How (not) to dose antidepressants and antipsychotics for children
Knowing pharmacokinetics can improve efficacy, help avoid adverse effects.
Exposure and half-life
Dr. Kowatch: Can you talk more about nonlinear kinetics?
In another example, the half-life of citalopram or escitalopram in adults is about 24 hours. In a small pilot study with adolescents, the half-life seemed to be about 19 hours.4 So what’s the half-life in younger children? We simply don’t know. If it’s even shorter than in teenagers, then maybe we should be dosing these drugs twice daily in children rather than once daily as we do with adults.
Dr. Kowatch: So clinicians need to consider at least 2 different factors: shorter half-lives with most SSRIs in children and the possibility of nonlinear kinetics.
Dr. Findling: Yes, and there is greater between-subject variability in PK parameters in children than in adults, based on age and size differences. With sertraline, for example, if you give young people 200 mg/d, the PK parameters are very similar to those of adults. With lower doses, however, sertraline appears to have a shorter half-life that is dose-related. This suggests that if you use dosages
Table 1
SSRIs in children and adolescents: What PK studies found
| Antidepressant | Findings | Dosing recommendations |
|---|---|---|
| Fluoxetine | With chronic 20-mg dosing, blood levels were ~2 times higher in children ages 6 to 12) than adolescents (ages 13 to 18) | Perhaps start with 10 mg/d for prepubertal children and 20 mg/d for adolescents |
| Sertraline | With | Twice-daily dosing might be reasonable for youths receiving |
| Paroxetine | 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 | Consider starting with 10 mg/d; if no response, increasing to 20 mg/d may be reasonable |
| Citalopram | 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 | Twice-daily dosing might be reasonable for adolescents or children |
| Escitalopram | 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 | Twice-daily dosing for adolescents or children might be a rational consideration |
| PK: pharmacokinetic | ||
| SSRIs: selective serotonin reuptake inhibitors | ||
| Source: Reference 1 | ||
Different doses, different results?
Dr. Kowatch: Your study found that some SSRI dosages used in placebo-controlled trials of children with major depression were not supported by data from PK studies. Do you think different dosing would have changed the outcomes?
Dr. Findling: That’s an empiric question, but I think the odds for different results are high. For example, I just alluded to dosing
Dr. Kowatch: What about the increased risk of suicidality in children and adolescents that was seen in clinical trials with paroxetine and venlafaxine (Table 2)? If those antidepressants had been dosed differently, would that adverse effect have disappeared?
Dr. Findling: It might not have been as strong. Again, it’s an empiric question.
Dr. Kowatch: So how does dosing affect the risk of suicidality?
Dr. Findling: Among SSRIs, paroxetine was reported in clinical trials to have the highest risk of suicidality. Is that because it has nonlinear kinetics and was dosed much higher than was optimal?
PK data suggest an appropriate starting dose of 10 mg/d, with an increase to 20 mg/d after a month, if needed.5 In the pivotal randomized, controlled efficacy trial, however, the starting dose and escalation rate were much higher. Based on the PK data, a lower starting dose with a more gradual titration strategy might have been used.Dr. Kowatch: So better dosing studies are needed?
Dr. Findling: Yes. Clinicians are limited by the lack of methodologically rigorous dosing studies that ascertain PK parameters in children.
Table 2
Non-SSRI antidepressants in children and adolescents:
What PK studies found
| Antidepressant | Findings | Comment |
|---|---|---|
| Venlafaxine | One PK study exists (6 children, 6 adolescents); systemic exposure was lower than reported in adults when given at ~2 mg/kg/d | Not found more efficacious than placebo in 2 studies of youth ages 7 to 17 with MDD; little evidence exists to support dosages used in these studies, which found the highest risk of suicidality with venlafaxine, compared with other antidepressants |
| Nefazodone | In open-label, flexible-dose trial, depressive symptoms improved substantially with mean dosages of 233 mg/d in children and 342 mg/d in adolescents | Children may do better using lower dosages than are optimal for adolescents |
| Mirtazapine | In a single-dose trial of youths age 7 to 17, half-life increased significantly with increasing weight (range 17.8 to 48.4 hours), and blood levels decreased with increasing age | 8 weeks of dosing at 15 to 45 mg/d were not superior to placebo in 2 studies of youth ages 7 to 17 with MDD |
| MDD: major depressive disorder | ||
| PK: pharmacokinetic | ||
| SSRI: selective serotonin reuptake inhibitor | ||
| Source: References 1,5 | ||
Antipsychotics and weight gain
Dr. Kowatch: What about dosing second-generation antipsychotics (SGAs)? Clinicians tend to treat children with lower doses than are used for adults.
Dr. Findling: Right, although that practice is not entirely evidenced-based. We learned from an early pilot PK study of aripiprazole6 that initially giving adult doses to kids produced emesis and sedation. This suggested that kids respond to this drug differently than adults, and lower starting doses and gradual upward titration were needed to make the drug more safe and effective in kids. That’s a perfect example of a dose-ranging study with PK parameter estimates that provide the requisite data to design pivotal studies.
Dr. Kowatch: How do pharmacokinetics affect weight gain in children treated with SGAs?
Dr. Findling: Weight gain with SGAs is worse in kids than in adults, but I have yet to see compelling evidence that suggests why. In order of weight-gain effect, I would say clozapine and olanzapine are similar, although clozapine probably has the greatest effect. Next would be risperidone and quetiapine having equal effects, followed by aripiprazole and ziprasidone. Aripiprazole seems to cause modest but not terribly problematic weight gain, and ziprasidone seems weight neutral.
But there is some PK variability from patient to patient. In a recent pilot study of quetiapine,7 we found that most kids gained weight early and leveled out at a certain threshold, even though dosing remained the same. Only one youngster had problematic weight gain, and we suspect this was because he had higher exposure because of intersubject PK variability.
Dr. Kowatch: In children, how do you manage weight gain associated with SGAs and other psychotropics?Dr. Findling: Our group is pretty conservative. We usually don’t prescribe weight-loss medications to kids. We also don’t send everyone to a dietitian; that’s not financially feasible for many families. And studies with risperidone suggest that psychostimulants don’t ameliorate weight gain.8
That leaves us with preparing pediatric patients for increased appetite when they start SGAs. We talk about healthy snacks—such as unbuttered popcorn instead of potato chips—and advise against drinking soda and juice, which are loaded with calories. We also try to get sedentary kids up and moving. Some kids enjoy video games where they can dance on mats based on prompts on the screen. We also can switch SGAs if a patient is gaining weight; we’ve got lots of options.
Dosing is ‘not haphazard’
Dr. Kowatch: Any final thoughts?
Dr. Findling: Dosing is not a haphazard event. It needs to be rigorously and scientifically determined and characterized with well-described studies that often involve ascertaining PK parameter estimates. Can you imagine if somebody gave a new medicine to 10 adults, found some degree of benefit, and then started large-scale, phase-3 studies? No one would think that was reasonable, yet that’s what happens with kids all the time.
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.
- 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
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.
