Risperidone does not affect steady-state pharmacokinetics of divalproex sodium in patients with bipolar disorder.
OBJECTIVE
Divalproex sodium can interact with many drugs in which combination treatments are used; it can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of other medications by displacing them from plasma proteins. The combination of risperidone and divalproex sodium is used to treat the manic phase of bipolar disorder. However, the effect of risperidone on the pharmacokinetics of valproate has not previously been systematically studied. The aims of this study were to determine the effect of repeated doses of oral risperidone on the pharmacokinetics of valproate in subjects stabilised on divalproex sodium and to document the safety of this combination.


METHODS
A multicentre, observational, randomised, parallel group, single-blind, placebo-controlled drug interaction study.


METHODS
Twenty-two patients with bipolar disorder, in remission, were studied.


METHODS
All subjects were treated with divalproex sodium 1000 mg/day monotherapy on days 1-14. Thereafter, subjects continued to take divalproex sodium for days 15-28; they also received adjunctive treatment with either placebo (n = 11) or risperidone (n = 11) 2mg once daily on days 15 and 16, and 4 mg once daily on days 17-28. Serial blood sampling was performed throughout to determine the plasma concentrations of valproate, risperidone and 9-hydroxy-risperidone.


RESULTS
On analysis, steady-state pharmacokinetic parameters (peak plasma concentrations [C(max)], time to C(max,) area under the concentration-time curve) of valproate were of the same order of magnitude on day 14 (monotherapy) and day 28 (valproate plus risperidone or placebo), with no period effect. The parameters on day 28 were similar in the risperidone and placebo treatment groups, showing that risperidone, as adjunctive treatment, had no influence on the steady-state pharmacokinetics of valproate. Although there were more adverse events reported in the risperidone group compared with the placebo group (ten vs seven, respectively), none of them were serious or necessitated withdrawal. No clinically relevant changes in laboratory parameters, vital signs or ECG-tracings were observed in either group.


CONCLUSIONS
These results indicate that adjunctive risperidone treatment had no influence on the steady-state pharmacokinetics of valproate and this combination was safe and well tolerated.
Centre for Addiction and Mental Health, Toronto, Ontario, Canada. arun_ravindran@camh.net
Arun
A
Ravindran
Peter
P
Silverstone
Denis
D
Lacroix
Erno
E
van Schaick
An
A
Vermeulen
Jennifer
J
Alexander
D000293:Adolescent; D000328:Adult; D000368:Aged; D018692:Antimanic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D001714:Bipolar Disorder / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D018967:Risperidone / Q000009:adverse effects*; D014635:Valproic Acid / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D018692:Antimanic Agents; D014150:Antipsychotic Agents; D014635:Valproic Acid; D018967:Risperidone