Use of antidepressants in children

August 2004

Depression occurs not uncommonly (3%-8%) in children and adolescents. Therapy is often multimodal, with pharmacotherapy a significant component. To coincide with the current special focus of this edition of Infectious Diseases in Children about the emotional needs of children, this month’s Pharmacology Consult will discuss the use of antidepressants, particularly selective serotonin reuptake inhibitors (SSRI), in the therapy of pediatric depression. Important differences exist among the available SSRIs, and their use remains controversial, with concerns over adverse effects as well as efficacy.

Available SSRIs and their differences

Five SSRIs are commercially available to clinicians for the treatment of depression: citalopram (Celexa, Forest Labs), escitalopram (Lexapro, Forest Labs), fluoxetine (Prozac, Lilly, and generics), paroxetine (Paxil, GlaxoSmithKline, and generics), and sertraline (Zoloft, Pfizer). Only fluoxetine is FDA-approved for major depressive disorder in children (8-17 years of age). Fluvoxamine (Luvox, Solvay, and generics) is another available SSRI; it is FDA-approved for pediatric obsessive-compulsive disorder and not major depressive disorder.

The efficacies of the various SSRIs in the treatment of adult major depressive disorder are similar, although patients may respond more favorably to one SSRI over another. Evidence of SSRI efficacy in children is more limited, however, and agent choice is more selective as compared with therapy in adults.

SSRIs are often favored in the treatment of depression, largely because of their wider therapeutic index when compared with other drug classes, such as the tricyclic antidepressants or monoamine oxidase inhibitors.

SSRIs may differ in terms of adverse effects, pharmacokinetics and the potential for drug-drug interactions. While all SSRIs may cause gastrointestinal complaints (diarrhea, nausea), insomnia, headaches, nervousness, fatigue and sexual dysfunction, individuals may tolerate some agents more favorably. Paroxetine may cause more sexual dysfunction and symptoms of the discontinuation syndrome (eg, anxiety, confusion, diarrhea, sensory disturbances). The SSRIs used in the therapy of major depressive disorder are hepatically metabolized by the cytochrome P450 system and are highly bound to plasma proteins; thus, they may adversely interact with other medications. These interactions may be more clinically significant with paroxetine and fluoxetine, because of their increased potency of inhibition of specific P450 isoenzymes.

Recent controversies in use

In March 2004, the FDA issued a public health advisory on the use of the above SSRIs and several other antidepressants for the potential for worsening depression or the emergence of suicidal tendencies in children and adults (www.fda.gov/cder/drug/antidepressants/default.htm). This advisory followed the issuance of two previous warnings in June and October of 2003 on the potential for an increased risk of suicide in children receiving antidepressants. The March 2004 advisory requests that manufacturers adjust their product labeling to reflect this risk, and it cautions clinicians and patients of the possibility for increased adverse effects. Although a definitive link between antidepressant use and these adverse effects has not been proved, the FDA believed a warning was justified.

Clinicians should monitor patients receiving these antidepressants closely for worsening symptoms of depression (eg, anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania) or suicidal ideation, especially as pharmacotherapy is begun or as doses are increased.

Concern over the potential for antidepressant-induced suicidal thoughts and ideation arose in June 2003 after more than 100 reports of adverse effects, mostly psychiatric in nature, had been made from the use of paroxetine in children and adolescents. These reports included suicidal ideation and several completed suicides. A direct cause-and-effect relationship, however, has not been proved.

Several months later, in October 2003, the FDA issued a public health advisory on the potential for increased adverse effects of suicidal ideation and other psychiatric events possibly associated with the use of additional antidepressants, after a preliminary review of 15 studies of pediatric major depressive disorder. Anecdotal reports by patients’ families of antidepressant adverse effects made during public hearings contributed to the FDA’s concerns.

Conclusions have not been made about a definitive association between these adverse effects and antidepressant use, yet it was important to raise the concern to clinicians and patients. It is the intent of the FDA to further evaluate these data from clinical trials and to further define and assess any potential risks. Another report is due by late summer.

Reports of adverse events associated with (and potentially induced by) paroxetine and data from unpublished clinical trials investigating paroxetine for pediatric obsessive-compulsive disorder led the U.K.’s Committee on Safety of Medicines to recommend against the use of paroxetine in June 2003. The FDA followed with a similar recommendation in June 2003.

Conclusions

While several SSRIs are available to clinicians for the treatment of major depressive disorder, only one, fluoxetine, is approved by the FDA for use in children. Several other SSRIs, however, are FDA-approved for use in children in the therapy of other psychiatric disorders (eg, obsessive-compulsive disorder).

Evidence for the beneficial effects of SSRIs in the treatment of major depressive disorder is limited for the pediatric population. The SSRIs are generally believed to be the agents of choice for major depressive disorder in adults due to their efficacy and lower adverse effect profiles as compared with other classes of antidepressants.

Clinicians should familiarize themselves with the recent concerns and recommendations issued by the FDA and should appropriately monitor their patients for adverse effects, especially with drug therapy initiation or dosage increases. It is also prudent to consider that these recent concerns are preliminary and definitive conclusions or associations have not been made. Published editorials appropriately discuss the many benefits of SSRI therapy in the treatment of major depressive disorder (ie, decrease in depressive symptoms and depression-related suicide) and recommend that clinicians and patients consider these benefits, avoiding the inclination to dismiss the use of all SSRIs in children and adolescents.

While adverse events possibly caused by paroxetine have been reported, other data indicate paroxetine may effectively treat major depressive disorder in adolescents. Some have suggested that the FDA’s recommendation to avoid paroxetine is unfounded, while others have suggested not initiating therapy with it, while also not withdrawing therapy in patients who have responded to it.

In addition, beneficial effects of sertraline in treating major depressive disorder have recently been shown in published studies of children and adolescents, although sertraline is not labeled for use in this population. While pharmacotherapy can be a beneficial treatment modality in the therapy of pediatric major depressive disorder, clinicians should continue to take advantage of nondrug therapies, such as cognitive behavioral or interpersonal psychotherapy.

For more information:

• FDA statement regarding the antidepressant Paxil for pediatric population. www.fda.gov/cder/drug/infopage/paxil/default.htm.
• Are SSRIs safe for children? Med Lett Drugs Ther. 2003;45:53-54.
• Keller MB. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Amer Acad Child Adolesc Psychiatry. 2001;40:762-772.
• Wagner KD. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. Two randomized controlled trials. JAMA. 2003;290:1033-1041.
• Varley CK. Psychopharmacological treatment of major depressive disorder in children and adolescents. JAMA. 2003;290:1091-1093.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children's Hospital, Des Moines, Iowa.