Antidepressant medications reduce subcortical-cortical resting-state functional connectivity in healthy volunteers

Studies have revealed abnormalities in resting-state functional connectivity in those with major depressive disorder specifically in areas such as the dorsal anterior cingulate, thalamus, amygdala, the pallidostriatum and subgenual cingulate. However, the effect of antidepressant medications on human brain function is less clear and the effect of these drugs on resting-state functional connectivity is unknown. Forty volunteers matched for age and gender with no previous psychiatric history received either citalopram (SSRI; selective serotonergic reuptake inhibitor), reboxetine (SNRI; selective noradrenergic reuptake inhibitor) or placebo for 7 days in a double-blind design. Using resting-state functional magnetic resonance imaging and seed based connectivity analysis we selected the right nucleus accumbens, the right amygdala, the subgenual cingulate and the dorsal medial prefrontal cortex as seed regions. Mood and subjective experience were also measured before and after drug administration using self-report scales. Despite no differences in mood across the three groups, we found reduced connectivity between the amygdala and the ventral medial prefrontal cortex in the citalopram group and the amygdala and the orbitofrontal cortex for the reboxetine group. We also found reduced striatal-orbitofrontal cortex connectivity in the reboxetine group. These data suggest that antidepressant medications can decrease resting-state functional connectivity independent of mood change and in areas known to mediate reward and emotional processing in the brain. We conclude that hypothesis-driven seed based analysis of resting-state fMRI supports the proposition that antidepressant medications might work by normalising the elevated resting-state functional connectivity seen in depressed patients.

Enhanced neural response to anticipation, effort and consummation of reward and aversion during Bupropion treatment

Background We have previously shown that the selective serotonergic re-uptake inhibitor, citalopram, reduces the neural response to reward and aversion in healthy volunteers. We suggest that this inhibitory effect might underlie the emotional blunting reported by patients on these medications. Bupropion is a dopaminergic and noradrenergic re-uptake inhibitor and has been suggested to have more therapeutic effects on reward-related deficits. However, how bupropion affects the neural responses to reward and aversion is unclear. Methods 17 healthy volunteers (9 female, 8 male) received 7 days of bupropion (150 mg/day) and 7 days of placebo treatment, in a double-blind crossover design. Our functional Magnetic Resonance Imaging task consisted of 3 phases; an anticipatory phase (pleasant or unpleasant cue), an effort phase (button presses to achieve a pleasant taste or to avoid an unpleasant taste) and a consummatory phase (pleasant or unpleasant tastes). Volunteers also rated wanting, pleasantness and intensity of the tastes. Results Relative to placebo, bupropion increased activity during the anticipation phase in the ventral medial prefrontal cortex (vmPFC) and caudate. During the effort phase, bupropion increased activity in the vmPFC, striatum, dorsal anterior cingulate cortex and primary motor cortex. Bupropion also increased medial orbitofrontal cortex, amygdala and ventral striatum activity during the consummatory phase. Conclusions Our results are the first to show that bupropion can increase neural responses during the anticipation, effort and consummation of rewarding and aversive stimuli. This supports the notion that bupropion might be beneficial for depressed patients with reward-related deficits and blunted affect.

Fast separation of selective serotonin reuptake inhibitors antidepressants in plasma sample by nonaqueous capillary electrophoresis

A simple, fast, and sensitive liquid-liquid extraction method followed by nonaqueous capillary electrophoresis (LLE/NACE) was developed and validated for Simultaneous determination of four antidepressants (fluoxetine, sertraline, citalopram and paroxetine) in human plasma. Several experimental separation conditions using aqueous and nonaqueous media separation were tested by varying the electrolyte pH value (for aqueous medium) and the ionic strength concentration considering the similar mobility of the compounds. High-resolution separation was achieved with a mixture of 1.25 mol L(-1) of phosphoric acid in acetonitrile. The quantification limits of the LLE/CE method varied between 15 and 30 ng mL(-1), with a relative standard deviation (RSD) lower than 10.3%. The method was successfully applied in therapeutic drug monitoring and should be employed in the evaluation of plasma levels in urgent toxicological analysis. (C) 2009 Elsevier B.V. All rights reserved.

Polydimethylsiloxane/polypyrrole stir bar sorptive extraction and liquid chromatography (SBSE/LC-UV) analysis of antidepressants in plasma samples

A new polymeric coating consisting of a dual-phase, polydimethylsiloxane (PDMS) and polypyrrole (PPY) was developed for the stir bar sorptive extraction (SBSE) of antidepressants (mirtazapine, citalopram, paroxetine, duloxetine, fluoxetine and sertraline) from plasma samples, followed by liquid chromatography analysis (SBSE/LC-UV). The extractions were based on both adsorption (PPY) and sorption (PDMS) mechanisms. SBSE variables, such as extraction time, temperature, pH of the matrix, and desorption time were optimized, in order to achieve suitable analytical sensitivity in a short time period. The PDMS/PPY coated stir bar showed high extraction efficiency (sensitivity and selectivity) toward the target analytes. The quantification limits (LOQ) of the SBSE/LC-UV method ranged from 20 ng mL(-1) to 50 ng mL(-1), and the linear range was from LOQ to 500 ng mL(-1), with a determination coefficient higher than 0.99. The inter-day precision of the SBSE/LC-UV method presented a variation coefficient lower than 15%. The efficiency of the SBSE/LC-UV method was proved by analysis of plasma samples from elderly depressed patients. (C) 2008 Elsevier B.V. All rights reserved.

Applicatiion of Almost ideal demand system for a pharmaceutical

This thesis is an application of the Almost Ideal Demand System approach of Deaton and Muellbauer,1980, for a particular pharmaceutical, Citalopram, in which GORMAN´s (1971) multi-stage budgeting approach is applied basically since it is one of the most useful approach in estimating demand for differentiated products. Citalopram is an antidepressant drug that is used in the treatment of major depression. As for most other pharmaceuticals whose the patent has expired, there exist branded and generic versions of Citalopram. This paper is aimed to define its demand system with two stage models for the branded version and five generic versions, and to show whether generic versions are able to compete with the branded version. I calculated the own price elasticities, and it made me possible to compare and make a conclusion about the consumers’ choices over the brand and generic drugs. Even though the models need for being developed with some additional variables, estimation results of models and uncompensated price elasticities indicated that the branded version has still power in the market, and generics are able to compete with lower prices. One important point that has to be taken into consideration is that the Swedish pharmaceutical market faced a reform on October 1, 2002, that aims to make consumer better informed about the price and decrease the overall expenditures for pharmaceuticals. Since there were not significantly enough generic sales to take into calculation before the reform, my paper covers sales after the reform.

Brachioradial pruritus - Descriptive analysis of Brazilian case series

Background The epidemiology and clinical features of brachioradial pruritus are variably described in the literature. We sought to analyze these features in a large group of Brazilian patients. Patients and Methods In a descriptive, observational study, we identified all patients with a final diagnosis of brachioradial pruritus seen over a one-year period and re-trospectively reviewed their records. The diagnosis was made after clinical-laboratory investigation had ruled out other causes of chronic pruritus. Demographic and clinical variables were collected along with pruritus characteristics, and analyzed using des-criptive statistics. Results Forty-three patients were identified; their mean age was 55.9 years, with predominance of women (81.4%) and Caucasians (86%). In 52%, the pruritus worsened with heat and sun exposure; 58.1% had intermittent complaints; the ice-pack sign was present only in 20.9%. The arms involving dermatomes C5-C6-C7-C8 (62.8%) were the most affected sites, while psychoactive drugs were the most frequently prescribed therapy. Conclusions Although uncommon, brachioradial pruritus should not be neglected in dermatological diagnosis. This case series analysis indicated that Brazilian patients from a tropical climate show characteristics similar to those described in other series from more temperate regions. © Blackwell Verlag GmbH, Berlin.

Aspectos fisiológicos de Chrysomya megacephala (F.) (Diptera: Calliphoridae): metabolismo energético, termorregulação e neurofisiologia

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Anxiolytic-Like Property of Risperidone and Olanzapine as Examined in Multiple Measures of Fear in Rats

Atypical antipsychotics are also used in the treatment of anxiety-related disorders. Clinical and preclinical evidence regarding their intrinsic anxiolytic efficacy has been mixed. In this study, we examined the potential anxiolytic-like effects of risperidone and olanzapine, and compared them with haloperidol, chlordiazepoxide (a prototype of sedative–anxiolytic drug) or citalopram (a selective serotonin reuptake inhibitor). We used a composite of two-way avoidance conditioning and acoustic startle reflex model and examined the effects of drug treatments during the acquisition phase (Experiment 1) or extinction phase (Experiments 2 and 3) on multiple measures of conditioned and unconditioned fear/anxiety-like responses. In Experiment 4, we further compared risperidone, olanzapine, haloperidol, citalopram and chlordiazepoxide in a standard elevated plus maze test. Results revealed three distinct anxiolytic-like profiles associated with risperidone, olanzapine and chlordiazepoxide. Risperidone, especially at 1.0 mg/kg, significantly decreased the number of avoidance responses, 22 kHz ultrasonic vocalization, avoidance conditioning-induced hyperthermia and startle reactivity, but did not affect defecations or time spent on the open arms. Olanzapine (2.0 mg/kg, sc) significantly decreased the number of avoidance responses, 22 kHz vocalization and amount of defecations, but it did not inhibit startle reactivity and time spent on the open arms. Chlordiazepoxide (10 mg/kg, ip) significantly decreased the number of 22 kHz vocalization, avoidance conditioning-induced hyperthermia and amount of defecations, and increased time spent on the open arms, but did not decrease avoidance responses or startle reactivity. Haloperidol and citalopram did not display any anxiolytic-like property in these tests. The results highlight the importance of using multiple measures of fear-related responses to delineate behavioral profiles of psychotherapeutic drugs.

LIQUID-PHASE MICROEXTRACTION FOR SIMULTANEOUS CHROMATOGRAPHIC ANALYSIS OF THREE ANTIDEPRESSANT DRUGS IN PLASMA

A method using Liquid Phase Microextraction for simultaneous detection of citalopram (CIT), paroxetine (PAR) and fluoxetine (FLU), using venlafaxine as internal standard, in plasma by high performance liquid chromatography with fluorescence detection was developed. The linearity was evaluated between 5.0 and 500 ng mL(-1) (r > 0.99) and the limit of quantification was 2.0, 3.0 and 5.0 ng mL-1 for CIT. PAR and FLU, respectively. Therefore, it can be applied to therapeutic drug monitoring, pharmacokinetics or bioavailability studies and its advantages are that it necessary relatively inexpensive equipment and sample preparation techniques.

Evaluation of Solid-Phase Microextraction using a Polythiophene Film and Liquid Chromatography with Spectrophotometric Detection for the Determination of Antidepressants in Plasma Samples

Polythiophene (PTh) phase electropolymerized on the stainless steel wire was evaluated as solid-phase microextraction (SPME), and analysis by liquid chromatography with spectrophotometric detection (LC-UV) for determination of new-generation antidepressants, selective serotonin reuptake inhibitors (SSRIs) (citalopram, paroxetine, fluoxetine and sertraline), in plasma samples. The influence of electropolymerization variables (scan rate, potential range and scan cycles) was evaluated on SPME performance. The SPME variables (extraction time, temperature, matrix pH, ionic strength and desorption procedure), as well as the influence of plasma proteins on sorption mechanisms were also evaluated. The SPME/LC-UV method developed for determination of antidepressants in plasma sample presented a linear range between the limit of quantification (LOQ, 200-250 ng mL(-1)) to 4000 ng mL(-1), and interday precision with coefficient of variation (CV) ranged from 11 to 15%. The proposed method can be a useful tool for the determination of antidepressants in human plasma samples in urgent toxicological analysis after the accidental or suicidal intake of higher doses of medications.

Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder

OBJECTIVES: Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers. METHODS: Patients with obsessive-compulsive disorder were classified as either responders or non-responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1D beta gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene. RESULTS: The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non-responders) than in the controls (p<0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p<0.01). The CC genotype of the serotonin receptor subtype 1D beta G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p<0.01 and p<0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p<0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders.

Liquid-phase microextraction for simultaneous chromatographic analysis of three antidepressant drugs in plasma

A method using Liquid Phase Microextraction for simultaneous detection of citalopram (CIT), paroxetine (PAR) and fluoxetine (FLU), using venlafaxine as internal standard, in plasma by high performance liquid chromatography with fluorescence detection was developed. The linearity was evaluated between 5.0 and 500 ng mL-1 (r > 0.99) and the limit of quantification was 2.0, 3.0 and 5.0 ng mL-1 for CIT, PAR and FLU, respectively. Therefore, it can be applied to therapeutic drug monitoring, pharmacokinetics or bioavailability studies and its advantages are that it necessary relatively inexpensive equipment and sample preparation techniques.

Evaluation of solid-phase microextraction using a polythiophene film and liquid chromatography with spectrophotometric detection for the determination of antidepressants in plasma samples

Polythiophene (PTh) phase electropolymerized on the stainless steel wire was evaluated as solid-phase microextraction (SPME), and analysis by liquid chromatography with spectrophotometric detection (LC-UV) for determination of new-generation antidepressants, selective serotonin reuptake inhibitors (SSRIs) (citalopram, paroxetine, fluoxetine and sertraline), in plasma samples. The influence of electropolymerization variables (scan rate, potential range and scan cycles) was evaluated on SPME performance. The SPME variables (extraction time, temperature, matrix pH, ionic strength and desorption procedure), as well as the influence of plasma proteins on sorption mechanisms were also evaluated. The SPME/LC-UV method developed for determination of antidepressants in plasma sample presented a linear range between the limit of quantification (LOQ, 200-250 ng mL-1) to 4000 ng mL-1, and interday precision with coefficient of variation (CV) ranged from 11 to 15%. The proposed method can be a useful tool for the determination of antidepressants in human plasma samples in urgent toxicological analysis after the accidental or suicidal intake of higher doses of medications.

Sensitivity enhancement in NMR by using parahydrogen induced polarization

Enhancing the sensitivity of nuclear magnetic resonance measurements via hyperpolarization techniques like parahydrogen induced polarization (PHIP) is of high interest for spectroscopic investigations. Parahydrogen induced polarization is a chemical method, which makes use of the correlation between nuclear spins in parahydrogen to create hyperpolarized molecules. The key feature of this technique is the pairwise and simultaneous transfer of the two hydrogen atoms of parahydrogen to a double or triple bond resulting in a population of the Zeeman energy levels different from the Boltzmann equation. The obtained hyperpolarization results in antiphase peaks in the NMR spectrum with high intensities. Due to these strong NMR signals, this method finds arnlot of applications in chemistry e.g. the characterization of short-lived reaction intermediates. Also in medicine it opens up the possibility to boost the sensitivity of medical diagnostics via magnetic labeling of active contrast agents. Thus, further examination and optimization of the PHIP technique is of significant importance in order to achieve the highest possible sensitivity gain.rnrnIn this work, different aspects concerning PHIP were studied with respect to its chemical and spectroscopic background. The first part of this work mainly focused on optimizing the PHIP technique by investigating different catalyst systems and developing new setups for the parahydrogenation. Further examinations facilitated the transfer of the generated polarization from the protons to heteronuclei like 13C. The second part of this thesis examined the possibility to transfer these results to different biologically active compounds to enable their later application in medical diagnostics. Onerngroup of interesting substances is represented by metabolites or neurotransmitters in mammalian cells. Other interesting substances are clinically relevant drugs like a barbituric acid derivative or antidepressant drugs like citalopram which were investigated with regard to their applicability for the PHIP technique and the possibility to achievernpolarization transfer to 13C nuclei. The last investigated substrate is a polymerizable monomer whose polymer was used as a blood plasma expander for trauma victims after the first half of the 20th century. In this case, the utility of the monomer for the PHIP technique as a basis for later investigations of a polymerization reaction using hyperpolarized monomers was examined.rnrnHence, this thesis covers the optimization of the PHIP technology, hereby combining different fields of research like chemical and spectroscopical aspects, and transfers the results to applications of real biologally acitve compounds.

Metabolismus von Psychopharmaka durch das Cytochrom P450-Enzymsystem im Alter

Altern geht mit einer Reihe physiologischer Veränderungen einher. Da in höherem Lebensalter überdurchschnittlich viele Arzneistoffe eingenommen werden und häufig mehrere Erkrankungen gleichzeitig vorliegen, können Auffälligkeiten in den Arzneimittelkonzentrationen im Blut nicht nur altersbedingt, sondern auch krankheitsbedingt oder durch Arzneimittelwechselwirkungen verursacht sein.rnrnDie vorliegende Arbeit untersucht die Fragestellung, ob der Arzneimittelmetabolismus bei Alterspatenten generell, oder nur bei Patienten mit Multimorbidität und –medikation verändert ist, und in welchem Lebensalter diese Veränderungen einsetzen. Im Mittelpunkt stand dabei die Frage, ob die Aktivitäten distinkter Arzneimittel-abbauender Enzyme der Cytochrom P450-Enzym-Familie (CYP) verändert sind. Da viele Psychopharmaka nur bei Patienten im Alter zwischen 18 und 65 Jahren zugelassen sind, wurde die Hypothese geprüft, dass sich Patienten im Alter über und unter 65 Jahren in ihren Medikamentenspiegeln unterscheiden.rnrnFür die Untersuchungen wurde eine Datenbank aus Blutspiegelmessungen erstellt, die im Rahmen des pharmakotherapiebegleitenden TDM erhoben worden waren. Die Blutspiegel stammten von insgesamt 4197 Patienten, die mit Amisulprid, Aripiprazol, Citalopram, Clozapin, Donepezil, Escitalopram, Mirtazapin, Quetiapin, Risperidon, Sertralin, Venlafaxin oder Ziprasidon behandelt wurden. Die Messungen wurden ergänzt mit Angaben aus den TDM-Anforderungsscheinen bezüglich Tagesdosis, Begleitmedikamenten, Schweregrad der Erkrankung, Therapieerfolg und Verträglichkeit der Medikation. Zusätzlich wurden klinische Befunde der Leber- und Nierenfunktion einbezogen, sowie Angaben zur Berechnung des BMI. Die in vivo-CYP-Enzymaktivitäten wurden anhand von metabolischen Ratios (Serumkonzentrationen Metabolit/ Serumkonzentration Muttersubstanz) beurteilt.rnrnIm Mittel stieg der Schweregrad der Erkrankung mit dem Alter und der Therapieerfolg verschlechterte sich. Dies betraf im Einzelnen nur Patienten, die mit Amisulprid oder Clozapin behandelt worden waren. Ältere Patienten litten häufiger an Nebenwirkungen als jüngere.rnUnter Aripiprazol, Quetiapin, Sertralin und Venlafaxin erreichten Alterspatienten mit niedrigeren Tagesdosen gleiche Therapieerfolge wie jüngere Patienten.rnPatienten, die mit Clozapin oder Amisulprid behandelt wurden, zeigten im Alter schlechtere Behandlungserfolge bei gleicher (Clozapin) bzw. niedrigerer (Amisulprid) Tagesdosis.rnTherapieerfolg und mittlere Tagesdosis änderten sich bei Patienten, die Ziprasidon, Donepezil, Citalopram, Escitalopram und Mirtazapin einnahmen, nicht altersabhängig.rnrnAltersabhängige Unterschiede der Serumspiegel zeigten sich für Amisulprid, Aripiprazol, Donepezil, Mirtazapin, Desmethylmirtazapin, Quetiapin und DesmethylsertralinrnAllerdings lagen die Altersgrenzen außer bei Donepezil deutlich niedriger als die gängig angenommene, nämlich bei 35 Jahren (Aripiprazol), 70 Jahren (Donepezil), 55 Jahren (D-Sertralin), 41 Jahren (Amisulprid), 49 Jahren (Quetiapin) und 58 Jahren (Mirtazapin).rnEs bestand kein Zusammenhang zwischen dem Auftreten veränderter Serumspiegel im Alter und dem Verteilungsvolumen, der Plasmaproteinbindung oder der Eliminationshalbwertszeit der untersuchten Wirkstoffe.rnrnBei Patienten ohne Comedikation fand sich in keinem Fall eine altersabhängige Veränderung der Ratio. Es ergab sich daher kein Hinweis auf eine Veränderung der CYP-Aktivität im Alter. Die Einnahme von Comedikation nahm mit dem Alter zu, hierfür ließ sich eine Altersgrenze von 49 Jahren definieren. Unter Polytherapie wurden Veränderungen der CYP-Aktivität beobachtet.rnrnDer Einfluss veränderter Leber- oder Nierenfunktion auf die Biotransformation von Pharmaka wurde anhand von Serumspiegeln von Patienten, die mit Donepezil, Venlafaxin, Citalopram oder Escitalopram behandelt wurden, untersucht. rnBei keinem Wirkstoff wurden unter auffälligen Leber- oder Nierenparametern signifikant veränderte Serumspiegel gemessen.rnEine Abhängigkeit der Serumspiegel vom Körpergewicht wurde nur für Desmethylsertralin gefunden. Die Spiegel waren bei Patienten mit einem Body Mass Index unter 20 signifikant höher als bei Patienten mit einem Index über 20. Aufgrund der kleinen Fallgruppe und der Tatsache, dass der Serumspiegel der Muttersubstanz nicht stieg, konnte nicht zwingend von einem Alterseinfluss aufgrund der veränderten Körperzusammensetzung ausgegangen werden.rnInsgesamt ergaben sich aus den Untersuchungen Hinweise auf moderate altersabhängige Veränderungen der Pharmakokinetik. Es ließen sich allerdings keine allgemeinen Dosierempfehlungen für Alterspatienten ableiten. Es zeigte sich jedoch, dass mit altersabhängigen Veränderungen der Pharmakokinetik bereits nach dem 50. Lebensjahr zu rechnen ist. Weitere Untersuchungen sollten auch den Alterseffekt auf gastrointestinale Transporter einbeziehen, die die aktive Aufnahme von Arzneistoffen ins Blut bewerkstelligen. Unklar ist auch die Rolle des Alterns auf die Aktivität des P-Glykoproteins. rn