1. Effectiveness of Cognitive Behavioral Therapy and Selective Serotonin Reuptake Inhibitors in Adolescents with Depression Megan Boose, PA-S Evidence Based Medicine Spring 2009

2. PICO Question Patient – adolescents aged 13-18Patient – adolescents aged 13-18 Intervention – Cognitive Behavioral Therapy (CBT) plus a Selective Serotonin Reuptake Inhibitor (SSRI)Intervention – Cognitive Behavioral Therapy (CBT) plus a Selective Serotonin Reuptake Inhibitor (SSRI) Comparison – SSRI (sertraline, paroxetine, citalopram, or fluoxetine)Comparison – SSRI (sertraline, paroxetine, citalopram, or fluoxetine) Outcome – Effectiveness at relieving symptoms of major depression using the Children’s Depression Rating Scale-Revised (CDRS-R) and the Clinical Global Impressions Improvement score (CDI)Outcome – Effectiveness at relieving symptoms of major depression using the Children’s Depression Rating Scale-Revised (CDRS-R) and the Clinical Global Impressions Improvement score (CDI)

3. PICO Question In adolescents aged 13-18, is CBT plus an SSRI more effective than an SSRI alone at relieving symptoms of major depression using the CDRS-R and the CGI score?

4. Impact of Depression Prevalence: 4-8% of adolescents Up to 70% of adolescents are inadequately treated 40-90% have comorbid disorders: –Anxiety –Attention Deficit Hyperactive Disorder –Substance Abuse –Bipolar Disorder

5. Impact of Depression High morbidity and mortality including: –Suicidal behavior –Completed suicide –Substance abuse –Behavioral problems –Poor academic performance –Difficulties with relationships –Legal Problems –Early Pregnancy –Physical Illness

6. Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV): Criteria for Major Depressive Disorder A. Five (or more) of the following symptoms have been present for two weeks; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.A. Five (or more) of the following symptoms have been present for two weeks; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

7. DSM-IV Criteria continued (1) Depressed mood (2) Diminished interest or pleasure in activities (3) Weight loss or weight gain (4) Insomnia or hypersomnia (5) Psychomotor agitation or retardation

8. DSM-IV Criteria continued (6) Fatigue or loss of energy (7) Feelings of worthlessness or guilt (8) Diminished ability to think or concentrate (9) Recurrent thoughts of death, suicidal ideation with or without a plan, or a suicide attempt

9. Cognitive Behavioral Therapy (CBT) Depression is caused by depressive thoughts and poor positive reinforcement Treatment includes individual and family sessions lasting 50-60 minutes: –Education –Goal setting –Monitoring mood –Social problem solving

10. Mechanism of Action of SSRIs

11. CGI Scale 1.Very much improved 2.Much improved 3.Minimally Improved 4.No change 5.Minimally worse 6.Much worse 7.Very much worse

12. CDRS-R 17 depressive symptoms17 depressive symptoms –14 symptoms are based on child or adult response –3 symptoms are assessed by the clinician Symptoms are rated on a 5 or 7 point scaleSymptoms are rated on a 5 or 7 point scale Score ranges from 17-113Score ranges from 17-113

13. Study 1 Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents

14. SSRI compared with Placebo for Depression in Adolescents ParoxetineSertralineCitalopramFluoxetine CDRS-R 2.55 4.56 2.13 5.63 CGI 49-67% 69% 69% 36-46% 36-46% 41-61% 41-61%

15. SSRI compared with Placebo for Depression in Adolescents Paroxetine (Paxil)Paroxetine (Paxil) –No statistical significant decrease in depressive symptoms Decreased CDRS-R by 2.55 Decreased CDRS-R by 2.55 –No statistically significant decrease response rate 49-67% treatment versus 46-58% placebo49-67% treatment versus 46-58% placebo

16. SSRI compared with Placebo for Depression in Adolescents Citalopram (Celexa)Citalopram (Celexa) –No statistical significant decrease in depressive symptoms Decreased CDRS-R by 2.13Decreased CDRS-R by 2.13 –Statistically significant increase in response rate 36-46% treatment versus 24-38% placebo36-46% treatment versus 24-38% placebo

17. SSRI compared with Placebo for Depression in Adolescents Sertraline (Zoloft)Sertraline (Zoloft) –Statistically significant decrease in depressive symptoms Decreased CDRS-R by 4.56Decreased CDRS-R by 4.56 –No statistically significant increase in response rate 69% treatment versus 59% placebo69% treatment versus 59% placebo

18. SSRI compared with Placebo for Depression in Adolescents Fluoxetine (Prozac)Fluoxetine (Prozac) –Statistically significant decrease in depressive symptoms Decreased CDRS-R by 5.63Decreased CDRS-R by 5.63 –Statistically significant increase in response rate 41-61% treatment versus 20-35% placebo41-61% treatment versus 20-35% placebo

19. Study 2 Fluoxetine, Cognitive-Behavioral Therapy, and Their Combination for Adolescents with Depression

20. Fluoxetine, CBT, and Combination Fluoxetine AloneFluoxetine Alone –Decreased CDRS-R from 58.94 to 36.30 –Baseline CGI was 4.66 with a 60.6% response rate CBT AloneCBT Alone –Decrease the baseline CDRS-R from 59.64 to 42.06 –Baseline CGI was 4.77 with a 43.2% response rate

21. Fluoxetine, CBT, and Combination Placebo AlonePlacebo Alone –Decreased CDRS-R from 61.18 to 41.77 –Baseline CGI was 4.84 with a 34.8% response rate CBT plus FluoxetineCBT plus Fluoxetine –Decreased CDRS-R from 60.79 to 33.79 –Baseline CGI was 4.79 with a 71.0% response rate

22. Fluoxetine, CBT, and Combination

25. Study 3 Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents with SSRI- Resistant Depression

26. Switching to another SSRI or to Venlafaxine with or without CBT Switching to another SSRISwitching to another SSRI –Decreased the CDRS-R from 59.8 to 37.9 –Decreased CGI from 4.5 to 2.9 with a 47.0% response rate Switching to VenlafaxineSwitching to Venlafaxine –Decreased the CDRS-R from 57.8 to 37.0 –Decreased CGI from 4.4 to 2.8 with a 48.2% response rate

27. Switching to another SSRI or to Venlafaxine with or without CBT Use of either SSRI or Venlafaxine without CBTUse of either SSRI or Venlafaxine without CBT –Decreased CDRS-R from 58.4 to 38.1 –Decreased CGI from 4.5 to 3.0 with a 40.5% response rate Use of either an SSRI or Venlafaxine plus CBTUse of either an SSRI or Venlafaxine plus CBT –Decreased CDRS-R from 59.2 to 36.9 –Decreased CGI from 4.5 to 2.7 with a 54.8% response rate

28. Switching to another SSRI or to Venlafaxine with or without CBT

30. Study 4 A Randomized Controlled Trial of Fluoxetine and Cognitive Behavioral Therapy in Adolescents With Major Depression, Behavioral Problems, and Substance Use Disorders

31. Fluoxetine and CBT in adolescents with Substance Use Disorders (SUD) and behavioral problems Fluoxetine plus CBTFluoxetine plus CBT –Decreased CDRS-R from 50.75 to 25.99 –Baseline CGI was 4.84 with an 84.1% response rate Placebo plus CBTPlacebo plus CBT –Decreased CDRS-R from 49.44 to 30.55 –Baseline CGI was 4.68 with a 77.8% response rate

32. Fluoxetine and CBT in adolescents with SUD and behavioral problems

35. Study 5 A Randomized Controlled Trial of Cognitive Behavioral Therapy in Adolescents with Major Depression Treated by Selective Serotonin Reuptake Inhibitors. The ADAPT Trial

36. Fluoxetine, CBT, and combination in adolescents receiving outpatient therapy Fluoxetine AloneFluoxetine Alone –Decreased CDRS-R from 59.0 to 40.0 after 12 weeks and 40.0 to 34.6 after 28 weeks with a 94% response rate –Decreased baseline HoNOSCA from 25.5 to 18.0 after 12 weeks and 18.0 to 14.5 after 28 weeks

37. Fluoxetine, CBT, and combination in adolescents receiving outpatient therapy Fluoxetine plus CBTFluoxetine plus CBT –Decreased CDRS-R from 58.9 to 42.5 after 12 weeks and 42.5 to 36.4 after 28 weeks with a response rate of 98% –Decreased baseline HoNOSCA from 25.1 to 17.1 after 12 weeks and 17.1 to 15.4 after 28 weeks

38. Fluoxetine, CBT, and combination in adolescents receiving outpatient therapy

39. Conclusions Fluoxetine is effective at relieving depressive symptoms in adolescents Combination therapy is effective at relieving depressive symptoms in adolescents with major depression The combination of another SSRI plus CBT may be an effective alternative for adolescents who are resistant to one SSRI

40. Questions?

41. References Lundbeck Institute (2005). The mechanism of action of specific 5-HT re-uptake inhibitors. Retrieved on February, 11, 2009 from the CNSforum of Lundbeck Institute at the Website: http://www.cnsforum.com/imagebank/item/Drug_SSRI_2/default.aspxLundbeck Institute (2005). The mechanism of action of specific 5-HT re-uptake inhibitors. Retrieved on February, 11, 2009 from the CNSforum of Lundbeck Institute at the Website: http://www.cnsforum.com/imagebank/item/Drug_SSRI_2/default.aspx http://www.cnsforum.com/imagebank/item/Drug_SSRI_2/default.aspx American Academy of Child Adolescent Psychiatry (2009). Child and Adolescent Depression. Retrieved on February 11, 2009 from the Children and Adolescent Resource Center at the American Academy of Child Adolescent Psychiatry at the Website: http://www.aacap.org/cs/ChildAdolescentDepression.ResourceCenterAmerican Academy of Child Adolescent Psychiatry (2009). Child and Adolescent Depression. Retrieved on February 11, 2009 from the Children and Adolescent Resource Center at the American Academy of Child Adolescent Psychiatry at the Website: http://www.aacap.org/cs/ChildAdolescentDepression.ResourceCenter Birmaher, B. & Brent, D. (2007). Practice Parameter for the Assessment and Treatment of Children and Adolescents With Depressive Disorders. Journal of American Academy of Child Adolescent Psychiatry, 46(11):1503Y1526.Birmaher, B. & Brent, D. (2007). Practice Parameter for the Assessment and Treatment of Children and Adolescents With Depressive Disorders. Journal of American Academy of Child Adolescent Psychiatry, 46(11):1503Y1526. Bhatia, S. K. & Bhatia, S. C. (2007). Childhood and Adolescent Depression. American Academy of Family Physicians, 75:73-80, 83-84.Bhatia, S. K. & Bhatia, S. C. (2007). Childhood and Adolescent Depression. American Academy of Family Physicians, 75:73-80, 83-84. Hetrick, S. E., Merry, S. N., McKenzie, J., Sindahl, P. & Proctor, M. (2007). Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD004851. DOI: 10.1002/14651858.CD004851.pub2.Hetrick, S. E., Merry, S. N., McKenzie, J., Sindahl, P. & Proctor, M. (2007). Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD004851. DOI: 10.1002/14651858.CD004851.pub2.

42. References March, J., Silva, S., Petrycki, S., Curry, J., Wells, K., Fairbank, J., et al. (2004). Fluoxetine, cognitive behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. Journal of American Medical Association, 292(7):807-820.March, J., Silva, S., Petrycki, S., Curry, J., Wells, K., Fairbank, J., et al. (2004). Fluoxetine, cognitive behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. Journal of American Medical Association, 292(7):807-820. Brent, D., Emslie, G., Clarke, G., Wagner, K. D., Asarnow, J. R., Keller, M., et al. (2008). Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression. The TORIDA Randomized Controlled Trial.Brent, D., Emslie, G., Clarke, G., Wagner, K. D., Asarnow, J. R., Keller, M., et al. (2008). Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression. The TORIDA Randomized Controlled Trial. American Psychiatric Association (1994). Desk Reference to the Diagnostic Criteria from DSM-IV. Washington, DC: American Psychiatric Association.American Psychiatric Association (1994). Desk Reference to the Diagnostic Criteria from DSM-IV. Washington, DC: American Psychiatric Association. Goodyer, I. M., Dubicka, B., Wilkinson, P., Kelvin R., Roberts, C., Byford, S., et al. (2008). A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial. Health Technology Assessment, 12(14):1-80.Goodyer, I. M., Dubicka, B., Wilkinson, P., Kelvin R., Roberts, C., Byford, S., et al. (2008). A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial. Health Technology Assessment, 12(14):1-80. The HoNOSCA Project (2008). Health of the Nation Outcome Scales for Children and Adolescents. Retrieved on February 11, 2009 from the HoNOSCA Website: http://www.liv.ac.uk/honosca/Downloads.htmThe HoNOSCA Project (2008). Health of the Nation Outcome Scales for Children and Adolescents. Retrieved on February 11, 2009 from the HoNOSCA Website: http://www.liv.ac.uk/honosca/Downloads.htm