A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF CITALOPRAM WITH AND WITHOUT LITHIUM IN THE TREATMENT OF THERAPY-RESISTANT DEPRESSIVE PATIENTS -A CLINICAL, PHARMACOKINETIC, AND PHARMACOGENETIC INVESTIGATION

Sixty-nine depressive patients (DSM III criteria: 296.2, 296.3, 296.5, 300.4) were treated with 40 to 60 mg citalopram (CIT) daily for 4 wee ks. Among them, 45 responded to treatment (improvement > 50% on the 21 -item Hamilton Rating Scale for Depression [HAM-D]) and continued thei r treatment for another week before being released from the study. The 24 nonresponders were randomized and comedicated under double-blind c onditions with lithium carbonate (Li) (2 x 400 mg/day) (CIT-Li group) or with placebo (CIT-PI group) from days 29 to 35. For days 36 to 42, the patients of both subgroups were treated openly with Li (800 mg/day ) in addition to the ongoing CIT treatment. On day 35, 6 of 10 patient s responded to the CIT-Li combination, whereas 2 of 14 patients only r esponded to the CIT-P1 combination. This group difference reached sign ificance (p < 0.05) on day 35 with lower HAM-D total scores in the CIT -Li group. No evidence was seen of a pharmacokinetic interaction betwe en CIT and Li, and this combination was well tolerated. Patients were phenotyped with dextromethorphan and mephenytoin at baseline and at da y 28. As evaluated at baseline, three patients (responders) were poor metabolizers of dextromethorphan and six patients (three responders an d three nonresponders) of mephenytoin. On day 28, the ratio CIT/N-desm ethylCIT (DCIT) in plasma was significantly higher in poor than in ext ensive metabolizers of mephenytoin (p = 0.0001), and there was a signi ficant positive correlation between the metabolic ratio of dextrometho rphan and the ratio DCIT/N-didesmethylCIT in plasma (p < 0.001). These findings illustrate the role of CYP2D6 and CYP2C19 in the metabolism of CIT. It can be concluded that Li addition to CIT is effective in pa tients not responding to CIT alone without any evidence of an accentua tion or provocation of adverse events.