Melperone is an Inhibitor of the CYP2D6 Catalyzed O-demethylation of Venlafaxine

INTRODUCTION Melperone, a butyrophenone neuroleptic, is frequently used for its sleep-inducing properties. Despite its common use for more than 30 years, it is not yet characterized regarding its effects on cytochrome P450 s (CYPs). In an open pilot study, effects of melperone on the steady-state blood levels of venlafaxine, a recently introduced serotonin- and noradrenaline reuptake inhibiting antidepressant, were assessed. METHODS The dose-corrected serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed retrospectively in a therapeutic drug-monitoring (TDM) database comprising 94 patients. In addition, three patients received venlafaxine and melperone concomitantly a…

Sex differences in GABAA receptor binding in rat brain measured by an improved in vitro binding assay.

The distribution of GABAA receptor sites was studied in female and male rat brain by an improved in vitro binding assay using 3H-muscimol and carefully washed membrane fractions. The binding studies revealed a single class of binding sites exhibiting the properties of GABAA receptors. The specific binding of 3H-muscimol was measured in four brain areas: the preoptic brain area, mediobasal hypothalamus, corticomedial amygdala and cerebral cortex. The equilibrium dissociation constants (KD) ranged from 11.2 to 23.3 nM in diestrous females and from 13.1 to 50.4 nM in males, the maximal number of binding sites (Bmax) from 3290 to 10240 fmol/mg protein in females and from 5495 to 17449 fmol/mg p…

10 How valid are therapeutic reference ranges for psychotropic drugs?

Serum Concentrations of Fluvoxamine and Clinical Effects: A prospective open clinical trial

This pilot study examined prospectively blood serum concentrations of fluvoxamine, side effects and therapeutic response after a fixed dosage of 100 mg fluvoxamine/day for 14 days. Twenty male and female patients who met the DSM-IV criteria of a major depression received 50 mg fluvoxamine b.i.d. for two weeks. On days 7 and 14 side effects and therapeutic response were registered and serum concentrations of fluvoxamine were determined. A Receiver Operating Characteristic (ROC) curve was constructed to determine a possible relationship between serum concentrations and clinical effects. The serum concentrations of fluvoxamine were highly variable, even when dosages were corrected for body wei…

Inhibition of dextromethorphan metabolism by moclobemide.

This pilot study was conducted to evaluate the potential of the new antidepressant moclobemide to inhibit the cytochrome enzyme P4502D6 (CYP2D6) using the cough suppressant dextromethorphan as a substrate in four extensive metabolizers (EM) of debrisoquine. The subjects received seven oral doses of 20 mg dextromethorphan at 4-h intervals over 2 days (1 and 2) and subsequently moclobemide (300 mg b.i.d.) for 9 days. On days 10 and 11, they received seven doses of 20 mg dextromethorphan in addition to moclobemide. During monotreatment and combined treatment, blood was collected on days 2 and 11, respectively, for determination of dextromethorphan and its demethylated metabolites using automat…

Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical conditions?

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCA) is established in the treatment of depression to optimize outcome and safety. However, there are few reports on TDM under naturalistic clinical conditions. In the present study, we investigated a TDM group (TDM) and a randomly assigned parallel group without TDM (no-TDM) while on TCA treatment. Serum levels were analyzed in both cohorts, but feedback and dose recommendation were only provided for the TDM group. Serum levels of TCA were assessed by high-performance liquid chromatography (HPLC). The outcome was measured weekly using the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions Scale (CGI), and…

Gender aspects in the clinical treatment of schizophrenic inpatients with amisulpride: a therapeutic drug monitoring study.

INTRODUCTION: It is assumed that female and male schizophrenic patients respond differentially to acute and chronic treatment with antipsychotics because of pharmacokinetic and pharmacodynamic factors linked to hormonal and constitutional gender differences. However, to date no empirical evidence exists in support of this notion. METHODS: In a naturalistic clinical study, we investigated gender differences in a sample of schizophrenic inpatients with acute exacerbation treated with the atypical antipsychotic amisulpride, a selective dopamine D2/D3 receptor antagonist with proven antipsychotic efficacy. Prescribed amisulpride dose, plasma level, clinical response (CGI), and side effects (UKU…

Reduction of clozapine-induced hypersalivation by pirenzepine is safe.

Introduction Hypersalivation is known as a frequent, disturbing, and socially stigmatizing side effect of therapy with the atypical antipsychotic clozapine. It has been shown that the addition of the anticholinergic pirenzepine is able to reduce clozapine-induced hypersalivation, probably by blocking M4-receptors. Nevertheless, a pharmacokinetic interaction between both compounds cannot be excluded. Methods In this pilot study, 29 schizophrenic patients (ICD-10; 51.7 % female; age: 36.7 +/- 8.7 years [mean +/- SD]) were included. Serum concentrations of clozapine and its pharmacologically active metabolite N-desmethylclozapine were determined under steady-state conditions by automated HPLC …

Pharmacodynamic effects of aripiprazole and ziprasidone with respect to p-glycoprotein substrate properties.

Introduction Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on dopamine D2 and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein (P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp deficient mouse model by studying the effects of aripiprazole and of ziprasidone on motor coordination. Methods The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(-/-)] mice was investigated on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone. For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor ligands buspirone and ketanserin were also applied. …

Amisulpride doses and plasma levels in different age groups of patients with schizophrenia or schizoaffective disorder.

Abstract Because of a unique pharmacodynamic profile, amisulpride seems appropriate for treatment of elderly patients with schizophrenia. In a large-scale naturalistic therapeutic drug monitoring study, daily amisulpride dose, trough and dose-corrected amisulpride plasma levels, co-medication, clinical effectiveness (CGI) and side effects (UKU) were compared between age groups in 395 patients with schizophrenia or schizoaffective disorder (46% women; mean age 39.1 ± 14.2 years, range 18–83 years) under amisulpride therapy. Mean amisulpride doses (574 ± 269 mg/day), plasma levels (304 ± 274 ng/mL), dose-corrected amisulpride plasma levels (C/D ratios, 0.52 ± 0.41 ng/mL:mg), clinical respons…

Addition of Low-Dose Fluvoxamine to Low-Dose Clozapine Monotherapy in Schizophrenia: Drug Monitoring and Tolerability Data from a Prospective Clinical Trial

Combining fluvoxamine and clozapine may be a strategy to improve therapeutic effects on negative symptoms in schizophrenic patients. Fluvoxamine, however, markedly inhibits the metabolism of clozapine, and hazardous side effects may result. This study prospectively investigated the safety and tolerability of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvoxamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse events, laboratory parameters, EEG and ECG recordings, orthostatic hypotension and their psychopatholog…

Early Improvement and Serum Concentrations of Citalopram to Predict Antidepressant Drug Response of Patients with Major Depression

Post hoc analyses of clinical trials have shown that early improvement around day 14 is highly predictive for later response. More- over, evidence has been given that suffi ciently high concentrations of antidepressant drugs in blood are required to attain response. In this study, we determined cut-off levels for citalo- pram serum concentrations and clinical improve- ment during the early phase of treatment to predict later response and the predictive power of these measures either alone or in combination. Methods: Inpatients with depressive disorder according to ICD-10 who received citalopram were included. Psychopathology was assessed by the 17-item Hamilton Depression (HAMD-17) rating s…

Influence of concomitant medications on the total clearance and the risk for supra-therapeutic plasma concentrations of Citalopram. A population-based cohort study.

Introduction: The main objective of this study was to investigate the influence of the use of multiple medications and other risk factors on citalopram plasma concentrations. Methods: A retrospective cohort study with a naturalistic population of 957 patients for whom routine therapeutic drug monitoring (TDM) of citalopram had been requested between 2006 and 2013 was conducted. Results: Concomitant drugs inhibiting at least 2 different CYP subtypes involved in the metabolism of citalopram decreased statistically significantly the total clearance (Clt). Compared to younger patients over 64-year-old patients had on average a 4.5 times higher risk rate of supra-therapeutic plasma concentration…

Serum Levels of Sulpiride Enantiomers after Oral Treatment with Racemic Sulpiride in Psychiatric Patients: a Pilot Study1

Sulpiride (SULP), a substituted benzamide with high selectivity for D 2 -like dopamine receptors, has a chiral structure and is used in most countries as the racemate. In an open pilot study, we investigated 26 inpatients (13 female, 13 male) with schizophrenic or depressive disorder treated with SULP (mean daily dosage 64-1062 mg) administered orally, either as a monotherapy or as an add-on treatment to a stable and unchanged medication for 3-60 days. Serum levels of total SULP and of its enantiomers were measured by high-performance liquid chromatography (HPLC) procedures. Clinically relevant indicators of hepatic and renal function as well as retrospectively assessed clinical outcome par…

Effects of GABA-transporter (GAT) inhibitors on rat behaviour in open-field and elevated plus-maze.

The behavioural consequences of inhibition of gamma-aminobutyric acid (GABA) uptake were studied. Two GABA uptake inhibitors, tiagabine and SKF 89976-A, were administered to rats, and behaviour was analysed 30 min later in a standard open field, an enriched open field, and an elevated plus-maze. Eight groups of animals received either saline (0.9%), tiagabine, or SKF 89976-A. At a dose of 18.5 mg/kg, tiagabine, an established antiseizure drug, impaired motor coordination, enhanced exploratory activity and reduced anxiety related behaviour. SKF 89976-A exhibited minimal effects over the dose range tested. These results indicate that inhibition of GABA uptake might be a pharmacological strate…