A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents

A total of 178 patients (93 in the citalopram group and 85 in the placebo group) were randomly assigned to double-blind treatment. Four patients (three children and one adolescent), all randomly assigned to the citalopram group, were lost to follow-up and did not receive study medication. These patients were not included in the intent-to-treat analyses. Thus, the intent-to-treat population consisted of 89 patients (45 children and 44 adolescents) assigned to citalopram and 85 patients (38 children and 47 adolescents) assigned to placebo. Of these, 18 patients from each group discontinued double-blind treatment prematurely. Demographic and clinical characteristics of the patient population at baseline are summarized in Table 1. There were no significant differences in age, gender, race, or weight between the placebo and citalopram groups. The mean age was 12.1 years in both treatment groups, and there were no differences between groups in the mean ages of children and adolescents. Additionally, responses to the K-SADS-PL (administered at the screening visit) indicated there were no clinically meaningful differences between the citalopram and placebo treatment groups in depression history. Ongoing secondary psychiatric disorders other than depression were reported in 23 patients, the most common diagnosis being dysthymia (citalopram group: 5.6%, placebo group: 1.2%) and enuresis (citalopram group: 4.5%, placebo group: 3.5%). A previous diagnosis of ADHD had been made in four citalopram-treated patients (4.5%) and one placebo-treated patient (1.2%); there were no reports of ongoing ADHD. Approximately 80% of the patients who participated in the study were experiencing a single episode of depression with a mean duration of 2 years. The mean duration of the current depressive episode was about 20 months. The age at onset was approximately 7 years for children and 12 years for the adolescent group. Twenty percent of the patients in the citalopram group and 18% of patients in the placebo group received previous antidepressant treatment, and approximately 15% of the patients in the citalopram group and 16% of the patients in the placebo group had a history of nonresponse to antidepressant treatment. Mean Children’s Depression Rating Scale—Revised scores at baseline were 58.8 (SD=10.9) and 57.8 (SD=11.1) in the citalopram and placebo groups, respectively, indicative of moderately severe illness.

As noted in the Method section, investigators had the option to increase the dose of study medication to 40 mg/day citalopram or placebo equivalent any time after the week 4 visit. By the end of the study, medication dose had been increased in 53 placebo-treated patients (62.4%) and in 48 citalopram-treated patients (53.9%). In the citalopram group, the mean daily dose over the 8-week treatment period was 23.3 mg/day (SD=5.0) for the children and 24.4 mg/day (SD=5.0) for the adolescents.

Citalopram treatment showed statistically significant improvement compared with placebo on the Children’s Depression Rating Scale—Revised as early as week 1 (F=6.58, df=1, 150, p<0.05), which persisted throughout the study (Figure 1). At week 8, the effect size on the primary outcome measure, Children’s Depression Rating Scale—Revised (last observation carried forward), was 2.9. Additionally, at endpoint more citalopram-treated patients (36%) met the prospectively defined criterion for response than did placebo-treated patients (24%), a difference that was statistically significant (χ²=4.178, df=1, p<0.05). The proportion of patients with a CGI improvement rating ≤2 at week 8 was 47% for the citalopram group and 45% for the placebo group (last observation carried forward values). For the CGI severity rating, baseline values were 4.4 for the citalopram group and 4.3 for the placebo group, and endpoint values (last observation carried forward) were 3.1 for the citalopram group and 3.3 for the placebo group.

Citalopram treatment was well tolerated. All treatment-emergent adverse events that occurred with a frequency >5% in the citalopram group, and with an incidence in citalopram-treated patients that exceeded that in placebo-treated patients, are listed in Table 2. Of these, nausea, rhinitis, and abdominal pain were the only adverse events occurring in ≥10% of citalopram-treated patients. There were no reports of mania. The rate of discontinuation due to adverse events was comparable in the placebo and citalopram groups (5.9% versus 5.6%, respectively). The only adverse events that led to the discontinuation of more than one patient were aggravated depression (two placebo, no citalopram) and agitation (no placebo, two citalopram). No clinically significant ECG results, laboratory values, or weight changes were found. No serious adverse events were observed in any patient treated with citalopram in this study.

This randomized, placebo-controlled, double-blind trial provides evidence that citalopram produces a statistically and clinically significant reduction in depressive symptoms in children and adolescents. Specifically, citalopram was superior to placebo on the primary efficacy measure, score on the Children’s Depression Rating Scale—Revised, as early as week 1 with efficacy continuing throughout the trial. Reported adverse events were mild, and the rate of discontinuation due to adverse events was similar in the placebo and citalopram groups.

The results of this trial are in agreement with previous open-label trials (20) and case reports (21), which suggest that citalopram is efficacious and safe in children and adolescents with depression. In the current trial, citalopram-treated patients demonstrated significant improvement in depressive symptoms compared with placebo at week 1, an earlier time point than has been reported in other published trials of SSRIs in children and adolescents (10–12), although one placebo-controlled trial demonstrated significance for fluoxetine at week 1 (11). This is a potentially important observation, since therapeutic treatment options in these young patients remain limited, and early amelioration of symptoms may serve to enhance adherence to an adequate course of therapy.

In our study, the prospectively defined criterion of response was an endpoint score of ≤28 on the Children’s Depression Rating Scale—Revised. In the Emslie et al. study of fluoxetine (11), a Children’s Depression Rating Scale—Revised endpoint total score ≤28 was defined as remission. It is noteworthy, therefore, that the rates of response for citalopram (36%) were similar to the remission rates for fluoxetine (41%).

It is tempting to speculate that similar clinical results would be achieved in children and adolescents treated with the recently developed single isomer compound escitalopram, since the serotonin reuptake activity of citalopram is attributable to its S-isomer (26). This hypothesis is being tested in a multicenter, randomized, double-blind study of escitalopram in pediatric patients that is currently under way.

The mean citalopram dose for children and adolescents over the 8-week trial was approximately 25 mg/day, which is similar to the minimum dose shown to be effective in adults (27). There were no serious adverse events observed in the citalopram group. In fact, the overall adverse event profile was similar to that reported in adult trials, with no new or unexpected adverse events reported. Notably absent in this population of children and adolescents were dizziness and somnolence, two events frequently reported by adult patients (18). In this study, psychiatric adverse events were reported infrequently by patients randomly assigned to citalopram. For example, adverse events associated with behavioral activation (such as insomnia or agitation) were not prevalent in this trial.

The consistent and significant reduction in Children’s Depression Rating Scale—Revised score in citalopram-treated patients compared with placebo-treated patients at weeks 1, 2, and 4 suggests that citalopram, 20 mg/day, is an effective dose in this population, since the citalopram dose was fixed throughout the first 4 weeks of the trial.

Of interest, early and sustained improvements in Children’s Depression Rating Scale—Revised scores were observed with citalopram treatment in this study despite a relatively high rate of placebo response (which is common in pediatric trials with antidepressants). The study was not powered sufficiently to detect treatment differences by age group. Other limitations include the low number of patients with comorbid conditions and concomitant medication use, both of which are common in younger patients. It is not known whether the presence of comorbid psychiatric disorders such as ADHD would have affected the observed outcomes of this trial; however, the exclusion criteria employed produced a study population comparable to those of Emslie et al. (11) and Wagner et al. (12).

In conclusion, citalopram treatment significantly improved depressive symptoms compared with placebo within 1 week in this population of children and adolescents. No serious adverse events were reported, and the rate of discontinuation due to adverse events among citalopram-treated patients was comparable to that of placebo. These findings further support the use of citalopram in children and adolescents suffering from major depression.

Presented in part at the 155th annual meeting of the American Psychiatric Association, Philadelphia, May 18–23, 2002. Received Dec. 4, 2002; revisions received Aug. 20 and Oct. 28, 2003; accepted Dec. 4, 2003. From the Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston; Children’s National Medical Center, Washington, D.C.; University Hospitals of Cleveland; Forest Laboratories, Inc., New York; and Lexicon Pharmaceuticals, Princeton, N.J. Address reprint requests to Dr. Wagner, Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77755-0188; [email protected] (e-mail). Supported by funding from Forest Pharmaceuticals.