Similarities in Response to Fluoxetine in the Treatment of Children and Adolescents with Obsessive-Compulsive Disorder

Similarities in Response to Fluoxetine in the Treatment of Children and Adolescents with Obsessive-Compulsive Disorder DANIEL A. GELLER, M.B.B.S., F.R.A.C.P., JOSEPH BIEDERMAN, M.D., ELLEN D. REED, B.A., THOMAS SPENCER, M.D., AND TIMOTHY E. WILENS, M.D.

ABSTRACT Objective: Obsessive-compulsive disorder (OCD) is a relatively common disorder that frequently has its onset in

childhood and is associated with substantial morbidity and dysfunction despite availability of new treatments. However, antiobsessional agents have not been systematically evaluated in young children and their effectiveness beyond the short term has not been well studied. The purpose of this study was to evaluate the usefulness of fluoxetine in the long-term treatment of both children and adolescents with OCD. Method: All pediatric patients with a OSM-III-R diagnosis of OCD who were treated with fluoxetine were ascertained from retrospective chart reviews of a pediatric psychopharmacology clinic. Response to treatment was evaluated by experienced clinicians using the Clinical Global Impression Scale. Results: Of 38 identified patients, 28 (74%) showed moderate to marked improvement of OCD symptoms on doses averaging 50 mg/day (1.0 mg/kg per day) over an average follow-up period of 19 months. Similar effects were observed in children and adolescents. Conclusion: Although limited by their retrospective nature, these findings indicate that fluoxetine may be effective in prepubertal children and that the effect can be sustained over time.

J. Am. Acad. Child Ado/esc. Psychiatry, 1995, 34, 1:36-44. Key Words: obsessive-compulsive disorder, fluoxetine, children, adolescents.

Research over the last decade has greatly increased our knowledge and understanding of obsessive-compulsive disorder (OeD) across the life span. Recent epidemiological data have shown OCD to be as common a psychiatric disorder in juveniles as in adults. In the only pediatric epidemiological study to date, Flament et al. (1988, 1989) found point and lifetime prevalence rates for OCD of 1.0% and 1.9%, respectively, in a survey of more than 5,000 adolescents. This finding is consistent with prevalence data reported in the US Epidemiological Catchment Area survey of rates of 1.9% to 3.3% among adults (Karno et al., 1988) and the finding that 65% of obsessive individuals develop their illness before age 25 years (Rasmussen and Tsuang, Accepted June 16, 1994. From the Joint Program in Pediatric Psychopharmacology: Massachusetts General Hospital, Boston, MA, and Mclean Hospital, Belmont, MA. Reprint requeststo Dr. Geller, Pediatric Psychopharmacology Unit, McLean Hospital, 115 Mill Street, Belmont, MA 02178; telephone: (617) 855-2846; ftx: (617) 855-3722. 0890-8567/95/340 1-0036$03.00/0© 1995 by the American Academy of Child and Adolescent Psychiatry.

36

1984). Because of the clinical similarities between juvenile and adult forms of OCD (Rapoport et al., 1992; Swedo et al., 1989), this disorder is less vulnerable to the diagnostic uncertainties facing other childhood disorders. In recent years, several controlled investigations established the efficacy and relative safety of the serotonergic tricyclic antidepressant clomipramine (CM!) in the short-term treatment of juvenile OCD. Using crossover designs, initial studies conducted at the National Institute of Mental Health (NIMH) showed that CMI treatment was clearly superior to a placebo in the treatment of children and adolescents with OCD (Flament et al., 1985; Leonard et al., 1988, 1989, 1991). In the most comprehensive study of CMI in juvenile OCD to date, DeVeaugh-Geiss et al. (1992) reported results from a multisite controlled study of CMI versus placebo using a parallel design methodology. Despite highly statistically significant results, the overall rate of improvement was not larger than 60% with an effect size of up to 40%. Although encouraging, these

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 34:1, JANUARY 1995

f'LUOXET IN E I N JU V ENIL E O CD

results also ind icate that CMI treatment of juveniles with OCD leaves many subjects un imp roved and that th ose who im prove may cont inue to have substant ial residu al sympto matology. In addition, treatment with C M I was associated with a variety of adverse effects including ant icholinergic sym ptoms (i.e., dry mouth, 63 % ; tremor, 33%), dizziness (4 1%), and sedation (46%) , making it difficult to tolerate for some pat ients even in the cont ext of a robust clin ical response (DeVeaugh-G eiss et aI., 1992). Taken togeth er, these results suppo rt the continued search for alternative safe and effective treatments for juveniles with OCD. O ne such alternative treatment is th e selective serotonin uptake inhibitor fluoxetine. Flu oxetine is a bicyclic compound widely used in the treatment of adult depression. Fluoxetine is a long- acting agent with a half-life of approxima tely 7 days for the parent compound and its active metabolit e norfluoxetine. Four small reports (<15 subjects), including three open-label and one cont rolled trial (Table 1), have suggested that this medicin e may also be efficacious in the short- term management of children and ado lescents with O CD (Como and Kurian, 1991; Liebowitz et al., 1990 ; Riddl e et aI., 1990a, 1992 ). Riddl e et al. (1992) reported results of the onl y controlled study of fluoxetine in 14 patients using a crossover design. Their results showe d that altho ugh Huoxet ine was super ior to a placebo, the effect size was not larger than 44% (Riddle et aI., 1992). One reason for a relatively mod est response to Huoxetine could be related to dosing. For exam ple, in Riddle and cowo rkers' study, the average daily dose used was only 20 mg. Studies of Huoxetine in adults with OCD suggest that relatively high doses of this medication are needed to treat OCD patients. For example, Fontaine and C ho uinard (1986 ), T urne r et al. (1985 ), and

Jen ike et al. (1989) all used doses of 80 mg da ily an d reported significant imp rovement in O CD sym pto matology. Considering an average ad ult weight of 70 kg, this would represent approx ima tely 1 mg/k g per day. T his daily dose is mu ch higher that th e estimated less than 0.5 mg/kg per day in th e Riddl e study. Thus, it is possible that high er doses of fluoxetine may have produced more robu st result s. D espite the increasing recogn ition that OCD affects both pre- and postpubertal juven iles, almost all available data on the pharmacotherapy of th is disorder are from ado lescent subjects. For exampl e, in two separate studies from the NIMH reporting results of double-blind controlled trials of CMI in juvenile OCD, the mean age of participating subjects was 15 years (Flament et aI., 1985; Leonard et aI., 199 1). A similar mean age for partici pating subjects was reported in the largest ph arm acotherapy study of juvenile O CD to dat e by DeVeaugh-Geiss (1992 ). Similarly, as sum marized in T able 1, the experien ce of Huoxetine in juven ile O CD reported so far includes mostly ado lescents. C onside ring that earlier treatment of thi s disord er may be imp ortant to avoid th e secondary morbidi ty arising from ch ronic untreated sym pto ms, more informatio n is needed regard ing efficacy and tolerance of Huoxetine in prepubertal childre n with OCD. Since th e existing literature on selective sero to nin reupta ke inh ibitors in juvenile OCD addressed onl y th e sho rt- term effects of th ese treatm ents, an important limitation in interpreting the available results pertains to th eir long-term effects. Considering that the available follow-up data in juveniles docum ent the persistence of O C D symptoms over many years in the majority of cases (Flament et aI., 1990 ; H ollin gsworth et aI., 1980 ; Leon ard et al., 1993 ), th ere is a need to evaluate

TABLE 1 Review of Pub lished Repo rts of Fluoxetine in Juven ile O bsessive-Compu lsive Disord er Mean D ose (mg/ day)

Mean Length of T reatment (wk)

Responder s (0/0)

Effect Size (0/0)

20 70 30 20

4-20 ~ 8 28 20

50 50 54-85 NA

30-57 50 35 33-44

Fluo xer ine

Stu dy Riddle er al., 1990a Liebowitz er al., 1990 Co mo & Kuria n, 199 1 Riddle et al., 1992

De sign O pen O pen Open Co ntrolled

N (% :$ 12 yr)

10 8 13 14

(33) (0) (NA) (50)

Age Range (M ean, yr)

8-15 12-1 7 6-1 7 8- 15

(12.2) (NA) (12) (11.8)

Note: NA ; no t available.

] . AM . ACA D . C H I LD ADOLE S C . PSYC H IATRY . 3 4 : 1, JANUARY 19 9 5

37

GELLER ET AL.

whether the therapeutic effects of treatment persist beyond the short term. The purpose of this report is to fill some of the gaps in our available knowledge about the role of fluoxetine in juvenile OCD as it is used clinically in a naturalistic setting. Specifically, we wanted to assess (1) whether robust doses of this medicine are needed to achieve an adequate clinical response; (2) whether the effects of fluoxetine can be sustained over time; and (3) whether fluoxetine is efficacious and well tolerated in both prepubertal and postpubertal subjects. To this end we conducted a systematic chart review of all children and adolescents diagnosed with OCD and treated with fluoxetine at our center. We hypothesized that (1) high doses of fluoxetine would be necessary for a clinical response in children and adolescents with OCD; (2) treatment response could be maintained over time; and (3) there are no differences in response between children and adolescents. To our knowledge, this represents the largest series of fluoxetine treatment of juvenile OCD in a naturalistic setting reported to date and one of the largest pharmacological series of OCD in juveniles.

METHOD Subjects in this study were ascertained from a specialized pediatric psychopharmacology center. Computerized records were searched for all parienrs diagnosed with DSM-Ill-R OCD and treated with Auoxetine from June 1991 (the start of the computerized data base) unril the ptesenr. The complete medical records of all identified subjects (n = 38) were reviewed for age and duration of symptoms at presentation, the presence and frequency of comorbid diagnoses, family history of Axis I psychiatric diagnoses, previous and concurrenr medication trials, treatment with behavioral therapy, adverse effects, and response to treatmenr as recorded by the clinicians. Clinical diagnoses were made by the treating child psychiatrists using DSM-Ill-R criteria based on inrerviews with the parenrs and child and upon review of school and psychological testing information. Family history data represenr a review of information available in the patient's medical record. The dose of Auoxetine was adjusted by the clinicians depending on response and adverse effects with the aim of using the lowest dose that achieved an acceptable clinical response. For the purpose of this report doses of Auoxetine were coded as total daily doses in milligrams per day and also as weight-corrected doses. For patients without available recorded weights (n = 15), weights were imputed using the 50th percenrile value for children of the same age and sex from standardized growth charts. The extenr of response of obsessive-compulsive symptoms to Auoxetine treatment was evaluated by the treating child psychiatrist by review of the clinical notes and verified by the senior author (D.A.G). The rating scales used were the subscales of the Clinical Global Impression (CGl) scale, which includes a Severity scale

38

(I = not ill, 7 = extremely ill) and an Improvemenr scale (I = markedly improved, 4 = no change, 7 = very much worse) (NIMH, 1985). Conrinuous data between groups were analyzed by unpaired Student's t tests and within groups across time by paired Student's t tests. Categorical data were examined by X2 analyses. All tests were two tailed and statistical significance was defined at the 5% level. Associations between continuous variables were evaluated using Pearson correlations.

RESULTS Systematic review of records identified 38 patients with a diagnosis of OCD who had received treatment with fluoxetine; 20 were children (aged 12 years or younger) and 18 were adolescents (overall mean age ± SEM = 12.3 ± 0.53 years). Males (n = 24) outnumbered females (n = 14) by a ratio of 1.7 to 1. Mean (±SEM) duration of symptoms at presentation was 25 (±3) months (range 1 through 84 months). Two thirds of patients (n = 27) had at least one comorbid diagnosis. The average number of comorbid diagnoses per subject was 1.3 (Table 2). The most common DSM-III-R diagnoses seen were disruptive disorders (n = 13), mood disorders (n = 9), anxiety disorders (n = 7), and chronic tic disorders (n = 6). There were no significant differences between children and adolescents or between genders in the number of comorbid diagnoses at the time of evaluation (p > .5). In 79% of cases family histories were positive (n = 30) for the presence of at least one Axis I psychiatric illness (Table 2). Fifty-five percent of subjects (n = 21) had received no medication treatment before receiving fluoxetine (Table 3). Children and adolescents were equally likely to have been medication-free at initial presentation. The remaining 45% (n = 17) of the subjects had received previous psychoactive medication, often for the management of comorbid conditions. Of these cases, four (11%) had been previously treated with CMI unsuccessfully. Six subjects (16%) had received fluoxetine before evaluation and treatment in our center, including two patients who subsequently responded to increased dosage (20 mg/day increased to 60 mg/ day) and two whose fluoxetine had been discontinued because of the emergence of suicidal ideation and hypomanic symptoms. In both of these latter cases, fluoxetine was successfully reintroduced in our clinic (in one case with the addition of lithium) and found to be effective. However, increasing the dosage (to

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 34:1, JANUARY 1995

FLUOXETINE IN JUVENILE OeD

TABLE 2 Clinical Characteristics of Subjects (N

Age group Child (6-12 yr) Adolescent (13-18 yr) Sex Male Female Comorbid diagnoses" Disruptive disorders ADHD Oppositional disorder Mood disorders Unipolar depression Bipolar depression Anxiety disorders Overanxious disorder Separation anxiety Chronic tic disorder Pervasive developmental disorder Psychosis NOS Other None Family history" Alcohol/substance Mood disorders Unipolar depression Bipolar depression Anxiety disorders Obsessive-compulsive disorder Other anxiety disorders Learning disorders Chronic tic disorder ADHD Psychosis Other None

=

38)

No.

%

20 18

53 47

24 14

63 37

13 12 2 9 8 1 7 5 2 6 3 2 6 11

34 32 5 24 21 3 18 13 5 16 8 5 16 29

11

29 21 18 5 24 21 3 16 11 13 8 13 21

8 7 2 9 8 1 6 4 5 3 5 8

Note: Mean (::'::SEM) age was 12.3 (::'::0.53) years. "Categories are not mutually exclusive. NOS = not otherwise specified; ADHD = attenrion-deficit hyperactivity disorder.

60 and 80 mg/day, respectively) of fluoxetine was ineffective in the remaining two children previously judged to be resistant to fluoxetine treatment. Other previous medication trials included tricyclic antidepressants other than CMI (n = 10), methylphenidate (n = 3), and antipsychotics (n = 2). One subject was receiving carbamazepine for a complex partial seizure disorder. Concurrent medications (Table 3) were used with fluoxetine in 15 subjects (39%), mostly for the treatment of comorbid conditions, and included tricyclic antidepressants other than CMI (n = 5), mood stabilizers (n = 5), benzodiazepines (n = 7), anripsychotics (n = 3), stimulants (n = 3), buspirone (n = 2), and

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 34:1, JANUARY 1995

clonidine (n = 1). CMI was used concurrently to augment the treatment of OCD in three patients, but it was not tolerated in one case and not effective in another (Table 3). Eleven subjects (29%) received some form of concurrent behavioral treatment from different therapists; in general, their baseline symptoms scores were slightly higher than the scores of those who did not receive behavioral treatment, but the difference was not statistically significant. Age and gender were examined for associations with the frequency and type of comorbid diagnoses, frequency of previous and concurrent medication trials, behavior therapy, and family psychiatric history. At baseline the children were indistinguishable from the adolescents with only one notable exception: family histories positive for the presence of OCD occurred almost entirely in the younger age group (X2 = 4.0, P < .05). Gender had little association with any dependent measure. The mean daily dose for the whole group was 50 mg (:+::26 mg) or 1.0 mg/kg per day (:+::0.4 mg/kg per day) when expressed as a weight-corrected value. When the dose was calculated for each age group, children received an average of 35 mg/day (0.9 mg/kg per day), TABLE 3 Previous and Concurrenr Medication Trials (N

Previous trials" Anriobsessionals Fluoxetine Clomipramine Tricyclic anridepressanrs Stimulants Anripsychotics Benzodiazepines Anriconvulsanrs None Concurrenr trials" Benzodiazepines Lithium Desipramine Nortriptyline Clomipramine Stimulants Antipsychotics Buspirone Carbamazepine Clonidine No~

=

38)

No.

%

8

10

21 16 16 26

3

8

2 2

5 5

6 6

1

3

21

55

7

18

4 3 2

11 8

3

8 8 8

3 3 2

2

5

5 5

1

3

23

61

"Categories ate not mutually exclusive.

39

GELLER ET AI..

and adolescents averaged 64 mg/day (1.1 mg/kg per day) (Table 4). Subjects were treated with fluoxet ine for an average of 19 months (range 4 to 34 months) . As wou ld be expected , those with marked improvement were treated for longer periods (mean = 24 months) and had sustained symptom remission compared to the patients without a clinically significant response (mean = 11 months). At the time of the last follow-up assessment, overall clinical global impressions of improvement were rated as much or very mu ch improved in 74% of pat ient s after treatment with Huoxerine; 15 patients (39%) were considered "very much improved," 13 (34%) "much improved," and 10 (26 %) "not improved" (Table 4). Severity of symptoms changed from 5.5 :±: 0.2 at baseline (marke dly to severely ill) to 3.4 :±: 0.2 at follow-up (mildly to moderately ill) (t = 11.44, P = .000 1), reflecting an overall effect size of 47% in symptom reduction for the group. Treatment appeared equally efficacious in pre- and postpubertal age groups (T able 4) and between sexes and was not influenced - by the presence of comorbid mood or anxiety diagnoses, or other treatments, including behavior therapy. Those subjects (n = 23) who received concurrent medications had similar baseline and posttreatment CG I scores (and CGI Improvement scores) compared to those without concurrent medications. Subjects with comorbid disrupti ve disorders (n

Fluo xetine was generally well tolerated. Side effect profiles did not cluster by age or sex and are shown in Table 5. Of interest, the eight subjects who developed behavioral activation/d yscontrol (Table 6) received a lower average dose of Huoxerine than the group as a who le (0.71 mg/kg per day versus 1.09 mg/kg per day; p = .03). Nevertheless, their OCD symptoms were equally responsive to treatment and they were not more likely to have had a coexisting mood or anxiety disorder. DISCUSSION

In the largest series to date of pediatric OCD subjects treated with Huoxetine in a naturalistic outpatient sett ing represent ing an entire clinic's experience, we found that (1) 74% of our juvenile patients with OCD required relatively high doses of fluoxetine to improve their OCD symptoms; (2) a clinical response could be sustained over a follow-up treatment period averaging 19 months; (3) children and adolescents responded similarly to treatment with fluoxetine; and (4) the effect size of fluoxetine treatm ent was not larger than 50%. These findings add new data to the small body of available literature on the dosing responsivity and efficacy of Huoxetine over a long treatment period in juvenile OCD, and they extend the examination of the antiobsessional properties of fluoxetine to prepubertal children.

3) showed a t rend toward

Our findings of a clinically ro b us t response to Huoxc -

greater improvement (p = .06) of their OCD symptoms compared to the grou p as a whole, as did tho se with a greater num ber of comorbid diagnoses (p = .04). No dose-response relatio nsh ip was found (r = .05).

tine in juveni le OCD are con sistent with several reports documenting the efficacy of serotonergic anti depres sant s in this disorder (DeVeaugh-Geiss et a!', 1992; Flament et a!', 1985; Leonard et a!', 1991; Riddle

=

]

TABLE 4 Fluoxetine Treatment by Age G roups

Age (yr ::':: SEM) Total daily dose (rug/day) W eight -correct ed dose (mg/kg /day) CG I baseline CG I Auoxetine Length of treatment (mo nt hs ::':: SEM) Imp rovement (%) Marked Moderate Minimal

C hild ren (n = 20)

Adolescents (n = 18)

T otal (N = 38)

9.9 ::':: 1.7

15.2::':: 1.5 64 I.I

12.3::':: 3.2 50 1.0 5.47 3.37* 19 ::':: 2

35 0.9 5.40 3.2' 15 ::':: 3

40 35

39 33

39.5 34 .2

25

28

26.3

, Versus C linical Global Impression (CG I) scale baseline; paired Student 's t test,

40

5.56 3.35' 21 ::':: 3

p < .000 1.

J. AM . ACA D . C H I LD AD O LESe. PSYCHI ATRY. 34:1. JA N UARY 19 9 5

FLUOXET IN E IN J UV ENI LE O C D

TABLE 5 Side Effecrs Repon ed on Fluoxerine (N Side Effecr None Beh avior al activation/dysconr rol In somnia Letha rgy/som no lence We ight cha nge Apperire cha nge Dry mouth H eada ch es M yoclonus In creased anxiety Brui sing Increased tics Picking at skin Stomach com plaints

=

38)

No .

%

15

39

8 6

21

4

II 8

3 3 2

2 I I I I I I

16

8

5 5 3 3

3 3 3 3

N ote: Ca tegories are nor m u tually exclusive.

et al., 1990a, 1992 ). While th ree large-scale controlled studies (DeVeaugh-Ge iss et al., 1992; Flament et al., 1985 ; Leon ard et al., 1991) do cumented the efficacy of CMI in juvenile O CD, there is only one small controlled (n = 14) and three small op en-label (n ~ 13) trials of fluoxetine in juvenile OCD (Table 1). Moreover, the only double-blind, placebo-controlled study of fluoxetine used a crossover design, which may not be ideal for a dru g with a very lon g half-life (7 days) such as Huo xerin e; even though the authors atte m pted to allow for th is by increasing the time on th e second agent by 4 weeks, the re rem ains an inh erent potential confounder of a carryover effect. The respon se rate of 74% observed in our sampl e was high er th an the 50 % response rate noted in the previously reported smaller series with fluoxetine (Liebowitz et al., 1990 ; Riddle et al., 1990 a, 1992 ). While this finding may be accounted for by the retrospective TABLE 6 Behavioral Acrivario n/Dysconrrol on Fluo xetinc (/1 = 8) Subject

2 3 4 5 6 7 8

Effecr Sclf-dcst rucrive out bursts; increas ed agitatio n and aggression Episodi c dyscontrol with aggressive out bursts M c rori e activation Agitation ; hypo man ia Mc rori e activation; aggression In creased agitation Moro ric activation, increased irritat ion In creased impulsivity; grandios ity; disinh ibiti on; hypom an ia

J . AM. ACA D. C H ILD AD O LESC. PSYCHIAT RY• .3 4 : 1, JANUAR Y 199 5

nature of our assessment methods, it could also be attributed to the higher daily doses used in our sam ple. The mean daily dose of Huoxetine of 50 mg/day used in our series was 2.5 times higher than the 20- mg dose used by Riddl e er a1. (1992) in their controlled study (Ta ble 1). Convert ing total da ily doses to weightcorr ected doses, the mean daily dose of f1uo xetine in this series was close to 1.0 mg/kg per day, con sistent with dosing levels of approximately 80 mg reported in studies of f1uoxetine in ad ult O CD subjects (Fonta ine and C ho uinard, 1986; Jenike et al., 1989; Levine et al., 1989; Pigott et al., 1990). Considering that children and adole scents gener ally have more active pharmacokinetic profiles and met abolize psycho tropics more rapidly than their adult counterparts (Bieder man et al., 1989; Preskorn , 1993; Wi lens et aI., 1992 ), they may need relat ively highe r doses than th ose required in adult samples to achieve comparable effects. Another possible explan ation for our respons e rate of 74% may be that this was du e to the use of con cur rent medications. However, in most cases the concurrent medications were used to treat com orbid disorders. This may suggest that adequ ate attention to the presence and treatment of com orbid conditions is a factor influenci ng the assessme nt of anriobsessional treatm ent. The response rate of 74% of juveniles with O eD treated with Huo xet ine observed in our sam ple is also consistent with tho se reported for C M I in juven ile OCD (De Veaugh-Ge iss et al., 1992 ; Flament et al., 1985; Leonard et al., 1989, 1991). If confirmed under controlled conditions, thi s result suggests that relatively high doses of Huox etine may have efficacy similar to that of C M f for juveniles with O CD . The response to Huoxerine observed in this study could have been du e to the open assessment method used. H owever, these result s are unlikely to be du e solely to assessment bias since previous stu dies of treatment of OCD in pediatric and adult sam ples have generally documented a low placebo response rate (D ominguez, 1992; Go odman et al., 1989; M avissakalian et al., 1990). For example, of the 60 patients in the multicenter CMf study (De Veaugh-Geiss et al., 1992), onl y 8% dem on strated a placebo respon se. While Leon ard (1989) also noted a low placebo response rate in juvenile OCD, other authors have reported higher rates in ch ildren with O eD (Flament er al., 1985; Foa et al., 1987; Riddle et al., 1992 ).

41

GELLER ET AL.

Although our results show that 74% of subjects were considered to be substantially improved, we found an effect size (a change in CGI scores from baseline to the fluoxetine-treated condition) of only 47%. Effect size refers to the degree to which core symptoms of the targeted syndrome are reduced or improved. This observed effect size is of the same order as that noted in previous studies of juveniles or adults with OCD (Clomipramine Collaborative Study Group, 1991; DeVeaugh-Geiss et al., 1992; Dominguez, 1992; Goodman et al., 1989, 1990; Riddle et al., 1992). Although the change was often experienced subjectively as great clinical relief, our results indicate that there remains substantial residual symptomatology in the majority of children with OCD, supporting the need for additional, more effective treatments for juveniles with this disorder. In contrast to previous reports on fluoxetine in juvenile OCD (Table 1), our sample included a sizable number of both children (:S12 years; n = 20) and adolescents (n = 18), which permitted comparison across the two age groups (Table 4). Our results showing a similar pattern of response to fluoxetine in children and adolescents at similar weight-adjusted doses provide support for the hypothesis that treatment response may not be affected by age group. Considering that the impairments associated with childhood-onset OCD may be further compounded by interference with the unique developmental tasks and milestones of childhood, early intervention with the affected prepubertal child may lead to a more successful outcome in adolescence and adulthood. The treatment response with fluoxetine was sustained over an average follow-up period of 19 months. Although current evidence indicates that most juvenile OCD patients appear to require long-term treatment to maintain symptomatic relief, most investigations to date have examined only the acute effects of drug treatments in juvenile OCD. In a recent report of long-term follow-up (mean = 3.4 years) of 54 children and adolescents with OCD, Leonard et al. (1993) found that 43% of subjects continued to meet diagnostic criteria for this condition and 70% were taking psychoactive medication at the time of follow-up. Our current findings, although preliminary, appear to indicate the potential long-term efficacy of fluoxetine in the treatment of juveniles with OCD.

42

Two of five subjects previously unresponsive to CMI responded to fluoxetine. In one of these two subjects, emergent side effects precluded the use of adequate doses of CMI, while in the other even apparently sufficient doses of CMI failed to produce an adequate response. Hence some OCD patients may respond to alternative serotonergic antidepressants when unresponsive to an initial drug trial. In this sample, the use of behavioral therapy in those subjects who received this form of treatment concurrently with fluoxetine did not appear to confound the analysis of their outcome as the magnitude of their response to treatment was identical with that of the remainder of the group. However, since this treatment was not systematically studied, this observation can only be construed as preliminary until confirmed in a controlled investigation. The clinical characteristics of our sample were similar to those of previously reported series of juvenile patients with OCD. The preponderance of males in early-onset OCD patients was noted by Swedo and Rapoport (1989) in an NIMH sample, whereas the somewhat older age group of the epidemiological study (Flament et al., 1988, 1989) had only a slight male preponderance (55%). These findings suggest an earlier age of onset of OCD in male pediatric subjects (Karno et al., 1988). Our findings of high levels of psychiatric comorbidity among juveniles with OCD (Table 2) are consistent with previous reports (Riddle et al., 1990b; Sweda et

al., 1989). In fact, only 29% of our sample had OCD as a single diagnosis. The finding that OCD subjects had high rates of depression and anxiety is consistent with other studies. Although limited by their retrospective nature, our findings suggest that treatment response appears to be independent of the presence of a comorbid mood or anxiety disorder. This outcome is consistent with results in adult samples which document that response to CMI was independent of comorbid depression (Goodman et al., 1990, 1992). This suggests that the observed response may have been due to the antiobsessional effects of the treatment rather than a nonspecific antidepressant or antianxiety effect of fluoxetine. A family history of OCD was positive in 20% of cases (n = 8), consistent with other reports (Lenane et al., 1990; Riddle et al., 1990b). It has been suggested that earlier onset of illness may be associated with increased genetic loading (Lenane et al., 1990). Our

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 34:1, JANUARY 1995

FLUOXETINE IN JUVENILE OeD

finding that seven of eight cases of pOSItive family history for OCD occurred in the youngest subjects may support this hypothesis, although it is also possible that parents with OCD may recognize the symptoms and seek treatment for their children earlier. More work needs to be done to clarify this important question. Previous follow-up reports have found that the presence in the family of any Axis I psychiatric disorder is associated with a poorer outcome in children and adolescents with OCD (Leonard et al., 1993). We found a similar trend in that those subjects with such a family history (Table 2) were more likely to be rated by their treating psychiatrist as unimproved. Side effects of Huoxetine treatment were generally well tolerated (Table 5). Thirty-nine percent (n = 16) of subjects did not report any adverse effect despite the relatively high doses used. The spectrum of Huoxetineassociated adverse effects is consistent with previous reports (Riddle et al., 1992) and is much more modest than that associated with CMI. We found no differences between the two age groups in the frequency or severity of adverse experiences. The most common side effect in our sample was of episodic behavioral dyscontrol, agitation, and motoric activation (21 %, n = 8) (Table 6). Others (King et al., 1991; Liebowitz et al., 1990; Riddle et al., 1990a, 1992) have noted similar effects. Of those subjects experiencing such side effects, two of six with unsuccessful previous trials responded well to treatment when fluoxetine was reintroduced and emergent side effects were managed more aggressively. For example, the addition of a mood-stabilizing agent in those who had nevertheless experienced a substantial positive clinical effect with fluoxetine allowed these patients to continue to benefit from relief of their OCD symptoms. The possibility that these symptoms represented an unmasking of hypomania in bipolar mood disorder by fluoxetine needs to be considered when using this medicine for OCD subjects, although we did not find these subjects more likely to have a comorbid mood or anxiety disorder or, indeed, a family history of mood or anxiety disorders. The findings discussed in this report should be viewed against their methodological limitations. The data presented are retrospective and as such are subject to observation and assessment biases. Diagnoses were made clinically without the use of structured interviews and may therefore suffer from underreporting. Specific and quantitative OCD rating scales were not always

J. AM. ACAD. CHII.D ADOI.ESC. PSYCHIATRY, 34:1, JANUARY 1995

available and global clinical ratings were made. In addition, assessments were not made independently by the treating physician and the senior author. Family history data were gathered from a review of the medical record, a method that may underreport psychiatric diagnoses in relatives. As this was a naturalistic study, the use of concurrent medications was not controlled for and their effect could not be systematically studied. Blood levels of Huoxetine and its metabolite were not routinely measured by treating psychiatrists, presumably because their clinical usefulness has not been established. Thus, the effect of concurrent medications on the pharmacokinetic properties of Huoxetine could not be determined. Pubertal status could not be ascertained from the clinical record. Finally, the high rate of comorbidity may reflect ascertainment bias since patients referred to a specialized clinic may be more likely to be treatment refractory. However, our series represents allcases treated with Huoxetine at our center, and our sample resembles other reported series in most respects. Despite these limitations, this retrospective chart review of a large series of pediatric OCD patients treated naturalistically with Huoxetine suggests that doses approximating 1.0 mg/kg per day may be needed to achieve a sustained clinical effect in children and adolescents with this condition. The magnitude and persistence of the response over a prolonged period are noteworthy and support previous findings of the therapeutic role of fluoxetine in pediatric OCD. This work supports the need for more controlled studies of serotonergic agents in juvenile OCD with particular attention to the developmental issues associated with a very early onset of the disorder.

REFERENCES Biederman J, Baldessarini R, Wright V, Knee D, Harmatz J, Goldblatt A (1989), A double-blind placebo conrrolled study of desipramine in the treatment of attention deficit disorder II: serum drug levels and cardiovascular findings. JAm Acad ChildAdolesc PsychiatlJ 28:90.'3-911 Clomipramine Collaborative Study Group (1991), Clomipramine in the u'catmcu r of patients with obscssivc-corupulxivc disorder. Arch

GCII

Psychiatry 48:730-738 Como pG, Kurian R (1991), An open-label trial of lIuoxetine fell" obsessivecompulsive disorder in Gilles de Ia Touretrc's syndrome. Neurology 41:872-874 DeVeaugh-Geiss J, Moroz G, Biederman J er al, (1992), Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder: a multicenter trial. JAm Acad Child Adolesc Psychiatry .'31:45-49 Dominguez RA (1992), Serotonergic anridepressanrs and their efficacy in obsessive compulsive disorder. J Clin Psychiatry 5.'3:56-59

43

GELLER ET AL.

Flamcnt MF, Koby E, Rapoport JL ct al. (1990), Childhood obsessivecompulsive disorder: a prospective follow-up study. J Child Psychol Psychiatry 31 :363-380 Flamcnt MF, Rapoport JL, Berg CJ er al. (1985), Clomipramine treatment of childhood obsessive-compulsive disorder: a double-blind controlled study. Arch Gen Psychiatry 42:977-983 Flament MF, Whitaker A, Rapoport JL ct al. (1988), Obsessive compulsive disorder in adolescence: an epidemiological study. J Am Acad Child

Adolesc Psychiatry 27:764-771 Flamcnr M, Whitaker A, Rapoport JL, Davies M, Berg CZ, Shaffer 0 (1989), An epidemiological study of obsessive-compulsive disorder in adolescence. In: Obsessive-Compulsive Disorders in Children and Adolescents, Rapoport JL, cd. Washington, DC: American Psychiatric Press, pp 253-267 Foa E, Steketee G, Kozak M, Dugger 0 (1987), Imipramine and placebo in the treatment of obsessive-compulsives: their effect on depression and obsessional symptoms. Psycbopbarmacol Bull 23:8-1 I Fontaine R, Chouinard G (1986), An open clinical trial of lIuoxetine in the treatment of obsessive-compulsive disorder. J Clin Psychopharmacol 6:98-101 Goodman W, McDougle C, Price L (1992), Pharmacotherapy of obsessive compulsive disorder. J Clin Psychiatry 53:29-38 Goodman W, Price L, Delgado P (1990), Specificity of serotonin reuptake inhibitors in the rrcatmcntof OCD: comparison of lIuvoxamine and desipramine. Arch Gen Psychiatry 47:577-585 Goodman WK, Price LH, Rasmussen SA, Delgado PI" Heninger GR, Charney DS (1989), The efficacy oflluvoxamine in obsessive compulsive disorder: a double blind comparison with placebo. Arch Gen Psychia-

tl] 46:36-44 Hollingsworth C, Tanguay P, Grossman 1" Pabst P (1980), Long-term outcome of obsessive compulsive disorder in childhood. J Am Acad Child Adolesc Psychiatry 19: 136-144 [cnikc MA, Buttolph L, Bacr L, Ricciardi J, Holland A (1989), Open trial of lIuoxetine in obsessive-compulsive disorder. Am J Psychiatry 146:909-911 Karno M, Golding JM, Sorenson SB, Burnam A (1988), The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen

Psychiatl] 45:1094-1099 King RA, Riddle MA, Chappell PB et al. (1991), Emergence of selfdestructive phenomena in children and adolescents during lIuoxetine treatment. JAm Acad Child Adolesc Psychiatry 30:179-186 Lcnnuc Me, Swcdo SF, Leonard 1-1, Pauls DL. Scccry W, Rapoport JL (1990), Psychiatric disorders in first degree relatives of children and adolescents with obsessive compulsive disorder. JAm Acad Child Adolesc

Psychiatry 29:407-412 Leonard HI" Swedo SE, Lcnane MC cr al. (1991), A double-blind desipramine substitution during long-term clomipramine treatment in children and adolescents with obsessive-compulsive disorder. Arch Gen Psychia-

tl] 48:922-927 Leonard H, Swedo S, Lcnane M, Hamburger S, Bartko J, Rapoport J (1993), A 2- to 7-year follow-up study of 54 obsessive-compulsive children and adolescents. Arch Gen Psychiatry 50:429-440

44

Leonard HL, Swedo SE, Rapoport JL er al. (1989), Treatment of obsessive compulsive disorder with clomipramine and desipramine in children and adolescents: a double-blind crossover comparison. Arch Gen Psychia-

try 46:1088-1092 Leonard H, Swedo S, Rapoport jl., Coffey M, Cheslow 0 (1988), Treatment of childhood obsessive compulsive disorder with clomipramine and desmethylimipramine: a double-blind crossover comparison. Psychopbar-

macol Bull 24:93-95 Levine R, Hoffman JS, Knepple ED, Kenin M (1989), Long-term lIuoxetine rreatment of a large number of obsessive-compulsive patients. J Clin

Psychopharmacol 9:281-283 Liebowitz MR, Hollander E, Fairbanks J, Campeas R (1990), Fluoxetine for adolescents with obsessive compulsive disorder. Am J Psychiatry 147:370-371 Mavissakalian MR, Jones B, Olson S (1990), Absence of placebo response in obsessive-compulsive disorder. J Nerv Ment Dis 178:268-270 National Institute of Mental Health (1985), CGI (Clinical Global Impression) Scale-NIMH. Psychopharmacol Bull 21 :839-844 Pigott TA, Pato MT, Bernstein SE et a!' (1990), Controlled comparisons of clomipramine and lIuoxetine in the treatment of obsessive-compulsive disorder: behavioral and biological results. Arch Gen Psychiatry 47:926-932 Preskorn S (1993), Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry 54: 14-34 Rapoport J, Swedo S, Leonard H (1992), Childhood obsessive compulsive disorder. J Clin Psychiatry 53:11-16 Rasmussen SA, Tsuang MT (1984), The epidemiology of obsessive compulsive disorder. J Clin Psychiatry 45:450-457 Riddle MA, Hardin MT, King R, Scahill L, Woolston JL (1990a), Fluoxetine rrcatrncnr of children and adolescents with Tourettc's and obsessive compulsive disorders: preliminary clinical experience. JAm Acad Child

Adolesc Psychiatry 29:45-48 Riddle MA, Scahill L, King R et a!' (1990b), Obsessive compulsive disorder in children and adolescents: phenomenology and family history, JAm

Acad Child Adolesc Psychiatry 29:766-772 Riddle M, Scahill L, King R et al. (1992), Double-blind, crossover trial of Huoxetinc and placebo in children and adolescents with obsessivecompulsive disorder. JAm Acad Child Adolesc Psychiatry 31: 1062-1 069 Swedo SE, Rapoport JL (1989), Phenomenology and differential diagnosis of obsessive compulsive disorder in children and adolescents. In: ObsessiveCompulsive Disorders in Children and Adolescents, Rapoport JL, ed. Washington, DC: American Psychiatric Press, pp 13-31

Swedo SE, Rapoport JL, Leonard H, Lenane M, Cheslow 0 (1989), Obsessive-compulsive disorder in children and adolescents. Arch Gen

Psychiatry 46:335-341 Turner SM, Jacob RG, Beidel DC, Himmelhoch J (1985), Fluoxetine treatment of obsessive-compulsive disorder. J Clin Psychopharmacol 5:207-212 Wilens TE, Biederman J, Baldessarini RJ, Puopolo PR, Flood JG (1992), Developmental changes in serum concentrations of desipramine and 2-hydtoxydesipramine during treatment with desipramine. JAm Acad Child Adolesc Psychiatry 31 :691-698

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