Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol.
BACKGROUND
Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D(2), D(1) and 5-HT(2A) receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol's interaction with 5-HT(2A) and/or D(1) receptors.


OBJECTIVE
To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 +/- 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 +/- 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 +/- 5.5 mg/day).


METHODS
Each patient underwent two PET scans with 3-N-[(11)C]methylspiperone (target: frontal 5-HT(2A)), [(11)C]SCH23390 (striatal D(1)) or [(11)C]raclopride (striatal D(2)). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls.


RESULTS
D(2)-RO under FLX was between 50% and 70%, indicating an ED(50) of about 0.7 ng/ml serum. 5-HT(2A) and D(1)-RO was 20 +/- 10% and 20 +/- 5% (mean, SEM). Under HAL, D(1)-RO was 14 +/- 6% and under RIS not significantly different from zero.


CONCLUSIONS
We were able to demonstrate a moderate 5-HT(2A) and D(1) occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol's efficacy on negative symptoms is based on its interaction with 5-HT(2A) and/or D(1) receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D(1) or 5-HT(2A) antagonism may contribute to flupentixol's efficacy on negative symptoms.
Reimold
M
M
Department of Nuclear Medicine/PET Center, University of Tuebingen, Tuebingen, Germany. matthias.reimold@uni-tuebingen.de
Solbach
C
C
Noda
S
S
Schaefer
J-E
JE
Bartels
M
M
Beneke
M
M
Machulla
H-J
HJ
Bares
R
R
Glaser
T
T
Wormstall
H
H
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects; D005260:Female; D005475:Flupenthixol / Q000627:therapeutic use*; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000187:drug effects; D006220:Haloperidol / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D012565:Schizophrenic Psychology
D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D005475:Flupenthixol; D006220:Haloperidol; D018967:Risperidone