How (not) to dose antidepressants and antipsychotics for children

Knowing pharmacokinetics can improve efficacy, help avoid adverse effects.

Where do you turn for help in dosing an antidepressant for a child with major depressive disorder? You might be misinformed if you rely on methods used in multicenter, randomized, placebo-controlled trials, according to Robert L. Findling, MD, an expert in child and adolescent pharmacokinetics (PK).

In a recent review, Dr. Findling and colleagues at University Hospitals, Case Medical Center, and Case Western Reserve University concluded that:

* Data from PK studies do not support the dosing strategies used in many placebo-controlled efficacy trials of antidepressants in children and adolescents
* Excessively low or high dosages may explain—at least in part—why antidepressants failed to show efficacy or were associated with agitation, hostility, or increased suicidality among depressed pediatric patients in some studies.

To provide Current Psychiatry readers with more information on this topic, Section Editor Robert A. Kowatch, MD, PhD, interviewed Dr. Findling about pediatric PK studies and what they can tell clinicians about dosing antidepressants and antipsychotics in children and adolescents.

Clinical Point Excessive doses may explain in part why antidepressants caused agitation, hostility, and suicidality in some trials with depressed pediatric patients

Not 'small adults'

Dr. Kowatch: Warnings about a risk of suicidality in young people taking antidepressants have increased physicians’ concern about accurate dosing for children. How do pediatric pharmacokinetic parameters differ from those of adults?

Dr. Findling: Children and adolescents are not, of course, simply small adults. Significant differences in absorption rate, volume of distribution, and elimination affect PK parameters, such as half-life, throughout the life cycle.

Dr. Kowatch: What determines these differences? Are they based on factors such as weight, age, puberty, or gender?

Dr. Findling: In general, PK differences observed with antidepressants have been dependent on the patient’s age or weight, rather than on gender differences or sexual maturation. To assume that drug exposure is weight-proportional across the life cycle is fraught with peril and is not true for many compounds, including psychotropics.

Dr. Kowatch: In which age groups would clinicians see the greatest differences in drug exposure?

Dr. Findling: It depends on the compound. Exposure to lithium, for example, is determined by the glomerular filtration rate, which often is much higher and necessitates higher weight-adjusted dosing in a younger child than in a teenager or adult. Drug exposure becomes more complicated with more complex compounds, with differing volumes of distribution, absorption rates, and perhaps multiple enzymes involved in bio-disposition.