peds ocd
TRANSCRIPT
Pharmacotherapy for Pediatric OCD
A Systematic Review
Objectives
• Review randomized placebo-controlled trials in pediatric OCD
• Discuss a published meta-analysis of SSRIs in pediatric OCD
Method
• OVID Medline 1950 to December 2007:– Child [MeSH] or Adolescent [MeSH] or
pediatric [keyword] or paediatric [keyword]
AND– Obsessive-Compulsive Disorder [MeSH]
• Resulted in 2453 hits
Inclusion Criteria
• Randomized placebo-controlled trial• Subjects aged 0-18 with DSM
diagnosis of Obsessive-Compulsive disorder
• Intervention is pharmacological• English language• Parallel or Cross-over design
Exclusion Criteria
• Less than 30 subjects for parallel design, less than 15 for cross-over
• Principal diagnosis of Tourette’s Disorder or Developmental Disorder
Child Yale-Brown Obsessive Compulsive
Scale• C-YBOCS:
– 10 item scale, range of 0-4• Obsessions and Compulsions• Time occupied, Interference, Distress,
Personal Control, Resistance
– Range of scale 0-40– 8-15 is mild, 16-23 moderate, >24
severe
Clomipramine
(Anafranil)
Clomipramine
• DeVeaugh et al, 1992• Subjects: 10-17 years• CMI started at 25mg/d, titrated up
to 75mg/d by second week, then titrated to 200mg/d (or 3mg/kg/d)
• N=60, 31 had CMI vs. 29 PBO• Duration: 2 weeks of PBO lead-in,
then 8 week trial
Clomipramine
0
5
10
15
20
25
30
35
40
week 0 week 8
ClomipraminePlacebo
*
Clomipramine
• One year open-label extension: 25/47 of subjects continuing to use CMI
ClomipramineCMI (N=31)
PBO (N=29)
Dry Mouth 63.0% 15.9%
Somnolence 45.7% 11.4%
Dizziness 41.3% 13.6%
Fatigue 34.8% 9.1%
Tremor 32.6% 2.3%
Clomipramine
CMI (N=31)
PBO
(N=29)
Constipation 21.7% 2.3%
Anorexia 21.7% 2.3%
Dyspepsia 13.0% 2.3%
Hepatic Enzyme Inc. 1 subj. 0
Clomipramine
• Limits:– Side effects of CMI compromises
blinding– Small sample size– No mention of suicidal ideation– Sponsored by Ciba-Geigy
Fluoxetine
(Prozac)
Fluoxetine (1)
• Geller et al, 2001• Subjects: 7-17• FLX started at 10mg/d, titrated up
to 20-60mg/d• N=103, 71 had FLX vs. 32 PBO• Duration: 13 weeks
Fluoxetine (1)
0
5
10
15
20
25
30
35
40
Week 0 Week 13
Fluoxetine
Placebo
*
Fluoxetine (1)
• Effect Size = 0.5• Mean dose of FLX was 24.6mg• Effects comparable between
children and adolescents
Fluoxetine (1)
• No adverse effect that was significantly different from placebo
• Diarrhea and Hyperkinesia found more in Fluoxetine group
Fluoxetine (1)
• Limits:– Many subjects dropped out
• 31% of FLX, 37.5% of PBO• No difference in reasons for drop out
– Sponsored by Eli Lilly
Fluoxetine (2)
• Liebowitz et al, 2002• Subjects: 6-18 years old• FLX 20mg/d titrated up to 80mg/d• N=43, 21 had FLX, 22 had PBO• Duration: 8 weeks + 8 weeks of
maintenance for responders
Fluoxetine (2)
0
5
10
15
20
25
30
35
40
Week 0 Week 8 Week 16
Fluoxetine
Placebo
NS*
Fluoxetine (2)
• Significant difference only in maintenance extension
• Mean dose of FLX 64.8mg/d
Fluoxetine (2)
FLX (N=21)
PBO (N=22)
Palpitations 19% 0%
Weight loss 33.3% 4.5%
Drowsiness 38.1% 4.5%
Nightmares 28.6% 0%
Muscle Ache 33.3% 4.5%
Fluoxetine (2)
• Significance only found on post-hoc analysis of extension group
• Sponsored by Eli Lilly and NIMH
Paroxetine
(Paxil)
Paroxetine
• Geller et al, 2004• Subjects: 7-17• PRX:started at 10mg/d, titrated up
to 50mg/d• N=203: 98 had PRX, 105 had PBO• Duration: 10 weeks
Paroxetine
0
5
10
15
20
25
30
35
40
week 0 week 10
Paroxetine
Placebo*
Paroxetine
• Stronger effect in more severe OCD
• Stronger effect in younger age• Mean dose: 20mg/d for children,
26.8mg/d for adolescents
Paroxetine
PRX N=98
PBO N=105
Hyperkinesia 12% 6%
Trauma (?) 10% 3%
Decreased appetite 9% 1%
Hostility 9% 1%
Diarrhea 8% 2%
Paroxetine
PRX N=98
PBO N=105
Asthenia 8% 1%
Vomiting 6% 2%
Agitation 5% 2%
Neurosis (?) 5% 1%
Suicidal Ideation (?situation) 1 subj. 0
Paroxetine
• Limits:– High drop out rate (in children only)
• 33% of PRX vs. 24% of PBO
– Sponsored by GlaxoSmithKline
Fluvoxamine
(Luvox)
Fluvoxamine
• Riddle et al, 2001• Subjects: 8-17 years old• FLV started at 25mg qhs, titrated
up to 100mg bid (200mg/d)• N=120, 57 had FLV, 63 had PBO• Duration: 10 weeks
Fluvoxamine
0
5
10
15
20
25
30
35
40
Week 0 Week 10
Fluvoxamine
Placebo*
Fluvoxamine
• Higher response in younger age• Statistically significant differences
between groups as early as week 1• Mean dose was 165mg/d
Fluvoxamine
FLV N=57
PBO N=63
Insomnia (mean onset at 45d)
29.8% 9.5%
Asthenia (mean onset ~20d)
26.3% 15.9%
Fluvoxamine
• Limits:– Many dropouts:
• 33% of FLV vs. 43% of PBO
– Sponsored by Solvay
Sertraline
(Zoloft)
Sertraline (1)
• March et al 1998• Subjects: 6-17• Sertraline started at 25mg/d,
titrated up to 50-200mg• N=187: 92 had SRT, 95 had PBO• Duration: 1 week PBO lead-in, 12
week trial
Sertraline (1)
0
5
10
15
20
25
30
35
40
week 0 week 12
Sertraline
Placebo*
Sertraline (1)
• Mean dose of SRT was 167mg/d
Sertraline (1)
SRT N=92
PBO N=95
Insomnia 37% 13%
Nausea 17% 7%
Agitation 13% 2%
Tremor 7% 0%
Sertraline (1)
• Limits:– 12/92 withdrew from SRT due to
adverse events vs. 3/95 in PBO– Sponsored by Pfizer
Sertraline (2)
• Pediatric OCD Treatment Study (POTS), 2004
• Subjects: 7-17• Sertraline: 25mg/d up to 200mg/d• N=112: 28 had SRT+CBT, 28 had
CBT, 28 had SRT, 28 had PBO
Sertraline (2)
0
5
10
15
20
25
30
35
40
week 0 week 12
Sertraline+CBTSertralinealoneCBT alone
Placebo
Sertraline (2)
0
5
10
15
20
25
30
35
40
week 0 week 12
Sertraline
Placebo
Sertraline (2)
• Effect size compared to placebo:– Combined: 1.4 (NNT = 2)– CBT: 0.97 (NNT = 3)– Sertraline: 0.67 (NNT = 6)
Sertraline (2)
SRT, N=56
PBO, N=28
Decreased appetite 16% 0%
Diarrhea 10% 4%
Enuresis 7% 0%
Motor Overactivity 12% 4%
Nausea 21% 4%
Stomach ache 21% 2%
Sertraline (2)
• Limits: – Those assigned to CBT or combined
group not blinded at all - expectancy effects
– Sponsored by NIMH and Pfizer
0
10
20
30
40
50
60
70
80
90
100
FLX PBO PRX PBO FLV PBO SRT PBO CMI PBO
% CGI responders
Meta-analysis
• Geller et al, 2003• 12 randomized controlled-trials• Included smaller studies,
withdrawl design, cross-over design and active-comparator trials
Meta-analysis
• On CYBOCS: overall effect size of 0.47, statistically significant
• No evidence of publication bias• Clomipramine had significantly
more effect than SSRIs• SSRIs equal amongst each other• Fail-safe N of 973
Conclusions
• Serotonin reuptake inhibitors are effective for pediatric OCD
• Moderate effect size• Response rates: 30-60%• Common adverse events:
insomnia, hyperkinesia, asthenia, diarrhea, nausea, weight loss
Future research
• Dosing• Length of treatment• Treatment resistant cases• CMI > SSRIs?• Safety: suicidal ideation, sexual
side effects
References
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
References
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
References
• 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
References
• 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
References
• 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
References
• 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
References
• 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
References
• 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
Credits
• Principal Investigator, Producer, Music and Narration: Darren Courtney, M.D., B.Sc.
• Supervisor: Dr. Clare Gray• Technical Support: Dr. Michael
Cheng• Children’s Hospital of Eastern
Ontario