- Email: [email protected]
Fluoxetine Treatment for Obsessive-Compulsive Disorder in Children and Adolescents: A Placebo-Controlled Clinical Trial
Fluoxetine Treatment for Obsessive-Compulsive Disorder in Children and Adolescents: A Placebo-Controlled Clinical Trial DANIEL A. GELLER, M.D., SHARON L. HOOG, M.D., JOHN H. HEILIGENSTEIN, M.D., RANDALL K. RICARDI, D.O., ROY TAMURA, PH.D., STACY KLUSZYNSKI, M.S., JENNIE G. JACOBSON, PH.D., AND THE FLUOXETINE PEDIATRIC OCD STUDY TEAM
ABSTRACT Objective: This study assesses the efficacy and tolerability of fluoxetine in the acute treatment of child and adolescent obsessive-compulsive disorder (OCD) during a 13-week, double-blind, placebo-controlled study. Method: Eligible patients aged 7 to 17 (N = 103) were randomized at a ratio of 2:1 to receive either fluoxetine or placebo. Dosing was initiated at 10 mg daily for 2 weeks, then increased to 20 mg daily. After 4 weeks of treatment, and again after 7 weeks of treatment, nonresponders could have their dosage increased by 20 mg daily, for a maximum possible dosage of 60 mg daily. Primary measure of efficacy was improvement in OCD symptoms as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). All analyses were intent-to-treat. Results: Fluoxetine was associated with significantly greater improvement in OCD as assessed by the CY-BOCS ( p = .026) and other measures than was placebo. Fluoxetine was well tolerated and had a rate of discontinuation for adverse events similar to that of placebo ( p = 1.00). Conclusions: Fluoxetine 20 to 60 mg daily was effective and well tolerated for treatment of OCD in this pediatric population. J. Am. Acad.
Child Adolesc. Psychiatry, 2001, 40(7):773–779. Key Words: obsessive-compulsive disorder, fluoxetine, selective serotonin reuptake inhibitors.
Obsessive-compulsive disorder (OCD) occurs in as many as 2% to 4% of juveniles (Douglass et al., 1995; Tadai et al., 1995; Zohar, 1999). If left untreated, OCD can severely impair academic, family, and social functioning. Studies suggest that even though the phenotypic features of OCD are similar in children, adolescents, and adults, some clinical characteristics may show developmental Accepted February 9, 2001. Dr. Geller is Director of the Pediatric OCD Clinic, McLean Hospital, Belmont, MA. Dr. Ricardi is with the Department of Behavior and Development, Phoenix Children’s Hospital, Phoenix, AZ. Drs. Hoog, Heiligenstein, Tamura, Jacobson, and Ms. Kluszynski are with Eli Lilly and Company, Indianapolis. The Fluoxetine Pediatric OCD Study Team: Drs. Howard Abikoff, Joseph Biederman, Richard L. Buccigross, Joan Busner, Graham J. Emslie, James Ferguson, Donna S. Holland, Saleem Ishaque, Stuart Kaplan, Brian Klee, Chris Kratochvil, Tanya K. Murphy, Julie Oldroyd, Michael G. Plopper, Elizabeth Reeve, Adelaide S. Robb, David R. Rosenberg, Murray H. Rosenthal, Keith E. Saylor, Bela A. Sood, Karen Dineen Wagner, Kelda Harris Walsh, and Scott A. West. This work was supported by Eli Lilly and Company. Reprint requests to Dr. Hoog, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285; e-mail: [email protected]. 0890-8567/01/4007–0773䉷2001 by the American Academy of Child and Adolescent Psychiatry.
specificity (Geller et al., 1998; March et al., 1995). Studies in juveniles with OCD have shown that the most effective therapies are behavioral therapy, pharmacological treatment with a serotonin reuptake inhibitor, or a combination of the two (American Academy of Child and Adolescent Psychiatry, 1998). There have been few double-blind, controlled studies of pediatric OCD. In one study, DeVeaugh-Geiss and colleagues found that 60% of patients receiving clomipramine were much or very much improved (score of 1 or 2 on the Clinical Global Impressions [CGI]-Improvement scale). Clomipramine, although generally well tolerated, is consistently associated with adverse events such as dizziness, dry mouth, fatigue, somnolence, and tremor (DeVeaugh-Geiss et al., 1992; Flament et al., 1985; Leonard et al., 1989). Fluvoxamine has been reported in an abstract to be effective for pediatric OCD (Riddle et al., 1996), although a full description of this clinical trial has not been published. Sertraline was found to be effective for treatment of pediatric OCD in a 12-week double-blind, placebo-
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
773
GELLER ET AL.
controlled study (March et al., 1998). Forty-two percent of patients in the sertraline treatment group were rated as much improved or very much improved (a score of 1 or 2 on the CGI-Improvement scale). Sertraline was reported to be generally well tolerated, but was also associated with insomnia, nausea, agitation, and tremor statistically more often than was placebo. In addition, significantly more sertraline-treated patients than placebo-treated patients discontinued the study as a result of adverse events (March et al., 1998). Open studies of citalopram and paroxetine also suggest that these agents may have some efficacy in treating OCD, but controlled data are lacking (Rosenberg et al., 1999; Thomsen, 1997). Thus, there continues to be a need for information from double-blind, placebocontrolled trials in the pediatric population regarding the safety and efficacy of pharmaceutical agents for the treatment of OCD. Fluoxetine has been shown to be efficacious and well tolerated in double-blind placebo-controlled clinical trials of OCD in adults (Montgomery et al., 1993; Tollefson et al., 1994a,b). In addition, a small (N = 14) single-site, double-blind trial of OCD in children and adolescents found fluoxetine to be well tolerated and to significantly reduce OCD symptom severity (Riddle et al., 1992). In a naturalistic study of pediatric outpatients with OCD (N = 38), 74% of patients were retrospectively rated as much or very much improved (score of 1 or 2 on the CGI-Improvement scale) after treatment with fluoxetine. The average mean dose of 50 mg/day was generally well tolerated (Geller et al., 1995). In a double-blind study of children and adolescents with depression, Emslie and colleagues reported that patients experienced “minimal” adverse events (Emslie et al., 1997). This study presents data concerning the efficacy and safety of fluoxetine in the acute treatment of child and adolescent OCD in 103 patients during a 13-week doubleblind, placebo-controlled clinical trial.
addition, patients were required to have a baseline score greater than or equal to 7 on the National Institute of Mental Health Global OCD Scale (NIMH GOCS) and a Children’s Depression Rating ScaleRevised (CDRS-R) score of less than or equal to 40. Patients were also required to have laboratory results and ECGs without significant abnormalities and to be above the 10th percentile for weight for their age and gender. Patients were excluded from the study if they had any of the following coexisting disorders: major depressive disorder as a primary diagnosis, schizophrenia, bipolar disorder, neurological disorders including Tourette’s syndrome, attention deficit/hyperactivity disorder, pervasive developmental disorders, posttraumatic stress disorder, or borderline personality disorder. If present, concurrent depression must have been secondary to OCD in the investigator’s opinion. Patients were also excluded if they were involved in ongoing therapy for OCD or depression other than supportive psychotherapy. An investigational review board (IRB) reviewed the study at each of the 21 study sites. An informed consent document approved by the IRBs was signed by the patients’ parents or guardians. Patients may also have provided assent or consent depending on the requirements of each IRB.
Participants in the trial were male and female children and adolescents (at least 7 but less than 18 years of age) with a primary psychiatric diagnosis of OCD as defined by the DSM-IV (American Psychiatric Association, 1994). To be enrolled in this study, patients must have had obsessive-compulsive symptoms of at least moderate severity, defined as scores greater than or equal to 4 on the CGI-Severity scale and greater than or equal to 16 on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). At least one of the obsessive-compulsive symptoms must have been present for 6 months or more prior to study entry. In
Study Design The study consisted of an initial 1-week evaluation period (during which patients received no study medication) followed by a 13-week, double-blind acute treatment phase for which patients were randomized in a 2:1 ratio to fluoxetine and placebo treatment groups. Patients randomized to fluoxetine treatment received one 10-mg fluoxetine capsule and two placebo capsules daily for the first 2 weeks of treatment and then one 20-mg fluoxetine capsule and two placebo capsules daily. After 4 weeks of treatment, a patient’s dosage of fluoxetine could be increased to 40 mg daily if the CGI-Severity score was unchanged or worsened from baseline. Three weeks later the dosage of fluoxetine could again be increased 20 mg (to 40 mg or 60 mg daily) if the CGI-Severity score was unchanged or worsened from baseline. Patients who did not tolerate a dosage increase (to either 40 mg or 60 mg daily) could have the dosage reduced to 20 or 40 mg daily, respectively. Once a dose was reduced to a tolerated level, no further dose adjustments were permitted. Patients randomized to the placebo treatment group received three placebo capsules daily throughout the study. The primary efficacy measure was the CY-BOCS (Goodman et al., 1989). The CY-BOCS is a 10-item anchored ordinal scale (0–4) that rates the clinical severity of the disorder by scoring the time occupied, degree of life interference, subjective distress, internal resistance, and degree of control for both obsessions and compulsions. It has been validated for use with pediatric subjects. Five items are specific for compulsive symptoms, and the other five are specific for obsessive symptoms (Scahill et al., 1997). Other measures used to assess severity of OCD were the CGI-Severity Scale (Guy, 1976), the CGI-Improvement Scale (Guy, 1976), the Patients Global Impressions (PGI) Scale (Guy, 1976), the NIMH GOCS (Murphy et al., 1982) and the OCD Impact Scale (Piacentini, 1999). In addition, patients were assessed for depression and anxiety with the CDRS-R (Poznanski et al., 1985) and the Multidimensional Anxiety Scale for Children (MASC) (March et al., 1997), respectively. Patients were seen 10 times during the course of the study: 1 week prior to randomization (visit 1), at randomization/baseline (visit 2), weekly for the first 5 weeks of treatment (visits 3–7) biweekly for the next 4 weeks of treatment (visits 8 and 9) and at the end of the 13week treatment period (visit 10). The CY-BOCS, NIMH GOCS, and CGI-Severity scales were evaluated at every visit. The CGIImprovement scales (rated by parent and by clinician) and the PGI scale were collected at each postbaseline visit. At weeks 0, 5, and 13
774
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
METHOD Patient Selection Criteria
FLUOXETINE IN PEDIATRIC OCD
and at early discontinuation, the CDRS-R and MASC were administered. The OCD Impact Scale was administered 1 week before baseline, at weeks 5 and 13, and at early discontinuation. Adverse events, blood pressure, heart rate, height, and weight were monitored and recorded at each visit. Adverse events were noted by general inquiry rather than by use of a checklist or other structured inquiry. Blood for electrolyte, liver, and renal function and complete blood count assay was drawn at weeks –1 and at week 10 or early discontinuation. Statistical Method The sample size of the study was chosen to ensure that a 4.8-unit treatment difference in CY-BOCS Total score would be detected with approximately 80% power. All analyses were intent-to-treat. For evaluation of continuous efficacy and safety data, the last-observationcarried-forward change from baseline to endpoint or endpoint score was analyzed with analysis of variance (ANOVA), with treatment and investigator as independent factors in the model. Effect size was calculated as the difference in treatment least square means divided by the square root of the mean square error. Forty percent or greater reduction in CY-BOCS total score was the a priori definition of response for this study. The percentage of responders was evaluated across treatment groups using an exact Mantel-Haenszel test with investigator as the stratification variable. The percentage of patients rated as much or very much improved by clinicians, parents, and patients on the CGI-Improvement and PGI scales (post hoc analyses) were also evaluated across treatment groups with an exact Mantel-Haenszel test. Repeated-measures analysis of the CY-BOCS total score was conducted to assess the temporal change over visits. For analyses of safety categorical data, Fisher exact test was used. For subgroup analyses of categorical data, the Breslow-Day test for homogeneity of odds ratio was used. Investigators with fewer than two randomized patients per treatment group were pooled for statistical analysis. RESULTS Patient Characteristics and Baseline Severity
Of 148 patients who initially entered the study, 103 met eligibility criteria after the baseline evaluation period, were randomized to either fluoxetine (n = 71) or placebo (n = 32), and had at least one postbaseline visit. Demographic data and baseline OCD severity were similar for both groups (Table 1). The mean daily dose for the fluoxetine treatment group was 24.6 mg. Of the 71 patients enrolled in the fluoxetine treatment group, 16 (23%) had a final dose of 40 mg daily, and 15 (21%) had a final dose of 60 mg daily.
TABLE 1 Baseline Demographics, Patient Characteristics, and Severity of Disease
Gender Female Male Age (years) Age category Childrene Adolescents f Race White Hispanic African descent Asian descent Other or mixed Height (cm) Weight (kg) CY-BOCS Total g CY-BOCS Obs h CY-BOCS Comp i NIMH OCD j OCD Impact k CGI-Severity l
Fluoxetine a
Placebob
p Value
37 (52) 34 (48) 11.4 ± 3.0
17 (53) 15 (47) 11.4 ± 2.8
1.00c
51 (72) 20 (28)
24 (75) 8 (25)
.814c
62 (87) 4 (6) 2 (3) 0 3 (4) 146.7 ± 16.6 46.2 ± 20.9 24.5 ± 5.1 11.9 ± 3.3 12.6 ± 2.9 9.0 ± 1.4 40.8 ± 25.7 4.6 ± 0.7
27 (84) 3 (9) 0 1 (3) 1 (3) 144.4 ± 14.3 41.6 ± 13.6 26.3 ± 4.6 12.6 ± 3.1 13.7 ± 2.5 9.5 ± 1.6 36.4 ± 22.6 4.8 ± 0.8
.538c
.847d
.574d .287d .132d .443d .094d .157d .110d .115d
Note: Values represent number (percent) or mean ± SD. OCD = obsessive-compulsive disorder. a n = 71 for all values, except OCD Impact for which n = 60. b n = 32 for all values, except OCD Impact for which n = 29. c p Value determined using Fisher exact test. d p Value determined using type III sum of squares from an analysis of variance: PROC GLM model = investigator and treatment. e Children = at least 7 and younger than 13 years of age. f Adolescents = at least 13 and younger than 18 years of age. g Children’s Yale-Brown Obsessive Compulsive Scale total score. h CY-BOCS Obsessions subtotal score. i CY-BOCS Compulsions subtotal score. j National Institute of Mental Health Global OCD Scale. k Obsessive Compulsive Disorder Impact Scale. l Clinical Global Impressions-Severity Scale.
Compared with placebo, fluoxetine was associated with significant reduction of OCD severity as measured by total CY-BOCS score (p = .026) (Table 2 and Fig. 1). The difference between fluoxetine and placebo tended toward significance at week 5 (p = .086) and was significant (p < .05) at all subsequent patient visits (Fig. 1). The
consistency of efficacy in CY-BOCS total score was examined in an additional ANOVA that included factors for age category (children aged 7–12 versus adolescents aged 13–17) and the interaction of age by treatment. The effects of fluoxetine treatment on OCD symptoms were comparable in children and adolescents (age by treatment interaction, p = .819). In this study, patients with a 40% or greater reduction in their CY-BOCS total score from baseline to endpoint were classified as responders. In the fluoxetine treatment group, 35 of 71 patients (49%) were responders. In the placebo group, 8 of 32 patients (25%) were responders. This difference was significant (Mantel-Haenszel exact test p value = .030).
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
775
Efficacy
GELLER ET AL.
TABLE 2 Change in Severity of Disease From Baseline to Endpoint Analyses
CY-BOCS Totald CY-BOCS Obs e CY-BOCS Comp f NIMH OCD g OCD Impact h CGI-Severity i
Fluoxetinea
Placebob
p Value c
Effect Size
–9.5 ± 9.2 –4.7 ± 4.8 –4.8 ± 5.0 –3.1 ± 3.0 –16.4 ± 19.2 –1.3 ± 1.3
–5.2 ± 7.4 –3.0 ± 4.3 –2.2 ± 4.5 –1.3 ± 2.2 –7.1 ± 15.4 –0.6 ± 1.0
.026 .102 .015 .003 .017 .009
0.5 0.4 0.5 0.7 0.6 0.6
Note: There was no significant treatment by investigator interaction in any of the above variables; all scores are presented as mean ± SD. All analyses are intent-to-treat. a For CY-BOCS Total, CY-BOCS Obsessions, CY-BOCS Compulsions, NIMH OCD, and CGI-Severity, n = 71. For OCD Impact, n = 55. b For CY-BOCS Total, CY-BOCS Obsessions, CY-BOCS Compulsions, NIMH OCD, and CGI-Severity, n = 32. For OCD Impact, n = 28. c p Value determined using type III sum of squares from an analysis of variance: PROC GLM model = investigator and treatment. d Children’s Yale-Brown Obsessive Compulsive Scale total score. e CY-BOCS Obsessions subtotal score. f CY-BOCS Compulsions subtotal score. g National Institute of Mental Health Global OCD Scale. h Obsessive Compulsive Disorder Impact Scale. i Clinical Global Impressions-Severity Scale.
Clinicians rated 55.0% of fluoxetine-treated patients as much improved or very much improved (a score of 1 or 2 on the CGI-Improvement scale), compared with 18.8% of placebo-treated patients (p < .001). Parents’ and patients’ ratings of much or very much improved were also more prevalent for the fluoxetine treatment group than for the placebo treatment group (score of 1 or 2 on the CGI-Improvement scale as assessed by parents: 57.7% and 9.4%, respectively, p < .001; score of 1 or 2 on the PGI scale: 59.1% and 21.9%, respectively, p < .001). Fluoxetine was not associated with increased anxiety; change in MASC total score was –9.0 ± 18.6 for fluoxetine and –4.5 ± 16.5 for placebo (p = .163). The difference between fluoxetine and placebo for improvement in CDRS-R total score, used to assess depression, was not significant (–1.6 ± 7.6 and 0.5 ± 7.6, respectively, p = .118). The CDRS-R Mood subtotal was the only subtotal for which change from baseline was significantly different between treatment groups (fluoxetine: –1.0 ± 2.6, placebo: 0.0 ± 2.5, p = .004). Safety
Fig. 1 Temporal assessment of change in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score. Repeated-measures analysis of the change from baseline in least square means of CY-BOCS for placebo and fluoxetine treatment groups at each scheduled visit. Asterisks indicate time points at which there is a statistically significant difference between the mean fluoxetine and placebo values (p < .05).
The percentage of patients who completed the study was similar for both groups (fluoxetine: 49 [69.0%] of 71 patients; placebo: 20 [62.5%] of 32 patients, p = .651). There was no significant difference between study groups in the percentage of patients who discontinued because of lack of efficacy (fluoxetine: 10 [14.1%] of 71 patients; placebo: 8 [25%] of 32 patients, p = .261). One patient in the fluoxetine treatment group discontinued because of protocol requirement, and three patients in this treatment group discontinued because of patient decision. No patients in the placebo treatment groups discontinued for either of these reasons (p = 1.00 and 0.550, respectively). One patient in each treatment group discontinued as a result of physician decision (p = .527). One patient in each treatment group was lost to follow-up (p = .527). The percentage of discontinuations because of adverse events was similar in both groups (fluoxetine: 6 [8.5%] of 71 patients; placebo: 2 [6.3%] of 32 patients, p = 1.00). The fluoxetinetreated patients discontinued because of headache, hyperkinesia, abnormal liver function tests, manic reaction, nervousness, or somnolence. The placebo-treated patients discontinued because of hyperkinesia or nervousness. Of the 103 randomized patients in this study, 80 (78%) reported at least one treatment-emergent adverse event. There was no significant difference between treatment groups in the number of patients who reported adverse
776
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
FLUOXETINE IN PEDIATRIC OCD
events. In addition, no single treatment-emergent adverse event occurred significantly more often in fluoxetinetreated patients compared with placebo-treated patients (Table 3). There were no statistically significant differences in treatment-emergent abnormal (out-of-referencerange) laboratory values between the two treatment groups. In addition, subgroup analyses of adverse events suggested there were no clinically significant differences in safety profile for subgroups by age or gender. Vital signs, including sitting blood pressure and heart rate, height, and weight, were recorded at each visit. Table 4 summarizes the change from baseline to endpoint for the vital signs collected during the study. There were significant differences between the treatment groups for the change in weight (p = .002), sitting systolic blood pressure (p = .044), and sitting diastolic blood pressure (p = .026). Fluoxetine was associated with mild weight loss and slight decreases in blood pressure, whereas placebo was associated with mild weight gain and small increases in blood pressure.
TABLE 4 Change From Baseline to Endpoint Analysis in Vital Statistics
Weight (kg) Height (cm) Systolic BP Diastolic BP Heart rate
Fluoxetine n = 71
Placebo n = 32
p Valuea
–0.2 ± 2.0 0.9 ± 1.7 –0.1 ± 11.6 –0.7 ± 9.8 –0.2 ± 13.1
1.0 ± 1.3 1.2 ± 2.0 4.0 ± 11.7 4.8 ± 15.9 3.2 ± 14.1
.002 .823 .044 .026 .225
Note: Intent-to-treat analysis. Vital statistics are presented as mean ± SD. BP = blood pressure. a p Value determined were determined using type III sum of squares from an analysis of variance: PROC GLM model = investigator and treatment.
p Value determined with Fisher exact test; intent-to-treat analysis.
Fluoxetine 20 to 60 mg daily was significantly more effective than placebo in the treatment of OCD in this pediatric population, as demonstrated by greater reductions from baseline to endpoint in CY-BOCS total score. Fluoxetine-treated patients also demonstrated higher rates of response (defined as 40% or greater reduction in CY-BOCS total score from baseline to endpoint) compared with placebo-treated patients. The results of this study are consistent with the growing body of evidence that shows the efficacy of fluoxetine for the treatment of OCD in children as well as adults (Montgomery et al., 1993; Riddle et al., 1992; Tollefson et al., 1994a,b; Zitterl et al., 1999). Comparisons of drug effects across clinical trials are problematic because of differences in methodologies, protocols, inclusion/exclusion criteria, clinical study populations, and study duration. Although these limitations must be considered, our findings suggest that fluoxetine may be comparable to other agents in reducing OCD symptom severity. For example, in an 8-week trial of clomipramine and a 12-week trial of sertraline, 60% and 42%, respectively, of patients receiving study drug were rated by clinicians as much or very much improved (CGI-Improvement score of 1 or 2) (DeVeaugh-Geiss et al., 1992; March et al., 1998). In this study 55% of patients receiving fluoxetine were rated as much or very much improved. Repeated-measures analyses of CY-BOCS total score were performed to assess temporal changes in score over the course of the study (Fig. 1). The difference between treatment groups in mean change in CY-BOCS total score tended toward significance as early as week 5 (p = .086) and was statistically significant at each subsequent visit for the duration of the study. This time to onset of significant clinical improvement is slightly longer than that reported for other antidepressants (DeVeaugh-Geiss et al., 1992;
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
777
DISCUSSION
In a double-blind study evaluating 13 weeks of acute therapy with fluoxetine 10 to 60 mg daily (n = 71) versus placebo (n = 32) in pediatric outpatients with OCD, fluoxetine was shown to be both effective and well tolerated. A total of 69 patients (49 fluoxetine, 20 placebo) completed the entire study. The treatment groups were well balanced with respect to demographic characteristics and clinical features at baseline. TABLE 3 Adverse Events Reported by at Least 10% of Patients in Fluoxetine Treatment Group, by Body System Fluoxetine
Overall Body as a whole Headache Abdominal pain Fever Respiratory system Rhinitis Pharyngitis Digestive system Nausea Diarrhea Nervous system Hyperkinesia Insomnia a
Placebo
n = 71
%
n = 32
%
p Valuea
53
74.6
27
84.4
.317
20 11 8
28.2 15.5 11.3
9 6 2
28.1 18.8 6.3
1.000 .776 .720
19 10
26.8 14.1
8 5
25.0 15.6
1.000 1.000
9 9
12.7 12.7
4 1
12.5 3.1
1.000 .167
9 9
12.7 12.7
1 3
3.1 9.4
.167 .750
GELLER ET AL.
March et al., 1998; Riddle et al., 1996). A more gradual titration schedule with a 2-week lead-in period, during which patients received only 10 mg/day of fluoxetine, may have contributed to the more gradual onset of effect. However, stepwise dosing presumably also allowed acclimation and increased tolerability. One measure of secondary depression (the CDRS-R Mood subtotal) showed a significantly greater improvement in fluoxetine-treated subjects (p = .004). Other indices of anxiety and depression (MASC and CDRS-R total scores) did not reach statistical significance. Because the protocol exclusion criteria resulted in a population with a low incidence of secondary major depressive disorder (5% of subjects) our findings do not permit any conclusions to be drawn from this trial with regard to the efficacy of fluoxetine for comorbid depression in pediatric OCD subjects. The safety profile of fluoxetine in the children and adolescents in this study compares favorably with that that observed by Riddle and colleagues (1992) in children and adolescents and by Tollefson and colleagues (1994a,b) in adults with OCD. No statistically significant differences in treatment-emergent, out-of-reference-range laboratory values were found between the two groups. In addition, fluoxetine and placebo treatment groups were comparable in terms of the total percentage of patients reporting adverse events and the percentage of patients reporting any single adverse event. Although diarrhea and hyperkinesia were reported more frequently in fluoxetine-treated patients than in placebo-treated patients (13% versus 3%), there was no statistical difference between treatment groups in the number of patients reporting either of these adverse events. None of the patients in either group discontinued the study as a result of the occurrence of diarrhea; one patient each in the fluoxetine and placebo treatment groups discontinued as a result of hyperkinesia. The percentage of patients completing this study was comparable across treatment groups. However, the completion rate was slightly lower than has been reported for other controlled clinical trials of treatments for pediatric OCD (DeVeaugh-Geiss et al., 1992; Flament et al., 1985; Leonard et al., 1989; March et al., 1998), all of which were of a shorter duration than the trial reported here. Statistically significant but clinically insignificant differences in weight change and blood pressure were noted between treatment groups over the course of this study. Slight weight loss has been observed in acute fluoxetine treatment studies of adults (Michelson et al., 1999;
Tollefson et al., 1994b). Similarly small but statistically significant differences in weight change between active drug and placebo were also found in studies of clomipramine (DeVeaugh-Geiss et al., 1992) and sertraline (March et al., 1998) treatment of pediatric OCD. Although these changes were not considered clinically relevant in this study, the findings suggest clinicians should monitor these parameters during treatment.
778
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
Limitations
Although this study found that dose titration of fluoxetine to a maximum of 60 mg/day significantly reduced the severity of OCD symptoms in children and adolescents, the design of the study did not allow for a comparison of efficacy between fixed doses of fluoxetine. Dosage increases were given to all patients who did not respond to 4 weeks of treatment with fluoxetine. Thus, for those patients who did not respond in the first 4 weeks, but later responded to 40 or 60 mg daily, it is not possible to determine how much the improvement in symptomology was caused by the dosage increase and how much improvement, if any, would have occurred with a longer trial of fluoxetine 20 mg. Patients who enrolled in this study were predominantly white. Although no significant differences between whites and members of ethnic minority groups were observed in this study, the number of ethnic minority group members was too small to conclude that fluoxetine efficacy and safety are constant across ethnic groups. In addition, this study does not provide information regarding the longer-term (6 months and longer) safety and efficacy of fluoxetine for the treatment of pediatric OCD. Clinical Implications and Conclusions
Fluoxetine 20 to 60 mg daily was associated with significantly greater reduction on multiple measures of OCD symptom severity compared with placebo. In addition, fluoxetine 20 to 60 mg daily was well tolerated in these children and adolescents. REFERENCES American Academy of Child and Adolescent Psychiatry (1998), Practice parameters for the assessment and treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 37:27S–45S American Psychiatric Association (1994), Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Washington, DC: American Psychiatric Association DeVeaugh-Geiss J, Moroz G, Biederman J et al. (1992), Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder: a multicenter trial. J Am Acad Child Adolesc Psychiatry 31:45–49
FLUOXETINE IN PEDIATRIC OCD
Douglass HM, Moffitt TE, Dar R, McGee R, Silva P (1995), Obsessivecompulsive disorder in a birth cohort of 18-year-olds: prevalence and predictors. J Am Acad Child Adolesc Psychiatry 34:1424–1431 Emslie GJ, Rush AJ, Weinberg WA et al. (1997), A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–1037 Flament MF, Rapoport JL, Berg CJ et al. (1985), Clomipramine treatment of childhood obsessive-compulsive disorder: a double-blind controlled study. Arch Gen Psychiatry 42:977–983 Geller DA, Biederman J, Jones J, Shapiro S, Schwartz S, Park KS (1998), Obsessive-compulsive disorder in children and adolescents: a review. Harvard Rev Psychiatry 5:260–273 Geller DA, Biederman J, Reed ED, Spencer T, Wilens TE (1995), Similarities in response to fluoxetine in the treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 34:36–44 Goodman WK, Price LH, Rasmussen SA et al. (1989), The Yale-Brown Obsessive Compulsive Scale. Arch Gen Psychiatry 46:1006–1011 Guy W (1976), Assessment Manual for Psychopharmacology, Revised (DHEW Publication ABM 76-366). Washington, DC: US Government Printing Office Leonard HL, Swedo SE, Rapoport JL et al. (1989), Treatment of obsessivecompulsive disorder with clomipramine and desipramine in children and adolescents: a double-blind crossover comparison. Arch Gen Psychiatry 46:1088–1092 March JS, Biederman J, Wolkow R et al. (1998), Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA 280:1752–1756 March JS, Leonard HL, Swedo SE (1995), Neuropsychiatry of obsessivecompulsive disorder in children and adolescents. Compr Ther 21:507–512 March JS, Parker JD, Sullivan K, Stallings P, Conners CK (1997), The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity, J Am Acad Child Adolesc Psychiatry 36:554–565 Michelson D, Amsterdam JD, Quitkin FM et al. (1999), Changes in weight during a one-year trial with fluoxetine. Am J Psychiatry 156:1170–1176 Montgomery SA, McIntyre A, Osterheider M et al. (1993), A double-blind, placebo-controlled study of fluoxetine in patients with DSM-III-R obsessive-compulsive disorder. Eur Neuropsychopharmacol 3:143–152 Murphy DL, Pickar D, Alterman IS (1982), Methods for the quantitative assessment of depressive and manic behavior. In: The Behavior of Psychi-
atric Patients, Burdock EL, Sudilovsky A, Gershon S, eds. New York: Marcel Dekker pp 355–392 Piacentini J (1999), Cognitive behavior therapy of childhood OCD. Child Adolesc Psychiatr Clin N Am 8:599–616 Poznanski EO, Freeman LN, Mokros HB (1985), Children’s Depression Rating Scale-Revised. Psychopharmacol Bull 21:979–989 Riddle MA and Pediatric OCD Research Group (1996), Fluvoxamine in the treatment of OCD in children and adolescents: a multicenter, doubleblind, placebo-controlled trial (abstract NR-197). Presented at the Annual Meeting of the American Psychiatric Association, New York Riddle MA, Scahill L, King RA et al. (1992), Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessivecompulsive disorder. J Am Acad Child Adolesc Psychiatry 31:1062–1069 Rosenberg DR, Stewart CM, Fitzgerald KD, Tawile V, Carroll E (1999), Paroxetine open-label treatment of pediatric outpatients with obsessivecompulsive disorder. J Am Acad Child Adolesc Psychiatry 38:1180–1185 Scahill L, Riddle MA, McSiggin-Hardin M et al. (1997), Children’s YaleBrown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry 36:844–852 Tadai T, Nakamura M, Okazaki S, Nakajima T (1995), The prevalence of obsessive compulsive disorder in Japan: a study of students using the Maudsley Obsessional-Compulsive Inventory and DSM-III-R. Psychiatry Clin Neurosci 49:39–41 Thomsen PH (1997), Child and adolescent obsessive-compulsive disorder treated with citalopram: findings from an open trial of 23 cases. J Child Adolesc Psychopharmacol 7:157–166 Tollefson GD, Birkett M, Koran L, Genduso L (1994a), Continuation treatment of OCD: double-blind and open-label experience with fluoxetine. J Clin Psychiatry 55:69–78 Tollefson GD, Rampey AH Jr., Potvin JH et al. (1994b), A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 51:559–567 Zitterl W, Meszaros K, Hornik K et al. (1999), Efficacy of fluoxetine in Austrian patients with obsessive-compulsive disorder. Wien Klin Wochenschr 111:439–442 Zohar AH (1999), The epidemiology of obsessive-compulsive disorder in children and adolescents. Child Adolesc Psychiatr Clin N Am 8:445–460
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
779
ABSTRACT Objective: This study assesses the efficacy and tolerability of fluoxetine in the acute treatment of child and adolescent obsessive-compulsive disorder (OCD) during a 13-week, double-blind, placebo-controlled study. Method: Eligible patients aged 7 to 17 (N = 103) were randomized at a ratio of 2:1 to receive either fluoxetine or placebo. Dosing was initiated at 10 mg daily for 2 weeks, then increased to 20 mg daily. After 4 weeks of treatment, and again after 7 weeks of treatment, nonresponders could have their dosage increased by 20 mg daily, for a maximum possible dosage of 60 mg daily. Primary measure of efficacy was improvement in OCD symptoms as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). All analyses were intent-to-treat. Results: Fluoxetine was associated with significantly greater improvement in OCD as assessed by the CY-BOCS ( p = .026) and other measures than was placebo. Fluoxetine was well tolerated and had a rate of discontinuation for adverse events similar to that of placebo ( p = 1.00). Conclusions: Fluoxetine 20 to 60 mg daily was effective and well tolerated for treatment of OCD in this pediatric population. J. Am. Acad.
Child Adolesc. Psychiatry, 2001, 40(7):773–779. Key Words: obsessive-compulsive disorder, fluoxetine, selective serotonin reuptake inhibitors.
Obsessive-compulsive disorder (OCD) occurs in as many as 2% to 4% of juveniles (Douglass et al., 1995; Tadai et al., 1995; Zohar, 1999). If left untreated, OCD can severely impair academic, family, and social functioning. Studies suggest that even though the phenotypic features of OCD are similar in children, adolescents, and adults, some clinical characteristics may show developmental Accepted February 9, 2001. Dr. Geller is Director of the Pediatric OCD Clinic, McLean Hospital, Belmont, MA. Dr. Ricardi is with the Department of Behavior and Development, Phoenix Children’s Hospital, Phoenix, AZ. Drs. Hoog, Heiligenstein, Tamura, Jacobson, and Ms. Kluszynski are with Eli Lilly and Company, Indianapolis. The Fluoxetine Pediatric OCD Study Team: Drs. Howard Abikoff, Joseph Biederman, Richard L. Buccigross, Joan Busner, Graham J. Emslie, James Ferguson, Donna S. Holland, Saleem Ishaque, Stuart Kaplan, Brian Klee, Chris Kratochvil, Tanya K. Murphy, Julie Oldroyd, Michael G. Plopper, Elizabeth Reeve, Adelaide S. Robb, David R. Rosenberg, Murray H. Rosenthal, Keith E. Saylor, Bela A. Sood, Karen Dineen Wagner, Kelda Harris Walsh, and Scott A. West. This work was supported by Eli Lilly and Company. Reprint requests to Dr. Hoog, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285; e-mail: [email protected]. 0890-8567/01/4007–0773䉷2001 by the American Academy of Child and Adolescent Psychiatry.
specificity (Geller et al., 1998; March et al., 1995). Studies in juveniles with OCD have shown that the most effective therapies are behavioral therapy, pharmacological treatment with a serotonin reuptake inhibitor, or a combination of the two (American Academy of Child and Adolescent Psychiatry, 1998). There have been few double-blind, controlled studies of pediatric OCD. In one study, DeVeaugh-Geiss and colleagues found that 60% of patients receiving clomipramine were much or very much improved (score of 1 or 2 on the Clinical Global Impressions [CGI]-Improvement scale). Clomipramine, although generally well tolerated, is consistently associated with adverse events such as dizziness, dry mouth, fatigue, somnolence, and tremor (DeVeaugh-Geiss et al., 1992; Flament et al., 1985; Leonard et al., 1989). Fluvoxamine has been reported in an abstract to be effective for pediatric OCD (Riddle et al., 1996), although a full description of this clinical trial has not been published. Sertraline was found to be effective for treatment of pediatric OCD in a 12-week double-blind, placebo-
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
773
GELLER ET AL.
controlled study (March et al., 1998). Forty-two percent of patients in the sertraline treatment group were rated as much improved or very much improved (a score of 1 or 2 on the CGI-Improvement scale). Sertraline was reported to be generally well tolerated, but was also associated with insomnia, nausea, agitation, and tremor statistically more often than was placebo. In addition, significantly more sertraline-treated patients than placebo-treated patients discontinued the study as a result of adverse events (March et al., 1998). Open studies of citalopram and paroxetine also suggest that these agents may have some efficacy in treating OCD, but controlled data are lacking (Rosenberg et al., 1999; Thomsen, 1997). Thus, there continues to be a need for information from double-blind, placebocontrolled trials in the pediatric population regarding the safety and efficacy of pharmaceutical agents for the treatment of OCD. Fluoxetine has been shown to be efficacious and well tolerated in double-blind placebo-controlled clinical trials of OCD in adults (Montgomery et al., 1993; Tollefson et al., 1994a,b). In addition, a small (N = 14) single-site, double-blind trial of OCD in children and adolescents found fluoxetine to be well tolerated and to significantly reduce OCD symptom severity (Riddle et al., 1992). In a naturalistic study of pediatric outpatients with OCD (N = 38), 74% of patients were retrospectively rated as much or very much improved (score of 1 or 2 on the CGI-Improvement scale) after treatment with fluoxetine. The average mean dose of 50 mg/day was generally well tolerated (Geller et al., 1995). In a double-blind study of children and adolescents with depression, Emslie and colleagues reported that patients experienced “minimal” adverse events (Emslie et al., 1997). This study presents data concerning the efficacy and safety of fluoxetine in the acute treatment of child and adolescent OCD in 103 patients during a 13-week doubleblind, placebo-controlled clinical trial.
addition, patients were required to have a baseline score greater than or equal to 7 on the National Institute of Mental Health Global OCD Scale (NIMH GOCS) and a Children’s Depression Rating ScaleRevised (CDRS-R) score of less than or equal to 40. Patients were also required to have laboratory results and ECGs without significant abnormalities and to be above the 10th percentile for weight for their age and gender. Patients were excluded from the study if they had any of the following coexisting disorders: major depressive disorder as a primary diagnosis, schizophrenia, bipolar disorder, neurological disorders including Tourette’s syndrome, attention deficit/hyperactivity disorder, pervasive developmental disorders, posttraumatic stress disorder, or borderline personality disorder. If present, concurrent depression must have been secondary to OCD in the investigator’s opinion. Patients were also excluded if they were involved in ongoing therapy for OCD or depression other than supportive psychotherapy. An investigational review board (IRB) reviewed the study at each of the 21 study sites. An informed consent document approved by the IRBs was signed by the patients’ parents or guardians. Patients may also have provided assent or consent depending on the requirements of each IRB.
Participants in the trial were male and female children and adolescents (at least 7 but less than 18 years of age) with a primary psychiatric diagnosis of OCD as defined by the DSM-IV (American Psychiatric Association, 1994). To be enrolled in this study, patients must have had obsessive-compulsive symptoms of at least moderate severity, defined as scores greater than or equal to 4 on the CGI-Severity scale and greater than or equal to 16 on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). At least one of the obsessive-compulsive symptoms must have been present for 6 months or more prior to study entry. In
Study Design The study consisted of an initial 1-week evaluation period (during which patients received no study medication) followed by a 13-week, double-blind acute treatment phase for which patients were randomized in a 2:1 ratio to fluoxetine and placebo treatment groups. Patients randomized to fluoxetine treatment received one 10-mg fluoxetine capsule and two placebo capsules daily for the first 2 weeks of treatment and then one 20-mg fluoxetine capsule and two placebo capsules daily. After 4 weeks of treatment, a patient’s dosage of fluoxetine could be increased to 40 mg daily if the CGI-Severity score was unchanged or worsened from baseline. Three weeks later the dosage of fluoxetine could again be increased 20 mg (to 40 mg or 60 mg daily) if the CGI-Severity score was unchanged or worsened from baseline. Patients who did not tolerate a dosage increase (to either 40 mg or 60 mg daily) could have the dosage reduced to 20 or 40 mg daily, respectively. Once a dose was reduced to a tolerated level, no further dose adjustments were permitted. Patients randomized to the placebo treatment group received three placebo capsules daily throughout the study. The primary efficacy measure was the CY-BOCS (Goodman et al., 1989). The CY-BOCS is a 10-item anchored ordinal scale (0–4) that rates the clinical severity of the disorder by scoring the time occupied, degree of life interference, subjective distress, internal resistance, and degree of control for both obsessions and compulsions. It has been validated for use with pediatric subjects. Five items are specific for compulsive symptoms, and the other five are specific for obsessive symptoms (Scahill et al., 1997). Other measures used to assess severity of OCD were the CGI-Severity Scale (Guy, 1976), the CGI-Improvement Scale (Guy, 1976), the Patients Global Impressions (PGI) Scale (Guy, 1976), the NIMH GOCS (Murphy et al., 1982) and the OCD Impact Scale (Piacentini, 1999). In addition, patients were assessed for depression and anxiety with the CDRS-R (Poznanski et al., 1985) and the Multidimensional Anxiety Scale for Children (MASC) (March et al., 1997), respectively. Patients were seen 10 times during the course of the study: 1 week prior to randomization (visit 1), at randomization/baseline (visit 2), weekly for the first 5 weeks of treatment (visits 3–7) biweekly for the next 4 weeks of treatment (visits 8 and 9) and at the end of the 13week treatment period (visit 10). The CY-BOCS, NIMH GOCS, and CGI-Severity scales were evaluated at every visit. The CGIImprovement scales (rated by parent and by clinician) and the PGI scale were collected at each postbaseline visit. At weeks 0, 5, and 13
774
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
METHOD Patient Selection Criteria
FLUOXETINE IN PEDIATRIC OCD
and at early discontinuation, the CDRS-R and MASC were administered. The OCD Impact Scale was administered 1 week before baseline, at weeks 5 and 13, and at early discontinuation. Adverse events, blood pressure, heart rate, height, and weight were monitored and recorded at each visit. Adverse events were noted by general inquiry rather than by use of a checklist or other structured inquiry. Blood for electrolyte, liver, and renal function and complete blood count assay was drawn at weeks –1 and at week 10 or early discontinuation. Statistical Method The sample size of the study was chosen to ensure that a 4.8-unit treatment difference in CY-BOCS Total score would be detected with approximately 80% power. All analyses were intent-to-treat. For evaluation of continuous efficacy and safety data, the last-observationcarried-forward change from baseline to endpoint or endpoint score was analyzed with analysis of variance (ANOVA), with treatment and investigator as independent factors in the model. Effect size was calculated as the difference in treatment least square means divided by the square root of the mean square error. Forty percent or greater reduction in CY-BOCS total score was the a priori definition of response for this study. The percentage of responders was evaluated across treatment groups using an exact Mantel-Haenszel test with investigator as the stratification variable. The percentage of patients rated as much or very much improved by clinicians, parents, and patients on the CGI-Improvement and PGI scales (post hoc analyses) were also evaluated across treatment groups with an exact Mantel-Haenszel test. Repeated-measures analysis of the CY-BOCS total score was conducted to assess the temporal change over visits. For analyses of safety categorical data, Fisher exact test was used. For subgroup analyses of categorical data, the Breslow-Day test for homogeneity of odds ratio was used. Investigators with fewer than two randomized patients per treatment group were pooled for statistical analysis. RESULTS Patient Characteristics and Baseline Severity
Of 148 patients who initially entered the study, 103 met eligibility criteria after the baseline evaluation period, were randomized to either fluoxetine (n = 71) or placebo (n = 32), and had at least one postbaseline visit. Demographic data and baseline OCD severity were similar for both groups (Table 1). The mean daily dose for the fluoxetine treatment group was 24.6 mg. Of the 71 patients enrolled in the fluoxetine treatment group, 16 (23%) had a final dose of 40 mg daily, and 15 (21%) had a final dose of 60 mg daily.
TABLE 1 Baseline Demographics, Patient Characteristics, and Severity of Disease
Gender Female Male Age (years) Age category Childrene Adolescents f Race White Hispanic African descent Asian descent Other or mixed Height (cm) Weight (kg) CY-BOCS Total g CY-BOCS Obs h CY-BOCS Comp i NIMH OCD j OCD Impact k CGI-Severity l
Fluoxetine a
Placebob
p Value
37 (52) 34 (48) 11.4 ± 3.0
17 (53) 15 (47) 11.4 ± 2.8
1.00c
51 (72) 20 (28)
24 (75) 8 (25)
.814c
62 (87) 4 (6) 2 (3) 0 3 (4) 146.7 ± 16.6 46.2 ± 20.9 24.5 ± 5.1 11.9 ± 3.3 12.6 ± 2.9 9.0 ± 1.4 40.8 ± 25.7 4.6 ± 0.7
27 (84) 3 (9) 0 1 (3) 1 (3) 144.4 ± 14.3 41.6 ± 13.6 26.3 ± 4.6 12.6 ± 3.1 13.7 ± 2.5 9.5 ± 1.6 36.4 ± 22.6 4.8 ± 0.8
.538c
.847d
.574d .287d .132d .443d .094d .157d .110d .115d
Note: Values represent number (percent) or mean ± SD. OCD = obsessive-compulsive disorder. a n = 71 for all values, except OCD Impact for which n = 60. b n = 32 for all values, except OCD Impact for which n = 29. c p Value determined using Fisher exact test. d p Value determined using type III sum of squares from an analysis of variance: PROC GLM model = investigator and treatment. e Children = at least 7 and younger than 13 years of age. f Adolescents = at least 13 and younger than 18 years of age. g Children’s Yale-Brown Obsessive Compulsive Scale total score. h CY-BOCS Obsessions subtotal score. i CY-BOCS Compulsions subtotal score. j National Institute of Mental Health Global OCD Scale. k Obsessive Compulsive Disorder Impact Scale. l Clinical Global Impressions-Severity Scale.
Compared with placebo, fluoxetine was associated with significant reduction of OCD severity as measured by total CY-BOCS score (p = .026) (Table 2 and Fig. 1). The difference between fluoxetine and placebo tended toward significance at week 5 (p = .086) and was significant (p < .05) at all subsequent patient visits (Fig. 1). The
consistency of efficacy in CY-BOCS total score was examined in an additional ANOVA that included factors for age category (children aged 7–12 versus adolescents aged 13–17) and the interaction of age by treatment. The effects of fluoxetine treatment on OCD symptoms were comparable in children and adolescents (age by treatment interaction, p = .819). In this study, patients with a 40% or greater reduction in their CY-BOCS total score from baseline to endpoint were classified as responders. In the fluoxetine treatment group, 35 of 71 patients (49%) were responders. In the placebo group, 8 of 32 patients (25%) were responders. This difference was significant (Mantel-Haenszel exact test p value = .030).
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
775
Efficacy
GELLER ET AL.
TABLE 2 Change in Severity of Disease From Baseline to Endpoint Analyses
CY-BOCS Totald CY-BOCS Obs e CY-BOCS Comp f NIMH OCD g OCD Impact h CGI-Severity i
Fluoxetinea
Placebob
p Value c
Effect Size
–9.5 ± 9.2 –4.7 ± 4.8 –4.8 ± 5.0 –3.1 ± 3.0 –16.4 ± 19.2 –1.3 ± 1.3
–5.2 ± 7.4 –3.0 ± 4.3 –2.2 ± 4.5 –1.3 ± 2.2 –7.1 ± 15.4 –0.6 ± 1.0
.026 .102 .015 .003 .017 .009
0.5 0.4 0.5 0.7 0.6 0.6
Note: There was no significant treatment by investigator interaction in any of the above variables; all scores are presented as mean ± SD. All analyses are intent-to-treat. a For CY-BOCS Total, CY-BOCS Obsessions, CY-BOCS Compulsions, NIMH OCD, and CGI-Severity, n = 71. For OCD Impact, n = 55. b For CY-BOCS Total, CY-BOCS Obsessions, CY-BOCS Compulsions, NIMH OCD, and CGI-Severity, n = 32. For OCD Impact, n = 28. c p Value determined using type III sum of squares from an analysis of variance: PROC GLM model = investigator and treatment. d Children’s Yale-Brown Obsessive Compulsive Scale total score. e CY-BOCS Obsessions subtotal score. f CY-BOCS Compulsions subtotal score. g National Institute of Mental Health Global OCD Scale. h Obsessive Compulsive Disorder Impact Scale. i Clinical Global Impressions-Severity Scale.
Clinicians rated 55.0% of fluoxetine-treated patients as much improved or very much improved (a score of 1 or 2 on the CGI-Improvement scale), compared with 18.8% of placebo-treated patients (p < .001). Parents’ and patients’ ratings of much or very much improved were also more prevalent for the fluoxetine treatment group than for the placebo treatment group (score of 1 or 2 on the CGI-Improvement scale as assessed by parents: 57.7% and 9.4%, respectively, p < .001; score of 1 or 2 on the PGI scale: 59.1% and 21.9%, respectively, p < .001). Fluoxetine was not associated with increased anxiety; change in MASC total score was –9.0 ± 18.6 for fluoxetine and –4.5 ± 16.5 for placebo (p = .163). The difference between fluoxetine and placebo for improvement in CDRS-R total score, used to assess depression, was not significant (–1.6 ± 7.6 and 0.5 ± 7.6, respectively, p = .118). The CDRS-R Mood subtotal was the only subtotal for which change from baseline was significantly different between treatment groups (fluoxetine: –1.0 ± 2.6, placebo: 0.0 ± 2.5, p = .004). Safety
Fig. 1 Temporal assessment of change in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score. Repeated-measures analysis of the change from baseline in least square means of CY-BOCS for placebo and fluoxetine treatment groups at each scheduled visit. Asterisks indicate time points at which there is a statistically significant difference between the mean fluoxetine and placebo values (p < .05).
The percentage of patients who completed the study was similar for both groups (fluoxetine: 49 [69.0%] of 71 patients; placebo: 20 [62.5%] of 32 patients, p = .651). There was no significant difference between study groups in the percentage of patients who discontinued because of lack of efficacy (fluoxetine: 10 [14.1%] of 71 patients; placebo: 8 [25%] of 32 patients, p = .261). One patient in the fluoxetine treatment group discontinued because of protocol requirement, and three patients in this treatment group discontinued because of patient decision. No patients in the placebo treatment groups discontinued for either of these reasons (p = 1.00 and 0.550, respectively). One patient in each treatment group discontinued as a result of physician decision (p = .527). One patient in each treatment group was lost to follow-up (p = .527). The percentage of discontinuations because of adverse events was similar in both groups (fluoxetine: 6 [8.5%] of 71 patients; placebo: 2 [6.3%] of 32 patients, p = 1.00). The fluoxetinetreated patients discontinued because of headache, hyperkinesia, abnormal liver function tests, manic reaction, nervousness, or somnolence. The placebo-treated patients discontinued because of hyperkinesia or nervousness. Of the 103 randomized patients in this study, 80 (78%) reported at least one treatment-emergent adverse event. There was no significant difference between treatment groups in the number of patients who reported adverse
776
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
FLUOXETINE IN PEDIATRIC OCD
events. In addition, no single treatment-emergent adverse event occurred significantly more often in fluoxetinetreated patients compared with placebo-treated patients (Table 3). There were no statistically significant differences in treatment-emergent abnormal (out-of-referencerange) laboratory values between the two treatment groups. In addition, subgroup analyses of adverse events suggested there were no clinically significant differences in safety profile for subgroups by age or gender. Vital signs, including sitting blood pressure and heart rate, height, and weight, were recorded at each visit. Table 4 summarizes the change from baseline to endpoint for the vital signs collected during the study. There were significant differences between the treatment groups for the change in weight (p = .002), sitting systolic blood pressure (p = .044), and sitting diastolic blood pressure (p = .026). Fluoxetine was associated with mild weight loss and slight decreases in blood pressure, whereas placebo was associated with mild weight gain and small increases in blood pressure.
TABLE 4 Change From Baseline to Endpoint Analysis in Vital Statistics
Weight (kg) Height (cm) Systolic BP Diastolic BP Heart rate
Fluoxetine n = 71
Placebo n = 32
p Valuea
–0.2 ± 2.0 0.9 ± 1.7 –0.1 ± 11.6 –0.7 ± 9.8 –0.2 ± 13.1
1.0 ± 1.3 1.2 ± 2.0 4.0 ± 11.7 4.8 ± 15.9 3.2 ± 14.1
.002 .823 .044 .026 .225
Note: Intent-to-treat analysis. Vital statistics are presented as mean ± SD. BP = blood pressure. a p Value determined were determined using type III sum of squares from an analysis of variance: PROC GLM model = investigator and treatment.
p Value determined with Fisher exact test; intent-to-treat analysis.
Fluoxetine 20 to 60 mg daily was significantly more effective than placebo in the treatment of OCD in this pediatric population, as demonstrated by greater reductions from baseline to endpoint in CY-BOCS total score. Fluoxetine-treated patients also demonstrated higher rates of response (defined as 40% or greater reduction in CY-BOCS total score from baseline to endpoint) compared with placebo-treated patients. The results of this study are consistent with the growing body of evidence that shows the efficacy of fluoxetine for the treatment of OCD in children as well as adults (Montgomery et al., 1993; Riddle et al., 1992; Tollefson et al., 1994a,b; Zitterl et al., 1999). Comparisons of drug effects across clinical trials are problematic because of differences in methodologies, protocols, inclusion/exclusion criteria, clinical study populations, and study duration. Although these limitations must be considered, our findings suggest that fluoxetine may be comparable to other agents in reducing OCD symptom severity. For example, in an 8-week trial of clomipramine and a 12-week trial of sertraline, 60% and 42%, respectively, of patients receiving study drug were rated by clinicians as much or very much improved (CGI-Improvement score of 1 or 2) (DeVeaugh-Geiss et al., 1992; March et al., 1998). In this study 55% of patients receiving fluoxetine were rated as much or very much improved. Repeated-measures analyses of CY-BOCS total score were performed to assess temporal changes in score over the course of the study (Fig. 1). The difference between treatment groups in mean change in CY-BOCS total score tended toward significance as early as week 5 (p = .086) and was statistically significant at each subsequent visit for the duration of the study. This time to onset of significant clinical improvement is slightly longer than that reported for other antidepressants (DeVeaugh-Geiss et al., 1992;
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
777
DISCUSSION
In a double-blind study evaluating 13 weeks of acute therapy with fluoxetine 10 to 60 mg daily (n = 71) versus placebo (n = 32) in pediatric outpatients with OCD, fluoxetine was shown to be both effective and well tolerated. A total of 69 patients (49 fluoxetine, 20 placebo) completed the entire study. The treatment groups were well balanced with respect to demographic characteristics and clinical features at baseline. TABLE 3 Adverse Events Reported by at Least 10% of Patients in Fluoxetine Treatment Group, by Body System Fluoxetine
Overall Body as a whole Headache Abdominal pain Fever Respiratory system Rhinitis Pharyngitis Digestive system Nausea Diarrhea Nervous system Hyperkinesia Insomnia a
Placebo
n = 71
%
n = 32
%
p Valuea
53
74.6
27
84.4
.317
20 11 8
28.2 15.5 11.3
9 6 2
28.1 18.8 6.3
1.000 .776 .720
19 10
26.8 14.1
8 5
25.0 15.6
1.000 1.000
9 9
12.7 12.7
4 1
12.5 3.1
1.000 .167
9 9
12.7 12.7
1 3
3.1 9.4
.167 .750
GELLER ET AL.
March et al., 1998; Riddle et al., 1996). A more gradual titration schedule with a 2-week lead-in period, during which patients received only 10 mg/day of fluoxetine, may have contributed to the more gradual onset of effect. However, stepwise dosing presumably also allowed acclimation and increased tolerability. One measure of secondary depression (the CDRS-R Mood subtotal) showed a significantly greater improvement in fluoxetine-treated subjects (p = .004). Other indices of anxiety and depression (MASC and CDRS-R total scores) did not reach statistical significance. Because the protocol exclusion criteria resulted in a population with a low incidence of secondary major depressive disorder (5% of subjects) our findings do not permit any conclusions to be drawn from this trial with regard to the efficacy of fluoxetine for comorbid depression in pediatric OCD subjects. The safety profile of fluoxetine in the children and adolescents in this study compares favorably with that that observed by Riddle and colleagues (1992) in children and adolescents and by Tollefson and colleagues (1994a,b) in adults with OCD. No statistically significant differences in treatment-emergent, out-of-reference-range laboratory values were found between the two groups. In addition, fluoxetine and placebo treatment groups were comparable in terms of the total percentage of patients reporting adverse events and the percentage of patients reporting any single adverse event. Although diarrhea and hyperkinesia were reported more frequently in fluoxetine-treated patients than in placebo-treated patients (13% versus 3%), there was no statistical difference between treatment groups in the number of patients reporting either of these adverse events. None of the patients in either group discontinued the study as a result of the occurrence of diarrhea; one patient each in the fluoxetine and placebo treatment groups discontinued as a result of hyperkinesia. The percentage of patients completing this study was comparable across treatment groups. However, the completion rate was slightly lower than has been reported for other controlled clinical trials of treatments for pediatric OCD (DeVeaugh-Geiss et al., 1992; Flament et al., 1985; Leonard et al., 1989; March et al., 1998), all of which were of a shorter duration than the trial reported here. Statistically significant but clinically insignificant differences in weight change and blood pressure were noted between treatment groups over the course of this study. Slight weight loss has been observed in acute fluoxetine treatment studies of adults (Michelson et al., 1999;
Tollefson et al., 1994b). Similarly small but statistically significant differences in weight change between active drug and placebo were also found in studies of clomipramine (DeVeaugh-Geiss et al., 1992) and sertraline (March et al., 1998) treatment of pediatric OCD. Although these changes were not considered clinically relevant in this study, the findings suggest clinicians should monitor these parameters during treatment.
778
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
Limitations
Although this study found that dose titration of fluoxetine to a maximum of 60 mg/day significantly reduced the severity of OCD symptoms in children and adolescents, the design of the study did not allow for a comparison of efficacy between fixed doses of fluoxetine. Dosage increases were given to all patients who did not respond to 4 weeks of treatment with fluoxetine. Thus, for those patients who did not respond in the first 4 weeks, but later responded to 40 or 60 mg daily, it is not possible to determine how much the improvement in symptomology was caused by the dosage increase and how much improvement, if any, would have occurred with a longer trial of fluoxetine 20 mg. Patients who enrolled in this study were predominantly white. Although no significant differences between whites and members of ethnic minority groups were observed in this study, the number of ethnic minority group members was too small to conclude that fluoxetine efficacy and safety are constant across ethnic groups. In addition, this study does not provide information regarding the longer-term (6 months and longer) safety and efficacy of fluoxetine for the treatment of pediatric OCD. Clinical Implications and Conclusions
Fluoxetine 20 to 60 mg daily was associated with significantly greater reduction on multiple measures of OCD symptom severity compared with placebo. In addition, fluoxetine 20 to 60 mg daily was well tolerated in these children and adolescents. REFERENCES American Academy of Child and Adolescent Psychiatry (1998), Practice parameters for the assessment and treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 37:27S–45S American Psychiatric Association (1994), Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Washington, DC: American Psychiatric Association DeVeaugh-Geiss J, Moroz G, Biederman J et al. (1992), Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder: a multicenter trial. J Am Acad Child Adolesc Psychiatry 31:45–49
FLUOXETINE IN PEDIATRIC OCD
Douglass HM, Moffitt TE, Dar R, McGee R, Silva P (1995), Obsessivecompulsive disorder in a birth cohort of 18-year-olds: prevalence and predictors. J Am Acad Child Adolesc Psychiatry 34:1424–1431 Emslie GJ, Rush AJ, Weinberg WA et al. (1997), A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–1037 Flament MF, Rapoport JL, Berg CJ et al. (1985), Clomipramine treatment of childhood obsessive-compulsive disorder: a double-blind controlled study. Arch Gen Psychiatry 42:977–983 Geller DA, Biederman J, Jones J, Shapiro S, Schwartz S, Park KS (1998), Obsessive-compulsive disorder in children and adolescents: a review. Harvard Rev Psychiatry 5:260–273 Geller DA, Biederman J, Reed ED, Spencer T, Wilens TE (1995), Similarities in response to fluoxetine in the treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 34:36–44 Goodman WK, Price LH, Rasmussen SA et al. (1989), The Yale-Brown Obsessive Compulsive Scale. Arch Gen Psychiatry 46:1006–1011 Guy W (1976), Assessment Manual for Psychopharmacology, Revised (DHEW Publication ABM 76-366). Washington, DC: US Government Printing Office Leonard HL, Swedo SE, Rapoport JL et al. (1989), Treatment of obsessivecompulsive disorder with clomipramine and desipramine in children and adolescents: a double-blind crossover comparison. Arch Gen Psychiatry 46:1088–1092 March JS, Biederman J, Wolkow R et al. (1998), Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA 280:1752–1756 March JS, Leonard HL, Swedo SE (1995), Neuropsychiatry of obsessivecompulsive disorder in children and adolescents. Compr Ther 21:507–512 March JS, Parker JD, Sullivan K, Stallings P, Conners CK (1997), The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity, J Am Acad Child Adolesc Psychiatry 36:554–565 Michelson D, Amsterdam JD, Quitkin FM et al. (1999), Changes in weight during a one-year trial with fluoxetine. Am J Psychiatry 156:1170–1176 Montgomery SA, McIntyre A, Osterheider M et al. (1993), A double-blind, placebo-controlled study of fluoxetine in patients with DSM-III-R obsessive-compulsive disorder. Eur Neuropsychopharmacol 3:143–152 Murphy DL, Pickar D, Alterman IS (1982), Methods for the quantitative assessment of depressive and manic behavior. In: The Behavior of Psychi-
atric Patients, Burdock EL, Sudilovsky A, Gershon S, eds. New York: Marcel Dekker pp 355–392 Piacentini J (1999), Cognitive behavior therapy of childhood OCD. Child Adolesc Psychiatr Clin N Am 8:599–616 Poznanski EO, Freeman LN, Mokros HB (1985), Children’s Depression Rating Scale-Revised. Psychopharmacol Bull 21:979–989 Riddle MA and Pediatric OCD Research Group (1996), Fluvoxamine in the treatment of OCD in children and adolescents: a multicenter, doubleblind, placebo-controlled trial (abstract NR-197). Presented at the Annual Meeting of the American Psychiatric Association, New York Riddle MA, Scahill L, King RA et al. (1992), Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessivecompulsive disorder. J Am Acad Child Adolesc Psychiatry 31:1062–1069 Rosenberg DR, Stewart CM, Fitzgerald KD, Tawile V, Carroll E (1999), Paroxetine open-label treatment of pediatric outpatients with obsessivecompulsive disorder. J Am Acad Child Adolesc Psychiatry 38:1180–1185 Scahill L, Riddle MA, McSiggin-Hardin M et al. (1997), Children’s YaleBrown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry 36:844–852 Tadai T, Nakamura M, Okazaki S, Nakajima T (1995), The prevalence of obsessive compulsive disorder in Japan: a study of students using the Maudsley Obsessional-Compulsive Inventory and DSM-III-R. Psychiatry Clin Neurosci 49:39–41 Thomsen PH (1997), Child and adolescent obsessive-compulsive disorder treated with citalopram: findings from an open trial of 23 cases. J Child Adolesc Psychopharmacol 7:157–166 Tollefson GD, Birkett M, Koran L, Genduso L (1994a), Continuation treatment of OCD: double-blind and open-label experience with fluoxetine. J Clin Psychiatry 55:69–78 Tollefson GD, Rampey AH Jr., Potvin JH et al. (1994b), A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 51:559–567 Zitterl W, Meszaros K, Hornik K et al. (1999), Efficacy of fluoxetine in Austrian patients with obsessive-compulsive disorder. Wien Klin Wochenschr 111:439–442 Zohar AH (1999), The epidemiology of obsessive-compulsive disorder in children and adolescents. Child Adolesc Psychiatr Clin N Am 8:445–460
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 7 , J U LY 2 0 0 1
779