A monitorização terapêutica permite a individualização do regime de dosagem, assegurando a eficácia clínica e minimizando os efeitos adversos dos fármacos, prescritos na clínica. Os antidepressivos têm sido monitorados, pois, apresentam intervalos terapêuticos bem estabelecidos, ou seja, a maioria dos pacientes, que apresentam concentrações plasmáticas dentro deste intervalo fixo, tem as desordens psiquiátricas mantidas sob controle e efeitos adversos aceitáveis. Os antidepressivos tricíclicos (ADTs): imipramina, amitriptilina, nortriptilina e desipramina, embora eficazes e ainda muito utilizados, apresentam efeitos adversos, não desejáveis. Os antidepressivos, inibidores seletivos da recaptação de serotonina (ISRSs): citalopram e sertralina, apresentam eficácia clínica comparável aos clássicos ADTs, mas destituídos dos efeitos adversos associados aos mesmos. Os métodos convencionais, empregados no tratamento de amostras biológicas, para análises de antidepressivos por técnicas cromatográficas, têm sido a extração líquido-líquido e extração em fase sólida. A extração sortiva em barra de agitação (SBSE), técnica recente de preparo de amostras para a préconcentração de compostos orgânicos presentes em amostras biológicas, baseiase na extração estática, através do polímero polidimetilsiloxano (PDMS), no qual ocorre a dissolução (sorção, partição) do analito. Neste trabalho, as técnicas SBSE e cromatografia líquida de alta eficiência foram avaliadas para a análise simultânea dos antidepressivos em amostras de plasma para fins de monitorização terapêutica. As condições cromatográficas de análise, assim como as variáveis SBSE de extração (tempo, temperatura, força iônica, pH da matriz) e tempo de dessorção, foram otimizadas, visando adequada sensibilidade analítica. A validação analítica foi realizada segundo normas da ANVISA, em diferentes concentrações plasmáticas, as quais contemplam o intervalo terapêutico. O método SBSE/HPLC padronizado apresentou linearidade na faixa de concentração plasmática de 20 a 1000 ng mL-1, precisão interensaio com coeficientes de variação menor que 14% e recuperação relativa de 83 a 110%. Segundo a validação analítica, a metodologia SBSE/HPLC apresentou linearidade, alta sensibilidade, seletividade e precisão analítica adequadas para a análise dos antidepressivos: imipramina, amitriptilina, nortriptilina, desipramina, citalopram e sertralina, em amostra de plasma, para fins de monitorização terapêutica. / Therapeutic drug monitoring allows individualization of drug dosage assuring its clinical efficacy and at the same time minimizing adverse effects of the drugs prescribed in clinics. The antidepressants have been monitored since they present a very well established therapeutic interval. In this sense, most of the patients whose plasmatic concentrations are ranged at that interval present psychiatric disorders under control and drug adverse effects at bearable levels. Despite tricyclic antidepressants (TCAs) such as imipramine, amitriptyline, nortriptyline and desipramine are highly efficient and widely used, they also present undesirable adverse effects. The antidepressants: citalopram and sertraline, which are selective serotonin reuptake inhibitors (SSRIs), present clinical efficacy comparable to the classic TACs, but with no adverse effects associated to the last ones. Liquid-liquid extraction (LLE) and solid phase extraction (SPE) have been usually employed in biological sample pre-treatment for chromatographic analysis. A new technique named sorptive stir bar extraction (SBSE) for sample pre-concentration of organic compounds from biological samples was recently proposed. This technique is based on static extraction through the polymer polidimetilsiloxane (PDMS), in which analyte sorption occurs. In this work, SBSE and HPLC techniques have been evaluated for out antidepressants simultaneous analysis in plasma samples for therapeutic drug monitoring. The chromatographic conditions of analysis, as well as SBSE parameters (time, temperature, ionic strength, matrix pH, desorption time) have been optimized in order to obtain best analytical sensitivity. Analytical validation was carried out according to the norms established by ANVISA, in different plasmatic concentrations, which represent the therapeutic interval. The SBSE/HPLC method developed showed linearity in a concentration plasmatic ranging from 20 to 1000 ng mL-1, inter assay precision with coefficient of the variation lower than 14%, and relative recovery from 83 a 110%. Based on analytical validation, the SBSE/HPLC methodology showed good linearity, high sensitivity, selectivity and suitable repeatability to the analyzed antidepressants: imipramine, amitriptyline, nortriptyline, desipramine, citalopram and sertraline in plasma samples for therapeutic drug monitoring.

Les transporteurs membranaires sont des éléments importants dans le devenir, l’efficacité, et la toxicité du médicament. Ils influencent la pharmacocinétique et la pharmacodynamie de ces derniers. Plusieurs interactions médicamenteuses observées cliniquement sont attribuables à la fois aux enzymes responsables du métabolisme des médicaments et aux transporteurs membranaires. Il est connu qu’une variabilité existe entre différents individus dans la réponse à un médicament et les polymorphismes génétiques retrouvés dans les gènes codant pour les transporteurs membranaires peuvent partiellement expliquer cette variabilité. OATP1A2 est un transporteur membranaire exprimé sur des organes importants, comme le cerveau et le rein. Plusieurs médicaments utilisés en clinique sont des substrats d’OATP1A2 et l’expression localisée de ce transporteur suggère un rôle important dans le devenir du médicament. Donc, mon projet de doctorat consistait à caractériser l’activité d’OATP1A2 en relation avec ses substrats et inhibiteurs, et de plus, à évaluer l’impact de différents variants génétiques d’OATP1A2 sur leur transport. Dans le premier article, la rosuvastatine a été utilisée comme substrat-type pour étudier le transport d’OATP1A2. Les expériences ont été menées en introduisant la rosuvastatine en compétition avec différent β-bloqueurs, une classe de médicaments rapportée dans la littérature comme substrats d’OATP1A2. Parmi les β-bloqueurs évalués, le carvédilol était l’inhibiteur le plus puissant. Dans la deuxième partie de l’étude, des médicaments ayant une structure similaire au carvédilol, tels que les antidépresseurs tricycliques, ont été évalués quant à leur potentiel d’inhibition sur OATP1A2. Une relation structure-activité a été définie à l’aide de ces données. Nous avons démontré que des composés tricycliques avec une courte chaîne aliphatique pouvaient inhiber OATP1A2. Dans le deuxième article, OATP1A2 a été étudié en considérant son expression et son rôle au sein de la barrière hémato-encéphalique (BHE). Des études précédentes ont démontré qu’OATP1A2 est exprimé sur la membrane luminale des cellules endothéliales formant la BHE. Nos données démontrent que les triptans, une classe de médicaments couramment utilisées pour traiter la crise migraineuse, sont des substrats d’OATP1A2 et que les composés tricycliques identifiés comme inhibiteurs d’OATP1A2 dans nos études précédentes peuvent inhiber le transport des triptans par OATP1A2. Ces résultats sont importants puisque: 1) il a été suggéré que les triptans peuvent agir au niveau du système nerveux central en se liant aux récepteurs trouvés sur les neurones centraux; 2) comme les triptans sont des molécules hydrophiles, un mécanisme de transport facilité est nécessaire pour qu’ils pénètrent la BHE et OATP1A2 pourrait être l’élément clé; 3) l’inhibition d’OATP1A2 par les composés tricycliques pourrait limiter l’accès des triptans à leur site d’action. Le troisième article caractérise l’activité associée à deux variants génétiques d’OATP1A2 (OATP1A2*2 et *3). Leur capacité à transporter les triptans et leur potentiel d’inhibition par les médicaments tricycliques ont été évalués. Des résultats supplémentaires caractérisant OATP1A2, mais sans liens directs avec les trois articles, seront présentés en annexe. Dans l’ensemble, les résultats présentés dans cette thèse servent à caractériser le transporteur membranaire OATP1A2 en relation avec ses substrats et inhibiteurs, et en fonction de ses variants génétiques. / Drug transporters are important determinants in drug disposition, efficacy, and toxicity. They influence the pharmacokinetics and pharmacodynamics of drugs. Several clinically-observed drug-drug interactions are mediated through drug metabolizing enzymes and drug transporters. It is well known that there is an interindividual variability in the response to medications and polymorphisms found in genes encoding for drug transporters partially account for it. OATP1A2 is a membrane drug transporter expressed on important organs, such as the brain and the kidney. A wide spectrum of drugs used in the clinic are substrates of OATP1A2. Its localisation suggests an essential role in drug disposition. Thus, my PhD project consisted of characterizing the activity of OATP1A2 in regards to its substrates, inhibitors, and different protein variants due to genetic polymorphisms. In the first article, rosuvastatin was used as the probe substrate to study OATP1A2 transport activity. Experiments were conducted by putting rosuvastatin in competition with different β-blockers, a class of drugs known in the literature to be transported by OATP1A2. One of the drugs evaluated, carvedilol, inhibited OATP1A2 with much more potency than the others. In the second part of the study, drugs with a structure similar to carvedilol, such as tricyclic antidepressants, were tested for their potential to inhibit OATP1A2. A structure-activity relationship was defined using the data. It was demonstrated that drugs composed of a tricyclic ring with a short aliphatic amine chain were potent OATP1A2 inhibitors. In the second article presented, OATP1A2 was studied in the context of its localization at the blood-brain barrier (BBB). OATP1A2 expression at the luminal membrane of the endothelial cells making up the BBB was demonstrated in the literature. Our article showed that triptans, a class of commonly used anti-migraine drugs, were OATP1A2 substrates. The tricyclic drugs previously evaluated were shown to potently inhibit triptan transport through OATP1A2. These findings are important for three reasons: 1) it has been postulated that triptans may act at the central nervous system by binding to receptors found on central neurons; 2) as triptans are hydrophilic molecules, a facilitated transport mechanism is required for them to penetrate the BBB and OATP1A2 may be the key player; and 3) the inhibition of OATP1A2 by the tricyclic drugs may limit the entrance of triptans to their site of action. The third article characterized the transport activity of two OATP1A2 protein variants (OATP1A2*2 and *3). Their capacities to transport triptans and their potential of being inhibited by tricyclic drugs were evaluated. Additional data characterizing OATP1A2 but considered out of the scope of the three articles will be presented in appendices. In overall, the central theme of this thesis looks into the characterization of the OATP1A2 membrane drug transporter in regards to its substrates, inhibitors, and proteins variants.

Background: Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain. Methods: Systematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis. results: Out of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects. conclusion: Our synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.

No description available.

Background: Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain. Methods: Systematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis. results: Out of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects. conclusion: Our synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.

Irritable bowel syndrome (IBS) is a functional disorder that affects the gastrointestinal tract and especially the large intestine. The pathogenesis of the disease is not fully understood, for that reason there is still no cure and current therapy focuses on symptom relief. The disease manifests itself in the form of abdominal pain, bloating, constipation or diarrhoea. New studies have shown a link between IBS and communication between the central nervous system and the gut. Serotonin and norepinephrine seem to be important for the course of the disease. The purpose of this literature review was to study the efficacy and safety of certain antidepressant preparations belonging to tricyclic antidepressants and selective serotonin reuptake inhibitors in the treatment of IBS. This work focused on the effect of preparations and how tolerable they are with respect to their side effects. Articles presented in this work were found in the PubMed database with the keywords "irritable bowel syndrome", "serotonin reuptake inhibitor", " tricyclic antidepressants ". Amitriptyline 10 mg and imipramine 25 mg provided a statistically significant symptom relief in IBS with diarrhoea (IBS-D) compared to placebo. In addition, tianeptine 12.5 mg 3 times / day, which belongs to the selective serotonin reuptake enhancer (SSRE) group, gave a corresponding symptom relief as amitriptyline 10 mg once / day. The difference between the two was not statistically significant, but the study was open label and non-placebo-controlled, which made it difficult to draw any conclusions. Fluoxetine, which belongs to the selective serotonin reuptake inhibitor (SSRI) group, produced a statistically significant effect compared to placebo in the treatment of constipation IBS (IBS-C). In contrast, paroxetine-CR did not have any statistically significant effect on abdominal pain in IBS-C compared with placebo. However, more patients in the paroxetine group achieved the secondary outcome (clinical global improvement) with scores of 1-2 on the scale Clinical Global Impressions-Improvement (CGI-I). Based on the studies presented in this literature study, it is concluded that a low dose of TCA is an effective and safe treatment for IBS-D while SSRIs are effective and safe in the treatment of IBS-C compared to placebo. / Irritable bowel syndrome (IBS), är funktionella störningar som drabbar gastrointestinalkanalen och framför allt kolon. Patogenesen till sjukdomen är inte helt klarlagd, av den anledningen saknas fortfarande någon botande behandling och dagens terapi fokuserar på symtomlindring. Sjukdomen yttrar sig i form av buksmärta, uppblåsthet, förstoppning eller diarré. Senaste studier har visat en koppling mellan IBS och kommunikation mellan centrala nervsystemet och tarmen. Serotonin och noradrenalin verkar ha betydelse för sjukdomsförlopp. Syftet med detta litteraturarbete var att studera effektivitet och säkerhet för några antidepressiva preparat som tillhör tricykliska antidepressiva och selektiva serotonin återupptagshämmare vid behandling av IBS. Detta arbete fokuserade på effekten av preparaten och hur tolererbara de är med avseende på deras biverkningar. Artiklar som presenteras i detta arbete söktes i databasen Pubmed med sökord ”irritable bowel syndrome”, ”serotonin reuptake inhibitors”, ” tricyclic antidepressants”. Amitriptylin 10mg och imipramin 25mg gav en statistiskt signifikant symtomlindring vid IBS med diarré (IBS-D) jämfört med placebo. Dessutom gav tianeptin 12,5mg 3 gånger/dag, som tillhör läkemedelsgruppen selektiv serotonin återupptagsenhancer (SSRE), en likvärdig symtomlindring som amitriptylin 10mg en gång/dag. Skillnaden mellan de två var inte statistiskt signifikant, däremot var studien openlabel och icke-placebokontrollerad vilket gör det svårt att dra någon slutsats. Fluoxetin, som tillhör läkemedelsgruppen selektiva serotonin återupptagshämmare SSRI, gav en statistiskt signifikant effekt jämfört med placebo vid behandling av IBS med förstoppning (IBS-C). Däremot gav paroxetin-CR ingen statistiskt signifikant effekt på buksmärta vid IBS-C jämfört med placebo, dock uppnådde fler i paroxetingruppen den sekundära utfallsvariabeln (global klinisk förbättring) och fick poäng mellan 1 – 2 på skalan Clinical Global Impressions-Improvement (CGI-I).  Baserat på studierna som presenteras i denna litteraturstudie dras slutsatsen att en låg dos TCA är en effektiv och säker behandling vid IBS-D medan SSRI är effektiva och säkra vid behandling av IBS-C jämfört med placebo.

No description available.

These British Association for Psychopharmacology guidelines cover the range and aims of treatment for anxiety disorders. They are based explicitly on the available evidence and are presented as recommendations to aid clinical decision making in primary and secondary medical care. They may also serve as a source of information for patients and their carers. The recommendations are presented together with a more detailed review of the available evidence. A consensus meeting involving experts in anxiety disorders reviewed the main subject areas and considered the strength of evidence and its clinical implications. The guidelines were constructed after extensive feedback from participants and interested parties. The strength of supporting evidence for recommendations was rated. The guidelines cover the diagnosis of anxiety disorders and key steps in clinical management, including acute treatment, relapse prevention and approaches for patients who do not respond to first-line treatments.

Text in English / Pharmacological treatment is often required in the management of psychiatric disorders. Non-adherence to medication represents a significant health concern that prevents patients from fully benefitting from their treatment, and can lead to negative consequences for individuals, their families and the healthcare system. The adherence rates to antidepressant medications in a sample of psychiatric outpatients in the Johannesburg Metropolitan district of Gauteng Province were examined. A descriptive survey method was employed to systematically collect data from n=377 patients using a structured, non-clinical questionnaire and the 8-item Morisky Medication Adherence Questionnaire. Variables were analysed using descriptive and correlational statistical methods. Antidepressant adherence rates were reported as 47.7% (low), 31.3% (medium) and 21% (high). These high rates represent a concern in antidepressant treatment, and health care practitioners and health systems must take this into consideration when planning and developing interventions to improve adherence in this area. The current study found significant correlations between antidepressant adherence rates and some medication-, health system- and moderating variables. Based on these findings, interventions that provide appropriate health-related education about treatment and improved social support systems may be effective in addressing antidepressant non-adherence in psychiatric outpatients in this region. / Psychology / M. Soc.Sc. (Psychology)

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.