Stereoselective metabolism of citalopram in plasma and cerebrospinal fluid of depressive patients: relationship with 5-HIAA in CSF and clinical response.
Plasma and cerebrospinal fluid (CSF) concentrations of the enantiomers of citalopram (CIT), its N-demethylated metabolite demethylcitalopram (DCIT) and its deaminated metabolite citalopram propionic acid derivative (CIT-PROP) were measured in plasma and CSF in 22 depressed patients after a 4-week treatment with 40 mg/d citalopram, which was preceded by a 1-week washout period. CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured at baseline and after the 4-week CIT medication period. Patients were assessed clinically, using the Hamilton Depression Rating Scale (21-item HAM-D): at baseline and then at weekly intervals. CSF concentrations of S-CIT and R-CIT were 10.6 +/- 4.3 and 20.9 +/- 6 ng/mL, respectively, and their CSF/plasma ratios were 52% +/- 9% and 48% +/- 6%, respectively. The CIT treatment resulted in a significant decrease (28%) of 5-HIAA (P < 0.0001) and a significant increase (41%) of HVA in the CSF. Multiple linear regression analyses were performed to identify the impact of plasma and CSF CIT enantiomers and its metabolites on CSF monoamine metabolites and clinical response. There were 10 responders as defined by a > or =50% decrease of the HAM-D score (DeltaHAM-D) after the 4-week treatment. DeltaHAM-D correlated (Spearman) significantly with CSF S-CIT (r = - 0.483, P < 0.05), CSF S-CIT-PROP (r = -0.543, P = 0.01) (a metabolite formed from CIT by monoamine oxidase [MAO]) and 5-HIAA decrease (Delta5-HIAA) (r = 0.572, P = 0.01). The demonstrated correlations between pharmacokinetic parameters and the clinical outcome as well as 5-HIAA changes indicate that monitoring of plasma S-CIT, CSF S-CIT and CSF S-CIT-PROP may be of clinical relevance.
Nikisch
Georg
G
Department of Psychiatry and Psychotherapy, Box 2364, Klinikum Fulda, D-36013 Fulda, Germany. Georg.Nikisch.Psychiatrie@klinikum-fulda.de
Mathé
Aleksander A
AA
Czernik
Adelheid
A
Eap
Chin B
CB
Jiménez-Vasquez
Patricia
P
Brawand-Amey
Marlyse
M
Baumann
Pierre
P
D000328:Adult; D016009:Chi-Square Distribution; D015283:Citalopram / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D005260:Female; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D018709:Statistics, Nonparametric; D013237:Stereoisomerism
D015283:Citalopram; D006897:Hydroxyindoleacetic Acid; D006719:Homovanillic Acid