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, (1) 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.
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. (2)
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.
Factors that affect dosing
Dr. Kowatch: Clinically, what's the best way to determine safe, effective psychotropic dosing in children?
Dr. Findling: The short answer is to study the literature, and unfortunately most people find PK studies just about as interesting as watching paint dry. But a good PK study provides insight into a very important parameter, which is dosing.
Ultimately, we can't talk about a medicine's effectiveness or safety as a fixed statement. You can't say drug "x" is effective for this condition or drug "y" is associated with this rate of side effects because tolerability and effectiveness are dose-dependent. And if you don't know how to dose a medicine, you can't characterize its pharmacodynamic properties when prescribing it to a youngster.
So you have to know the literature; what happens at different doses is terribly important.
Dr. Kowatch: In children with psychiatric disorders, what does the literature say about whether the diagnosis determines the dose?
Dr. Findling: With children, dosing may be diagnosis-dependent for the same medications within the same age groups. For example, Tourette's syndrome or conduct disorder in children and adolescents can be managed with lower antipsychotic doses than those required for major psychotic illnesses or mania. …