A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 i…

Detection of TOAD-64 in adult rat brain as revealed by two-dimensional protein gel electrophoresis followed by MALDI mass spectrometry

The molecular mechanisms by which antipsychotic effects are achieved remain largely elusive. Possible mechanisms include the modulation of nerve cell gene expression. The antipsychotic drug haloperidol was administered orally (1.6 mg/kg) to adult rats for 3 weeks. Protein patterns in striata and forebrains were studied by two-dimensional gel electrophoresis (2-DE). One differentially regulated protein spot was identified by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) after trypsin digest. Turned on after devision-64 kD (TOAD-64), the identified protein, was present in all gels and, in addition, was up-regulated in the striata but not in the forebrains of the hal…

Micellar electrokinetic capillary chromatography for therapeutic drug monitoring of carbamazepine and its main metabolites.

In carbamazepine (CBZ) therapy the concomitant monitoring of concentrations of CBZ and its metabolites is strictly recommended, primarily to avoid toxic side effects. Currently, clinical routine monitoring of CBZ is accomplished by high-performance liquid chromatography or immunological methods. In this study a micellar electrokinetic capillary chromatographic (MECC) method was developed for routine drug monitoring of CBZ and its main metabolites, carbamazepine 10,11-diol and carbamazepine 10,11-epoxide, in human serum or plasma samples. The MECC method enabled baseline separation of all analytes within 2.5 min. The assay revealed sufficient precision and sensitivity and the results of eith…

Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy.

Abstract 1. Alterations in the serotonergic neurotransmission have been frequently described for patients suffering from alcoholism, anxiety disorders and narcolepsy. 2. The authors tested for association of the 5-HT2A receptor polymorphism (T102C) and the intron 7 tryptophan hydroxylase (TPH) polymorphism (A218C) among 176 alcohol dependent patients, 35 patients with panic disorder, 50 patients with generalized anxiety disorder, 55 patients with narcolepsy and 87 healthy controls. 3. Allele and genotype frequencies of the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH polymorphism (A218C) were almost similar between the patients suffering from alcohol dependence, panic disorder, ge…

Rotarod impairment: catalepsy-like screening test for antipsychotic side effects.

Extrapyramidal motoric symptoms are casual side effects under antipsychotic medication. New generation antipsychotics are expected to have a reduced risk due to different receptor affinities. Here, haloperidol and the new generation antipsychotics, risperidone, amisulpride, and aripiprazole, were examined with both catalepsy test and rotarod performance test to screen for their usability in mice. Mice treated with haloperidol, risperidone, and aripiprazole showed dose and time-dependent impairment. Amisulpride-treated mice showed no signs of catalepsy. Catalepsy test and rotarod performance test were useful methods to detect side effects of both generation antipsychotics. Catalepsy test pro…

Why do antidepressant therapies have such a poor success rate?

Major depression is one of the leading global diseases [1,2]. Treatment is required, because untreated patients suffer not only from impaired emotion [3,4], but also from cognitive [4–6] and somati...

Free-choice ethanol consumption under the influence of GABAergic drugs in rats.

Background: Neurobiological mechanisms leading from controlled alcohol consumption to addiction are poorly understood. Among multiple neurotransmitters γ-amino-butyric acid (GABA) is suggested to play a role. The present investigation studied effects of drugs interacting with the GABAergic system on the motivation of ethanol consumption. Methods: Fifty male PVG/OlaHsd rats were analyzed for free-choice ethanol drinking behavior without and with pre-exposure to drugs acting on the GABAergic system. For pretreatment, animals received the benzodiazepine agonists or antagonists diazepam, flumazenil, or Ro15-4513, or the GABA uptake inhibitor tiagabine via the drinking water for 4 weeks (day −21…

Automated determination of reboxetine by high-performance liquid chromatography with column-switching and ultraviolet detection.

A fully automated method including column-switching and isocratic high-performance liquid chromatography (HPLC) was developed for quantitative analysis of the new antidepressant reboxetine, a noradrenaline reuptake inhibitor. After serum injection into the HPLC system and on-line sample clean-up on a silica C8 (10x4.0 mm I.D.) clean-up column with an eluent consisting of 2.5% acetonitrile in deionized water, the chromatographic separation was performed on an analytical column (Lichrospher CN; 250x4.6 mm I.D.) with an eluent of acetonitrile-aqueous potassium phosphate buffer (0.008 M, pH 6.4) (50:50). The UV detector was set at 273 or 226 nm. The limit of quantification was about 15 ng/ml at…

Sex differences in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study

Polymorphisms in the serotonergic system are believed to play a role in the etiology and treatment of different psychiatric illnesses. The 5-HT2C receptor gene is X-linked, with a frequent mutation at nucleotide 68 leading to a Ser-->Cys transition at amino acid 23. Recent studies have demonstrated an impaired function of 5-HT2C receptors and an increased production of the major noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen et al., 1999). Biol. Psychiatry 46:821). We genotyped patients with alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy an…

Quantitation of GABA transporter 3 (GAT3) mRNA in rat brain by competitive RT-PCR.

Gamma-amino butyric acid is the major inhibitory neurotransmitter in the brain. GABA transporters (GATs) remove GABA from the synaptic cleft. Till now, five distinct GABA transporters have been cloned and termed consecutively GAT1 to GAT4 and vGAT. To study the mechanisms by which tolerance and dependence associated with drugs enhancing GABAergic transmission is brought upon we analysed the mRNA expression levels of GATs in various brain regions under different conditions. In this paper, we describe our protocol for measurement of GAT3 mRNA expression, and its validation through control experiments for the various steps. We performed competitive reverse transcription and polymerase chain re…

Increased CSF APPs-  levels in patients with Alzheimer disease treated with acitretin

Objective: We investigated induction of α-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, Munchen-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of α-secretase–derived amyloid precursor protein (APPs-α). Methods: Twenty-one patients clinically diagnosed with mild to moderate AD received acitretin (30 mg per day) or placebo in a 4-week double-blind study. Primary endpoint was the difference of CSF APPs-α ratios calculated from the APPs-α levels after treatment and at baseline. We monitored safety and tolerability of the treatment. In addition, we assessed biomarkers such …

P-515 - CGI Rating to predict antidepressant treatment under naturalistic conditions

Introduction Recent studies have shown that psychopathological rating by the Hamilton Depression Rating scale (HAMD) is well established and highly predictive for later response. In this study we aimed to find out if Clinical Global Impression (CGI) scale is suitable to guide antidepressive treatment under naturalistic conditions. Methods Inpatients with a major depressive disorder and treatment with citalopram were included and rated using in parallel the HAMD scale and the CGI scale weekly at baseline to day 35. According to CGI the sample has been divided in “CGI improver” (CGI = 2–4) and “CGI non-improver” (CGI = 5–6). Response was defined as HAMD sum score reduction by at least 50%. Re…

Determination of benperidol and its reduced metabolite in human plasma by high-performance liquid chromatography and electrochemical detection.

An isocratic high-performance liquid chromatographic method with electrochemical detection for the quantification of benperidol and its suggested reduced metabolite TVX Q 5402 in human plasma is described. The method included a two-step solid-phase extraction on reversed-phase and cation-exchange material, followed by separation on a cyanopropyl silica gel column (5 microns; 250 mm x 4.6 mm I.D.). The eluent was 0.15 M acetate buffer (pH 4.7) containing 25% acetonitrile (w/w). Spiperone served as internal standard. The inclusion of the cation-exchange step provided sample purity higher than those achieved with other methods. After extraction of 1 ml of plasma, concentrations as low as 0.5 n…

Strain Differences in Open-Field and Elevated Plus-Maze Behavior of Rats Without and With Pretest Handling

Behavior of two rat strains was analyzed with and without 1-week pretest handling. Male rats (150-200 g body weight) of the strains PVG/OlaHsd (PVG) and Hsd:Sprague-DawleySD (SPRD) were tested once in a standard open field and an enriched open field and twice in an elevated plus-maze. Behavioral analysis revealed significant differences between the two strains and differential effects of the pretest handling procedure. SPRD rats displayed higher levels of activity and exploratory behavior than the PVG rats, whereas PVG rats were obviously less anxious. One-week pretest handling had an "anxiolytic" effect and changed activity and exploration-related behavior of the animals in both strains. A…

Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates.

Abstract The pharmacokinetics of antipsychotic drugs has become an integral part in understanding their pharmacodynamic activity and clinical effects. In addition to metabolism aspects, carrier-mediated transport, particularly secretion by ABC transporters, has been discussed as potentially relevant for this group of therapeutics. In this study, the psychoactive compounds perphenazine, flupentixol, domperidone, desmethyl clozapine, haloperidol, fluphenazine, fluvoxamine, olanzapine, levome-promazine, perazine, desmethyl perazine, clozapine, quetiapine and amisulpride were characterized in terms of P-glycoprotein (P-gp) affinity and transport. Experimental methods involved a radioligand disp…

Automated Determination of Ziprasidone by HPLC With Column Switching and Spectrophotometric Detection

An isocratic high-performance liquid chromatography (HPLC) method with column switching and ultraviolet (UV) detection is described for quantitative analysis of the new antipsychotic drug ziprasidone. After centrifugation of serum or plasma samples and addition of fluperlapine as internal standard, the samples were injected into the HPLC system. On-line sample clean-up was conducted on a column (10 x 4.0 mm ID) filled with silica C8 material (20-microm particle size) using 8% (vol/vol) acetonitrile in deionized water as eluent. Ziprasidone was eluted and separated on ODS Hypersil C18 material (5 microm; column size 250 x 4.6 mm ID) using acetonitrile-water-tetramethylethylendiamine (50:49.6…

A systematic review and combined analysis of therapeutic drug monitoring studies for longacting risperidone

Introduction: This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations. Areas covered: Limited data is available on two formulations (RBP-7000 and in Situ Microparticle), but 20 TDM articles on the microsphere formulation were found. Risperidone TDM includes the serum concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, used for calculating: 1) the risperidone/9-hydroxyrisperidone (R/9-OH-R) ratio (a measure of CYP2D6; values >1 are indicative of a CYP2D6 poor metabolizer) and 2) the total risperidone concentration-to-dose (C/D) ratio (a measure of risperidone clearance with a normal value…

Fishing for a drug: solid-phase microextraction for the assay of clozapine in human plasma

Solid-phase microextraction (SPME) was investigated as a sample preparation method for assaying the neuroleptic drug clozapine in human plasma. A mixture of human plasma, water, loxapine (as internal standard) and aqueous NaOH was extracted with a 100-micron polydimethylsiloxane (PDMS) fiber (Supelco). Desorption of the fiber was performed in the injection port of a gas chromatograph at 260 degrees C (HP 5890; 30 m x 0.53 mm I.D., 1 micron film capillary; nitrogen-phosphorous selective detection). Fibers were used repeatedly in up to about 75 analyses. The recovery was found to be 3% for clozapine from plasma after 30 min of extraction. However, in spite of the low recovery, the analyte was…

Blood ethanol levels and adenylyl cyclase activity in lymphocytes of alcoholic patients

Abstract Background: The adenylyl cyclase (AC) signal transduction pathway is a target of acute and chronic ethanol actions. This study examined whether AC activity in lymphocyte membranes of male alcoholic patients correlated with blood concentrations of ethanol. Methods: Patients ( n = 13; mean age: 40 ± 8 years) were studied on the day of admission (day 0) and 2 days later under detoxification. Moreover, 13 age-matched male healthy controls (mean age 40 ± 9 years) were included. Lymphocyte membranes were prepared by differential centrifugation whereby blood ethanol was washed out. As a measure of AC activity the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphospha…

Automated Determination of Paroxetine and Its Main Metabolite by Column Switching and On-Line High-Performance Liquid Chromatography

An automated column-switching method coupled to isocratic high-performance liquid chromatography has been developed for simultaneous determination of blood levels of paroxetine and its nonconjugated main metabolite BRL 36610. The lower limits of detection were 9-15 nmol/L (3-5 ng/ml) and linearity between drug concentration and detector response was found for 0-1,500 nmol/L (0-500 ng/ml). The method could be applied to the analysis of serum samples obtained from depressed patients who were treated with daily oral doses of 20 or 40 mg of paroxetine. After the 20-mg dose, the mean blood level of paroxetine was 69 nM (23 ng/ml), whereas the metabolite BRL 36610 was detectable in only one of 5 …

Schizophrenia patients who smoke have a faster finger tapping rate

Rapid and reliable genotyping procedure for detection of alleles with mutations, deletion, or/and duplication of the CYP2D6 gene

Abstract Background Polymorphisms of cytochrome P450 2D6 (CYP2D6) have a significant effect on the pharmacokinetics of most tricyclic antidepressants. More than 150 alleles lead to four distinct phenotypes of drug metabolism. The phenotypes are described as ultrarapid, extensive, intermediate, and poor metabolizers. Therapeutic plasma levels of CYP2D6 substrates may be difficult to achieve. Here we describe a rapid and reliable procedure for CYP2D6*4, *3, *6, and *9 genotyping. Design and methods Serum concentrations of venlafaxine and its pharmacologically active metabolite, O-desmethylvenlafaxine, were measured in patients treated with the antidepressant venlafaxine, a substrate of CYP2D6…

The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia.

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior tem…

Behavioural Consequences of P-Glycoprotein Deficiency in Mice, with Special Focus on Stress-Related Mechanisms

P-glycoprotein (P-gp), an efflux transporter localised in the blood-brain barrier, limits the access of multiple xenobiotics to the central nervous system. Whether it is also implemented in the transport of the endogenous glucocorticoid corticosterone is a matter of debate. The P-gp knockout mouse model [abcb1a/b (-/-)] has been shown to differ in the functioning of the hypothalamic-pituitary adrenal (HPA) axis. In the present study, we investigated the behaviour of abcb1a/b (-/-) and wild-type mice with respect to stress-related tests and the effects of corticosterone. Behavioural activities were assessed in the open field (OF) test for 4 days, and in the forced swimming test (FST) and tai…

Genetic polymorphisms of the dopamine D2 and D3 receptor and neuroleptic drug effects in schizophrenic patients

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas

Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-li…

Fluvoxamine or placebo in the treatment of panic disorder and relationship to blood concentrations of fluvoxamine.

A six-week double-blind placebo-controlled trial of fluvoxamine was undertaken in 46 patients suffering from panic disorder with or without agoraphobia diagnosed by DSM-III-R guidelines. Average daily dosage of fluvoxamine was 160 mg, with a highest permitted dose of 300 mg/day. Weekly evaluation included a diary in which the number, severity, and duration of full-blown and limited panic attacks and the duration and severity of anticipating fear, CAS, GAS, CGI, HAM-D, adverse effects and the number of capsules not taken were noted. Fluvoxamine was not significantly superior to placebo with regard to the main outcome criterion, i.e., the reduction in the number of panic attacks, but it was s…

Dose-Related Concentrations of Neuroactive/Psychoactive Drugs Expected in Blood of Children and Adolescents

PURPOSE Therapeutic drug monitoring is highly recommended for children and adolescents treated with neurotropic/psychotropic drugs. For interpretation of therapeutic drug monitoring results, drug concentrations (C/D) expected in a "normal" population are helpful to identify pharmacokinetic abnormalities or nonadherence. Using dose-related concentration (DRC) factors obtained from pharmacokinetic data, C/D ranges expected under steady state can be easily calculated by multiplication of DRC by the daily dose. DRC factors, however, are defined only for adults so far. Therefore, it was the aim of this study to estimate DRC factors for children and adolescents and compare them with those of adul…

Low concentration of ziprasidone in human milk: a case report

Although second-generation antipsychotics are established as the first-line treatment for schizophrenia, female patients are often excluded from this efficient treatment for safety reasons in pregnancy or whilst breastfeeding. For this reason, research on this subject mostly relies on case reports, although there is a great need to establish modern guidelines for treatment. Milk-to-plasma (M:P) ratios have been reported for clozapine (2.79–4.32; Winans, 2001), olanzapine (0.10–0.84; Gardiner et al. 2003), risperidone/9-OH risperidone (0.10–0.42/0.24–0.50; Gentile, 2004) and aripiprazole (0.18–0.20; Schlotterbeck et al. 2007). According to one case report, the infant ingests 0.09–0.43% of th…

Tiagabine, a gamma-amino-butyric acid transporter inhibitor impairs spatial learning of rats in the Morris water-maze.

Abstract γ-Amino-butyric acid (GABA) is cleaved from the synaptic cleft by uptake via specific transporters. Inhibition of such transporters increases the effectiveness of physiologically released GABA. Increased GABAergic neurotransmission has an impact on learning and memory. Therefore, effects of tiagabine, a GABA-transporter inhibitor, were investigated on spatial orientation in the Morris water-maze. Rats were given four training trials per day for 4 days and a probe trial without platform on the 5th day. Compared to saline treated rats, rats treated daily with 20 mg/kg tiagabine showed impaired learning during the acquisition trials. Retrieval was impaired in rats treated only at the …

Schizophrenic patients who smoke have a faster finger tapping rate than non-smokers

The increased rate of smoking in schizophrenia patients remains unexplained and may reflect attempts at self-treatment. The effect sought from smoking may be related to nicotine's stimulating action. We tested this hypothesis by examining the relationship between smoking status and finger tapping rate, a measure of central processing, in schizophrenia patients treated with atypical antipsychotics. Smokers showed significantly faster finger tapping rates than non-smokers. This was not related to clinical state, illness chronicity, medication side-effects, antipsychotic dose or plasma concentrations. Nicotine can improve central processing in medicated schizophrenia patients and this may cons…

Differential Effects of Fluvoxamine and Other Antidepressants on the Biotransformation of Melatonin

Melatonin, the predominant product of the pineal gland, is involved in the maintenance of diurnal rhythms. Nocturnal blood concentrations of melatonin have been shown to be enhanced by fluvoxamine, but not by other serotonin reuptake inhibitors. Because fluvoxamine is an inhibitor of several cytochrome P450 (CYP) enzymes, the authors studied the biotransformation of melatonin and the effects of fluvoxamine on the metabolism of melatonin in vitro using human liver microsomes and recombinant human CYP isoenzymes. Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelatonin and N-acetylserotonin with a minimal contribution of CYP2C19. Both reactions were potently in…

Body mass index as a determinant of clozapine plasma concentrations: A pharmacokinetic-based hypothesis

Background: Knowledge regarding the impact of body composition measures on pharmacokinetics of antipsychotics is limited. Aims: Our aim was to investigate the impact of body weight and body mass index on clozapine pharmacokinetics using a therapeutic drug monitoring database. Methods: A large therapeutic drug monitoring dataset of clozapine plasma concentrations considering three patient subgroups was analysed: a control group (CLZ0, 20–30 kg/m2, n=266), a group with high body mass index (CLZhigh, body mass index ⩾30 kg/m2, n=162) and with low body mass index values (CLZlow, body mass index <20 kg/m2, n=27). Comparisons of plasma and dose-adjusted plasma concentrations (C/D) of clozapine…

Automated determination of clozapine and major metabolites in serum and urine.

Clozapine is an atypical neuroleptic that is increasingly used for the treatment of schizophrenia. An automated method was developed for the routine quantification of clozapine and its major metabolites, N-desmethylclozapine and clozapine N-oxide, in human serum and urine by column switching and online high-performance liquid chromatography with ultraviolet detection. The method included adsorption of clozapine and its metabolites on a cyanopropyl-coated clean-up column (10 microns; 10 mm x 4.0 mm ID), washing interfering serum constituents to waste by deionized water, and, after column switching, separation on C18 ODS Hypersil reversed-phase material (5 microns; 250 mm x 4.6 mm ID). The co…

Effect of chronic citalopram on serotonin-related and stress-regulated genes in the dorsal raphe nucleus of the rat

Using a model of depression in which chronic social stress induces depressive-like symptoms, we investigated effects of the selective serotonin-reuptake inhibitor (SSRI) citalopram on gene expression in the dorsal raphe nucleus of male rats. Expression of tryptophan hydroxylase (TPH) protein was found to be upregulated by the stress and normalized by citalopram, while mRNAs for genes TPH 1 and 2 were differentially affected. Citalopram had no effect on serotonin transporter mRNA but reduced serotonin-1A autoreceptor mRNA in stressed animals. The SSRI prevented the stress-induced upregulation of mRNA for CREB binding protein, synaptic vesicle glycoprotein 2b and the glial N-myc downstream-re…

Non-competitive inhibition of clomipramineN-demethylation by fluvoxamine

The selective serotonin reuptake inhibitor fluvoxamine interferes with the metabolism of tricyclic antidepressants. The present investigation was set out to characterize these interactions in vitro using rat liver microsomes and in vivo by analysing levels of clomipramine and metabolites in sera of depressed patients treated concomitantly with fluvoxamine and clomipramine. Clomipramine was N-demethylated and hydroxylated in vitro by microsomes to N-desmethyl-clomipramine, 8-hydroxyclomipramine, and 10-hydroxyclomipramine. Kinetic analyses revealed Km values of 6.2 microM for N-demethylation and 1.2 microM for 8-hydroxylation. Fluvoxamine was a non-competitive inhibitor for N-demethylation w…

WITHDRAWN: Association analysis between the early change of serum brain-derived neurotrophic factor (sBDNF) and final change of depression severity during antidepressant treatment: A pilot study.

This article has been withdrawn at the request of the Editor-in-Chief. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects.

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% (0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng…

Pharmacokinetic Interactions of Clozapine With Selective Serotonin Reuptake Inhibitors

Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and …

Serum concentrations of hydroxybupropion for dose optimization of depressed patients treated with bupropion.

Background Bupropion is a dopamine and norepinephrine reuptake inhibitor approved for the treatment of depression and smoking cessation. According to the recently published reviews, it is a candidate for therapeutic drug monitoring (TDM) to improve therapeutic outcomes and reduce risks of intolerability or intoxication. In practice, however, the use of TDM is limited due to the chemical instability of bupropion. This investigation sought to determine if the major, active, and chemically stable metabolite 4-hydroxybupropion is a suitable measure to guide antidepressant drug therapy with bupropion. Methods 4-Hydroxybupropion serum levels were measured using a newly developed and validated hig…

Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects

Aripiprazole, a novel antipsychotic drug, is metabolized by CYP3A4 and CYP2D6 forming mainly its active metabolite dehydroaripiprazole. In this study, aripiprazole and dehydroaripiprazole serum levels of psychiatric patients were measured and related to dose, comedication, and clinical effects including therapeutic and side effects. Patients were treated with mean doses of 20 +/- 8 mg/day of aripiprazole (median 15 mg, range 7.5-60 mg). Serum levels correlated significantly with the dose (r = 0.419; P0.01), with a mean value of aripiprazole of 214 +/- 140 ng/ml. Mean concentrations of the active metabolite dehydroaripiprazole amounted to 40% of the parent compound. Comedication with CYP3A4 …

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Contains fulltext : 238693.pdf (Publisher’s version ) (Open Access) Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic …

Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression – The EMC trial

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of < 20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy…

P-Glycoprotein Influence on the Brain Uptake of a 5-HT2A Ligand: [18F]MH.MZ

&lt;i&gt;Background/Aims:&lt;/i&gt; The serotonergic system, especially the 5-HT&lt;sub&gt;2A&lt;/sub&gt; receptor, is involved in various diseases and conditions. We have recently developed a new [&lt;sup&gt;18&lt;/sup&gt;F]-5-HT&lt;sub&gt;2A&lt;/sub&gt; receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [&lt;sup&gt;18&lt;/sup&gt;F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT&lt;sub&gt;2A&lt;/sub&gt; receptors in vivo. However, [&lt;sup&gt;18&lt;/sup&gt;F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier…

Radiosynthesis of (±)-(2-((4-(2-[18F]fluoro-ethoxy)phenyl)bis(4-methoxy-phenyl)methoxy)ethylpiperidine-3-carboxylic acid: a potential GAT-3 PET ligand to study GABAergic neuro-transmissionin vivo

A dysfunction of GABAergic neurotransmission is related to diseases such as epilepsy, Huntington-disease and Parkinson-syndrome. A new 18F-fluorine labelled GABA transporter ligand for the GABA-transporter subtype GAT-3 was developed which may allow the in vivo visualisation of GABAergic neurotransmission. The precursors ethyl (2-(4-hydroxyphenyl)bis(4-methoxyphenyl)-methoxy)ethyl)-piperidine-3-carboxylate and ethyl(2-((4-(2-tosylethoxy)phenyl)-bis(4-methoxyphenyl)-methoxy) ethyl)-piperidine3-carboxylate were synthesised and labelled by the use of 2-[18F]fluoroethyltosylate or [18F]fluoride. Subsequent cleavage of the ester moiety gave the final product (±)-(2-((4-(2-[18F]fluoroethoxy)pheny…

Adenylyl cyclase activity is increased in younger, but decreased in older, alcoholic patients after detoxification.

Acute and chronic administration of ethanol leads to alterations of the adenylyl cyclase (AC) signal transduction pathway. This study examined whether the formation of cAMP by AC in lymphocytes correlates with age in alcoholic patients and in healthy controls. Blood was drawn for preparation of lymphocyte membranes and for determination of basal, GTPgammaS-stimulated, and forskolin-stimulated AC activity from 68 actively drinking alcoholic patients (age, mean +/- SD: 45 +/- 10; range: 26-69 years) after ethanol detoxification. The patients' AC activity correlated negatively with age. In contrast, no effect of age was observed in the healthy controls (age, mean +/- SD: 42 +/- 11; range: 24-6…

Predicting the risk of drug–drug interactions in psychiatric hospitals: a retrospective longitudinal pharmacovigilance study

ObjectivesThe aim was to use routine data available at a patient’s admission to the hospital to predict polypharmacy and drug–drug interactions (DDI) and to evaluate the prediction performance with regard to its usefulness to support the efficient management of benefits and risks of drug prescriptions.DesignRetrospective, longitudinal study.SettingWe used data from a large multicentred pharmacovigilance project carried out in eight psychiatric hospitals in Hesse, Germany.ParticipantsInpatient episodes consecutively discharged between 1 October 2017 and 30 September 2018 (year 1) or 1 January 2019 and 31 December 2019 (year 2).Outcome measuresThe proportion of rightly classified hospital epi…

W05-01 - Rationale and Design of an RCT Comparing “EMC-Strategy” with TAU in Patients with Major Depression - the EMC Trial

IntroductionFor Major Depression, current guidelines recommend treatment durations of 3-8 weeks until optimisation in case of insufficient outcome. Many retrospective studies indicate that improvement (HAMD-17 decrease ≥20%) occurs usually within 10-14 days and that non-improvement after 14 days of treatment is highly predictive for poor clinical outcome.MethodsIn level 1 of the EMC trial, non-improvers after 14 days of antidepressant treatment will be randomised to “early medication change” (EMC) strategy or treatment according to current guidelines (TAU). EMC schedules treatment optimisations on day 15 and day 29 in case of non-improvement. TAU schedules a medication change after 28 days …

Automated Determination of Dextromethorphan and Its Main Metabolites in Human Plasma by High-Performance Liquid Chromatography and Column Switching

An automated column-switching technique coupled to isocratic high-performance liquid chromatography (HPLC) with fluorescence detection was developed for simultaneous determination of dextromethorphan and its three major metabolites, dextrorphan, hydroxymorphinan, and methoxymorphinan. After cleavage of conjugates by incubation with glucuronidasearylsulfatase at 37 degrees C for 15 h, plasma samples were injected directly into the HPLC system. Dextromethorphan and metabolites were retained on a cleanup column (10 x 4.6 mm internal diameter [ID]) filled with cyanopropyl (CN) material (Hypersil CPS, 10-microns article size) while interfering proteins and lipids were washed to waste. After colu…

Individualisierte Therapie mit trizyklischen Antidepressiva. Pharmakogenetik der Depression

Bei der medikamentosen Behandlung eines depressiven Patienten spricht bei weitem nicht jeder auf das verschriebene Antidepressivum und die gewahlte Dosis an. Infolgedessen sind haufig Anderungen der Therapie notwendig. Dies gilt fur trizyklische Antidepressiva ebenso wie fur alle anderen Antidepressiva.

P01-92 - Early Changes are Associated with late Changes of BDNF Serum Levels in Inpatients with Major Depression During Short-term Antidepressant Treatment

ObjectivesMean BDNF serum concentration is lower in patients with major depression (MD) as compared to healthy controls. BDNF increases during the course of antidepressant treatment. This increase has been associated with symptom amelioration. The aim of this study was to analyse the relation between early and late BDNF changes during antidepressant treatment.MethodsForty-six patients with MD according to DSM-IV were included for this study. Patients were treated as clinically indicated. Depression severity was assessed by HAMD-17 by trained raters from baseline to week 6 in weekly intervals. Serum at each visit (baseline, V1-V6) was obtained from whole blood after centrifugation with 1.000…

1012 – Evaluation of a risk-scale for anticholinergic side-effects in elderly psychiatric inpatients

Introduction Many commonly prescribed drugs have anticholinergic properties which can induce side-effects e.g. delirium, especially in an ageing brain with increased sensitivity. Risk-assessment before starting therapy may prevent such sideeffects. Objectives We rated anticholinergic pharmacological properties of prescribed medication and compared the theoretical risk with side-effects in clinical practice. Aims The scale should improve the safety of pharmacotherapy in gerontopsychiatry. Methods Based on five publications that considered anticholinergic properties of drugs, a risk-scale was established. Riskpoints for all drugs were summarized to a total score. Patients were selected from T…

Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment.

Profound neuroplastic changes have been demonstrated in various limbic structures after chronic stress exposure and antidepressant treatment in animal models of mood disorders. Here, we examined in rats the effect of chronic social stress and concomitant antidepressant treatment on cell proliferation in the medial prefrontal cortex (mPFC). We also examined possible hemispheric differences. Animals were subjected to 5 weeks of daily social defeat by an aggressive conspecific and received concomitant, daily, oral fluoxetine (10 mg/kg) during the last 4 weeks. Bromodeoxyuridine (BrdU) labeling and quantitative stereological techniques were used to evaluate the treatment effects on proliferatio…

Cognitive Behavioral Therapy Versus Sertraline in Patients With Depression and Poorly Controlled Diabetes: The Diabetes and Depression (DAD) Study

OBJECTIVE This study compared the long-term efficacy of a diabetes-specific cognitive behavioral group therapy (CBT) with sertraline in patients with diabetes and depression who initially responded to short-term depression treatment. RESEARCH DESIGN AND METHODS A randomized controlled single-blind trial was conducted in 70 secondary care centers across Germany comparing 12 weeks of CBT with sertraline in 251 patients with type 1 or 2 diabetes (mean HbA1c 9.3%, 78 mmol/mol) and major depression (Structured Clinical Interview for DSM-IV [SCID]). After 12 weeks, treatment responders (≥50% reduction Hamilton Depression Rating Scale [HAMD-17]) were included in the 1-year study phase where CBT p…

Simultaneous Automated Determination of Catecholamines, Serotonin, and Their Metabolites in Brain Tissue by HPLC and Electrochemical Detection

Abstract A robust procedure with minimal tissue sample pretreatment, based on reversed-phase, ion-pair high performance liquid chromatography (HPLC) combined with electrochemical detection has been developed for the automated and simultaneous determination of the biogenic amines norepinephrine (NE), epinephrine (E), dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3,4-dihydroxyacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (H I A A) in as little as 0.5 mg brain tissue. The chromatographic conditions remain stable for at least 8 weeks. In particular small amounts of samples which do not allow reexamina…

The Chronic Psychosocial Stress Paradigm in Male Tree Shrews: Evaluation of a Novel Animal Model for Depressive Disorders

To improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews, which is based on the territorial behaviour of these animals that can be used to establish naturally occurring challenging situations under experimental control in the laboratory. Co-existence of two males in visual and olfactory contact leads to a stable dominant-subordinate relationship, with subordinates showing distinct stress-induced behavioural and neuroendocrine alterations that are comparable to the symptoms observed during episodes of depress…

Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein

According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (-/-) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose,…

Monitoring of Plasma Concentrations of Psychotropic Drugs in Pharmacovigilance

The primary aims of pharmacovigilance are supervision and prevention of medication-related problems under everyday conditions. Pharmacovigilance is an indication for monitoring plasma concentrations, i.e. conducting therapeutic drug monitoring (TDM). Using TDM, it can be clarified if observed unwanted drug effects may be attributed to abnormally high or low drug concentrations. Utmost benefits from TDM are obtained for pharmacovigilance when the method is adequately integrated into the clinical treatment process. How to do this is described in consensus guidelines for TDM in psychiatry. During the last 20 years, TDM was very successful for detection of multiple pharmacokinetic drug-drug int…

Risk of bleeding related to selective and non-selective serotonergic antidepressants: a case/non-case approach using data from two pharmacovigilance databases.

There is increasing evidence for an association between treatment with selective serotonin reuptake inhibitors (SSRI) and an increased risk of bleeding events. The most important underlying mechanism appears to be inhibition of serotonin uptake in platelets, an effect that is also present in antidepressants with non-selective serotonin-reuptake inhibition (NSRI). Accordingly, also NSRI may be associated with an increased risk of bleeding. However, there is little data in this regard.Based on data (spontaneous reports of adverse drug reactions) from 2 pharmacovigilance databases (WHO-database/Vigibase™; BfArM/AkdÄ-database in Germany) we used a case/non-case approach and calculated reporting…

EPA-0703 – Performance of the hamilton depression rating subscales to predict antidepressant treatment response in the early course of treatment

Early improvement ( EI ), i.e. a symptom reduction from baseline of at least 20% after 2 weeks, has been proven to be a clinically useful predictor for later treatment outcome. In most studies EI is identified by using the sum score of the Hamilton Depression Rating Scale (HAMD). Several unidimensional subscales of the HAMD exist, which have proven to be an economic measure of treatment change. Their ability to detect onset of improvement in comparison to the full HAMD has not been researched yet. The present study investigated in patients with major depression (MD) (1) whether the HAMD subscales are a valid and economic option to predict antidepressant treatment response in the early cours…

Diurnal Variations of Plasma Interleukin-6 in Man: Methodological Implications of Continuous Use of Indwelling Cannulae

Pharmakokinetik, Interaktionspotential und TDM: Wichtig bei atypischen Antipsychotika

Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine.

Summary Nocturnal hormone profiles were measured in patients with schizophrenia with predominantly negative symptoms both under drug-free baseline conditions and after subchronic administration of the atypical antipsychotic olanzapine, with the aim of characterizing its pharmacological properties on the neuroendocrine level. The following hormones were studied in the sleep laboratory under polysomnographic control: adrenocorticotrophic hormone, cortisol, growth hormone (GH), prolactin, testosterone, and melatonin. Blood samples were taken at regular time intervals over the night, and serum concentrations of the hormones were determined. Ten patients completed the study, two of them were exc…

Therapeutic Drug Monitoring for Patients With Alzheimer Dementia to Improve Treatment With Donepezil

BACKGROUND Aiming to verify that therapeutic drug monitoring has the potential to optimize treatment with acetylcholine esterase inhibitors of patients with Alzheimer dementia, this study investigated whether serum concentrations of donepezil are associated with clinical improvement. METHODS Clinical improvement was measured using the clinical global impression (CGI) scale, and donepezil concentrations were measured in serum by a high-performance liquid chromatographic method with spectrophotometric detection. RESULTS In total, 206 serum samples from 106 patients (49.5% female) were retrospectively available for analysis. Patients included were treated under everyday conditions. Their mean …

Polypharmacy and the risk of drug-drug interactions and potentially inappropriate medications in hospital psychiatry.

PURPOSE The aim of this study was to analyze the epidemiology of polypharmacy in hospital psychiatry. Another aim was to investigate predictors of the number of drugs taken and the associated risks of drug-drug interactions and potentially inappropriate medications in the elderly. METHODS Daily prescription data were obtained from a pharmacovigilance project sponsored by the Innovations Funds of the German Federal Joint Committee. RESULTS The study included 47 071 inpatient hospital cases from eight different study centers. The mean number of different drugs during the entire stay was 6.1 (psychotropic drugs = 2.7; others = 3.4). The mean number of drugs per day was 3.8 (psychotropic drugs …

Kavapyrone enriched extract fromPiper methysticum as modulator of the GABA binding site in different regions of rat brain

Regional differences in the modulation of [3H] muscimol binding to GABAA receptor complexes by kavapyrones, compounds of the rhizome of the plant Piper methysticum which possess sedative activity, were demonstrated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblongata (MED), and from brain centers outside the main kavapyrone effects as frontal cortex (FC) and cerebellum (CER). The kava extract enhanced the binding of [3H] muscimol in a concentration-dependent manner with maximal potentiation of 358% over control in HIP followed by AMY and MED (main target brain centers). Minimal stimulation was observed in C…

Formation and metabolism of catecholestrogens in depressed patients.

Abstract The evidence that catecholestrogens are formed in the brain and exert behavioral effects in animal models suggests that these steroids might have psychotropic activities. In the present investigation, the formation and metabolism of catecholestrogens were studied in depressed patients. Twenty-four-hr urine samples were collected from 6 male patients (59 ± 8 years) with endogenous retarded depression (subtype primary, endogenous, and recurrent according to Research Diagnostic Criteria) and from 12 male control subjects (51 ± 4 years). The patients were treated with the monoamine oxidase inhibitor tranylcypromine (10–40 mg/day for 3–4 weeks). The concentrations of primary estrogens, …

Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders.

Introduction The aim of this study was to describe the number and type of drugs used to treat depressive disorders in inpatient psychiatry and to analyse the determinants of potential drug-drug interactions (pDDI) and potentially inappropriate medication (PIM). Methods Our study was part of a larger pharmacovigilance project funded by the German Innovation Funds. It included all inpatients with a main diagnosis in the group of depressive episodes (F32, ICD-10) or recurrent depressive disorders (F33) discharged from eight psychiatric hospitals in Germany between 1 October 2017 and 30 September 2018 or between 1 January and 31 December 2019. Results The study included 14,418 inpatient cases.…

In vitro P-glycoprotein efflux inhibition by atypical antipsychotics is in vivo nicely reflected by pharmacodynamic but less by pharmacokinetic changes

Abstract Background P-glycoprotein (P-gp), an efflux transporter of the blood–brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). Thus drug-dependent inhibition, induction or genetic variation of P-gp impacts drug therapy. Methods We investigated atypical antipsychotics and their interaction with P-gp. Amisulpride, clozapine, N-desmethylclozapine, olanzapine, and quetiapine were assessed in vitro on their inhibitory potential and in vivo on their disposition in mouse serum and brain, and behaviourally on the RotaRod test. In vivo wildtype (WT) and mdr1a/1b double knockout mice (mdr1a/1b (−/−, −/−); KO) were investigated. Results In rhodamine 123 eff…

Aripiprazole in human milk

Second-generation antipsychotics are now the established first-line treatment for schizophrenia. However, there are limited data on the use of these compounds in pregnant and breastfeeding women with mental disorders. For ethical reasons, research on these subjects mostly relies on collection of single datasets of cases in order to establish treatment guidelines.

Striatal and extrastriatal D2/D3-receptor-binding properties of ziprasidone: a positron emission tomography study with [18F]Fallypride and [11C]raclopride (D2/D3-receptor occupancy of ziprasidone).

To elucidate the Batypicality( of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. ( 18 F)fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel ( 11 C)raclopride-PET stu…

The Effect of Age, Sex, Smoking and Co-Medication on Serum Levels of Venlafaxine and O-Desmethylvenlafaxine under Naturalistic Conditions

Venlafaxine (VEN) is a modern antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. In this study we examined the influence of age, sex, smoking, and co-medication on serum levels of VEN and its metabolite O-desmethylvenlafaxine (ODVEN) in patients treated with VEN under naturalistic conditions.We retrospectively evaluated 478 TDM analyses of VEN requested in the Pychiatric University Hospitals of Mainz, Regensburg, and Würzburg. The determination of serum levels was performed by virtually identical chromatographic methods in the TDM laboratories of the participating hospitals.Serum levels varied widely on each dose level. Women had about 30% higher dose-correct…

Distribution of clozapine and desmethylclozapine between blood and brain in rats.

Desmethylclozapine is the major metabolite of clozapine in serum. Although the metabolite is pharmacologically active in vitro, the occurrence of desmethylclozapine in brain under steady-state conditions and its role for clinical actions of clozapine are unclear. In this study 20 male Sprague-Dawley rats received five oral doses of clozapine 20 mg/kg at 1.5-h intervals. At 0.5, 1, 2 and 5 h after the last administration, at a time four animals were killed for analysis of clozapine and desmethylclozapine concentrations in serum and brain. The treatment yielded steady-state serum concentrations of clozapine that are considered as therapeutically effective in man. Desmethylclozapine concentrat…

Induction of c-fos gene expression by the selective sigma receptor ligand EMD 57445 in rat brain.

Based on animal studies it has been reasoned that ligands to sigma binding sites might be effective in the treatment of schizophrenic disorders and may also be used to investigate this largely elusive disorder on a molecular level. Expression patterns of c-fos in rat brain were studied following treatment with single doses of the sigma ligand EMD 57445 (0.3, 1, 3, 30 mg/kg s.c.). Specific c-fos gene expression was detected at all concentrations tested in various cortical areas. The signals observed were dose-dependent with the highest intensities in the piriform cortex. Strong signals were also detected in hippocampal areas CA 1,2,3 and the gyrus dentatus, as well as in the medial habenula …

Actions of sex hormones on the brain

1. The brain is a target for sex steroid hormones. As a result of sex hormone actions on the brain various behavioral changes are observed in animal and man. This paper gives a brief overview over the multiple central nervous functions that are under modulatory control of sexual hormones and describes the complex sex steroid actions on the brain by giving an example for "activating" and "organizing" effects of estrogens on noradrenergic neurons in the brain of rats. 2. Estradiol-17 beta induced sex specific alterations in the turnover of noradrenaline in the preoptic area and mediobasal hypothalamus showing "female" or "male" responses. 3. Neonatal manipulations of female rat pups by testos…

CYP2D6 genotype and phenotyping by determination of dextromethorphan and metabolites in serum of healthy controls and of patients under psychotropic medication

Fourteen drug free healthy volunteers and 22 psychiatric patients under psychotropic medication were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe drug. A solution containing 20 mg dextromethorphan was administered and blood was taken 60 min later for determination of dextromethorphan and metabolites in serum. For comparison, urine was collected over 8 h after ingestion of 20 mg dextromethorphan in a separate test. The CYP2D6 phenotype was determined from the ratio of dextromethorphan to dextrorphan. For genotyping, mutant alleles of the CYP2D6 gene were identified using allele-specific polymerase chain reactions. Genotyping revealed five poor metabolizer…

A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients.

Introduction: This article comprehensively reviews the clinical utility of the serum clozapine/norclozapine (CLO/NCLO) ratio. Areas covered: Fifty-four published studies used this ratio (21 from a PubMed search from onset to 10/21/18 and 33 identified by the authors). To estimate a combined mean of the CLO/NCLO ratio in published studies, a PubMed search on 10/21/18 identified 422 articles leading to 19 included. The systematic review focused on 1) the combined analysis, 2) CYP1A2 activity, 3) clinical response, 4) cognition, and 5) renal function. Expert opinion: Our combined analysis provided a weighted mean CLO/NCLO ratio of 1.73 in 2,317 adult patients from 19 studies, but the range in …

Effects of escitalopram on the regulation of brain-derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress.

Escitalopram (ES-CIT) is a widely used, highly specific antidepressant. Until now there has been very little evidence on how this drug under pathological conditions affects an important feature within the pathophysiology of stress-related disorders such as depression: the endogenous neurotrophins. By using a well-characterized rat model in which chronic stress induces depressive-like behavior, the levels of neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were determined in representative brain regions and serum using a highly sensitive improved fluorometric two-site ELISA system. There was a significant increase of BDNF in the left and right cortices aft…

Dopamine D2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia

Background Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). Methods An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature val…

Molecular cloning of rat G-protein-coupled receptor kinase 6 (GRK6) from brain tissue, and its mRNA expression in different brain regions and peripheral tissues

The rat G-protein-coupled receptor kinase 6 (GRK6) cDNA was cloned from rat brain tissue by a combination of reverse-transcription polymerase chain reactions (RT-PCR), based on homology to the cloned human GRK6, and rapid amplification of cDNA ends (RACE-PCR). We obtained a clone of 2817 bp with an open reading frame of 1731 bp encoding for a protein of 576 amino acids that is 96.7% identical and 97.9% similar to its human counterpart. mRNA was detectable in all brain areas examined. In addition, GRK6 was expressed in skeletal muscle, small intestine, aorta, liver, heart, lung, thymus, stomach, uterus and kidney.

Pharmacodynamic consequences of P-glycoprotein-dependent pharmacokinetics of risperidone and haloperidol in mice

Efflux transporters, like P-glycoprotein (P-gp), may limit the access of drugs to the brain via the blood-brain barrier. The antipsychotic drug risperidone and its active metabolite 9-hydroxyrisperidone (paliperidone) are substrates of P-gp. Motor behavior of P-gp deficient mice (mdr1a/1b (-/-, -/-)) and wild type animals on a rotarod after acute doses of risperidone or haloperidol, a nonsubstrate of P-gp, were analysed aiming to show that P-gp substrate properties of an antipsychotic drug have functional consequences. Behavioral tests revealed dose-dependent effects of 0.3-3 mg/kg risperidone in wild type animals 0.5-12 h after i.p. injection of the drug. In knockout mice the 0.3 mg/kg dos…

Day- and night-time contents of monoamines and their metabolites in the medial preoptic area of the rat hypothalamus.

The present study was conducted to investigate whether monoamines and their metabolites in the medial preoptic area (mPOA) of the rat hypothalamus exhibit differences in their contents between day and night. We therefore sampled the mPOA from adult animals of either sex at the middle of the light or dark period, respectively, and analyzed the tissue by means of high performance liquid chromatography with electrochemical detection. We found that, in female animals at mid-night, dopamine and 3,4-dihydroxyphenyl acetic acid (DOPAC) was reduced to 43 and 30%, respectively, of daytime levels, while the norepinephrine content was doubled. No significant differences were observed in male animals. …

Long-Term Effects of the Substituted Benzamide Derivative Amisulpride on Baseline and Stimulated Prolactin Levels

In the present study, we investigated the long-term effects of treatment with amisulpride, a substituted benzamide derivative, as compared with the effects of treatment with flupenthixol, a thioxanthene, on the prolactin levels in schizophrenic patients. After completing 6 weeks of medication with either amisulpride or flupenthixol, the patients entered a long-term maintenance treatment with amisulpride 200–600 mg/day or flupenthixol 5–15 mg/day for a maximum of 12 months with a subsequent drug-free follow-up until month 15. Eighteen initially included patients were still participating in the study at month 6. In the flupenthixol group, only 1 patient treated reached month 12, and none of t…

Non-adherence to psychotropic medication assessed by plasma level in newly admitted psychiatric patients: Prevalence before acute admission.

Aims Non-adherence or partial adherence to psychotropic medication is found in 18-70% of patients. Many previously used methods for the assessment of adherence (e.g. questionnaires, pill counts, and electronic systems), however, might underreport actual rates of non-adherence to medication. The aim of this study was to quantify adherence using plasma level. Methods We conducted a 6-week prospective study of all consecutive admitted patients at the Paracelsus Medical University of Salzburg, Clinics of Psychiatry and Psychotherapy, who had been treated with antipsychotics/antidepressants prior to admission (pre-medication dosage in 161 of 233). Plasma drug levels were determined and compared …

Automated determination of amisulpride by liquid chromatography with column switching and spectrophotometric detection.

A fully automated chromatographic method including on-line blood serum or plasma clean-up, isocratic high-performance liquid chromatography (HPLC) and spectrophotometric detection was developed for quantitative analysis of the new antipsychotic drug amisulpride. After injection of serum or plasma onto the HPLC system and clean-up on a pre-column (10x4.0 mm I.D.) filled with Silica CN 20 micrometer (pore size 10 nm) by an eluent consisting of 8% acetonitrile in deionized water, the chromatographic separation was performed on Lichrospher CN (5 micrometer; 250x4.6 mm I.D.) by an eluent consisting of 50% acetonitrile and 50% aqueous potassium phosphate buffer (0.008 M, pH 6.4). The UV detector …

Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment.

Analysis of post-mortem tissue from patients with affective disorders has revealed a decreased number of glial cells in several brain areas. Here, we examined whether long-term psychosocial stress influences the number and morphology of hippocampal astrocytes in an animal model with high validity for research on the pathophysiology of major depression. Adult male tree shrews were submitted to 5 weeks of psychosocial stress, after which immunocytochemical and quantitative stereological techniques were used to estimate the total number and somal volume of glial fibrillary acidic protein-positive astrocytes in the hippocampal formation. Stress significantly decreased both the number (-25%) and…

Preliminary assessment of the imaging capability of the YAP–(S)PET small animal scanner in neuroscience

The new and fully engineered version of the YAP–(S)PET small animal scanner has been tested at the University of Mainz for preliminary assessment of its imaging capability for studies related to neuropharmacology and psychiatry. The main feature of the scanner is the capability to combine PET and SPECT techniques. It allows the development of new and interesting protocols for the investigation of many biological phenomena, more effectively than with PET or SPECT modalities alone. The scanner is made up of four detector heads, each one composed of a 4 � 4c m 2 of YAlO3:Ce (or YAP:Ce) matrix, and has a field of view (FOV) of 4 cm axially � 4c m + transaxially. In PET mode, the volume resoluti…

Enhancement of human cortico-motoneuronal excitability by the selective norepinephrine reuptake inhibitor reboxetine

It has been proposed that norepinephrine plays a critical role in the modulation of cortical excitability, which in turn is thought to influence functional recovery from brain lesions. The purpose of the present experiments was to determine if it is possible to modulate cortical excitability with the selective norepinephrine reuptake inhibitor reboxetine in intact humans. Recruitment curve and intracortical facilitation, assessed by transcranial magnetic stimulation, were increased after oral intake of 8 and 4 mg reboxetine, in the absence of changes in motor threshold, intracortical inhibition, M-response, F-wave or H-reflex. These results demonstrate that reboxetine enhances cortical exci…

Chronic oral haloperidol and clozapine in rats: A behavioral evaluation.

The present study evaluated chronic oral treatment of rats with haloperidol or clozapine. Drugs were given in the drinking water for a 23-day period . Rat behavior was analyzed once a week in an open field. Rats ingested either 1.7 mg/kg haloperidol or 40 mg/kg clozapine daily. Blood serum analysis revealed concentrations of 6 ng/ml for haloperidol and 22 ng/ml for clozapine at the end of the treatment. Haloperidol decreased overall activity from the onset of treatment. Clozapine showed similar effects only on the last test day. Control animals showed a slight habituation in exploration-related parameters. In conclusion, these results indicate that oral drug administration through the drink…

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

AbstractTherapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug…

1023 – Therapeutic drug-monitoring of bupropion for depression

Introduction Therapeutic Drug-Monitoring (TDM) for bupropion is limited by bupropion's instability at room temperature and by the absence of a well-defined therapeutic reference range. Further it is unclear to what extent bupropion and its metabolites contribute to therapeutic effects, though hydroxybupropion seems to account for the major antidepressant effects. Aim The aim of this examination was to check if measurement of only hydroxybupropion is useful to guide the antidepressant therapy with bupropion. Methods Hydroxybupropion plasma levels were measured by high performance liquid chromatography with ultra violet detection and related to therapeutic effects measured by the Clinical Glo…

Study protocol of the Diabetes and Depression Study (DAD): a multi-center randomized controlled trial to compare the efficacy of a diabetes-specific cognitive behavioral group therapy versus sertraline in patients with major depression and poorly controlled diabetes mellitus

Background Depression is common in diabetes and associated with hyperglycemia, diabetes related complications and mortality. No single intervention has been identified that consistently leads to simultaneous improvement of depression and glycemic control. Our aim is to analyze the efficacy of a diabetes-specific cognitive behavioral group therapy (CBT) compared to sertraline (SER) in adults with depression and poorly controlled diabetes. Methods/Design This study is a multi-center parallel arm randomized controlled trial currently in its data analysis phase. We included 251 patients in 70 secondary care centers across Germany. Key inclusion criteria were: type 1 or 2 diabetes, major depress…

Association Between Citalopram Serum Levels and Clinical Improvement of Patients With Major Depression

Imaging studies have shown that serum concentrations of the selective serotonin reuptake inhibitor citalopram correlate with serotonin transporter (5-HTT) occupancy in vivo. In patients with major depressive disorders treated with citalopram, 80% 5-HTT occupancy was considered to be necessary for maximal therapeutic effects, which requires citalopram serum concentrations of at least 50 ng/mL. The aim of this study was to compare treatment outcome in patients with citalopram serum concentrations greater than and less than 50 ng/mL after 7 days of treatment. This study included inpatients with acute major depressive disorder according to International Classification of Disease, 10th Revision …

Appropriateness of Therapeutic Drug Monitoring for Antidepressants in Routine Psychiatric Inpatient Care

Although there is sufficient evidence of the benefits of therapeutic drug monitoring (TDM) for optimizing antidepressant therapy, its current use in routine care is far from optimal. As a prerequisite for developing improvement strategies, the appropriateness of TDM use was investigated in a psychiatric hospital in which TDM is applied routinely to a large extent. A retrospective analysis of all patients admitted in 2003 with a unipolar depressive disorder was performed. Based on detailed chart review, for all TDM tests, the time of blood sample taking in relation to the medication process and the consequences of the TDM results for clinical decision making were analyzed. Altogether, 748 pl…

New dopamine D2 receptor polymorphisms in rats and association with apomorphine-induced stereotypies.

Adult Wistar rats injected with the dopamine receptor agonist apomorphine display different types of motility patterns with respect to oral stereotypes and locomotor activities. It was tested whether phenotypes exhibiting either ‘sniffing’ or ‘non-sniffing’ behaviour differed in gene structures of dopamine receptors D1 or D2. Forty-five Wistar rats of both genders were tested after a single dose of apomorphine (2 mg/kg s.c.) for stereotyped behaviour. Sequence analysis of the 5′ flanking region, the 5′ untranslated region and the coding region of the two genes revealed a new sequence for the 5′ flanking region of the D1 receptor gene and two polymorphisms in the promoter region of the D2 re…

Cerebrospinal Fluid Tau Protein Levels and &lt;sup&gt;18&lt;/sup&gt;F-Fluorodeoxyglucose Positron Emission Tomography in the Differential Diagnosis of Alzheimer’s Disease

&lt;i&gt;Aims:&lt;/i&gt; In this study, we aimed to compare cerebrospinal fluid (CSF) levels of total tau (t-tau), phosphorylated tau (p-tau&lt;sub&gt;181&lt;/sub&gt;) and positron emission tomography with &lt;sup&gt;18&lt;/sup&gt;F-fluorodeoxyglucose (FDG-PET) in the differential diagnosis of Alzheimer’s disease (AD) under clinical conditions. &lt;i&gt;Method:&lt;/i&gt; In a cross-sectional, blinded, single-center study, we examined a sample of 75 unselected memory clinic patients with clinical diagnoses of dementia of Alzheimer type (DAT; n = 24), amnestic mild cognitive impairment (MCI; n = 16), other dementias (n = 13) and nondemented controls (n = 22). Discriminative accuracy, sensitiv…

Combination of open field and elevated plus-maze: a suitable test battery to assess strain as well as treatment differences in rat behavior.

Abstract 1. 1. A test battery consisting of a standard open field, an enriched open field and an elevated plus maze was used to study behavior in rats. 2. 2. Male rats of the strains PVG/OlaHsd (PVG) and Sprague-Dawely-Hsd (SPRD) (150–200g body wt) were used to assess interstrain differences as well as handling effects. In a subsequent experiment an other set of male PVG rats (150–200g body wt) treated either with diazepam or zolpidem was used to evaluate the test battery for pharmacological purposes. 3. 3. SPRD rats displayed higher motor activity levels and also higher levels of exploratory behavior than the PVG rats. In contrast plus-maze activity indicated more anxiety of SPRD than PVG …

Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients.

Bidirectional drug interactions between fluvoxamine and classical antidepressants were studied in depressed patients. A column switching technique combined with high performance liquid chromatography (HPLC) enabled automated analyses of plasma for simultaneous determination of fluvoxamine, tricyclic and tetracyclic antidepressants and demethylated and major hydroxylated metabolites in a single HPLC run. The measurements revealed that fluvoxamine inhibited N-demethylation of imipramine, clomipramine, amitriptyline and maprotiline whereas interferences with hydroxylation reactions were restricted to aromatic 8-hydroxylation of clomipramine. In patients under fluvoxamine monotherapy before com…

Problem solving in psychopharmacotherapy using pharmacokinetic and pharmacogenetic tests

Many problems such as non-response, pharmacokinetic interactions with clinical consequences and adverse effects (pharmacovigilance) may be observed in patients submitted to psychopharmacotherapy. These risks are increased in patients belonging to the category of “special populations”: elderly patients, children and adolescents, patients with a genetic particularity of metabolism or suffering from somatic or psychic comorbidities. Pharmacokinetic and pharmacogenetic tests are useful to solve problems in psychopharmacotherapy and thus improve efficacy and safety. Therapeutic drug monitoring (TDM) is particularly recommended in situations presented above and in patients who are non-compliant. …

Interactions and Monitoring of Antipsychotic Drugs

As a consequence of individualized antipsychotic pharmacotherapy, many patients need more than a single drug, since they do not respond sufficiently to monotherapy. Other patients suffer from comorbid diseases and therefore require additional drugs from other pharmacological classes. Drug combinations, however, can give rise to pharmacokinetic and/or pharmacodynamic drug–drug interactions. Evaluation of pharmacokinetic interactions with antipsychotic drugs must consider substrate, inhibitor, and inducer properties for the cytochrome P450 (CYP) isoenzymes of all combined drugs. For consideration of pharmacodynamic interactions, special attention must be given to effects on dopamine D2, hista…

Doxepin and its metabolites in plasma and cerebrospinal fluid in depressed patients

Little information exists on the concentrations of antidepressants and their metabolites in CSF. We measured plasma and CSF levels of trans-doxepin (trans-DOX) and DOX metabolites in 12 depressed patients treated with DOX (250 mg/day) for 6 days. Spinal taps and blood samples were taken on day 7, 10 h after drug administration. Trans-DOX, cis-desmethyldoxepin (cis-DM-DOX), trans-desmethyldoxepin (trans-DM-DOX) and di-desmethyldoxepin (DDM-DOX) were analyzed in CSF and plasma samples by HPLC with column-switching. Although DOX was given as a mixture of 85% trans-DOX and 15% of the pharmacologically more active cis-DOX, we found similar amounts of cis-DM-DOX and trans-DM-DOX in plasma (59.8 +…

Amphiphilic Copolymers Shuttle Drugs Across the Blood-Brain Barrier.

Medical treatment of diseases of the central nervous system requires transport of drugs across the blood-brain barrier (BBB). Here, it is extended previously in vitro experiments with a model compound to show that the non-water-soluble and brain-impermeable drug domperidone (DOM) itself can be enriched in the brain by use of an amphiphilic copolymer as a carrier. This carrier consists of poly(N-(2-hydroxypropyl)-methacrylamide), statistically copolymerized with 10 mol% hydrophobic lauryl methacrylate, into whose micellar aggregates DOM is noncovalently absorbed. As tested in a BBB model efficient transport of DOM across, the BBB is achievable over a wide range of formulations, containing 0.…

Medikamente zur Behandlung von sexuellen Störungen

Folgende Storungen sind im Rahmen der psychiatrischen Pharmakotherapie — weitgehend oder auch nur ansatzweise — zu beeinflussen: Erektionsstorungen bzw. Storungen der sexuellen Erregung bei der Frau, vermindertes sexuelles Verlangen, Ejaculatio praecox, gesteigertes sexuelles Verlangen und substanzinduzierte sexuelle Funktionsstorungen. Fur andere Diagnosen im Bereich sexueller Storungen sind keine pharmakotherapeutischen Studien bekannt.

Neuroendocrine response to antipsychotics: effects of drug type and gender

Abstract Background: To study the influences of drug type and gender on the neuroendocrine response to neuroleptic treatment, we compared the endocrine actions of two neuroleptics with different receptor affinity profiles—a substituted benzamide, amisulpride, a selective D 2 -like dopamine antagonist; and a thioxanthene, flupenthixol, a mixed D 1 /D 2 -like antagonist also blocking serotonin, H 1 , and D 1 receptors—on anterior pituitary hormone secretion in schizophrenic patients (DSM-III-R). Methods: Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing ho…

Automated analysis of quetiapine and other antipsychotic drugs in human blood by high performance-liquid chromatography with column-switching and spectrophotometric detection.

Abstract An automated HPLC method with column switching is described for the determination of quetiapine, clozapine, perazine, olanzapine and metabolites in blood serum. After clean-up on silica C8 material (20 μm particle size) drugs were separated on ODS Hypersil C18 material (5 μm; column size 250 mm × 4.6 mm i.d.) within 25 min and quantified by ultraviolet (UV) detection at 254 nm. The limit of quantification ranged between 10 and 50 ng/ml. At therapeutic concentrations of the drugs, the inter-assay reproducibility was below 10%. Analyses of drug concentrations in serum of 75–295 patients treated with therapeutic doses of the antipsychotic drugs revealed mean ± S.D. steady state concen…

Pharmacokinetics and bioavailability of benperidol in schizophrenic patients after intravenous and two different kinds of oral application

Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t1/2 beta), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance…

Severe Tremor After Cotrimoxazole-Induced Elevation of Venlafaxine Serum Concentrations in a Patient With Major Depressive Disorder

: We describe a female patient who was an extensive metabolizer of cytochrome P450 isoenzyme (CYP) 2D6 and an intermediate metabolizer of CYP2C19 (genotype: CYP2C19 *1/*2). She exhibited high serum concentrations of venlafaxine and O-desmethylvenlafaxine and developed severe tremor after comedication with cotrimoxazole (sulfamethazole/trimethoprim). Venlafaxine is mainly metabolized by O- and N-demethylation. O-demethylation is catalyzed by the highly polymorphic CYP2D6 and N-demethylation by several enzymes, CYP2C19, CYP2C9, and CYP3A4. The observed overall pharmacokinetic effect was most probably the result of decreased N-demethylation of venlafaxine by (1) reduced expression of CYP2C19 d…

“Krokodil”—Revival of an Old Drug with New Problems

In order to summarize current knowledge about the drug "Krokodil" a systematic review including a literature search of the databases PubMed, Embase, Scopus, and Google was conducted in December 2011. According to information acquired, "Krokodil" is a mixture of several substances and was first reported to have been used in Russia in 2003. The core agent of "Krokodil" is desomorphine, an opioid-analogue that can be easily and cheaply manufactured by oneself. Self-production results in a contaminated suspension that is injected intravenously. Due to its pharmacologic features, desomorphine shows a high potential to cause dependence. Against the background of first possible cases of "Krokodil"…

Determination of Drug Concentrations in Serum and Dopamine Receptor Occupancy in Brain for Optimal Antipsychotic Drug Therapy

Evidence has been given that antipsychotic effects of dopamine receptor antagonists are associated with 60 and 80% striatal dopamine D2 and D3 receptor occupancy. Receptor occupancy correlates well with concentrations of the antipsychotic drugs in serum or plasma, much better than the dose. The latter is consistent with weak correlations between antipsychotic dose and serum concentrations and explained by the high interindividual variabilities in drug metabolism. Using positron emission tomography (PET) for in vivo determination of dopamine receptor occupancy in conjunction with drug concentration measurements “therapeutic windows” could be calculated for the atypical antipsychotic drugs am…

The role of cytochrome P450 2D6 in the metabolism of moclobemide.

The metabolic fate of moclobemide (Ro 11-1163), a new reversible and selective inhibitor of monoamine oxidase type A (MAO-A), has been assessed in a pilot study in 2 debrisoquine poor metabolizers (PM) and 4 extensive metabolizers (EM) after multiple oral dosings of moclobemide with and without co-medication of dextromethorphan. Absorption and disposition parameters were not different between PM and EM. Concurrent application of dextromethorphan, a selective substrate of CYP2D6, did not affect the pharmacokinetics of moclobemide. These results indicate that the cytochromal isoenzyme CYP2D6 does not play a major role in the metabolic degradation of moclobemide. Limited CYP2D6 activities beca…

Therapeutic drug monitoring of drugs for treatment of substance-related disorders

IntroductionThe effect of pharmacotherapy of substance-related disorders is moderate at best.ObjectivesTherapeutic drug monitoring (TDM) could be an instrument to improve the outcomes. TDM is for most of these drugs not established yet.AimsThe authors built a literature based rating scale to evaluate the necessity of TDM for these pharmacological agents.MethodsA literature research was performed for TDM related properties of acamprosate, bupropion, buprenorphine, clomethiazole, disulfiram, methadone, naltrexone, and varenicline. A rating scale was established for evaluation. It included 28 items related to five categories (efficacy, toxicity, pharmacokinetics, patient characteristics and co…

Drug-Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms.

Drug-induced liver injury is a major problem of pharmacotherapy and is also frequent with antidepressive psychopharmacotherapy. However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepress ants. We performed a quantitative signal detection analysis using data from the Uppsala Monitoring Centre from the WHO that records adverse drug reaction (ADR) data from worldwide sources; we retrieved substance- and country-specific (Australia, France, Germany, Italy, Spain, the United Kingdom, and the United States) ADR data and calculated reporting odds ratios as measures for disproportionality within a case/noncase approach. To a…

Liver failure under valproic acid

Valproic acid (VPA, 2-propylvaleric acid) is originally an antiepileptic drug, which has been in use for more than 30 years in over 100 countries. The clinical application of VPA has expanded in the last years. Approval has been granted by the FDA for treatment of migraine and cluster headache in 1996, and for treatment of mania and long-term prophylaxis of bipolar affective disorder in 1995. In ongoing studies, VPA has been reported to inhibit growth of several types of cancer cells; in addition, effects on neurodegeneration, and on virus replication in HIV infection have been demonstrated potentially expanding the application of VPA in the future. Despite a good tolerability of the drug, …

Effects of fluoxetine on behavioral deficits evoked by chronic social stress in rats.

Recently, we described an advanced model of chronic social stress in male rats based on the resident intruder paradigm. In this model, rats subjected to daily social stress for 5 weeks showed behavioral changes resembling anhedonia and motivational deficits in humans. In the present study, male Wistar rats were subjected to 5 weeks of daily social defeat by an aggressive conspecific and concomitant treatment with the antidepressant drug fluoxetine (10 mg/kg) after the first week of stress. Compared with controls, rats exposed to chronic stress had significantly reduced locomotor and exploratory activity (rearing and sniffing) and diminished preference for sucrose solution. These effects wer…

Pharmakokinetik, Pharmakogenetik und therapeutisches Drug Monitoring

Um einen pharmakologischen Effekt zu erzeugen, muss ein Medikament den Wirkort in ausreichender Konzentration erreichen. Welche Menge den Wirkort erreicht, hangt wesentlich von der Dosis ab, aber auch von vielen weiteren Faktoren, die bestimmen, welche Mengen resorbiert werden und wie das Medikament im Korper verteilt, abgebaut und ausgeschieden wird. Diese Prozesse sind auch dafur verantwortlich, wie lange die Wirkung anhalt. Die Pharmakokinetik beschreibt und erklart diese Zusammenhange, insbesondere den zeitlichen Konzentrationsverlauf der Medikamente und ihrer Metaboliten in Flussigkeiten und Geweben des Korpers. Sie versucht auch, zu erklaren, welche biologischen Mechanismen fur diese …

Anxiolytic-like effects of acute and chronic GABA transporter inhibition in rats.

Acute GABA transporter inhibition can induce anxiolytic-like behaviors. The present analysis addressed whether chronic treatment (23 days via drinking water) with a GABA transporter inhibitor affects rat behavior similar to acute treatment and interferes with additional benzodiazepine-receptor agonistic treatment. Seventy-one rats divided into seven groups were acutely treated with either vehicle, diazepam (2 mg/kg), zolpidem (0.05 mg/kg), tiagabine (19 mg/kg) or chronically with tiagabine with or without acute diazepam or zolpidem. Animals were behaviorally characterized in an elevated plus-maze. None of the treatments induced changes in the activity of the animals. Acute and chronic treat…

Early reactions of brain-derived neurotrophic factor in plasma (pBDNF) and outcome to acute antidepressant treatment in patients with Major Depression.

Abstract In Major Depressive Disorder, a growing data base suggests that the onset of antidepressants’ action can be detected by improvement of depressive symptoms in the first 10–14 days of treatment. Previous studies showed that the mean concentration of the brain-derived neurotrophic factor (BDNF) in blood increases during antidepressant treatment and positively correlates with amelioration of MDD symptoms. We previously showed an association between very early changes of the serum BDNF concentration and treatment outcome ( Tadic et al., 2011 . Prog Neuropsychopharmacol Biol Psychiatry 35, 415–420). However, no study has yet investigated whether BDNF concentration in plasma increases in …

Therapeutic monitoring of new antipsychotic drugs.

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 c…

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

Background: According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the Senantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp. Methods: P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalop…

Column switching and high-performance liquid chromatography in the analysis of amitriptyline, nortriptyline and hydroxylated metabolites in human plasma or serum

A column-switching system for the direct injection of plasma or serum samples, followed by isocratic high-performance liquid chromatography and ultraviolet detection, is described for the simultaneous quantitation of the tricyclic antidepressant amitriptyline, its demethylated metabolite nortriptyline and the E- and Z-isomers of 10-hydroxyamitriptyline and 10-hydroxynortriptyline. The method included adsorption of amitriptyline and metabolites on a reversed-phase C8 clean-up column (10 microns; 20 mm x 4.6 mm I.D.), washing of unwanted material to waste and, after on-line column-switching, separation on a cyanopropyl analytical column (5 microns; 250 mm x 4.6 mm I.D.). The compounds of inte…

Therapeutic Drug Monitoring of Naltrexone and 6β-Naltrexol During Anti-craving Treatment in Alcohol Dependence: Reference Ranges.

Aims Aim of this study was to associate concentration of naltrexone and its major active metabolite 6β-naltrexol in blood with therapeutic outcome during treatment with naltrexone in subjects with alcohol dependence. Treatment with the μ-opiate receptor antagonist naltrexone has been shown to reduce craving for alcohol and alcohol intake in patients suffering from alcohol dependence. Short summary This article shows the use of therapeutic drug monitoring in alcohol dependent patients, who are treated with naltrexone. The plasma concentrations of naltrexone and 6β-naltrexol showed high inter-individual variability. They were predictive for treatment response, as they correlated significantly…

Plasma levels and cerebrospinal fluid penetration by duloxetine in a patient with a non-fatal overdose during a suicide attempt

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake with weak activity on dopamine reuptake (Wong et al. 1993). Daily doses of 60 mg are effective in the acute treatment of major depression. Duloxetine is extensively metabolized by cytochrome P450 isoenzymes (CYP) 1A2 and to a lesser extent 2D6 (Lobo et al. 2008) to numerous non-active metabolites. Maximum plasma concentration occurs after 6 h, steady-state within 3 d and the mean terminal half-life is 12 h. Fatal outcomes have been reported for acute overdoses as low as 1000 mg, and symptoms of duloxetine overdose are well described. However, information about plasma levels of duloxetine and correspondin…

Measurement of Duloxetine in Blood Using High-performance Liquid Chromatography with Spectrophotometric Detection and Column Switching

A method using high-performance liquid chromatography (HPLC) with column switching and ultraviolet (UV) spectroscopy was developed for the determination of duloxetine in human plasma. After centrifugation and addition of venlafaxine as internal standard, plasma samples were injected into the HPLC system and precleaned on a column (10 x 4.0 mm) filled with cyanopropyl (CN)-modified silica of 20 microm particle size, with use of 8% (vol/vol) acetonitrile in deionized water as eluent. Duloxetine was eluted and separated on a LiChrospher 100 CN (5-microm particle size; column size, 250 x 4.6 mm I.D.) using acetonitrile-water-potassium dihydrogenphosphate trihydrate buffer (pH, 6.4; 50:50 vol/vo…

SPCCTDM, a Catalogue for Analysis of Therapeutic Drug Monitoring Related Contents

Therapeutic drug monitoring (TDM) has consistently been shown to be useful for optimization of drug therapy. For the first time, a method has been developed for the text analysis of TDM in SPCs in that a catalogue SPC-ContentTDM (SPCCTDM) provides a codification of the content of TDM in SPCs. It consists of six structure-related items (dose, adverse drug reactions, drug interactions, overdose, pregnancy/breast feeding, and pharmacokinetics) according to implicit or explicit references to TDM in paragraphs of the SPC, and four theory-guided items according to the information about ranges of plasma concentrations and a recommendation of TDM in the SPC. The catalogue is regarded as valid for t…

Therapeutic Drug Monitoring for Drugs Used in the Treatment of Substance-Related Disorders: Literature Review Using a Therapeutic Drug Monitoring Appropriateness Rating Scale

Background The efficacy of drugs for the treatment of substance-related disorders is moderate at best. Therapeutic drug monitoring (TDM) could be an instrument to improve outcomes. Because TDM for most of those drugs is not established, the authors reviewed the literature and built a rating scale to detect the potential added value of TDM for these pharmacologic agents. Methods A literature search was performed for acamprosate, bupropion, buprenorphine, clomethiazole, disulfiram, methadone, naltrexone, and varenicline. The rating scale included 22 items and was divided in five categories: efficacy, toxicity, pharmacokinetics, patient characteristics, and cost-effectiveness. Three reference …

High striatal occupancy of D2-like dopamine receptors by amisulpride in the brain of patients with schizophrenia.

The 'atypicality' of the antipsychotic drug, amisulpride, has been attributed to preferential extrastriatal binding. Previous investigations of striatal D2 receptor occupancy by amisulpride revealed conflicting results. The aim of this PET study was to measure the striatal occupancy by amisulpride and to correlate it with the corresponding drug plasma concentrations. Nine amisulpride-treated patients and 12 healthy volunteers serving as controls were studied with PET and [18F]desmethoxyfallypride. Occupancy values and plasma concentrations were nonlinearly fitted to an E max model. Results showed 43-85% (putamen) and 67-90% (caudate) D2-like receptor occupancy. Plasma amisulpride concentrat…

Acitretin, an Enhancer of Alpha-Secretase Expression, Crosses the Blood-Brain Barrier and Is Not Eliminated by P-Glycoprotein

&lt;i&gt;Background:&lt;/i&gt; ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated to act as the main physiological α-secretase. Enzymatic activity of the α-secretase on the one hand prevents the formation of toxic Aβ peptides and on the other hand promotes the secretion of a neurotrophic and neuroprotective amyloid precursor protein fragment (APPs-α) by cleaving the amyloid precursor protein within its Aβ sequence. Enhancement of ADAM10’s gene expression may therefore present a valuable therapeutic approach for the treatment of Alzheimer’s disease (AD), where Aβ peptides are severely involved in the pathogenesis. &lt;i&gt;Objective:&lt;/i&gt; In cell culture and in a tran…

The HTR1B 861GC receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy.

Abstract The HTR1B receptor gene has been linked to antisocial alcoholism in a Finnish population and an American Indian tribe [Lappalainen et al., Arch. Gen. Psychiatry, 55 (1998) 989]. Using a candidate gene approach, we genotyped 209 patients with alcoholism, 108 patients with major depression, 32 patients with panic disorder, 50 patients with generalized anxiety disorder, 58 patients with narcolepsy and 74 healthy volunteers for the HTR1B 861G>C polymorphism. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (χ 2 =4.02, d.f.=2, P =0.04). However, the association resulted from higher frequencies of the opposite…

Determination of Homovanillic Acid in Human Plasma Using HPLC with Electrochemical Detection and Automated Solid Phase Extraction

Abstract An isocratic HPLC method with electrochemical detection for the quantification of homovanillic acid (HVA) is described. The method included automated solid phase extraction on C-18-reversed phase material, followed by separation on a 3-μm Nucleosil 100 C18 column (250 mm × 4.6 mm I. D.) with a 100 mM citric acid solution (pH 6.6) containing 4% acetonitrile (v/v) as eluent at a flow rate of 0.6 ml/min. Isovanillinic acid served as internal standard. Extractability of both analytes was ca. 80 %. After extraction of 1 ml of plasma, coefficients of variation of replicate analyses were below 10 % in the naturally occuring concentration range.

How Does the Benzamide Antipsychotic Amisulpride get into the Brain?—An In Vitro Approach Comparing Amisulpride with Clozapine

This study evaluated the disposition of the two atypical antipsychotics, amisulpride (AMS) and clozapine (CLZ), and its main metabolite N-desmethylclozapine (DCLZ), to their target structures in the central nervous system by applying an in vitro blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier based on monolayers of porcine brain microvessel endothelial cells (PMEC) or porcine choroid plexus epithelial cells (PCEC). Permeation studies through PMEC- and PCEC-monolayers were conducted for 60 min at drug concentrations of 1, 5, 10, and 30 muM applied to the donor compartment. PMEC were almost impermeable for AMS (permeation coefficient, P1 x 10(-7) cm/s) in the resorptive direct…

Automated Determination of Trimipramine and N-Desmethyl-Trimipramine in Human Plasma or Serum by HPLC With On-Line Solid Phase Extraction

A fully automated method including column-switching and isocratic high performance liquid chromatography (HPLC) was developed for determination of the tricyclic antidepressant trimipramine (T) and its N-demethylated metabolite N-desmethyltrimipramine (DT). The limit of quantification was below 10 ng/ml for T and DT. The assay revealed linearity between detector response and drug concentration in a therapeutically relevant range of 10 to 500 ng/ml. The mean intra- and interassay variabilities were 6.2 and 12.3%, respectively, for T and 4.7 and 8.7% respectively, for DT. The method can be applied to therapeutic drug monitoring of patients under T therapy and may be useful for pharmacokinetic …

Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice.

The molecular mechanism of action of the mood stabilizer lithium is assumed to involve changes in gene expression leading to neuronal adaptation. The transcription factor CREB (cAMP-responsive element binding protein) regulates the expression of many genes and has been implicated in important brain functions and the action of psychogenic agents. We here investigated the effect of lithium on cAMP-responsive element (CRE)/CREB-mediated gene transcription in the brain, using transgenic reporter mice that express the luciferase reporter gene under the control of four copies of the rat somatostatin gene promoter CRE. Chronic (21 days) but not acute (24 h) treatment with lithium (7.5 mmol/kg) sig…

Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service.

Therapeutic drug monitoring data of the new atypical neuroleptic drug olanzapine were used to study interactions with the selective serotonin reuptake inhibitors fluvoxamine and sertraline. The distribution of the ratio of concentration/daily dose (C/D; ng/mL per mg/d) of olanzapine was compared in three groups: patients treated with olanzapine (n = 134), patients treated with olanzapine plus fluvoxamine (n = 10) concomitantly, and patients treated with olanzapine plus sertraline (n = 21) concomitantly. No significant difference was seen between the olanzapine and the olanzapine plus sertraline groups. Patients receiving fluvoxamine in addition to olanzapine had C/D ratios that were in the …

Lebensqualität am Beispiel depressiver Patienten nach stationärer Behandlung

Wir kennen es alle: schlechte Laune und miserable Stimmung. Meist wissen wir den Grund. Zwischen diesen Gefuhlen und einer Depression besteht allerdings ein groser Unterschied. Die Stimmung der meisten Menschen wechselt. Jeden Tag reagieren sie auf Ereignisse, so dass sich Stimmungen in raschem Wechsel ablosen. Bei starken oder gehauften positiven beziehungsweise negativen Erlebnissen kann eine Stimmung auch uber Stunden, ja Tage anhalten, bis sie sich wieder andert. In diesem Sinn gehort der Wechsel von gedruckten Stimmungen, Ausgeglichenheit und gehobenen Stimmungen zum Gefuhlsspektrum eines jeden Menschen.

Therapeutisches Drugmonitoring in der Psychiatrie

Die Dosis bestimmt die Wirkung eines Arzneistoffs. Diese Gesetzmasigkeit ist seit gut 500 Jahren bekannt. Heute wissen wir es genauer: Die Konzentration am Wirkort bestimmt die Wirkung. Fur therapeutisch erwunschte Wirkungen von Psychopharmaka sind es die Konzentrationen im Gehirn. Da bei gleicher Dosis von Patient zu Patient sehr unterschiedliche Wirkstoffkonzentrationen resultieren konnen und die Konzentration im Blut gut mit den Konzentrationen im Gehirn korrelieren, ist es sinnvoll, die Psychopharmakotherapie durch Messung der Wirkstoffkonzentrationen im Blut zu steuern, durch sog. therapeutisches Drugmonitoring (TDM). Durch TDM konnen Hinweise auf Complianceprobleme, pharmkokinetische …

Simultaneous determination of olanzapine, clozapine and demethylated metabolites in serum by on-line column-switching high-performance liquid chromatography.

An automated method for simultaneous routine quantification of the antipsychotic drugs clozapine, olanzapine and their demethylated metabolites is described. The method included adsorption on a cyanopropyl (CPS) coated clean-up column (10 microm; 10 x 2.0 mm I.D.), washing off interfering serum constituents to waste, and separation on C18 ODS Hypersil reversed phase material (5 microm; 250 x 4.6 mm I.D.) using acetonitrile-water-tetramethylethylenediamine (37:62.6:0.4, v/v/v) adjusted to pH 6.5 with concentrated acetic acid. UV-detection was performed at 254 nm. The limit of quantification was 10-20 ng/ml. Relative day to day standard variations ranged between 4.5 and 13.5%. The method is s…

SPCCTDM, a Catalogue for Analysis of Therapeutic Drug Monitoring Related Contents in the Drug Prescription Information

Therapeutic drug monitoring (TDM) has consistently been shown to be useful for optimization of drug therapy. For the first time, a method has been developed for the text analysis of TDM in SPCs in that a catalogue SPC-ContentTDM (SPCCTDM) provides a codification of the content of TDM in SPCs. It consists of six structure-related items (dose, adverse drug reactions, drug interactions, overdose, pregnancy/breast feeding, and pharmacokinetics) according to implicit or explicit references to TDM in paragraphs of the SPC, and four theory-guided items according to the information about ranges of plasma concentrations and a recommendation of TDM in the SPC. The catalogue is regarded as valid for t…

Over-expression of two different forms of the α-secretase ADAM10 affects learning and memory in mice

Members of the ADAM family (adisintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid precursor protein within the region of the Abeta peptides preventing their aggregation in the brain. The increase of alpha-secretase activity in the brain provides a plausible strategy to prevent Abeta formation. Concerning this possibility two transgenic mouse lines (FVB/N) have been created: mice over-expressing the bovine form of the alpha-secretase (ADAM10) and mice over-expressing an inactive form of the alpha-secretase (ADAM10-E348A-HA; ADAM10-dn). For behavioral examination a F1 ge…

Therapeutic drug monitoring for antidepressant drug treatment.

The aim of antidepressant drug treatment is to produce remission without causing adverse effects during the acute phase of the illness and to prevent relapses or recurrences during continuation or maintenance therapy. To achieve these goals, drug choice and dosage must be optimized for each patient individually. Therapeutic drug monitoring (TDM), which is based on the assumption that clinical effects correlate better with blood levels than doses, can be helpful. When using tricyclic antidepressant drugs TDM enhances safety and efficacy. For newer antidepressant drugs, however, it is a matter of debate to which extend TDM can have beneficial effects. For many antidepressants there exist care…

Pharmacogenomics in psychiatry: from therapeutic drug monitoring to genomic medicine.

Psychiatry is increasingly combining new pharmacogenomic findings with therapeutic drug monitoring (TDM) to improve the safety and efficacy of pharmacotherapy. However, a distinction should be made between “nice to know” and “need to know” pharmacogenomic data because many results are statistically significant in meta-analyses but are not clinically relevant due to their low effect sizes. Some examples will illustrate this integration.

Evaluation of P-glycoprotein (abcb1a/b) modulation of [18F]fallypride in MicroPET imaging studies

[(18)F]Fallypride ([(18)F]FP) is an important and routinely used D2/D3 antagonist for quantitative imaging of dopaminergic neurotransmission in vivo. Recently it was shown that the brain uptake of the structurally related [(11)C]raclopride is modulated by P-glycoprotein (P-gp), an important efflux transporter at the blood-brain barrier. The purpose of this study was to determine whether the brain uptake of [(18)F]FP is influenced by P-gp. For examination of this possible modulation microPET studies were performed in a rat and a mouse model. Hence, [(18)F]FP was applied to Sprague Dawley rats, half of them being treated with the P-gp inhibitor cyclosporine A (CsA). In a second experimental s…

Chronical haloperidol and clozapine treatment in rats: Differential RNA display analysis, behavioral studies and serum level determination

1. Adult, female rats were treated orally for 23 days with 1.6 mg/kg haloperidol or 36 mg/kg clozapine per day, to study chronic effects of the two neuroleptics. 2. At five time points during the neuroleptic treatment, animal behavior was recorded in an open field and locomotive activity was analysed. At the end of the experiment, rats were decapitated, blood samples were collected and serum concentrations of haloperidol and clozapine were determined by a radioreceptor or HPLC assay, respectively. RNA was isolated from each brain, without cerebellum, and subjected to differential RNA display. 3. Mean serum concentrations were 8 ng/ml for haloperidol and 21 ng/ml for clozapine. Analysis of o…

O-18 - TDM in patients with substance related disorders

The effect of pharmacotherapy of substance-related disorders is moderate at best. Therapeutic drug monitoring (TDM) could be an instrument to improve the outcomes. Since TDM for these drugs is not well established, the authors built a literature based rating scale to evaluate the necessity of TDM for the use of these pharmacological agents. Methods A literature research was performed for acamprosate, bupropion, buprenorphine, clomethiazole, disulfiram, methadone, naltrexone, and varenicline. A rating scale including 22 items, divided in five categories (efficacy, toxicity, pharmacokinetics, patient characteristics and cost effectiveness) was established for evaluation and related to the amo…

Behavioral Effects of GABAA Receptor Stimulation and GABA-Transporter Inhibition

Abstract The present analysis addressed behavioral changes after treatment with 4.5 mg/kg or 18.5 mg/kg of the GABA-uptake inhibitor tiagabine combined with either the benzodiazepine diazepam (1.5 mg/kg) or the imidazopyridine zolpidem (0.05 mg/kg), the latter two acting differentially on GABA A receptor subtypes. The study included 97 male PVG/OIaHsd rats. A standard open field, an enriched open field, and an elevated plus-maze was used to study rat behavior. Treatment with the low dose of tiagabine alone induced no specific behavioral effects, whereas the high dose had an anxiolytic-like potential. Furthermore, diazepam but not zolpidem displayed anxiolytic-like effects. Combination of ea…

Pharmacokinetics of selective serotonin reuptake inhibitors

The five selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, have similar antidepressant efficacy and a similar side effect profile. They differ, however, in their pharmacokinetic properties. Under steady-state concentrations, their half-lives range between 1 and 4 days for fluoxetine (7 and 15 days for norfluoxetine) and between 21 (paroxetine) and 36 (citalopram) hr for the other SSRIs. Sertraline and citalopram show linear and fluoxetine, fluvoxamine, and paroxetine nonlinear pharmacokinetics. SSRIs underlie an extensive metabolism with high interindividual variability, whereby cytochrome P450 (CYP) isoenzymes play a major rol…

Macromol. Rapid Commun. 9-10/2011

Therapeutic drug monitoring for optimizing amisulpride therapy in patients with schizophrenia.

Amisulpride is a clinically effective antipsychotic drug in a broad dose range with low propensity for extrapyramidal symptoms (EPS). Daily doses and plasma levels of amisulpride were analyzed within a large-scale therapeutic drug monitoring (TDM) survey to find plasma level ranges for optimized treatment under naturalistic conditions. Data of 378 schizophrenic patients treated with amisulpride (100-1550 mg) were included (40% female). Amisulpride plasma levels were analyzed at steady state; assessment comprised improvement (CGI-I) and side-effects, particularly EPS. For detection of cut-off values regarding non-response or EPS, receiver operating characteristics (ROC) curves were applied a…

The use of ziprasidone in clinical practice: Analysis of pharmacokinetic and pharmacodynamic aspects from data of a drug monitoring survey

AbstractThis study related clinical effects to daily doses and serum concentrations of ziprasidone by retrospective analysis of data from a therapeutic drug monitoring (TDM) survey established for patients treated with the new antipsychotic drug. In the total sample of 463 patients ziprasidone doses ranged between 20 and 320 mg/d and correlated significantly (r2 = 0.093, P &lt; 0.01) with serum concentrations. The latter were highly variable within and between individual patients (between patients median 67 ng/ml, 25–75th percentile 40–103 ng/ml). Pharmacokinetic interactions with comedication played a minor role. According to the clinical global impressions (CGI) scale most of the 348 pati…

A common mechanism of action of the selective serotonin reuptake inhibitors citalopram and fluoxetine: Reversal of chronic psychosocial stress-induced increase in CRE/CREB-directed gene transcription in transgenic reporter gene mice

The transcription factor CREB regulates adaptive responses like memory consolidation, addiction, and synaptic refinement. Recently, chronic psychosocial stress as animal model of depression has been shown to stimulate CREB transcriptional activity in the brain; this stimulation was prevented by treatment with the antidepressant imipramine, which inhibits both noradrenaline and serotonin reuptake. However, it was unknown whether the selective inhibition of serotonin reuptake is sufficient for inhibition of stress-induced CREB activation, as it is for the clinical antidepressant effect. Therefore, the effect of two selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, wa…

Therapeutic Monitoring of Aripiprazole by HPLC with Column-Switching and Spectrophotometric Detection

Aripiprazole is a novel atypical antipsychotic drug for the treatment of schizophrenia and schizoaffective disorders (1)(2)(3). The drug is metabolized by the cytochrome P450 isoenzymes 3A4 and 2D6 (4). Because of high interindividual variability in the expression of these enzymes, the aripiprazole concentration varies among healthy individuals after administration of the drug (5). In patients, insufficient response or side effects, such as somnolence, akathisia, or nausea, may result from too low or too high drug concentrations. Therapeutic drug monitoring (TDM), which is established practice for many antipsychotic drugs (6)(7), may be helpful for patients treated with aripiprazole. We mea…

Drug safety related to agents used for opioid maintenance therapy

IntroductionThere is only little data regarding drug safety related to agents used for opioid maintenance therapy (OMT).Objectives/aimsTo study drug safety and the reporting behaviour of adverse drug reactions (ADR) related to OMT.MethodsA cross-sectional questionnaire-based telephone survey among physicians providing outpatient OMT in a federal state of Germany (n = 176; response rate = 55.7%) was conducted.ResultsMost of the respondents (n = 97/55.1%) reported that they observe ADR related to buprenorphine, [dihydro]codein and [levo]methdone rarely (n = 38/21.6%), very rarely (n = 39/22.2%) or never (n = 20/11.4%). Methadone was reported to be most frequently associated with the occurrenc…

Effects of pulsed high-frequency electromagnetic fields on the neuroendocrine system.

The influence of pulsed high-frequency electromagnetic fields emitted from a circularly polarized antenna on the neuroendocrine system in healthy humans was investigated (900 MHz electromagnetic field, pulsed with 217 Hz, average power density 0.02 mW/cm&lt;sup&gt;2&lt;/sup&gt;). Nocturnal hormone profiles of growth hormone (GH), cortisol, luteinizing hormone (LH) and melatonin were determined under polysomnographic control. An alteration in the hypothalamo-pituitary-adrenal axis activity was found with a slight, transient elevation in the cortisol serum level immediately after onset of field exposure which persisted for 1 h. For GH, LH and melatonin, no significant effects were found under…

Serotonergic modulation of response inhibition and re-engagement? Results of a study in healthy human volunteers

Objective Cognitive functions dependent on the prefrontal cortex, such as the ability to suppress behavior (response inhibition) and initiate a new one (response re-engagement) is important in the activities of daily life. Central serotonin (5-HT) function is thought to be a critical component of these cognitive functions. In recent studies, 5-HT failed to affect stop-signal reaction time (SSRT), a fundamental process in behavioral inhibition. We were interested if response inhibition and re-engagement are influenced through central 5-HT activity as mediated via the 5-HT transporter. Methods Here, using a stop-change task, we investigated the effects of acute and repeated treatment with 10 …

Automated determination of clomipramine and its major metabolites in human and rat serum by high-performance liquid chromatography with on-line column-switching

A fully automated method including column-switching and isocratic high-performance liquid chromatography (HPLC) was developed for simultaneous determination of the tricyclic antidepressant clomipramine and its metabolites demethylclomipramine, 2-, 8-, and 10-hydroxyclomipramine, 2-, and 8-hydroxydemethylclomipramine and didemethylclomipramine in serum. After serum injection into the HPLC system and on-line sample clean-up on a clean-up column (Hypersil CN; 10 x 4.6 mm) by an eluent consisting of 35% acetonitrile and 65% deionized water, the chromatographic separation was performed on an analytical column (LiChrospher CN; 250 x 4.6 mm I.D.) by an eluent consisting of 38% acetonitrile and 62%…

Induction of Drug Transporters Alters Disposition of Risperidone - A Study in Mice

Pharmacokinetic interactions, e.g. modulation of drug transporters like P-glycoprotein at the blood-brain barrier, can be a reason for treatment non-response. This study focuses on the influence of induction of drug transporters on the disposition of the antipsychotic drugs risperidone and 9-hydroxyrisperidone. Brain and serum concentrations of risperidone and its active metabolite 9-hydroxyrisperidone, which are known P-glycoprotein substrates, were measured after drug transporter induction with rifampicin, dexamethasone or 5-pregnene-3beta-ol-20-on-16alpha-carbonitrile using high performance liquid chromatography. Disposition of risperidone and 9-hydroxyrisperidone was dramatically decrea…

Rapid cloning of cDNA ends polymerase chain reaction of G-protein-coupled receptor kinase 6: an improved method to determine 5′- and 3′-cDNA ends

Abstract Rapid cloning of 5′- and 3′-cDNA ends polymerase chain reaction (5′-/3′-RACE-PCR) is useful to determine unknown 5′- and 3′-cDNA termini. Even if the method can yield complete cDNA sequences within a couple of days, the RACE procedure bears some characteristic traps and often results in amplification of unspecific PCR-products. Here we used improved 5′- and 3′-RACE-PCR protocols to obtain the complete cDNA sequence of the G-protein-coupled receptor kinase 6 (GRK6) from a rat brain cDNA library. The use of an anchored oligo-(dT) 16 -V-primer in the cDNA synthesis, the addition of single-sided PCR steps prior to the RACE-PCRs and the optimization of the dA-tailing reaction conditions…

Tyrosine hydroxylase Val-81-Met polymorphism associated with early-onset alcoholism

The present study examined the association of the Tyrosine hydroxylase Val-81-Met polymorphism with alcohol dependence. One hundred and fifty-nine patients in a psychiatric unit with alcohol dependence were genotyped as well as 92 healthy volunteers. The Val allele was more frequent in patients with alcohol dependence (69.5%) than in controls (62.5%). This effect was largely due to the association with early-onset alcoholism (77.8%), whereas no difference was noted between late-onset patients and controls. Our results suggest a role for tyrosine hydroxylase in early-onset alcoholism.

Assessing drug-drug interactions through therapeutic drug monitoring when administering oral second-generation antipsychotics.

Second-generation antipsychotics (SGAs) are frequently co-prescribed with drug metabolic inducers and inhibitors. SGA pharmacokinetic drug-drug interactions (DDIs) with inducers and inhibitors have not received enough attention in the literature but can be studied in by using therapeutic drug monitoring (TDM).The limited information available on oral SGA pharmacokinetic DDIs is reviewed. A systematic literature search on the available oral SGA TDM studies is completed. By integrating TDM studies with the information on in vitro metabolism studies, case report/series and prospective studies, a table is provided to manage average SGA patients taking inducers or inhibitors by using TDM and/or …

Therapeutic Drug Monitoring of the Antidepressant Mirtazapine and Its N-Demethylated Metabolite in Human Serum

Mirtazapine is a novel antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. Because very little is known about serum concentrations in relation to clinical effects, the use of therapeutic drug monitoring is so far unclear. A rapid automated HPLC method with fluorescence detection was developed for routine quantification of mirtazapine and its demethylated metabolite N-desmethylmirtazapine in human serum. The precision of the method was suitable because the day-to-day (n = 7) coefficient of variation (CV) of mirtazapine was 9.8, 4.2, and 5.1% for concentrations of 10, 40, and 80 ng/mL, respectively, and the CV for N-desmethylmirtazapine were 11.6, 10.3, and…

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

SUMMARY Background: Venlafaxine (V) is a mixed serotoninand noradrenaline reuptake inhibitor used as afirst-line treatment of depressive disorders. It ismetabolized primarily by the highly polymorphiccytochrome P450 (CYP) enzyme CYP2D6 to yielda pharmacologically active metabolite, O-des-methylvenlafaxine (ODV), and to a lesser extentby CYP3A4, to yield N-desmethylvenlafaxine(NDV).Objectives: The aim of this study was to assesswhether the O-demethylation phenotype of V hasan impact on the pharmacokinetics and clinicaloutcome.Method: In 100 patients treated with V, serumconcentrations of V, ODV and NDV and theratios of concentrations ODV/V as a measure ofO-demethylation were determined. Indiv…

Diazepam has no beneficial effects on stress-induced behavioural and endocrine changes in male tree shrews.

Abstract VAN KAMPEN, M., U. SCHMITT, C. HIEMKE AND E. FUCHS. Diazepam has no beneficial effects on stress-induced behavioural and endocrine changes in male tree shrews. PHARMACOL BIOCHEM BEHAV 65 (3) 539–546, 2000.—The present study evaluated the effect of subchronic oral treatment of psychosocially stressed male tree shrews with diazepam on locomotor activity, marking behavior, avoidance behavior, and urinary cortisol and noradrenaline. To mimic a realistic situation of anxiolytic intervention, the treatment started 14 days after the beginning of psychosocial stress; at that time, the stress-induced behavioral and endocrine alterations had been established. The drug (5 mg/kg/day) was admin…

Agomelatine and Hepatotoxicity: Implications of Cumulated Data Derived from Spontaneous Reports of Adverse Drug Reactions

Considering the antidepressant agomelatine (AGM) there is a discrepancy between the widespread knowledge of the potential of AGM to cause hepatotoxic adverse drug reactions (ADR) and the availability of corresponding published data. This impedes an adequate assessment of the hepatotoxicity profile of AGM. We conducted a query of the database of a German Medical Regulatory Body (BfArM) and analyzed spontaneous reports of hepatotoxic ADR. We identified n=58 cases of AGM-related hepatotoxic ADR. Most frequent ADR was asymptomatic increase of liver enzymes (79%); n=6 patients (10%) with AGM-related toxic hepatitis were reported. Characteristics of patients: female sex (69%), age > 50 years (mea…

Activity of the adenylyl cyclase in lymphocytes of male alcoholic patients is state dependent.

A decreased basal and/or stimulated activity of the G-protein/adenylyl cyclase (AC) system in peripheral blood cells has been proposed to represent a trait marker for alcoholism. However, AC activity may underlie state-dependent changes, which may impair a proper interpretation of AC activity measurements. Our study examined systematically the AC activity in peripheral lymphocytes of 73 male alcohol-dependent patients (according to DSM-IV criteria) at three different time points of measurement during the clinical course of detoxification (day 0 = at admission, while still ethanol-affected; day 2 = at the presumed peak of withdrawal symptoms; day E = after detoxification). Basal and stimulat…

Chronic psychosocial stress and antidepressant treatment in tree shrews: time-dependent behavioral and endocrine effects.

Abstract Social defeat has been shown to cause a number of behavioral, physiological, and central nervous changes in male tree shrews. The present study was designed to assess: (i) a potential time lag in the occurrence of behavioral alterations (locomotor activity, self-grooming, marking behavior, food and water intake, and avoidance behavior) after stress and long-term antidepressant treatment; and (ii) to investigate potential interactions between behavioral and endocrine variables (urinary cortisol and norepinephrine). Male tree shrews were submitted to chronic psychosocial stress for 39 days. In this paradigm, the stress-induced behavioral and endocrine alterations in subordinate anima…

Duloxetine serum concentrations and clinical effects. Data from a therapeutic drug monitoring (TDM) survey.

INTRODUCTION The aim of this study was to relate drug concentrations in serum and clinical effects in patients treated with the new antidepressant duloxetine. METHODS Data were obtained from a newly established therapeutic drug monitoring (TDM) survey. Duloxetine was measured using HPLC with UV detection and clinical effects by the clinical global impressions (CGI) scale for improvement. RESULTS The study included 103 depressed inpatients (69% female). Patients under duloxetine monotherapy who were very much improved according to CGI had significantly (p<0.05) higher serum levels than patients with moderate, minimal or lacking improvement (mean+/-SD and range, 93+/-53 ng/mL and 30-182 ng/mL…

Clozapine plasma level monitoring for prediction of rehospitalization schizophrenic outpatients.

INTRODUCTION: The aim of this naturalistic exploratory study was to examine whether blood antipsychotic drug concentrations can predict rehospitalizations in chronically medicated patients. METHODS: The study included schizophrenic outpatients under clozapine (CLZ) maintenance treatment, supervised by therapeutic drug monitoring (TDM). Patients were observed for a period of 21 months. Their on average monthly measured plasma levels and the date of rehospitalizations were recorded. The variability of the first 3 CLZ plasma levels, measured in 3.6 months, was compared between patients with and without rehospitalization. RESULTS: 23 patients participated of which 6 patients were rehospitalized…

The TPH intron 7 A218C polymorphism and TCI dimension scores in alcohol-dependent patients: hints to nonspecific psychopathology

Abstract Aims A linkage of certain alleles of the tryptophan hydroxylase (TPH) intron 7 A218C polymorphism to suicidality and antisocial behaviour has been described. The aim of our study was to find any association between dimensions of the Temperament and Character Inventory (TCI) indicating impulsivity and the TPH polymorphism alleles in unselected alcohol-dependent patients and age-matched controls. Methods We examined 159 alcohol-dependent patients and 161 controls with the TCI and genotyped them for the TPH intron 7 A218C polymorphism alleles. Results Although homozygous TPH genotypes were found more often in alcohol-dependent patients than in controls, an association between TCI dime…

Nonlinear pharmacokinetics of fluvoxamine and gender differences.

This prospective study assessed fluvoxamine serum concentrations under two different fixed doses. The study included 15 male and female patients who met the DSM-III-R criteria for major depression. They were prescribed 50 mg fluvoxamine twice a day for 2 weeks and 100 mg twice a day thereafter. Drug monitoring was carried out on days 14 and 28. Fluvoxamine serum concentrations were highly variable between patients. After the dose was doubled, the serum concentrations of fluvoxamine increased disproportionately (mean, 3.4-fold), and there was a significantly (p < 0.05) more pronounced increase in men (4.6-fold) than in women (2.4-fold). These results provide evidence of nonlinear, sex-depend…

QTc Time Correlates with Amitriptyline and Venlafaxine Serum Levels in Elderly Psychiatric Inpatients

Abstract Introduction Many antidepressants cause QT prolongation but the classification of cardiac risk of these drugs varies markedly in different published lists. This retrospective study analyzed the correlation of QTc time with amitriptyline and venlafaxine serum level in elderly psychiatric inpatients. Methods Elderly inpatients aged≥65 years for whom venlafaxine or amitriptyline serum level had been measured were selected retrospectively from a therapeutic drug monitoring database and screened for an electrocardiogram measurement at the time of blood withdrawal. The correlation of amitriptyline or venlafaxine serum levels with QTc time was examined by using Pearson’s correlation analy…

Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice

Abstract Background P-glycoprotein (P-gp), an efflux transporter localized in the blood–brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). For the new antipsychotic aripiprazole and its active metabolite dehydroaripiprazole differences in disposition in blood and brain were investigated after acute and sub-chronic administration in a P-gp knockout mouse model. Methods Serum and brain concentrations of both drugs were measured at several time points 1–24 h after i.p. injection of 10 mg/kg aripiprazole and after 11 days of sub-chronic administration in several tissues. Moreover, the expression of P-gp was determined by Western blot analysis after sub…

Elevated risperidone serum concentrations during acute inflammation, two cases

Inflammation-mediated changes in drug metabolism may lead to alterations in the absorption, distribution, and clearance of psychotropic drugs and thus elevate drug levels in blood and lead to intoxications. We report about two patients who developed an up to threefold increase of dose-related serum concentrations of risperidone’s active moiety (risperidone plus 9-hydroxyrisperidone) during acute inflammation indicated by elevated C-reactive protein. The two female patients (aged 56 and 38 years, respectively) had the diagnoses of paranoid schizophrenia and schizoaffective disorder. For both patients, there was a close time-dependent parallel fluctuation of drug levels and C-reactive protei…

Interferon-Alpha-2-Induced Stimulation of ACTH and Cortisol Secretion in Man

Short-term effects of interferon-alpha 2 on plasma concentrations of adrenocorticotrophic hormone (ACTH) and cortisol were measured in man in relation to interferon absorption. Interferon-alpha 2 was given subcutaneously at a dose of 3 x 10(6) IU at 17.00 h to 2 female and 5 male patients who suffered from chronic hepatitis B infection and who had not previously been treated with interferon. Plasma levels of ACTH, cortisol and interferon-alpha were determined at 30-min intervals between 16.00 and 24.00 h. In each patient a similar cortisol, ACTH and interferon-alpha profile was determined on a day, when no interferon-alpha treatment was given. Interferon-alpha plasma levels peaked around 21…

Increased bioavailability of oral melatonin after fluvoxamine coadministration*1

Background Fluvoxamine, a selective serotonin reuptake inhibitor, is known to elevate melatonin serum concentrations. It has not been clear whether these effects might be attributed to an increased melatonin production or to an decreased elimination of melatonin. The latter hypothesis was tested by this study. Methods Five healthy male volunteers (one CYP2D6 poor metabolizer) received 5 mg melatonin either with or without coadministration of 50 mg fluvoxamine. Serum concentrations of melatonin and fluvoxamine were assessed from 0 to 28 hours after melatonin intake. Results Coadministration of fluvoxamine, on average, led to an 17-fold higher (P <.05) area under concentration–time curve (AUC…

Steady state concentrations of clomipramine and its major metabolite desmethylclomipramine in rat brain and serum after oral administration of clomipramine.

Twenty male Sprague-Dawley rats received five oral doses of clomipramine 20 mg/kg at 4-h intervals. The animals were decapitated 1, 2, 3, 5 and 12 h after the last dose for determination of clomipramine and desmethylclomipramine in serum and frontal cerebral cortex. Time dependent concentrations of clomipramine and desmethylclomipramine paralleled in serum and brain. Half-lives were similar in serum and brain with 7.8 versus 6.2 h and 5.5 versus 5.0 h for clomipramine and desmethylclomipramine, respectively. Absolute concentrations, however, were markedly higher in brain than in serum - 12.5 fold for clomipramine and 7.4 fold for desmethylclomipramine. The data indicate that serum and brain…

HPMA Based Amphiphilic Copolymers Mediate Central Nervous Effects of Domperidone

In this study we give evidence that domperidone encapsulated into amphiphilic p(HPMA)-co-p(laurylmethacrylate) (LMA) copolymer aggregates is able to cross the blood-brain barrier, since it affected motor behaviour in animals, which is a sensitive measure for CNS actions. Carefully designed copolymers based on the clinically approved p(HPMA) were selected and synthesized by a combination of controlled radical polymerization and post-polymerization modification. The hydrodynamic radii (R(h) ) of amphiphilic p(HPMA)-co-p(LMA) alone and loaded with domperidone were determined by fluorescence correlation spectroscopy.

French summaries of product characteristics: content in relation to therapeutic monitoring of psychotropic drugs

The prescription information (summary of product characteristics, SPC) is compiled by the pharmaceutical industry as required by the national regulatory authorities. They vary in their content about the properties of drugs and about the usefulness of therapeutic drug monitoring (TDM) in the blood of patients. Based on a previous study carried out in Germany, the degree of agreement of French SPC for 59 psychotropic drugs with the existing medico-scientific evidence in the area of TDM was examined using a recently developed instrument. A summary score of SPC content (SPCC) related to TDM (SPCC TDM ) has been calculated and compared with the level of recommendation of TDM of the AGNP-TDM expe…

Stimulation of immediate early gene expression by desipramine in rat brain.

The stimulation of immediate early gene expression in brain and neuronal cell culture systems has been reported after various experimental paradigms such as chemiconvulsant-provoked seizures or specific drug applications. In particular, the induction of immediate early genes by adrenergic model substances has been demonstrated by several investigators. This report demonstrates that a single dose of desipramine (10 or 25 mg/kg), a classical tricyclic antidepressant drug acting on the adrenergic system, induced c-fos and zif268 expression in rat hippocampus without affecting c-jun. The observed immediate early gene response might reflect part of a signal transduction cascade involved in long-…

Behavioral analysis indicates benzodiazepine-tolerance mediated by the benzodiazepine binding-site at the GABA(A)-receptor.

Abstract 1. GABA A -receptor induced changes in locomotion and anxiety-like behaviors were studied in rats using an open-field and an elevated plus-maze. Acute and chronic doses of the benzodiazepine diazepam without and in combination with the GABA uptake inhibitor SKF-89976A were investigated. 2. Fifty-six male rats of the strain PVG/OlaHsd (PVG; 180–200g body wt) were used to assess the influence of the benzodiazepine binding-site to the development of tolerance. Rats were divided into six groups: The first receiving saline (0.9%), the second and third diazepam (10.0 mg/kg) daily for 23 days with or without an acute challenge of 2.0 mg/kg diazepam. The fourth group received diazepam (10.…

hs-CRP Predicts Improvement in Depression in Patients With Type 1 Diabetes and Major Depression Undergoing Depression Treatment: Results From the Diabetes and Depression (DAD) Study

hs-CRP is elevated in depression (1), but evidence on decreases of hs-CRP during depression treatment or the role of hs-CRP in the prediction of response to depression treatment is still controversial (2,3). To date, no study has examined this association in patients with diabetes. As elevated hs-CRP increases the risk of diabetes complications in diabetes (4), we aimed to explore hs-CRP in patients with diabetes and major depression undergoing depression treatment based on the data of the Diabetes and Depression (DAD) study (5). Participants were randomized to 12 weeks (short-term phase) of diabetes-specific group cognitive behavioral therapy or sertraline treatment and followed up for 15 …

Non-fatal and fatal liver failure associated with valproic acid.

Little is known about hepatotoxicity associated with valproic acid (VPA), a widely used substance in neuropsychiatry.All reported cases to the German Federal Institute for Drugs and Medical Devices between 1993 and 2009 of VPA-induced serious hepatic side effects were evaluated.A total of 132 cases of serious VPA-associated liver failure were identified. Approximately one third (34.8%) occurred under VPA monotherapy, while the majority was seen with VPA plus co-medication, most frequently antiepileptics (34.8%) and benzodiazepines (16.7%). A subgroup of 34 cases (25.8%) had a fatal outcome, the largest number reported to date. Of these, 32.4% were under VPA monotherapy and 67.6% under VPA p…

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone

Introduction: This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations. Areas covered: Limited data is available on two formulations (RBP-7000 and in Situ Microparticle), but 20 TDM articles on the microsphere formulation were found. Risperidone TDM includes the serum concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, used for calculating: 1) the risperidone/9-hydroxyrisperidone (R/9-OH-R) ratio (a measure of CYP2D6; values &gt;1 are indicative of a CYP2D6 poor metabolizer) and 2) the total risperidone concentration-to-dose (C/D) ratio (a measure of risperidone clearance with a normal value…