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Adolescents with SSRI-Resistant Depression: The TORDIA Trial 

Adolescents with SSRI-Resistant Depression: The TORDIA Trial
Chapter:
Adolescents with SSRI-Resistant Depression: The TORDIA Trial
Author(s):

Amalia Londono Tobon

, and Hanna E. Stevens

DOI:
10.1093/med/9780190625085.003.0008
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For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone . . . A switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects.

The TORDIA Investigators1

Research Question:

Should adolescents with selective serotonin reuptake inhibitor (SSRI) resistant depression be switched to another SSRI or to venlafaxine with or without cognitive behavioral therapy (CBT)?

Funding:

National Institute of Mental Health

Year Study Began:

2000

Year Study Published:

2008

Study Location:

Six academic and community clinics in the United States

Who Was Studied:

12 to 18 year old adolescents in treatment for major depressive disorder based on DSM-IV criteria, Children’s Depression Rating Scale–Revised (CDRS-R) score ≥40, and Clinical Global Impressions-Severity (CGI-S) subscale ≥4 (moderate severity or worse). Participants had SSRI-resistant depression, defined as persistent depression after a dose of fluoxetine 40 mg or an equivalent SSRI for eight weeks or more.

Who Was Excluded:

Patients with two or more SSRI trials or history of nonresponse to venlafaxine or CBT. Also excluded were those currently receiving CBT or diagnosed with bipolar disorder, psychosis, pervasive developmental disorders, eating disorder, substance use disorders, or hypertension. Pregnant, breastfeeding, and other females having unprotected sex were excluded.

How Many Participants:

334

Study Overview:

See Figure 8.1 for a summary of the study design.

Figure 8.1 Summary of Study Design

Figure 8.1 Summary of Study Design

notes: SSRI = selective serotonin reuptake inhibitor. CBT = cognitive behavioral therapy.

Study Interventions:

First, the current SSRI was tapered over two weeks (if fluoxetine, discontinuation was immediate). Then, patients were randomized to one of four interventions: (a) switch to another SSRI; (b) switch to venlafaxine; (c) switch to another SSRI + CBT; or (d) switch to venlafaxine + CBT. SSRIs were started at 10 mg per day of fluoxetine or equivalent for one week, and were increased to 20 mg for weeks two to six. Participants were started on low doses of SSRIs or venlafaxine, which were titrated as needed per protocol. The CBT groups received twelve weekly sessions (60–90 minutes) by at least a master’s degree level therapist, covering cognitive restructuring, behavior activation, emotion regulation, social skills, problem solving, and parent–child communication sessions. Assessments were made at baseline, six weeks, and twelve weeks.

Follow-Up:

Twelve weeks

Endpoints:

Primary outcomes: (1) “adequate clinical response” defined as (a) Clinical Global Impressions–Improvement (CGI-I) ≤2; (b) CDRS-R score decrease by at least 50%; (c) endpoint CDRS-R <40; and (2) changes in CDRS-R scores. Secondary outcomes: Beck Depression Inventory, the Suicide Ideation Questionnaire-Jr, and Children’s Global Adjustment Scale. Other outcomes included side effects to medications.

Results

  • CBT plus a switch to either medication regimen showed a higher response rate than a medication switch alone (Table 8.1).

  • There was no difference in response rate between venlafaxine and a second SSRI.

  • There were no differential treatment effects on CDRS-R scores with switch to either medication and/or CBT. In addition, change in self-ratings of depressive symptoms, suicidal ideation, or the rate of harm-related or any other adverse events all showed no significant differences between groups.

  • There was a greater increase in medically related side effects in venlafaxine than SSRI treatment including increases in diastolic blood pressure and pulse and more frequent occurrence of skin problems.

Table 8.1 Summary of TORDIA’s Key Findings

Outcome

Switch to 2nd SSRI

Switch to Venlafaxine

P value

No CBT

CBT

P value

Response Rate

47%

48.2%

0.83

40.5%

54.8%

0.009

CGI-I score ≤2

51.2%

55.4%

0.44

47.6%

59%

0.04

Change in CDRS-R ≥50%

56%

51.8%

0.45

47%

60.8%

0.01

Baseline CDRS-R Score (SD)

59.8 (10.6)

57.8 (10.1)

58.4 (9.7)

59.2 (11.0)

Week 12 CDRS-R Score (SD)

37.9 (13.7)

37.0 (13.1)

38.1 (12.9)

36.9 (13.9)

Notes: TORDIA = Treatment of Resistant Depression in Adolescents. SSRI = selective serotonin reuptake inhibitor. CBT = cognitive behavioral therapy. CGI-I = Clinical Global Impressions–Improvement. CDRS-R = Children’s Depression Rating Scale–Revised.

Criticisms and Limitations:

The patient population in this trial consisted primarily of White females with a mean age of 16 years, limiting the generalizability. Combined treatment participants had greater contact and attention from research staff, which was not accounted for in analyses. There was no CBT-only arm, preventing a comparison of CBT in isolation with continued pharmacotherapy. Lastly, blinding was compromised in some of the patients receiving CBT.

Other Relevant Studies and Information:

  • Few studies of treatment-resistant depression exist in adolescents.

  • Other studies in depressed adolescents comparing cognitive, family, and supportive psychotherapies have demonstrated that CBT is the most efficacious of these options.2

  • The American Academy of Child and Adolescent Psychiatry practice parameters for the treatment of children and adolescents with depression suggest that failure of SSRI response be followed by CBT and a switch to a second SSRI.3

Summary and Implications:

Adolescent depression is a common, recurring, impairing condition, and more than 40% of adolescent patients do not respond to a first antidepressant trial.4 Findings from this trial suggest that among patients not responsive to initial first-line therapy, combination treatment with CBT along with a different antidepressant results in a higher rate of clinical response than a medication switch alone. In this study, patients who were switched to SSRIs had fewer adverse effects compared to those switched to venlafaxine.

Clinical Case: SSRI-Resistant Depression

Case History

A 15-year-old girl presents has ongoing depressive symptoms despite citalopram 40 mg treatment for the past eight weeks. She continues to have increased sleep, anhedonia, and decreased school attendance. Based on the Treatment of Resistant Depression in Adolescents (TORDIA) study, how should this patient be treated?

Suggested Answer

This patient is typical of those included in the TORDIA trial, as she has SSRI-resistant depression. Clinical guidelines and the TORDIA trial suggest that in such patients, combination treatment of another SSRI or venlafaxine and CBT has a superior response rate to a medication switch alone. Prior to making a change, the clinician should carefully assess whether the patient is being adherent with treatment, as lower adherence, determined by pill-count remainder, was related to a lower response rate.5

The TORDIA trial did not address augmenting treatment with CBT, which could be an option before switching medication. In TORDIA, SSRIs showed better tolerability than venlafaxine. Other treatment strategies such as augmentation with a second antidepressant or other medication, strategies that are commonly used in adults, were not studied in this trial and had not been studied in youth at the time of this trial. Therapies other than CBT were also not studied in TORDIA. Therefore, appropriate clinical judgment may be useful to determine whether an alternative therapy such as family or supportive therapy may be helpful.

References

1. Brent, D., Emslie, G., Clarke, G., Wagner, K. D., Asarnow, J. R., Keller, M., . . . Birmaher, B. (2008). Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: The TORDIA randomized controlled trial. JAMA, 299(8), 901–913.Find this resource:

2. Brent, D. A., Holder, D., Kolko, D., Birmaher, B., Baugher, M., Roth, C., . . . Johnson, B. A. (1997). A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and supportive therapy. Archives of General Psychiatry, 54(9), 877–885.Find this resource:

3. Birmaher, B., Brent, D., & AACAP Work Group on Quality Issues. (2007). Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 46(11), 1503–1526.Find this resource:

4. Brent, D., Emslie, G., Clarke, G., Wagner, K. D., Asarnow, J. R., Keller, M., . . . Birmaher, B. (2008). Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: The TORDIA randomized controlled trial. JAMA, 299(8), 901–913.Find this resource:

5. Woldu, H., Porta, G., Goldstein, T., Sakolsky, D., Perel, J., Emslie, G., . . . Brent, D. (2011). Pharmacokinetically and clinician-determined adherence to an antidepressant regimen and clinical outcome in the TORDIA trial. Journal of the American Academy of Child & Adolescent Psychiatry 50(5), 490–498.Find this resource: