OCD vary from 20-60% of the population with the condition. 26, 35–40”
From Treatment resistance in psychiatry: state of the art and new directions (2022) · cites this paper as [39]
In the citing paper
“Timing may add heterogeneous features: certain individuals may change readily with respect to certain symptoms, whereas other subjects may have opposite tendencies [41].”
From The Deceptive Manifestations of Treatment Resistance in Depression: A New Look at the Problem (2020) · cites this paper as [41]
In the citing paper
“The basic flaw is to assume improvement to be a unitary phenomenon [41].”
From The Deceptive Manifestations of Treatment Resistance in Depression: A New Look at the Problem (2020) · cites this paper as [41]
In the citing paper
“Comorbidities such as substance use disorder can undermine previously effective maintenance therapy [18]”
In the citing paper
“Approximately only one in two patients with major depressive disorder (MDD) respond to their antidepressant treatment ( Rush et al., 2006 , Souery et al., 2007 , Thomas et al., 2013 )”
From Self-blame-selective hyper-connectivity between anterior temporal and subgenual cortices predicts prognosis in major depressive disorder (2023) · cites this paper as Souery et al., 2007
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Self-citationTreatment resistant depression in electronic health records: definitions matter
Iveson, M. H., Ball, E. L., Lo, C. W. H., Falis, M., Lewis, C. M., & Whalley, H. C. (2026) · BMC Psychiatry · doi:10.1186/s12888-026-08085-y · Cited by 3
Spectral model of therapy resistant depression
Mazo, G. E., Незнанов, Н. Г., & Krizhanovskii, A. S. (2015) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro20151151231-35 · Cited by 3
Attrition in treatment-resistant depression
Olgiati, P., Serretti, A., Souery, D., Kasper, S. F., Kraus, C., Montgomery, S., Zohar, J., & Mendlewicz, J. (2019) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000261 · Cited by 3
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Chapter 12. Toward Precision Cognitive-Behavioral Therapy Via Reinforcement Learning Theory
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A Psychodynamic Approach to Treatment Resistance
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Perspectives for an Integrated Biomarker Approach to Drug Discovery and Development
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Complementary and Alternative Therapies for Treatment-Resistant Depression: A Clinical Perspective
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Big Data Guided Interventions: Predicting Treatment Response
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“In clinical practice, patient response to antidepressant treatment often remains unsatisfactory, with 20–50% of MDD patients who had non-response from at least two antidepressant drug classes [8, 9].”
BackgroundFurther evidence of depressive symptomatology profile predicting treatment outcome
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Metadata
- Authors
- Souery, D., Oswald, P., Massat, I., Bailer, U., Bollen, J., Demyttenaere, K., Kasper, S., Lecrubier, Y., Montgomery, S., Serretti, A., Zohar, J., Mendlewicz, J., & Group for the Study of Resistant Depression (GSRD)
- Affiliations
- Université Libre de Bruxelles (BE)
- ORCID
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2007-07-15
- Volume
- 68
- Issue
- 07
- Pages
- 1062-1070
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W1969010498
- Cited by
- 521
- References
- 22
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 26 · 2023: 30 · 2022: 26 · 2021: 54 · 2020: 35 · 2019: 46 · 2018: 31 · 2017: 22 · 2016: 23 · 2015: 25 · 2014: 27 · 2013: 29 · 2012: 21
- FWCI
- 14.20
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Les Laboratories Pierre Fabre
- Fonds De La Recherche Scientifique - FNRS
- Servier
- H. Lundbeck A/S
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- treatment-resistant depression, major depressive disorder, antidepressant non-response, anxiety comorbidity, panic disorder, social anxiety disorder, personality disorders, suicide risk, melancholia, depression severity, hospitalization, recurrent depression, age of onset, risk factors
- MeSH terms
- Adult, Aged, Antidepressive Agents, Mental Disorders, Major Depressive Disorder, Drug Resistance, Europe, Female, Follow-Up Studies, Hospitalization, Humans, Male, Middle Aged, Recurrence, Comorbidity, Treatment Failure, Age of Onset
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