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