Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine.
Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naïve patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trail with 600 mg/day quetiapine. CSF monoamine metabolites levels were compared with dopamine D(2) receptor occupancy (DA-D(2)) using [(18)F]fallypride and positron emission tomography (PET). Quetiapine produced preferential occupancy of parietal cortex vs. putamenal DA-D(2), 41.4% (p<0.05, corrected for multiple comparisons). DA-D(2) receptor occupancies in the occipital and parietal cortex were correlated with CSF quetiapine and norquetiapine levels (p<0.01 and p<0.05, respectively). CSF monoamine metabolites were significantly increased after treatment and correlated with regional receptor occupancies in the putamen [DOPAC: (p<0.01) and HVA: (p<0.05)], caudate nucleus [HVA: (p<0.01)], thalamus [MHPG: (p<0.05)] and in the temporal cortex [HVA: (p<0.05) and 5-HIAA: (p<0.05)]. This suggests that CSF monoamine metabolites levels reflect the effects of quetiapine treatment on neurotransmitters in vivo and indicates that monitoring plasma and CSF quetiapine and norquetiapine levels may be of clinical relevance.
Nikisch
Georg
G
Department of Psychiatry and Psychotherapy, Klinikum Fulda gAG, Pacelliallee 4, 36043 Fulda, Germany. georg.nikisch@klinikum-fulda.de
Baumann
Pierre
P
Kiessling
Bernhard
B
Reinert
Michael
M
Wiedemann
Georg
G
Kehr
Jan
J
Mathé
Aleksander A
AA
Piel
Markus
M
Roesch
Frank
F
Weisser
Heike
H
Schneider
Peter
P
Hertel
Andreas
A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D001549:Benzamides / Q000378:metabolism; D015306:Biogenic Monoamines / Q000378:metabolism*; D001931:Brain Mapping; D003987:Dibenzothiazepines / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D005462:Fluorine Radioisotopes / Q000378:metabolism; D006719:Homovanillic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000097:blood / Q000134:cerebrospinal fluid; D008875:Middle Aged; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000378:metabolism; D000069348:Quetiapine Fumarate; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000097:blood / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000188:drug therapy*; D014316:Tritium / Q000493:pharmacokinetics; D055815:Young Adult
D014150:Antipsychotic Agents; D001549:Benzamides; D015306:Biogenic Monoamines; D003987:Dibenzothiazepines; D005462:Fluorine Radioisotopes; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; D000069348:Quetiapine Fumarate; D008734:Methoxyhydroxyphenylglycol; D006719:Homovanillic Acid