title: 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.
abstract: 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.
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum Fulda gAG, Pacelliallee 4, 36043 Fulda, Germany. georg.nikisch@klinikum-fulda.de
authors.forename: Georg
authors.initials: G
authors.lastname: Nikisch
authors.forename: Pierre
authors.initials: P
authors.lastname: Baumann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kiessling
authors.forename: Michael
authors.initials: M
authors.lastname: Reinert
authors.forename: Georg
authors.initials: G
authors.lastname: Wiedemann
authors.forename: Jan
authors.initials: J
authors.lastname: Kehr
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
authors.forename: Markus
authors.initials: M
authors.lastname: Piel
authors.forename: Frank
authors.initials: F
authors.lastname: Roesch
authors.forename: Heike
authors.initials: H
authors.lastname: Weisser
authors.forename: Peter
authors.initials: P
authors.lastname: Schneider
authors.forename: Andreas
authors.initials: A
authors.lastname: Hertel
mesh_terms: 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
chemical_list: 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