Pharmacodynamics of ziprasidone in children and adolescents: impact on dopamine transmission.
OBJECTIVE
Ziprasidone is an atypical antipsychotic with a high ratio of 5-HT(2A) to D(2) receptor antagonism. It is also an agonist at 5-HT(1A), which has been shown in rats to increase dopamine in prefrontal cortex. The objective of this study was to probe the dopamine agonist and antagonist pharmacodynamic properties of ziprasidone in youth.


METHODS
A single-dose, open-label study was conducted in 24 youths, 7 to 16 years of age, with Tourette syndrome or chronic tic disorder. Ziprasidone oral suspension (40 mg/mL) was given to achieve 0.2 to 0.3 mg/kg. Patients were subsequently assessed for serum ziprasidone, serum prolactin, and eye blink rates.


RESULTS
Serum ziprasidone peaked 4 hours postdose. Prolactin (baseline mean 7.2 ng/mL, 95% confidence interval [CI] 5.2-9.2) peaked at 4 hours (mean 27.5 ng/mL, 95% CI 22.6-32.3). Eyeblink rates per 5 minutes (baseline mean 60, 95% CI 42-79) peaked at 6 hours (mean 74, 95% CI 52-96).


CONCLUSIONS
Ziprasidone acutely blocks dopamine transmission, as indicated by increased prolactin levels, and, in a delayed fashion, appears to stimulate dopaminergic transmission, as indicated by the increase in spontaneous eye blinks. The mechanism of dopaminergic stimulation is presumed to be indirect, via 5-HT(1A) agonism.
Sallee
Floyd R
FR
Pharmacology Research Center, Children's Hospital Medical Center, USA. floyd.sallee@uc.edu
Gilbert
Donald L
DL
Vinks
Alexander A
AA
Miceli
Jeffrey J
JJ
Robarge
Lisa
L
Wilner
Keith
K
D000293:Adolescent; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D002908:Chronic Disease; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017397:Prefrontal Cortex / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005879:Tourette Syndrome / Q000188:drug therapy*
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D004298:Dopamine