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Treatment of Resistant Depression in Adolescents (TORDIA): Week 24 Outcomes
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OBJECTIVE: The purpose of this study was to report on the outcome of participants in the Treatment of Resistant Depression in Adolescents (TORDIA) trial after 24 weeks of treatment, including remission and relapse rates and predictors of treatment outcome. METHOD: Adolescents (ages 12-18 years) with selective serotonin reuptake inhibitor (SSRI)-resistant depression were randomly assigned to either a medication switch alone (alternate SSRI or venlafaxine) or a medication switch plus cognitive-behavioral therapy (CBT). At week 12, responders could continue in their assigned treatment arm and nonresponders received open treatment (medication and/or CBT) for 12 more weeks (24 weeks total). The primary outcomes were remission and relapse, defined by the Adolescent Longitudinal Interval Follow-Up Evaluation as rated by an independent evaluator. RESULTS: Of 334 adolescents enrolled in the study, 38.9% achieved remission by 24 weeks, and initial treatment assignment did not affect rates of remission. Likelihood of remission was much higher (61.6% versus 18.3%) and time to remission was much faster among those who had already demonstrated clinical response by week 12. Remission was also higher among those with lower baseline depression, hopelessness, and self-reported anxiety. At week 12, lower depression, hopelessness, anxiety, suicidal ideation, family conflict, and absence of comorbid dysthymia, anxiety, and drug/alcohol use and impairment also predicted remission. Of those who responded by week 12, 19.6% had a relapse of depression by week 24. CONCLUSIONS: Continued treatment for depression among treatment-resistant adolescents results in remission in approximately one-third of patients, similar to adults. Eventual remission is evident within the first 6 weeks in many, suggesting that earlier intervention among nonresponders could be important.
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“Blinding (performance bias and detection bias) Blinding of partici- pants/care providers | High risk | 'Participants were blind to medication type'. NB: unlikely that participants were blind if receiving adjunctive CBT treatment. pg. 785 (Emslie 2010)”
From Interventions for preventing relapse and recurrence of a depressive disorder in children and adolescents (2012) · cites this paper as Emslie 2010
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“Blinding (performance bias and detection bias) Blinding of outcome as- | Low risk | 'independent evaluators were blind to medication type. Independent evalua- tors were also blind to CBT treatment'”
From Interventions for preventing relapse and recurrence of a depressive disorder in children and adolescents (2012) · cites this paper as Emslie 2010
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“NB: 'In 64 cases, the blinding of the independent evaluator was compromised, most commonly because of participant disclosure of receiving CBT'. pg. 785 (Emslie 2010)”
From Interventions for preventing relapse and recurrence of a depressive disorder in children and adolescents (2012) · cites this paper as Emslie 2010
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Self-citationRepeated Ketamine Exposure Induces an Enduring Resilient Phenotype in Adolescent and Adult Rats
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MethodInfluentialSelf-citationPsychotherapeutic approaches to non-suicidal self-injury in adolescents
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“Unfortunately, not all adolescents respond to these standard interventions (March et al. 2006; Emslie et al. 2010; Maalouf and Brent 2012).”
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“…of resistant depression are similar to predictors of response in treatment-naïve depressed adolescents, and include severity, family conflict, and non-suicidal self-injury, drug and alcohol use and greater dysfunction at baseline (Asarnow et al., 2009; Emslie et al., 2010; Vitiello et al., 2010).”
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“…with a growing body of research within the depression treatment literature that has found that adolescents with comorbid anxiety experience worse depression outcomes than adolescents without this comorbidity (Brent et al., 1998; Curry et al., 2006; Emslie et al., 2010; Young et al., 2006a).”
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“Combined CBT and MMA (COMB) (24-Week Intervention) The MMA was developed by incorporating current practice parameters for depression(15,23,24) and HIV treatment in adults,(23,24) recent data from adult and adolescent depression trials,(25,26) and previously used algorithmic designs.(27,28) Modifications included rescu…”
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“Another large-scale RCT, the TORDIA study (Emslie et al., 2010), compared switching medication, and the combination of medication plus CBT in treating SSRI-resistant adolescent depression (i.”
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“The effects of depression include problems in the areas of daily functioning, family life, learning, and relationships, suicidal ideation, suicide attempts and nonsuicidal self-injurious behaviors (Birmaher et al. 2007; Emslie et al. 2010; Vitello et al. 2011).”
InfluentialSelf-citationKlimes‐Dougan, B., Schreiner, M. W., Thai, M., Gunlicks‐Stoessel, M., Reigstad, K. M., & Cullen, K. R. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.10.015 · Cited by 43
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“Further, the persistence of residual symptoms puts patients at higher risk of relapse (Brent et al. 2001; Emslie et al. 2010).”
Self-citationGhaziuddin, N., Shamseddeen, W. A., Gettys, G., & Ghaziuddin, M. (2020) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2019.0054 · Cited by 42
“The remission rate on the other hand was only 39% for the entire sample at week 24 (Brent et al. 2008; Emslie et al. 2010).”
Magavi, L. R., Reti, I. M., & Vasa, R. A. (2017) · International Review of Psychiatry · doi:10.1080/09540261.2017.1300574 · Cited by 41
“Only 40% of adolescents who fail to respond to initial treatments (i.e. treatment-resistant) respond to additional combined therapies (Emslie et al., 2010).”
InfluentialGunlicks‐Stoessel, M., & Mufson, L. H. (2011) · Depression and Anxiety · doi:10.1002/da.20849 · Cited by 40
Clinical practice guidelines for the management of depression in children and adolescents
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“Moreover, from a longitudinal perspective, acute treatment response is associated with better longer term outcome (Curry et al., 2011; Emslie et al., 2010; Vitiello et al., 2011), and in turn, is more likely to occur when the adolescent responds early within the acute period treatment (Gunlicks-Stoessel & Mufson, 2011…”
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“…and results of treatment efficacy, as well as predictors and moderators of response, in the Treatment of Resistant Depression in Adolescence (TORDIA) study at 12 and 24 weeks, have been reported in detail in previous publications (Brent et al. 2008; Asarnow et al. 2009; Emslie et al. 2010).”
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Strategies and challenges in the management of adolescent depression
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Psychological Treatments for Depression in Adolescents: More Than Three Decades Later
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“Considering the concern raised and the response rate to antidepressants of approximately 60% [172], the first option for treating depression in adolescents will likely be psychological [173].”
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“In keeping with findings in RCTs of EBTs for depressed adolescents, we hypothesized that greater functional impairment would predict treatment nonresponse (Asarnow et al., 2009; Curry et al., 2006; Emslie et al., 2010; Jayson et al., 1998; Rohde et al., 2006; Vitiello et al., 2011; Wilkinson et al., 2009).”
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Suresh, V., Mills, J. A., Croarkin, P. E., & Strawn, J. R. (2020) · Depression and Anxiety · doi:10.1002/da.23064 · Cited by 30
Findling, R. L., McCusker, E., & Strawn, J. R. (2020) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2019.0176 · Cited by 29
“However, as many as 40% of patients fail to adequately respond to SSRIs (The Treatment for Adolescents with Depression Study [TADS] 2009; Emslie et al. 2010).”
Predictors of Treatment Response in Adolescent Depression
Emslie, G. J., Kennard, B. D., & Mayes, T. L. (2011) · Pediatric Annals · doi:10.3928/00904481-20110512-05 · Cited by 29
Self-citationDysthymia in a cross-cultural perspective
Gureje, O. (2010) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e32834136a5 · Cited by 27
Predictors and Moderators of Relapse in Children and Adolescents With Major Depressive Disorder
Kennard, B. D., Mayes, T. L., Chahal, Z., Nakonezny, P. A., Moorehead, A., & Emslie, G. J. (2018) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.15m10330 · Cited by 28
Self-citationPractitioner Review: Therapeutics of unipolar major depressions in adolescents
Goodyer, I. M., & Wilkinson, P. O. (2018) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12940 · Cited by 28
Increased Serum Levels of Oxytocin in ‘Treatment Resistant Depression in Adolescents (TRDIA)’ Group
Sasaki, T. G., Hashimoto, K., Oda, Y., Ishima, T., 焼田まどか, Kurata, T., Kuno, M., Takahashi, J., Kamata, Y., Kimura, A., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0160767 · Cited by 27
“40% of depressed adolescent depressive patients who receive evidence-based treatments do not reach remission, so their group is called ‘treatment resistant depression in adolescents (TRDIA)’ [4,7,8].”
BackgroundBaldini, V., Gnazzo, M., Varallo, G., Vincenzo, M. D., Scorza, M., Franceschini, C., Ronchi, D. D., Fiorillo, A., & Plazzi, G. (2025) · Frontiers in Psychology · doi:10.3389/fpsyg.2025.1612067 · Cited by 30
“Regular follow-up appointments and open communication with the adolescent and their family are crucial for ensuring the safe and effective use of medications (Emslie et al., 2010).”
Evidence-Base Update of Psychosocial and Combination Treatments for Child and Adolescent Depression
Weersing, V. R., Goger, P., Schwartz, K. T. G., Baca, S. A., Angulo, F., & Kado-Walton, M. (2024) · Journal of Clinical Child & Adolescent Psychology · doi:10.1080/15374416.2024.2384022 · Cited by 24
Boylan, K., MacQUEEN, G. M., Kirkpatrick, R. H., Lee, J. C., & Santaguida, P. L. (2019) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-019-01341-5 · Cited by 25
“However, skin rash and cardiovascular events showed non-significantly increased rates with the use of venlaxafine [31].”
BackgroundMethodInfluentialZakhour, S., Nardi, A. E., Levitan, M. N., & Appolinário, J. C. (2020) · Trends in Psychiatry and Psychotherapy · doi:10.1590/2237-6089-2019-0033 · Cited by 25
Lu, C. Y., Penfold, R. B., Wallace, J., Lupton, C., Libby, A. M., & Soumerai, S. B. (2020) · Psychiatric Research and Clinical Practice · doi:10.1176/appi.prcp.20200012 · Cited by 23
“Thus, they do not receive first‐line evidence‐based treatments such as psychotherapies (6–8), including cognitive, behavioral, and interpersonal (9) or, when indicated, antidepressant medications (10, 11).”
BackgroundMood and suicidality outcomes 3–11 years following pediatric anxiety disorder treatment
Keeton, C. P., Caporino, N. E., Kendall, P. C., Iyengar, S., Lee, P. C., Peris, T. S., Sakolsky, D. J., Piacentini, J. C., Compton, S. N., Albano, A. M., et al. (2019) · Depression and Anxiety · doi:10.1002/da.22944 · Cited by 23
“IEs also administered the Brief Suicide Severity Rating Scale (B‐SSRS; Emslie et al., 2010) to code suicidal ideation (e.g., thoughts of death, active ideation with plan and intent) and behavior (e.g., preparatory acts, actual attempt) according to the Columbia Classification Algorithm for Suicide…”
MethodSelf-citationSystematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders
Maruf, A. A., Poweleit, E. A., Brown, L. C., Strawn, J. R., & Bousman, C. (2021) · Pharmacopsychiatry · doi:10.1055/a-1681-2047 · Cited by 22
Choe, C. J., Emslie, G. J., & Mayes, T. L. (2012) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2012.07.002 · Cited by 22
Self-citationOutside the Black Box: Re-assessing Pediatric Antidepressant Prescription.
Sparks, J. A., & Duncan, B. L. (2013) · Europe PMC (PubMed Central) · Cited by 20
Loades, M. E., Sheils, E., & Crawley, E. M. (2016) · BMJ Open · doi:10.1136/bmjopen-2016-012271 · Cited by 20
Holtmann, M. H., Mokros, L., Kirschbaum‐Lesch, I., Kölch, M. G., Plener, P. L., Ruckes, C., Schulte‐Markwort, M., & Legenbauer, T. (2018) · Trials · doi:10.1186/s13063-018-2949-0 · Cited by 19
Purper‐Ouakil, D., Cohen, D., & Flament, M. F. (2011) · Neuropsychiatrie de l Enfance et de l Adolescence · doi:10.1016/j.neurenf.2011.03.001 · Cited by 20
Hilton, R., Rengasamy, M. L., Mansoor, B., He, J., Mayes, T. L., Emslie, G. J., Porta, G., Clarke, G. N., Wagner, K. D., Birmaher, B. B., et al. (2013) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2013.02.013 · Cited by 17
Self-citationPrevention and treatment of child and adolescent depression: challenges and opportunities
Vitiello, B. (2011) · Epidemiology and Psychiatric Sciences · doi:10.1017/s2045796011000102 · Cited by 18
“The cumulative remission rate was 39% after 24 weeks of treatment and 61% by 72 weeks, thus confirming that, for at least one-third of cases, adolescent depression persists, although attenuated, over time (Emslie et al. 2010; Vitiello et al. 2010).”
BackgroundSelf-citationFaries, E., Mabe, L. A., Franzen, R. L., Murtaza, S., Nathani, K., Ahmed, B., Prokop, L. J., Mohammed, K., & Ahmed, A. T. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.08.212 · Cited by 19
Pettit, J. W., Silverman, W. K., Rey, Y., Marin, C. E., & Jaccard, J. J. (2015) · Journal of Clinical Child & Adolescent Psychology · doi:10.1080/15374416.2015.1038824 · Cited by 15
“…patients’ status at a posttreatment (post) reevaluation, and (d) move patients to a second-stage treatment if they did not show satisfactory improvement (Emslie et al., 2010; Fava et al., 2003; Rush et al., 2006; for an exception to the requirement that patients go through an entire first-stage…”
BackgroundMethodZhang, C., Zafarí, Z., Slejko, J. F., Castillo, W. C., Reeves, G. M., & dosReis, S. (2023) · American Journal of Epidemiology · doi:10.1093/aje/kwad022 · Cited by 16
Ayvaci, E. R., & Croarkin, P. E. (2023) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2023.02.007 · Cited by 14
Thai, M., Nair, A. U., Klimes‐Dougan, B., Albott, C. S., Silamongkol, T., Corkrum, M., Hill, D. C., Roemer, J. W., Lewis, C. P., Croarkin, P. E., et al. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.03.061 · Cited by 15
Wagner, K. D., Asarnow, J. R., Vitiello, B., Clarke, G., Keller, M. B., Emslie, G. J., Ryan, N. D., Porta, G., Iyengar, S., Ritz, L., et al. (2012) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2011.0045 · Cited by 14
“Approximately one-third of adolescents will achieve remission by 24 weeks of treatment, and there is a greater likelihood of remission for those adolescents who had a clinical response by 12 weeks (Emslie et al. 2010).”
Self-citationThe Psychopharmacology of Adolescent Depression
Emslie, G. J. (2012) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2012.2212 · Cited by 14
Self-citationBright Light Therapy for Major Depressive Disorder in Adolescent Outpatients: A Preliminary Study
Ballard, R., Parkhurst, J. T., Gadek, L. K., Julian, K. M., Yang, A., Pasetes, L. N., Goel, N., & Sit, D. K. Y. (2024) · Clocks & Sleep · doi:10.3390/clockssleep6010005 · Cited by 14
“Moreover, up to 40% of adolescents with major depression may not improve with adequate combined treatment [3,4].”
BackgroundMethodElectroconvulsive Therapy in an Adolescent with Severe Major Depression and Anorexia Nervosa
Andrews, P. J. T., Seide, M., Guarda, Á. S., Redgrave, G. W., & Coffey, D. B. J. (2014) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2014.2422 · Cited by 13
“Remission rate was higher and achieved more quickly in those who had shown, among other factors, clinical response by week 12, and in those with less severe depression, hopelessness, anxiety, suicidal ideation, and family conflict (Emslie et al. 2010).”
Wilcox, H. C., Kharrazi, H. H. K., Wilson, R. F., Musci, R. J., Susukida, R., Gharghabi, F., Zhang, A. W., Wissow, L. S., & Robinson, K. A. (2016) · Annals of Internal Medicine · doi:10.7326/m16-1281 · Cited by 15
“Summary of Intervention Characteristics Program or Study Name (If Applicable) Author, Year (Reference) Intervention Type/Purpose Setting/Population Adolescent suicide risk screening King et al, 2012 (26) Screening, follow-up Emergency department Attachment-based family therapy Diamond et al, 2010 (27) Psychotherapy, b…”
InfluentialWitt, K., Madsen, T., Berk, M., Dean, O. M., Chanen, A. M., McGorry, P. D., Cotton, S., Davey, C. G., & Hetrick, S. E. (2021) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867421998763 · Cited by 12
“Previous work has suggested that end-of-treatment response might predict long-term outcomes (Emslie et al., 2010; Kennard et al., 2009).”
BackgroundPardossi, S., Fagiolini, A. M., Scheggi, S., & Cuomo, A. (2024) · Children · doi:10.3390/children11070801 · Cited by 17
“The TORDIA trial demonstrated that combining medication switches with CBT can effectively improve outcomes for adolescents with TRD [17,25].”
BackgroundMethodMajor challenges in youth psychopathology: treatment-resistant depression. A narrative review
Menculini, G., Cinesi, G., Scopetta, F., Cardelli, M., Caramanico, G., Balducci, P. M., Giorgi, F. D., Moretti, P., & Tortorella, A. A. V. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1417977 · Cited by 13
Treating a broader range of depressed adolescents with combined therapy
Foster, S., & Mohler‐Kuo, M. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.08.027 · Cited by 12
Pediatric Psychopharmacology for Depressive and Anxiety Disorders
Strawn, J. R., Vaughn, S. E., & Ramsey, L. B. (2022) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.20210036 · Cited by 12
Light Therapy for Adolescent Depression: A Scoping Review
Ballard, R., Parkhurst, J. T., Julian, K. M., Pasetes, L. N., Fawcett, A. J., Li, A., Goel, N., & Sit, D. K. Y. (2023) · Current Psychiatry Reports · doi:10.1007/s11920-023-01437-5 · Cited by 11
Sultan, M. A., & Courtney, D. (2017) · Europe PMC (PubMed Central) · Cited by 11
Nilsen, T. S., Handegård, B. H., Eisemann, M. R., & Kvernmo, S. E. (2016) · Child and Adolescent Psychiatry and Mental Health · doi:10.1186/s13034-016-0098-3 · Cited by 11
“Secondly, high baseline symptom severity and depression with comorbid anxiety are associated with a poorer treatment outcome in several studies of primary depression [10–12, 42].”
BackgroundBenarous, X., Cravero, C., Jakubowicz, B., Morales, P., & Cohen, D. (2021) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2020.0138 · Cited by 10
“Finally, longer period of observation in an in-patient facility may be an opportunity to gain detailed information on the reasons why some of these patients do not respond to front-line treatments (Garno et al. 2005; Emslie et al. 2010).”
Metadata
- Authors
- Emslie, G. J., Mayes, T., Porta, G., Vitiello, B., Clarke, G., Wagner, K. D., Asarnow, J. R., Spirito, A., Birmaher, B., Ryan, N., Kennard, B., DeBar, L., McCracken, J., Strober, M., Onorato, M., Zelazny, J., Keller, M., Iyengar, S., & Brent, D.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Suburban Hospital (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2010-07-01
- Volume
- 167
- Issue
- 7
- Pages
- 782-791
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3257891
- OpenAlex
- W2140498388
- Cited by
- 217
- References
- 39
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 15 · 2023: 12 · 2022: 9 · 2021: 13 · 2020: 14 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 23 · 2015: 8 · 2014: 13 · 2013: 8 · 2012: 24
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- National Institute of Mental Health (MH61958, U01MH061856, MH-66371, U01MH061835, U01MH061869, MH-61869, U01MH062014, MH61856, MH-61835, MH61864, U01MH061958, P30MH066371, U01MH061864, MH62014)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Keywords
- treatment-resistant depression, adolescent depression, selective serotonin reuptake inhibitors, venlafaxine, cognitive behavioral therapy, remission, relapse, predictors of treatment outcome, hopelessness, suicidal ideation, family conflict, anxiety comorbidity, early intervention
- MeSH terms
- Venlafaxine Hydrochloride, Adolescent, Combined Modality Therapy, Cyclohexanols, Depressive Disorder, Female, Fluoxetine, Humans, Male, Psychiatric Status Rating Scales, Remission Induction, Time Factors, Cognitive Behavioral Therapy, Treatment Failure, Selective Serotonin Reuptake Inhibitors, Antidepressive Agents, Second-Generation
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