LETTERS TO THE EDITOR
VALPROIC ACID AND RISPERIDONE:
A DRUG INTERACTION?
To the Editor:
We read with interest the letter by van Wattum (2001) and
the commentary by Vitiello (2001) on a possible drug inter-
action between valproic acid and risperidone in a 10-year-old
boy. The serum concentration of valproate increased by 34%
(from 143 to 191 mg/L on a dose of 1,750 mg/day) after the
addition of risperidone. To extend the knowledge about this
possible drug interaction, we performed a prospective study
on serum samples received for the analysis of valproate in our
therapeutic drug monitoring laboratory.
During a period of 6 months, we identified four patients
using the combination valproate and risperidone and not tak-
ing drugs that are known to reduce the valproate levels, such
as carbamazepine, phenobarbitone, and phenytoin (Table 1).
For comparison, 172 samples from patients using valproate
without being concomitantly treated with carbamazepine, phe-
nobarbitone, or phenytoin were also reviewed. All four patients
on risperidone had remarkably similar valproate serum con-
centration/dose (C/D) ratios (Table 1). The mean valproate
C/D ratios in the four patients on risperidone and in the 172
controls were identical, 0.063. The patients taking risperidone
had serum concentrations of risperidone and its active metabo-
lite 9-hydroxyrisperidone in the recommended range, indi-
cating adequate compliance for this drug.
In two of the four patients, the serum valproate concentra-
tions had also been measured on occasions when the patients
were not taking risperidone. Patient 1 had a C/D ratio of 0.062
also without risperidone (valproate dose 1,200 mg/d; valproate
concentration 74 mg/L). Patient 2 had C/D ratios of 0.069
and 0.063 on two occasions without risperidone (valproate
doses 900 and 900 mg/day, respectively, and valproate con-
TABLE 1
Patient Characteristics, Doses, Concentrations, and Concentration/Dose (C/D) Ratios
of Four Patients Concomitantly Treated With Risperidone and Valproate
Patient No. Risperidone Valproate
(Gender, Age) Dose (mg/day) Dose (mg/day)
1 (male, 64) 1 1,500
2 (male, 66) 2 300
2 (male, 66) 2 600
3 (female, 49) 3 450
4 (male, 47) 9 150
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 1 , J A N U A RY 2 0 0 3
centrations 62 and 57 mg/L, respectively). These data further
argue against a drug interaction.
The authors of the case report (van Wattum, 2001) and of
the commentary (Vitiello, 2001) present two possible expla-
nations of the suggested interaction. The first alternative dis-
cussed is metabolic inhibition of valproate by risperidone, since
risperidone is a weak inhibitor of the hepatic cytochrome P-
450 isoenzyme CYP2D6, which is a minor pathway of val-
proate metabolism. We consider this possibility to be unlikely.
We are not aware of any publications demonstrating that the
CYP2D6 pathway accounts for a significant part of the total
metabolism of valproate. Thus even a complete inhibition of
this pathway will not be expected to affect the total clearance
of valproate. This is further substantiated by the fact that risperi-
done is a much weaker CYP2D6 inhibitor than, e.g., paroxe-
tine, for which it has been documented that no interactions
with valproate take place (Andersen et al., 1991).
The other alternative discussed is displacement of the protein
binding of valproate by risperidone. This alternative is extremely
unlikely. Risperidone is found in plasma in concentrations of 10
to 40 μg/L (0.01–0.04 mg/L), which is less than 1:1,000 of the
levels of valproate. Even if all risperidone were bound to albu-
min and were displacing valproate, only 0.01–0.04 mg of val-
proate per liter of plasma would be displaced. Valproate is bound
to albumin by approximately 90%. Thus, as an example, at a
total valproate concentration of 100 mg/L, 10 mg/L is unbound
and therapeutically active. A complete displacement of valproate
by risperidone will in this case increase the concentration of free
valproate from 10 mg/L to 10.01 to 10.04 mg/L, which is clearly
negligible. Moreover, even if the displacement were not negli-
gible, no differences in clinical effect would have been expected.
Because valproate is a low clearance drug, the liver metabolism
of free valproate would have been increased correspondingly,
rendering the unbound and therapeutically active concentration
principally unchanged (Rowland and Tozer, 1995).
Valproate Con- Valproate
centration (mg/L) C/D Ratio
93 0.062
19 0.063
39 0.065
24 0.053
11 0.073
1
LETTERS TO THE EDITOR
In conclusion, we were unable to confirm that any phar-
macokinetic interaction exists between risperidone and val-
proate. Moreover, given the known pharmacokinetic properties
of these drugs, we are unable to identify a theoretical rationale
for such an interaction.
Janne Kutschera Sund, M.Sc.Pharm.
Trond Aamo, M.D.
Olav Spigset, M.D.
Department of Clinical Pharmacology
St. Olav’s University Hospital
Trondheim, Norway
Andersen BB, Mikkelsen M, Vesterager A et al. (1991), No influence of the
antidepressant paroxetine on carbamazepine, valproate and phenytoin.
Epilepsy Rev 10:201–204
Rowland M, Tozer TN (1995), Clinical Pharmacokinetics: Concepts and
Applications, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, pp
270–276
van Wattum PJ (2001), Valproic acid and risperidone. J Am Acad Child Adolesc
Psychiatry 40:866–867
Vitiello B (2001), Valproic acid and risperidone (commentary). J Am Acad
Child Adolesc Psychiatry 40:867
DOI: 10.1097/01.CHI.0000024907.60748.E1
VALPROIC ACID AND RISPERIDONE
To the Editor:
Within the past year, the Journal has published two letters
and a commentary that outline a potential drug interaction
between valproic acid and risperidone. The nature and etiol-
ogy of the interaction remain controversial. The first case report
(van Wattum, 2001) was that of a 10-year-old boy whose val-
proic acid level rose into the toxic range after the initiation of
risperidone. It was proposed that competition for protein bind-
ing sites ultimately resulted in the displacement of valproic
acid into serum, resulting in increased serum concentrations
of the drug. The addition of risperidone was also reported to
cause a drop in valproic acid levels in a 15-year-old girl with
psychosis and a seizure disorder (Bertoldo, 2002). The latter
report noted that risperidone likely reduces serum valproate
levels by 30% through cytochrome P-450 2D6 interactions as
previously proposed by Dr. Vitiello (2001). This would be true
if risperidone were in fact an inducer of cyt 2D6, like carba-
mazepine. However, as Dr. Vitiello outlines, risperidone is
instead metabolized by and mildly inhibits the cyt 2D6 sys-
tem, which would result in increased levels of unmetabolized
valproic acid in plasma during combination therapy (i.e., poten-
tially toxic levels).
We propose that the longer-acting forms of valproic acid,
specifically divalproex sodium, might be less likely to cause such
interactions. This claim is supported by data presented by our
group at the American Psychiatric Association 2002 Annual
Meeting in Philadelphia. Our poster described a retrospective
2 J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 1 , J A N U A RY 2 0 0 3
chart review of 45 child and adolescent psychiatry inpatients
who were started on divalproex sodium for mood lability and
explosive temper outbursts. The goal of the study was to exam-
ine variables that may acutely alter dosage requirements for dival-
proex, such as drug combinations. For example, 29 of 45 patients
received concurrent treatment with atypical antipsychotics.
Coadministration of other psychotropic medications, includ-
ing atypical antipsychotics, did not significantly alter trough
serum valproate levels. Although the sample size limited the
power of some analyses, there did not appear to be a significant
difference in drug levels among those receiving divalproex +
risperidone versus divalproex + olanzapine versus divalproex
alone. Sedation was more common in children receiving com-
bination therapy than in children receiving divalproex alone.
In summary, combining neuroleptic medication with dival-
proex sodium does not appear to alter divalproex levels at clin-
ically effective doses. These observations, in light of previous
reports of potential drug interactions between risperidone and
valproic acid, emphasize the need to proceed with caution in
children requiring combination therapy to adequately control
mood lability and aggression.
Candace R. Good, M.D.
Christopher A. Petersen, M.D.
Valentins F. Krecko, M.D.
Department of Psychiatry
Penn State College of Medicine
Hershey, PA
Bertoldo M (2002), Valproic acid and risperidone (letter). J Am Acad Child
Adolesc Psychiatry 41:632
van Wattum PJ (2001), Valproic acid and risperidone (letter). J Am Acad Child
Adolesc Psychiatry 40:866–867
Vitiello B (2001), Valproic acid and risperidone (commentary). J Am Acad
Child Adolesc Psychiatry 40:867
DOI: 10.1097/01.CHI.0000024908.60748.05
PSYCHOPATHOLOGY IN THE PARENTS OF BOYS
WITH GENDER IDENTITY DISORDER
To the Editor:
In an essay in the Clinical Perspectives section of the Journal,
titled “Children With Gender Identity Issues and Their Parents
in Individual and Group Treatment,” Rosenberg (2002) made
a cursory remark regarding the psychiatric status of the par-
ents of the 12 child and adolescent patients in her current pro-
gram: “All of the parents in my sample have had a clinical
psychiatric examination…. Unlike Zucker and Bradley (1995),
I did not find parental psychopathology at a rate exceeding the
norm” (p. 620). Rosenberg then noted that one parent was “an
alcoholic in recovery for 15 years; one had been in treatment
for nonpsychotic depressive disorder, another for anxiety dis-
order” (p. 620).