A. Dragicevic

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

Background:  Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first‐line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O‐desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N‐desmethylvenlafaxine (NDV).

Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting.

ObjectiveThis evaluation focuses on polymorphisms of the cytochrome-P450 (CYP) isoenzymes 2C9, 2C19 and 2D6 and their association with plasma concentrations within a typical clinical setting. Side effects and treatment response were analysed in an exploratory approach in poor and ultra-rapid metabolisers.Patients and methodsWe analysed 136 Caucasian depressed inpatients treated with amitriptyline, citalopram, clomipramine, doxepin, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine, who underwent weekly plasma concentration measurements, assessment of the severity of illness and side effects during their stay in the hospital. Patients were genotyped with respect to CYP2C9 alleles *1 and *2, the CYP2C19 alleles *1, *2 and *3 and the CYP2D6 alleles *1 to *9 and CYP2D6 gene duplication.ResultsCYP2D6 poor metaboliser genotype and co-medication with inhibitors of CYP2D6 were associated with higher plasma concentrations than the drug-specific median plasma concentration when normalised to dose; plasma concentrations of CYP2C19 extensive metabolisers and smokers were significantly lower than the drug-specific median. Five of the six CYP2D6 poor metabolisers experienced side effects. Response was not associated with plasma concentrations above or below the lower limit of a presumed therapeutic range.ConclusionThese data indicate a significant influence of the CYP2D6 genotype, minor influence of the CYP2C19 genotype and no influence of the CYP2C9 genotype on plasma concentrations of patients taking mainly second-generation antidepressants. Because of the good tolerability of the latter and the flat dose–response relationship, genotyping should only be considered in cases of suspected side effects.

Therapeutic Monitoring of New Antipsychotic Drugs

Abstract: Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350–600 ng/mL), risperidone (20–60 ng/mL), and olanzapine (20–80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.

Standardized rater training for the Hamilton Depression Rating Scale (HAMD-17) in psychiatric novices

BACKGROUND Despite the long and widespread use of the Hamilton Depression Rating Scale (HAMD), standardized reliability studies in inexperienced raters are not available. METHODS Rater training was carried using three videotaped interviews with depressed patients in 21 psychiatric novices who had negligible previous experience with the HAMD. Chance-corrected coefficients of rating agreement with expert standards (weighted kappa, ICC) were computed for single items and the total score of the HAMD. RESULTS The results demonstrate sufficiently high interrater reliability (kappa>0.60) for most of the HAMD items and the total score (ICC=0.57-0.73). Three standardized HAMD training sessions seem adequate to establish satisfactory agreement among psychiatric novices. LIMITATIONS The sample of video-taped interviews and, hence, the generalizability of the results, was restricted. CONCLUSIONS High inter-rater reliability of the HAMD justifies the use by clinically inexperienced researchers after standardized training.

Population pharmacokinetic analysis of mirtazapine

ObjectiveMirtazapine belongs to the new generation of antidepressants that is commonly used in clinical routine. Therefore, we feel it mandatory to control compliance in the context of non-response, adverse events or other clinical situations by means of plasma concentration measurements. While controlled clinical studies have evaluated the effect of individual covariates on the pharmacokinetics of mirtazapine, our analysis aims to identify covariates within a naturalistic clinical setting.MethodsWe performed non-linear mixed-effects modelling with data from 65 depressed inpatients whose plasma concentrations were measured weekly during their stay in hospital. Each patient’s age, height, weight, co-medication, alcohol, coffee and cigarette consumption, weekly serum creatinine concentrations, liver enzyme activity, blood pressure and pulse was noted. From 49 patients, the genotype of cytochrome P450 (CYP) isoenzymes 2D6, 2C9 and 2C19 was analysed.ResultsThe clearance of CYP2D6 intermediate metabolisers was reduced by 26% compared with extensive metabolisers. No other factor significantly influenced the clearance of these patients.ConclusionThe variability of mirtazapine plasma concentrations in clinical routine is caused to a relevant degree by CYP2D6. This should be taken into account when therapeutic drug monitoring is carried out to check treatment adherence or when a special clinical situation, such as co-morbidity and add-on medication, demands careful dosing of this drug.

The serotonin transporter promoter polymorphism (5-HTTLPR) affects the relation between antidepressant serum concentrations and effectiveness in major depression.

INTRODUCTION Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. METHODS 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. RESULTS Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31). DISCUSSION In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.