Treating children and adolescents with depression is complicated by the fact that few clinical trials have evaluated the efficacy and safety of antidepressant medications in this population. Fortunately, this situation will improve during the next three to five years as new clinical trials increasingly focus on pediatric patients, said Karen D. Wagner, MD, PhD, at the annual meeting of the American Academy of Child and Adolescent Psychiatry. Dr. Wagner, who is Director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch, in Galveston, reviewed the small number of studies that have examined the pharmacologic treatment of depression in children and adolescents, and discussed some of the new multicenter trials that will help resolve some of the current clinical issues in treating this population.

Although parents frequently express concern about the use of psychotropic medications to treat their children, it is clear that untreated pediatric depression is a potentially lethal disease, Dr. Wagner emphasized. One recent study reported an 8% suicide rate among depressed adolescents who were followed into adulthood. “There are not very many medical disorders that have an 8% mortality rate,” Dr. Wagner noted. Therefore, clinicians need to be able to treat pediatric patients who have depression, but they must also be able to communicate with parents regarding the expected outcome of treatment and the strength of the evidence upon which treatment decisions are based.

A DATA DEFICIENCY

Thus far, the list of large placebo-controlled trials showing that antidepressant medications are beneficial in pediatric patients consists of exactly two studies. The first, published in the Archives of General Psychiatry in 1997, found that 56% of children or adolescents who were treated with fluoxetine (20 mg/d) for eight weeks were rated “much” or “very much” improved on the Clinical Global Impressions scale, compared with 33% of patients who were given placebo.(1) “Why this study is so important, and why it’s considered a landmark study, is that this is the first study that showed an antidepressant medication to be better than placebo in treating children and adolescents,” Dr. Wagner explained; earlier trials of tricyclic antidepressants had failed to show efficacy in pediatric populations. Even in this study, however, only one third of the patients in the fluoxetine group achieved complete remission.

Findings from a second completed study have been reported at medical conferences but have not yet been published. In this study, for which Dr. Wagner was a co-investigator, 275 patients ages 12 to 19 were randomized to one of three treatments: paroxetine at a dose of up to 40 mg/d; imipramine at a dose of up to 300 mg/d; or placebo. After eight weeks of treatment, 66% of the patients in the paroxetine group were considered “much” or “very much” improved, compared with 52% of patients who received imipramine and 48% of patients in the placebo group. The difference between the paroxetine and placebo groups was statistically significant, although the difference between the imipramine and placebo groups was not. Dr. Wagner noted that all participants in this study also received supportive psychotherapy, which may explain the strikingly high response rate among patients in the placebo group.

WHAT ABOUT SAFETY?

The study also included a detailed analysis of adverse effects. The incidence of cardiovascular side effects was low in patients receiving paroxetine (7%) or placebo (13%) but was much higher among those in the imipramine group (43%). In fact, about a third of imipramine-treated patients who withdrew from the study prematurely did so because of cardiovascular side effects, which included tachycardia, orthostatic hypotension, and electrocardiographic abnormalities. The incidence of gastrointestinal side effects (eg, nausea, vomiting) was similar in the three groups; insomnia and somnolence were more common in both active treatment groups than in the placebo group. Dizziness was more frequent with imipramine (47%) than with paroxetine (24%) or placebo (18%), due to the high incidence of orthostatic hypotension. Overall, treatment with paroxetine in these adolescent patients appeared to be associated with a favorable side effect profile, Dr. Wagner noted.

SUCCESS RATE PLUMMETS WITH COMORBID ADHD

The treatment of childhood depression in pediatric patients is often complicated by comorbid psychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD). A further analysis of data from the paroxetine/imipramine trial revealed that the presence of untreated ADHD greatly reduced patients’ response to antidepressant treatment. In the paroxetine group, the response rate among patients with comorbid ADHD was only 25%, compared with 71% among patients who did not have the disorder. Similarly, the response rates in the imipramine and placebo arms were significantly lower among patients with ADHD (31% and 13%, respectively) than among those without (64% and 59%). Overall, the response rate for all patients with ADHD was only 24%, less than half of the rate for patients without the disorder (59%). Dr. Wagner emphasized that there are numerous reasons why a case of pediatric depression may not respond to treatment, including choice of medication, medication dose, duration of treatment, and psychosocial issues. However, the data from this study suggest that in some instances a poor response to antidepressant therapy may be indicative of an untreated or inadequately treated comorbidity.

OTHER ANTIDEPRESSANT OPTIONS

At present, there are very few data in children and adolescents regarding the use of antidepressants other than the selective serotonin reuptake inhibitors (SSRIs). In one study,(2) 33 outpatients ages 8 to 17 were randomized to double-blind treatment with either venlafaxine or placebo (all subjects also underwent psychotherapy); adolescents received up to 25 mg of venlafaxine three times daily, whereas younger children received up to 12.5 mg three times daily. Unfortunately, the antidepressant was not significantly better than placebo in reducing symptoms of depression, although Dr. Wagner noted that the sample size was small and the venlafaxine doses were low. The most common side effects with venlafaxine were mild nausea and increased appetite; one child developed symptoms of mania.

In a recently published open-label study,(3) 28 patients between the ages of 7 and 17 were treated with nefazodone. Children received a maximum dose of 300 mg/d (mean, 233 mg); adolescents received up to 600 mg/d (mean, 342 mg). After six weeks of treatment, 86% of children and 69% of adolescents were “much” or “very much” improved. The most common adverse effects were nausea, vomiting, and sedation, although there were no clinically significant adverse events.

Finally, one small unpublished study found that eight weeks of treatment with sustained release bupropion, at an average dose of 362 mg/d, produced improvement in 79% of adolescent patients, according to Dr. Wagner.

ON THE HORIZON

Despite the small number of studies conducted so far in depressed children and adolescents, “the field is moving rapidly, and this is a very exciting time,” Dr. Wagner said. She noted that nearly every widely-used antidepressant medication is currently under study for treating children and adolescents with depression, including citalopram, fluoxetine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine.

Moreover, two of these new studies, both funded by the National Institute of Mental Health, are major multicenter trials that will shed light on important clinical issues regarding the treatment of pediatric depression. The first is the Treatment of Adolescent Depression Study (TADS). This 10-site trial, slated to enroll 432 adolescent outpatients with depression, will compare four treatment strategies: fluoxetine (up to 40 mg/d); cognitive behavior therapy; fluoxetine plus cognitive behavior therapy; and placebo. The study should help answer the question of whether combining cognitive behavior therapy with pharmacotherapy is superior to either approach alone. Children under 12, who may not be good candidates for cognitive behavior therapy, will not be included in this trial.

The second study, which will enroll 400 depressed adolescents who have failed to respond to an SSRI, is called the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial. This six-site study, Dr. Wagner said, will examine whether it is more effective to switch to a different class of medication when treatment has been unsuccessful or to change to another medication within the same class. Patients will be assigned to one of four 12-week interventions: another SSRI; venlafaxine; another SSRI plus cognitive behavior therapy; or venlafaxine plus cognitive behavior therapy. Subjects will also receive an additional 12 weeks of open-label treatment and will be followed for a full year to assess relapse and recurrence rates.

IN THE MEANTIME…

Given the long period of time required to enroll patients, analyze the data, and publish the findings, it might be three to five years before the results of these studies are known. Until better clinical trial data become available, how should clinicians select and use antidepressant medications for their pediatric patients? Side effects are an important consideration, and the SSRIs appear to be a good choice in this regard, Dr. Wagner said. These medications are also very safe in overdose and therefore may be well suited for treating adolescent patients who are at risk of substance abuse.

Dr. Wagner suggested that when treating a patient with a comorbid disorder, it is probably better to use two medications—a first-line treatment for each disorder—rather than attempting to use a single medication that treats both disorders but is first-line therapy for neither. It is also important to be sure that a medication has been tried for a sufficient length of time before deciding that it has not been effective. Dr. Wagner noted that in one open-label study of sertraline in adolescent patients, 65% exhibited a significant improvement after six weeks and 84% after 10 weeks.(4) “Had that medication been stopped and a switch made at six weeks, approximately 20% of adolescents who would have responded to medication would be considered treatment resistant and on another medication,” she said.

At present, clinicians have few studies to guide them when SSRIs fail to produce an adequate clinical response. However, during the next several years a significant amount of new, clinically relevant research should help to clarify the best ways to treat children and adolescents with depression.

—Mark Bowes, PhD

REFERENCES
1. Emslie GJ, Rush AJ, Weinberg WA, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry. 1997;54:1031-1037.
2. Mandoki MW, Tapia MR, Tapia MA, et al. Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacol Bull. 1997;33:149-154.
3. Findling RL, Preskorn SH, Marcus RN, et al. Nefazodone pharmacokinetics in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry. 2000;39:1008-1016.
4. Ambrosini PJ, Wagner KD, Biederman J, et al. Multicenter open-label sertraline study in adolescent outpatients with major depression. J Am Acad Child Adolesc Psychiatry. 1999;38:566-572.

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