Peds Ocd

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Peds Ocd

  1. 1. Pharmacotherapy for Pediatric OCD A Systematic Review
  2. 2. Objectives <ul><li>Review randomized placebo-controlled trials in pediatric OCD </li></ul><ul><li>Discuss a published meta-analysis of SSRIs in pediatric OCD </li></ul>
  3. 3. Method <ul><li>OVID Medline 1950 to December 2007: </li></ul><ul><ul><li>Child [MeSH] or Adolescent [MeSH] or pediatric [keyword] or paediatric [keyword] </li></ul></ul><ul><ul><li>AND </li></ul></ul><ul><ul><li>Obsessive-Compulsive Disorder [MeSH] </li></ul></ul><ul><li>Resulted in 2453 hits </li></ul>
  4. 4. Inclusion Criteria <ul><li>Randomized placebo-controlled trial </li></ul><ul><li>Subjects aged 0-18 with DSM diagnosis of Obsessive-Compulsive disorder </li></ul><ul><li>Intervention is pharmacological </li></ul><ul><li>English language </li></ul><ul><li>Parallel or Cross-over design </li></ul>
  5. 5. Exclusion Criteria <ul><li>Less than 30 subjects for parallel design, less than 15 for cross-over </li></ul><ul><li>Principal diagnosis of Tourette’s Disorder or Developmental Disorder </li></ul>
  6. 6. Child Yale-Brown Obsessive Compulsive Scale <ul><li>C-YBOCS: </li></ul><ul><ul><li>10 item scale, range of 0-4 </li></ul></ul><ul><ul><ul><li>Obsessions and Compulsions </li></ul></ul></ul><ul><ul><ul><li>Time occupied, Interference, Distress, Personal Control, Resistance </li></ul></ul></ul><ul><ul><li>Range of scale 0-40 </li></ul></ul><ul><ul><li>8-15 is mild, 16-23 moderate, >24 severe </li></ul></ul>
  7. 7. Clomipramine (Anafranil)
  8. 8. Clomipramine <ul><li>DeVeaugh et al, 1992 </li></ul><ul><li>Subjects: 10-17 years </li></ul><ul><li>CMI started at 25mg/d, titrated up to 75mg/d by second week, then titrated to 200mg/d (or 3mg/kg/d) </li></ul><ul><li>N=60, 31 had CMI vs. 29 PBO </li></ul><ul><li>Duration: 2 weeks of PBO lead-in, then 8 week trial </li></ul>
  9. 9. Clomipramine
  10. 10. Clomipramine <ul><li>One year open-label extension: 25/47 of subjects continuing to use CMI </li></ul>
  11. 11. Clomipramine Tremor Fatigue Dizziness Somnolence Dry Mouth 2.3% 32.6% 9.1% 34.8% 13.6% 41.3% 11.4% 45.7% 15.9% 63.0% PBO (N=29) CMI (N=31)
  12. 12. Clomipramine 0 1 subj. Hepatic Enzyme Inc. 2.3% 13.0% Dyspepsia 2.3% 21.7% Anorexia 2.3% 21.7% Constipation PBO (N=29) CMI (N=31)
  13. 13. Clomipramine <ul><li>Limits: </li></ul><ul><ul><li>Side effects of CMI compromises blinding </li></ul></ul><ul><ul><li>Small sample size </li></ul></ul><ul><ul><li>No mention of suicidal ideation </li></ul></ul><ul><ul><li>Sponsored by Ciba-Geigy </li></ul></ul>
  14. 14. Fluoxetine (Prozac)
  15. 15. Fluoxetine (1) <ul><li>Geller et al, 2001 </li></ul><ul><li>Subjects: 7-17 </li></ul><ul><li>FLX started at 10mg/d, titrated up to 20-60mg/d </li></ul><ul><li>N=103, 71 had FLX vs. 32 PBO </li></ul><ul><li>Duration: 13 weeks </li></ul>
  16. 16. Fluoxetine (1)
  17. 17. Fluoxetine (1) <ul><li>Effect Size = 0.5 </li></ul><ul><li>Mean dose of FLX was 24.6mg </li></ul><ul><li>Effects comparable between children and adolescents </li></ul>
  18. 18. Fluoxetine (1) <ul><li>No adverse effect that was significantly different from placebo </li></ul><ul><li>Diarrhea and Hyperkinesia found more in Fluoxetine group </li></ul>
  19. 19. Fluoxetine (1) <ul><li>Limits: </li></ul><ul><ul><li>Many subjects dropped out </li></ul></ul><ul><ul><ul><li>31% of FLX, 37.5% of PBO </li></ul></ul></ul><ul><ul><ul><li>No difference in reasons for drop out </li></ul></ul></ul><ul><ul><li>Sponsored by Eli Lilly </li></ul></ul>
  20. 20. Fluoxetine (2) <ul><li>Liebowitz et al, 2002 </li></ul><ul><li>Subjects: 6-18 years old </li></ul><ul><li>FLX 20mg/d titrated up to 80mg/d </li></ul><ul><li>N=43, 21 had FLX, 22 had PBO </li></ul><ul><li>Duration: 8 weeks + 8 weeks of maintenance for responders </li></ul>
  21. 21. Fluoxetine (2)
  22. 22. Fluoxetine (2) <ul><li>Significant difference only in maintenance extension </li></ul><ul><li>Mean dose of FLX 64.8mg/d </li></ul>
  23. 23. Fluoxetine (2) 4.5% 33.3% Muscle Ache 0% 28.6% Nightmares 4.5% 38.1% Drowsiness 4.5% 33.3% Weight loss 0% 19% Palpitations PBO (N=22) FLX (N=21)
  24. 24. Fluoxetine (2) <ul><li>Significance only found on post-hoc analysis of extension group </li></ul><ul><li>Sponsored by Eli Lilly and NIMH </li></ul>
  25. 25. Paroxetine (Paxil)
  26. 26. Paroxetine <ul><li>Geller et al, 2004 </li></ul><ul><li>Subjects: 7-17 </li></ul><ul><li>PRX:started at 10mg/d, titrated up to 50mg/d </li></ul><ul><li>N=203: 98 had PRX, 105 had PBO </li></ul><ul><li>Duration: 10 weeks </li></ul>
  27. 27. Paroxetine
  28. 28. Paroxetine <ul><li>Stronger effect in more severe OCD </li></ul><ul><li>Stronger effect in younger age </li></ul><ul><li>Mean dose: 20mg/d for children, 26.8mg/d for adolescents </li></ul>
  29. 29. Paroxetine 2% 8% Diarrhea 1% 9% Hostility 1% 9% Decreased appetite 3% 10% Trauma (?) 6% 12% Hyperkinesia PBO N=105 PRX N=98
  30. 30. Paroxetine 0 1 subj. Suicidal Ideation (?situation) 1% 5% Neurosis (?) 2% 5% Agitation 2% 6% Vomiting 1% 8% Asthenia PBO N=105 PRX N=98
  31. 31. Paroxetine <ul><li>Limits: </li></ul><ul><ul><li>High drop out rate (in children only) </li></ul></ul><ul><ul><ul><li>33% of PRX vs. 24% of PBO </li></ul></ul></ul><ul><ul><li>Sponsored by GlaxoSmithKline </li></ul></ul>
  32. 32. Fluvoxamine (Luvox)
  33. 33. Fluvoxamine <ul><li>Riddle et al, 2001 </li></ul><ul><li>Subjects: 8-17 years old </li></ul><ul><li>FLV started at 25mg qhs, titrated up to 100mg bid (200mg/d) </li></ul><ul><li>N=120, 57 had FLV, 63 had PBO </li></ul><ul><li>Duration: 10 weeks </li></ul>
  34. 34. Fluvoxamine
  35. 35. Fluvoxamine <ul><li>Higher response in younger age </li></ul><ul><li>Statistically significant differences between groups as early as week 1 </li></ul><ul><li>Mean dose was 165mg/d </li></ul>
  36. 36. Fluvoxamine 15.9% 26.3% Asthenia (mean onset ~20d) 9.5% 29.8% Insomnia (mean onset at 45d) PBO N=63 FLV N=57
  37. 37. Fluvoxamine <ul><li>Limits: </li></ul><ul><ul><li>Many dropouts: </li></ul></ul><ul><ul><ul><li>33% of FLV vs. 43% of PBO </li></ul></ul></ul><ul><ul><li>Sponsored by Solvay </li></ul></ul>
  38. 38. Sertraline (Zoloft)
  39. 39. Sertraline (1) <ul><li>March et al 1998 </li></ul><ul><li>Subjects: 6-17 </li></ul><ul><li>Sertraline started at 25mg/d, titrated up to 50-200mg </li></ul><ul><li>N=187: 92 had SRT, 95 had PBO </li></ul><ul><li>Duration: 1 week PBO lead-in, 12 week trial </li></ul>
  40. 40. Sertraline (1)
  41. 41. Sertraline (1) <ul><li>Mean dose of SRT was 167mg/d </li></ul>
  42. 42. Sertraline (1) 0% 7% Tremor 2% 13% Agitation 7% 17% Nausea 13% 37% Insomnia PBO N=95 SRT N=92
  43. 43. Sertraline (1) <ul><li>Limits: </li></ul><ul><ul><li>12/92 withdrew from SRT due to adverse events vs. 3/95 in PBO </li></ul></ul><ul><ul><li>Sponsored by Pfizer </li></ul></ul>
  44. 44. Sertraline (2) <ul><li>Pediatric OCD Treatment Study (POTS), 2004 </li></ul><ul><li>Subjects: 7-17 </li></ul><ul><li>Sertraline: 25mg/d up to 200mg/d </li></ul><ul><li>N=112: 28 had SRT+CBT, 28 had CBT, 28 had SRT, 28 had PBO </li></ul>
  45. 45. Sertraline (2)
  46. 46. Sertraline (2)
  47. 47. Sertraline (2) <ul><li>Effect size compared to placebo: </li></ul><ul><ul><li>Combined: 1.4 (NNT = 2) </li></ul></ul><ul><ul><li>CBT: 0.97 (NNT = 3) </li></ul></ul><ul><ul><li>Sertraline: 0.67 (NNT = 6) </li></ul></ul>
  48. 48. Sertraline (2) 2% 21% Stomach ache 4% 21% Nausea 4% 12% Motor Overactivity 0% 7% Enuresis 4% 10% Diarrhea 0% 16% Decreased appetite PBO, N=28 SRT, N=56
  49. 49. Sertraline (2) <ul><li>Limits: </li></ul><ul><ul><li>Those assigned to CBT or combined group not blinded at all - expectancy effects </li></ul></ul><ul><ul><li>Sponsored by NIMH and Pfizer </li></ul></ul>
  50. 51. Meta-analysis <ul><li>Geller et al, 2003 </li></ul><ul><li>12 randomized controlled-trials </li></ul><ul><li>Included smaller studies, withdrawl design, cross-over design and active-comparator trials </li></ul>
  51. 52. Meta-analysis <ul><li>On CYBOCS: overall effect size of 0.47, statistically significant </li></ul><ul><li>No evidence of publication bias </li></ul><ul><li>Clomipramine had significantly more effect than SSRIs </li></ul><ul><li>SSRIs equal amongst each other </li></ul><ul><li>Fail-safe N of 973 </li></ul>
  52. 53. Conclusions <ul><li>Serotonin reuptake inhibitors are effective for pediatric OCD </li></ul><ul><li>Moderate effect size </li></ul><ul><li>Response rates: 30-60% </li></ul><ul><li>Common adverse events: insomnia, hyperkinesia, asthenia, diarrhea, nausea, weight loss </li></ul>
  53. 54. Future research <ul><li>Dosing </li></ul><ul><li>Length of treatment </li></ul><ul><li>Treatment resistant cases </li></ul><ul><li>CMI > SSRIs? </li></ul><ul><li>Safety: suicidal ideation, sexual side effects </li></ul>
  54. 55. References <ul><li>DeVeaugh-Geiss, J., Moroz, G., Biederman, J., Cantwell, D., Fontaine, R., Greist, J.H., Reichler, R., Katz, R., Landau, P., Clomipramine Hydrochloride in Childhood and Adolescent Obsessive-Compulsive Disorder - a Multicenter Trial. J.Am. Acad. Child Adolesc. Psychiatry , 31:1, January 1992. 45-49 </li></ul>
  55. 56. References <ul><li>Geller, D., Hoog, S.L., Heiligenstein, J.H., Ricardi, R.K., Tamura, R., Kluszynski, S., Jacobson, J.G. Fluoxetine Treatment for Obsessive-Compulsive Disorder in Children and Adolescents: A Placebo-Controlled Clinical Trial. J. Am. Acad. Child Adolesc. Psychiatry , 40:7, July 2001, 773-779 </li></ul>
  56. 57. References <ul><li>Liebowitz, M.R., Turner, S.M., Piacentini, J., Beidel, D.C., Clarvit, S.R., Davies, S.O., Graae, F., Jaffer, M., Lin, S., Sallee, F.R., Schmidt, A., Simpson, H.B. Fluoxetine in Children and Adolescents with OCD: A Placebo-Controlled Trial. J. Am. Acad Child Adolesc Psychiatry 41:12, December, 2002, 1431-1438 </li></ul>
  57. 58. References <ul><li>Geller, D., Wagner, K., Emslie, G., Murphy, T., Carpenter, D.J., Wetherhold, E., Perera, P., Machin, A.,Gardiner, C. Paroxetine Treatment in Children and Adolescents with Obsessive-Compulsive Disorder: A Randomized, Multicenter, Double-Blind, Placebo-controlled Trial, J. Am. Acad. Child Adolesc. Psychiatry , 43:11, November 2004, 1387-1396 </li></ul>
  58. 59. References <ul><li>Riddle, M. A., Reeve, E. , Yaryura-Tobia, J.A., Yang, H., Claghorn, J.L., Gaffney, G., Greist, J.H., Holland, D.H., McConville, B.J., Pigott, T., Walkup, J.T., Fluvoxamine for Children and Adolescents with Obsessive-Compulsive Disorder: A Randomized, Controlled, Multicenter Trial, J.Am. Acad. Child Adolesc. Psychiatry , 40:2, February 2001, 222-229 </li></ul>
  59. 60. References <ul><li>March, J.S., Biederman, J., Wolkow, R., Safferman, A., Mardekian, J., Cook, E.H., Cutler, N.R., Dominguez, R., Ferguson, J., Muller, B., Riesenberg, R., Rosenthal, M., Sallee, F., Steiner, H, Wagner, K. Sertraline in Children and Adolescents with Obsessive-Compulsive Disorder. JAMA , 280: 20, November 1998, 1752-1756 </li></ul>
  60. 61. References <ul><li>Pediatric OCD Study Team: March, J., Foa, E. et al. Cognitive-Behavior Therapy, Sertraline and Their Combination for Children and Adolescents with Obsessive-Compulsive Disorder, JAMA , 292:16, October 2004, 1969-1976 </li></ul>
  61. 62. References <ul><li>Geller, D., Biederman, J., Stewart, S.E., Mullin, B., Martin, A., Spencer, T., Faraone, S., Which SSRI? A Meta-analysis of Pharmacotherapy Trials in Pediatric Obsessive-Compulsive Disorder, Am. J. Psychiatry 160:11, November 2003, 1919-1928 </li></ul>
  62. 63. Credits <ul><li>Principal Investigator, Producer, Music and Narration: Darren Courtney, M.D., B.Sc. </li></ul><ul><li>Supervisor: Dr. Clare Gray </li></ul><ul><li>Technical Support: Dr. Michael Cheng </li></ul><ul><li>Children’s Hospital of Eastern Ontario </li></ul>

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