Eur Child Adolesc Psychiatry (2009) 18:131 135 DOI 10.1007/s00787-007-0634-z ORIGINAL CONTRIBUTION Javad Alaghband-Rad Mitra Hakimshooshtary A randomized controlled clinical trial of Citalopram versus Fluoxetine in children and adolescents with obsessive-compulsive disorder (OCD) Accepted: 16 January 2007 Published online: 3 February 2009 J. Alaghband-Rad, MD (&) Dalhousie University 5217 Morris Street Halifax, NS B3J 1B7 Canada and Tehran University of Medical Sciences Tehran, Iran Fax: 902-470 7062 E-Mail: rad@dal.cd M. Hakimshooshtary, MD Iran University of Medical Sciences Tehran, Iran j Abstract Objective Several controlled trials have demonstrated the efficacy and safety of Fluoxetine in children and adolescents with Obsessive-Compulsive Disorder (OCD), but there is no controlled study on the effectiveness of Citalopram in this group. This report describes the use of Citalopram in comparison with Fluoxetine in childhood-onset OCD. Method This study is a randomized, double blind, fixeddoes (20mg) trial of Fluoxetine versus Citalopram in 29 children and adolescents (17 boys and 12 girls) with OCD, aged 7 18 years (mean 13.8 and SD 3.05). The length of study was 6 weeks. Obsessive-Compulsive symptom severity was measured by Yale Brown Obsessive-Compulsive Scale (CY-BOCS) and Clinician s Global Impression Scale (CGI). DICA (Diagnostic Interview of Children and Adolescents) was used to diagnose the psychiatric disorders. Results Each group showed significant improvement over the baseline as measured by the CY-BOCS (p < 0.01) but not by CGI (p = NS). The Comparison between two groups showed no significant differences in efficacy and safety of the drugs. Most common adverse effects were headache for Citalopram and tremor for Fluoxetine. Conclusion The results suggest that Citalopram is as safe and effective as Fluoxetine for children and adolescents with OCD. Further studies are needed to replicate our findings. j Key words Fluoxetine Citalopram children and obsessive-compulsive disorder Introduction Accumulating clinical and epidemiological data indicate that OCD is more common than previously recognized in both children and adults; recent estimates of prevalence range from 0.5% to 3.0% [1, 7]. Children and adolescents evaluated in clinical settings often have symptoms of severity to warrant treatment [4, 8, 12, 15], which may include behavioral therapy [10] and/or medication particularly SSRIs [3]. Controlled clinical trials with Fluoxetine indicate that it is effective in reducing obsessive-compulsive symptom severity in children and adolescents [2, 12, 13], but there are no controlled trial to support the use of Citalopram in children and adolescents with OCD. Citalopram is reported to be effective in early-onset Depression [8]. The purpose of this study was to compare the efficacy and side effects profile of these two drugs in children and adolescents with OCD. Assessment included severity ratings of obsessive-compulsive symptoms, functional impairment, presence of comorbidities and side effects. ECAP 634
132 European Child & Adolescent Psychiatry (2009) Vol. 18, No. 3 Ó Steinkopff Verlag 2009 Method From May 1999 through September 2002, 29 children and adolescents were evaluated in the child and adolescent psychiatry outpatient clinic at Roozbeh hospital, Tehran. To be included in the study, subjects had to meet DSM-IV criteria for OCD made by an experienced child psychiatrist (JA or MS), be between the ages of 8 years and 17 years, have at least moderate symptoms of OCD as measured on the Clinical Global Impression Severity Scale (CGI-S), and have written informed parental consent and assent in children old enough to understand the purpose of the study. Children with date table organic brain disorder; those with a significant medical condition or those currently receiving SSRI for OCD were excluded from the study. j Design After initial clinical evaluation, consenting subjects were randomly assigned to start with either Fluoxetine 20 mg/day or Citalopram 20 mg/day. The doubleblind treatment period lasted for 6 weeks with outcome and safety assessments done every 3 weeks. Compliance was monitored by pill counts. A 3- week supply of medication was provided at each visit, and parents were instructed to return all unused medication at each scheduled visit. No additional psychoactive medications were administered during the study. No subjects were receiving special educational programs or behavioral treatments. Interviewer conducted a semi structural interview and administered the symptom severity ratings, functional impairment and side effects instruments (Table 1). j Procedures Screening and baseline assessment In the screening visit, subjects received a thorough psychiatric, medical and neurological examination by an experienced child psychiatrist (JA or MS). This included a structured diagnostic interview, DICA [5, 6], to evaluate for exclusionary comorbid conditions. Table 1 Study design Measures Baseline 3 weeks 6 weeks Baseline assessment measures X CY-BOCS X X X CGI-OCD X X X DICA X Side effect ratings X X X Once deemed eligible for the study, an overall clinician rating of obsessive-compulsive symptoms CGI-S and functional impairment Children s Global Assessment Scale were administered. j Outcome measures The children s Yale Brown obsessive-compulsive Scale (CYBOCS) is a clinician-rated instrument for the measurement of obsessive-compulsive symptom severity in children with demonstrated reliability and validity (18). Obsessions and compulsions are on 5 separate scales yielding three summary s; Obsessive (0 20), Compulsions (0 20) and a Total (0 40). The CYBOCS was administrated by an experienced clinician (MS) repeated at weeks 3 and 6. The Clinical Global Impression-Improvement (CGI-I) compares current severity to baseline. A 1 or 2 corresponds with Very Much Improved and Much Improved; 3 denotes minimal change and 4 represents no change. Scores above 4 are used to indicate deterioration such that 5 equals Minimally Worse and 6 or 7 correspond with Much Worse or Very Much Worse. The CGI-I rated by the same clinician who administered the CYBOCS, was repeated at weeks 3 and 6. Side effects ratings: all positive Findings elicited during the interview were recorded. j Statistical analyses Student s t-test was used to compare Fluoxetine and Citalopram groups at baseline on all clinical symptoms as well as demographic and medical variables. Analysis of covariance (ANCOVA) was used to test for change on each clinical measure between baseline and 3-week s within each treatment group and then between 3-week s and 6-week s within each treatment group. Baseline versus six weeks change s for each subject was then compared across treatment groups for each clinical variable using student s t-test. All t- test were 2-tailed. Results During the study period, 29 children (17 boys and 12 girls) who met criteria for OCD were evaluated and entered the study. None of them had received previous treatment for OCD. There were 15 subjects in the Fluoxetine treatment group and 14 subjects in the Citalopram group. Twenty-four of the 29 subjects completed the 6 weeks trial. Four subjects dropped out after 3 weeks of treatment. The other patient was
J. Alaghband-Rad and M. Hakimshooshtary 133 Citalopram and OCD Table 2 Overall clinical response to fluoxetine treatment Variable Pre-treatment At third week Post-treatment Total CY-BOCS 26.66 22 15 <0.001 CGI 53 59 69.29 >0.001 p 16 14 12 CY-BOCS CY-BOCS 14 13.33 12.15 11.21 10 80 70 60 50 CGI f CGI p 53 50 59.29 54.23 69.29 66 CY 8 6 4 8.45 7.5 CGI 40 30 2 20 10 0 excluded because of occurring hypomanic episode. Data from 24 to 29 subjects who began the study were used in the analyses (Table 2). For all analyses we used the primary outcome measures, the CY-BOCS total and CGI-OCD (Figs. 1 and 2). There were no statistically significant differences between Fluoxetine and Citalopram groups across symptom-severity ratings, demographic characteristics or psychiatric comorbidities. obsessive-compulsive symptom severity was moderately high with an overall mean of 26.9 ± for the whole group. The mean CGI of 51.5 ± showed that as a group, these patients were substantially impaired. DICA indicated a high degree of comorbidities. The mean CGI indicated a lower degree of functional impairment in comparison with the clinically observed obsessive-compulsive symptoms. This may reflect perfectionistic traits in patients with OCD that prevents them from severe functional decline. j Efficacy: first three weeks third week Fig. 1 CGI changes during the 6 weeks of treatment sixth week After 3 weeks of treatment, obsessive-compulsive symptom severity for both groups decreased equally, as measured by CY-BOCS total s. On the CY- BOCS, s decreased for both obsessions and compulsions. CGI s didn t change significantly from baseline in both groups, however. 0 j Efficacy: third through sixth weeks At sixth week of treatment, obsessive-compulsive symptom severity for both groups decreased equally, as measured by CY-BOCS total s. On the CY- BOCS, s decreased for both obsessions and compulsions (p < 0.01). CGI didn t change significantly from baseline in both groups (p = NS). j Side effects The most frequently reported side effects were: Headache 1 (3.4%), Tremor 2 (6.8%), Insomnia 1 (3.4%), Hypomanic Episode 1 (3.4%) for fluoxetine. Headache 1 (3.4%), Hypomanic Episode 1 (3.4%) for citalopram. The frequency of comorbid current psychiatric diagnoses, made by consensus of the same clinicians using DICA [9, 10], was as it follows: Tic disorder: 7 (21.28%), Oppositional Defiant Disorder: 7 (21.28%), Mood disorder: 6 (20.4%), Phobia: 4 (13.6%), Attention-Deficit Hyperactivity Disorder: 3 (10.2%), Generalized Anxiety Disorder: 3 (10.2%), Trichotillomania: 1 (3.4%). It should be noted that in 66% of cases, OCD was reported in the families as well. Discussion third week Fig. 2 CY-BOCS changes during the first 6 weeks of treatment sixth week The findings of this study suggest that Citalopram is as safe and effective as Fluoxetine for short-term
134 European Child & Adolescent Psychiatry (2009) Vol. 18, No. 3 Ó Steinkopff Verlag 2009 Table 3 Overall clinical response to citalopram treatment Variable Pre-treatment At third week Post-treatment Total CY-BOCS 28 24 16.9 <0.001 CGI 50 56 66 >0.01 treatment of OCD in children and adolescents. In line with other studies, we also found that 73% of the patients had comorbid disorder especially tic disorder, ODD, ADHD and mood disorder. In 66% of cases, OCD was reported in the families as well. The medication side effects were not significant. Citalopram had to be discontinued in one subject who developed manic episode. Decreases in mean obsessive-compulsive symptom severity; averaged 56.1% depending on the assessment instrument used, and were seen after six weeks of treatment. Four subjects dropped out of the study because of noncompliance. We observed lower degree of functional impairment while high degrees of obsessive-compulsive symptoms were rated. It might be due to perfectionist traits that prevent them from severe functional decline. This is in line with previous studies. Taken together, these findings suggest that both drugs are equally effective and safe. However, larger number of children with OCD will need to be studied in order to definitively establish efficacy and safety of Citalopram. The degree of symptomatic improvement during Citalopram treatment observed in this study is comparable with those observed in trials of Fluoxetine in children and adolescents (Table 3). In a 20-week, double blind, crossover trial of Fluoxetine and placebo involving 14 subjects [11], obsessive-compulsive symptom severity decreased 44% across CGI-OCD during Fluoxetine treatment. In a 13-week, double blind, placebo-controlled study of Fluoxetine involving 103 subjects [2], obsessive-compulsive symptom P showed greater improvement, as assessed by CY- BOCS (p = 0.026). Most of the observed side effects, such as insomnia, headache, and tremor, were expected, on the basis of our earlier experience with Citalopram in open-label trials [9, 16]. Citalopram had to be discontinued in only one subject because of occurring hypomanic episode. j Clinical Implications OCD can create emotional distress and functional impairment. There is no controlled trial about prescribing citalopram in children and adolescents. Investigation into the use of Citalopram is a necessity. Citalopram has a shorter half-life than fluoxetine and can be effective in some special cases [14]. It also has few side effects. As SSRIs have increasingly become the first choice treatment of OCD in children and adolescents, it is very important to have efficacy and safety data on as many of them as possible. This would help us to handle the wide individual differences in drug metabolism. There might also be subgroups of OCD patients who respond differentially to various SSRIs. Therefore, further investigation into the use of Citalopram is needed. j Limitations The most important limitation of our study includes the small sample size. Also, our patients admitted at a tertiary referral center are more likely to present with psychiatric comorbidities than patients who do not seek treatment. The other limitation is comparing two active treatments without considering placebo group. Moreover, we have used only one OCD severity measure before giving the medications. j Acknowledgment The authors thankfully acknowledge the helpful and rewarding comments made by Dr. Larry Scahill, Yale child study center (New Haven, USA). References 1. Flament MF, Whitaker A, rapport JL, Davies M, Berg CZ, Kalikow K (1998) Obsessive Compulsive Disorder in adolescence: an epidemiological study. J Am Acad Child Adolesc Psychiatry 27:764 771 2. Geller DA, Hoog SL, Heilligensein JH, Ricardi K, Tamura R, Kluszyski S, Jacobson JG (2001) Fluoxetine treatment of obsessive compulsive disorder in children and adolescents, a placebocontrolled clinical trial. J Am Acad Child Adolesc Psychiatry 40:113 119 3. Grados M, Scahill L, Riddle MA (1999) Pharmacotherapy in children and adolescents with obsessive-compulsive disorder. Child Adolesc Psychiatry Clin N Am 8(3):617 634, Review 4. Hanna GL, Yuwiler A, Coates JK (1995) Whole blood serotonin and disruptive behaviors in juvenile obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 34(1):28 35
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