Major Depressive Disorder (MDD) may be composed of some symptom clusters with distinct neurochemical disturbances, suggesting the importance of the factor analysis of depressive symptoms; however, the results of previous studies using the Montgomery-Asberg Depression Rating Scale (MADRS) have been inconsistent. In the present study, factor analysis of the MADRS was performed in 132 Japanese patients (range 23-74 years, mean 47.6 years) with MDD without any psychiatric comorbidity. The principal component analysis with Varimax rotation identified three factors, accounting for 61% of the total variance: The first factor, labeled dysphoria, included pessimistic thoughts, suicidal thoughts, and reported sadness; the second factor, labeled retardation, included lassitude, inability to feel, apparent sadness, and concentration difficulties; and the third factor, labeled vegetative symptoms, included reduced sleep, reduced appetite, and inner tension. The score of the vegetative factor showed a significant positive correlation with age and was significantly higher in females than in males. This study suggests that the symptoms of MDD, as assessed by the MADRS, cluster into three factors (dysphoria, retardation, and vegetative symptoms).

Pantoprazole, a proton pump inhibitor, is administered as a racemic mixture. To determine the role of cytochrome P450 (CYP) 2C19 in the stereoselective metabolism of pantoprazole, we investigated the pharmacokinetic disposition of (+)- and (-)-pantoprazole in 7 extensive metabolizers and 7 poor metabolizers of S-mephenytoin. All of the subjects received an oral 40-mg dose of racemic pantoprazole as the enteric-coated formulation. In the extensive metabolizers, the mean clearance of (-)-pantoprazole was only slightly lower than that of (+)-pantoprazole and no significant differences in the other pharmacokinetic parameters between (+)- and (-)-pantoprazole were observed. The mean (+)/(-) ratios for maximum concentration, area under the plasma concentration-time curve from 0 to infinity, and elimination half-life were 0.94, 0.82, and 0.90, respectively. In contrast, in the poor metabolizers, the clearance values of both enantiomers were significantly lower than those in the extensive metabolizers, and a significant difference in pharmacokinetics between (+)- and (-)-pantoprazole was observed. The mean elimination half-life for (+)-pantoprazole was 3.55-fold longer than that of (-)-pantoprazole, and the mean maximum concentration and area under the plasma concentration-time curve from 0 to infinity for (+)-pantoprazole were 1.31- and 3.59-fold greater, respectively, than those for (-)-pantoprazole. These results indicate that the stereoselective metabolism of pantoprazole depends on S-mephenytoin 4'-hydroxylase (CYP2C19). The metabolism of (+)-pantoprazole was impaired to a greater extent than (-)-pantoprazole in the poor metabolizers.

Pharmacogenetic studies have shown that several cytochrome P450 (CYP) enzymes exhibit genetic polymorphisms. Several benzodiazepines (BZPs) are metabolized predominantly or partly by polymorphic CYP2C19 and CYP3A4/5. The pharmacokinetics of diazepam, etizolam, quazepam and desmethylclobazam have been shown to be affected by CYP2C19 polymorphism. The CYP3A5 polymorphism has been reported to affect the pharmacokinetics of alprazolam, but its effect on midazolam kinetics has been inconclusive. For etizolam and desmethylclobazam, some data suggest that CYP2C19 deficiency leads to side-effects or toxicity. For the remaining BZPs the clinical significance of the observed pharmacokinetic changes remains unclear. Further studies on the effects of genetic polymorphisms of CYP enzymes on the pharmacokinetics and pharmacodynamics of BZPs are necessary to guide treatment individualization and optimization.

These data indicated that the metabolic disposition of pantoprazole is under the pharmacogenetic control of S-mephenytoin 4'-hydroxylase (CYP2C19).

Previous studies have demonstrated that subjects with one or two A1 alleles of dopamine D2 receptor (DRD2) polymorphism at the Taq1 A locus have lower DRD2 density than those with no A1 allele. The present study aimed to examine whether the Taq1 A DRD2 genotypes are related to therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. The subjects were 25 acutely exacerbated schizophrenic inpatients who had received no medication for at least 1 month before the study. The fixed dose (18 mg/day) of nemonapride was administered to each patient for 3 weeks. The clinical status was prospectively monitored by the Brief Psychiatric Rating Scale (BPRS) before, and 3 weeks after, the treatment. The Taq1 A genotypes (A1 and A2 alleles) were determined by the polymerase chain reaction method. Three patients were homozygous for the A1 allele, 11 were heterozygous for the A1 and A2 alleles, and 11 were homozygous for the A2 allele. The patients with one or two A1 alleles (n = 14) showed significantly higher percentage improvement in total BPRS and positive symptoms than those with no A1 allele (n = 11) after 3-week treatment while the percentage improvement in other subgrouped symptoms (negative, anxiety-depression, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the Taq1 A DRD2 polymorphism is related to early therapeutic response to nemonapride in schizophrenic patients, possibly by modifying the efficiency of DRD2 antagonism of the drug in the central nervous system.

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