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.

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.

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. Unfortunately, we see youngsters with major psychotic illnesses or mania who have been prescribed the lower antipsychotic doses used to treat conduct disorder, and we see youngsters with conduct disorder who have been given 2 or 3 times the recommended antipsychotic dosages for that condition.

As you increase the dose you get higher exposure, and with higher exposure you have more side effects. Across the 3 antipsychotics we’ve studied—risperidone, quetiapine, and aripiprazole—youngsters with conduct disorder need about half or less of the medication needed by those with psychotic illness or mania.

Dr. Kowatch: What about dosing selective serotonin reuptake inhibitor (SSRI) antidepressants?

Dr. Findling: For some SSRIs, daily weight-adjusted doses are similar across the life cycle. However, there are exceptions. With paroxetine, for example, you get greater drug exposure in young people than in adults, even if you control for weight differences. And paroxetine has nonlinear kinetics in adults and in young patients; when you double the dose, you more than double the exposure.

SSRIs in children and adolescents: What PK studies found

Fluoxetine
Findings
With chronic 20-mg dosing, blood levels were ~2 times higher in children ages 6 to 12) than adolescents (ages 13 to 18)
Dosing recommendations
Perhaps start with 10 mg/d for prepubertal children and 20 mg/d for adolescents

Sertraline
Findings
With <200 mg/d dosing, shorter half life was seen in youths when compared with adults
Dosing recommendations
Twice-daily dosing might be reasonable for youths receiving <200 mg/d

Paroxetine
Findings
Increasing dosage from 10 mg to 20 mg increased blood level 7-fold in youths (nonlinear PK); dosages used in most clinical trials exceeded those supported by PK studies
Dosing recommendations
Consider starting with 10 mg/d; if no response, increasing to 20 mg/d may be reasonable

Citalopram
Findings
With chronic 20-mg dosing, S-citalopram half-life (19.2 hours) was shorter in adolescents than reported in adults; no PK data available for children
Dosing recommendations
Twice-daily dosing might be reasonable for adolescents or children

Escitalopram
Findings
Half-life of a single 10-mg dose was shorter in adolescents than adults; exposure ~15% greater in adults than adolescents; no PK data available for children
Dosing recommendations
Twice-daily dosing for adolescents or children might be a rational consideration

PK: pharmacokinetic
SSRIs: selective serotonin reuptake inhibitors

Related resources

 
• Connor DF, Metzler BM. Pediatric psychopharmacology: fast facts. New York: W.W. Norton & Company; 2006.  
• Findling RL, Steiner H, Weller EB. Use of antipsychotics in children and adolescents. J Clin Psychiatry 2005;66(suppl 7):29-40.

Drug brand names

    Aripiprazole • Abilify
    Citalopram • Celexa
    Clozapine • Clozaril
    Escitalopram • Lexapro
    Fluoxetine • Prozac
    Mirtazapine • Remeron
    Nefazodone • Serzone
    Olanzapine • Zyprexa
    Paroxetine • Paxil
    Quetiapine • Seroquel
    Risperidone • Risperdal
    Sertraline • Zoloft
    Venlafaxine • Effexor
    Ziprasidone • Geodon

Disclosures

Dr. Findling receives research support or is a consultant to Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Celltech-Medeva, Cypress Biosciences, Forest Pharmaceuticals, Glaxo-SmithKline, Johnson & Johnson, Eli Lilly and Co., New River Pharmaceuticals, Novartis, Organon, Otsuka America, Pfizer Inc., sanofi-aventis, Sepracore, Shire, Solvay, Supernus Pharmaceuticals, and Wyeth. He is a speaker for Johnson & Johnson and Shire.

Dr. Kowatch receives research support from Bristol-Myers Squibb, Stanley Research Foundation, National Institute of Mental Health, and National Institute of Child Health and Human Development and is a speaker for AstraZeneca and Abbott Laboratories.
References

  1. Findling RL, McNamara NK, Stansbrey RJ, et al. The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression. J Child Adolesc Psychopharmacol 2006;16:131–45.
  2. Wiznitzer M, Findling RL. Why do psychiatric drug research in children? Lancet 2003;361:1147–8.
  3. Findling RL, Reed MD, Myers C, et al. Paroxetine pharmacokinetics in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 1999;38:952–9.
  4. Periclou A, Rao N, Sherman T, et al. Single-dose pharmacokinetic study of escitalopram in adolescents and adults.Poster presented at: Annual Meeting of the American College of Clinical Pharmacy; November 2-5, 2003; Atlanta, GA.
  5. Findling RL, Myers C, O’Riordan MA, et al. An open-label dosing study of paroxetine in depressed children and adolescents. Curr Ther Res 2002;63:588–601.
  6. Findling R, Blumer J, Kauffman R, et al. Pharmacokinetic effects of aripiprazole in children and adolescents with conduct disorder [abstract]. Int J Neuropsychopharmacol 2004;7(suppl 1):S440.
  7. Findling RL, Reed MD, O’Riordan MA, et al. A 26-week open-label study of quetiapine in children with conduct disorder. J Child Adolesc Psychopharmacol 2007;17:1–9.
  8. Aman MG, Binder C, Turgay A. Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ. J Child Adolesc Psychopharmacol 2004;14(2):243–54.

Robert L. Findling, MD;
Professor of psychiatry and pediatrics, Case Western Reserve University; director of child and adolescent psychiatry, University Hospitals, Case Medical Center, Cleveland, OH.

Robert A. Kowatch, MD, PhD
Current Psychiatry section editor for child and adolescent psychiatry; professor of psychiatry and pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

Source: Current Psychiatry - Dowden Health Media