Zugl.: Regensburg, Univ., Diss., 2009

O citalopram (CITA), inibidor seletivo da recaptação da serotonina, é disponível na clínica como mistura racêmica dos enantiômeros (+)-(S) e (-)-(R) ou como enantiômero puro (+)-(S)-CITA. O CITA é metabolizado pelo CYP2C19, CYP2D6 e CYP3A ao desmetilcitalopram (DCITA) e pelo CYP2D6 ao didesmetilcitalopram. O estudo investiga a influência de inibidores enzimáticos no metabolismo enantiosseletivo do CITA em ratos e em voluntários sadios. Os ratos machos Wistar (n=6 para cada grupo) foram tratados com dose única de 20 mg/Kg de CITA (grupo controle) ou pré-tratados com 80 mg/Kg de quinidina (grupo quinidina), 10 mg/Kg de fluvoxamina (grupo fluvoxamina) ou 50 mg/Kg de cetoconazol (grupo cetoconazol). As amostras de sangue foram colhidas dos ratos até 20 h após a administração do CITA. Os voluntários sadios fenotipados como metabolizadores extensivos (EM) do CYP2C19 (omeprazol como fármaco marcador), EM do CYP2D6 (debrisoquina como fármaco marcador) e com atividade normal do CYP3A (midazolam como fármaco marcador) receberam dose única p.o. de 20 mg de CITA racêmico associado ou não ao omeprazol (20 mg/dia durante 18 dias). Os enantiômeros do CITA e do DCITA foram analisados no sistema LC-MS/MS, com a coluna quiral Chiralcel OD-R e fase móvel constituída por acetonitrila:metanol:água (30:30:40 v/v/v) contendo 0,05 % de dietilamina. O método foi linear no intervalo de concentrações de 0,1 20 ng de cada enantiômero do CITA e DCITA/mL de plasma humano e de de 0,1 500 ng de cada enantiômero do CITA e DCITA/mL de plasma de rato. Os coeficientes de variação obtidos nos estudos da precisão e a inexatidão foram inferiores a 15 % para plasma humano e plasma de ratos. A disposição cinética do CITA é enantiosseletiva nos ratos dos grupos controle (razão de AUCS/R de 0,4), quinidina (razão de AUCS/R de 0,5) e cetoconazol (razão de AUCS/R de 0,8). A inibição do CYP2D pela quinidina resultou em inibição do metabolismo do CITA e do DCITA de maneira não enantiosseletiva. A inibição do CYP2C pela fluvoxamina e do CYP3A pelo cetoconazol resultou em inibição somente do metabolismo do (+)-(S)-CITA. A disposição cinética do CITA em voluntários sadios é enantiosseletiva na ausência de tratamento com o omeprazol com observação de maior proporção plasmática do enantiômero (-)-(R)-CITA. A razão de AUCS/R obtida para o CITA foi de 0,56 e para o metabólito DCITA foi de 1,06. A administração de CITA racêmico a voluntários sadios em tratamento com o omeprazol exibe perda da enantiosseletividade na farmacocinética do CITA. A razão de AUCS/R foi de 0,96 para o CITA e de 0,92 para o DCITA. A administração de omeprazol em doses múltiplas a voluntários sadios inibe de maneira enantiosseletiva o metabolismo do eutômero (+)-(S)-CITA com aumento das concentrações plasmáticas em aproximadamente 140%. / Citalopram (CITA), a selective serotonin reuptake inhibitor, is available for clinical use as a racemic mixture of the (+)-(S) and (-)-(R) enantiomers or as the pure (+)-(S)-CITA enantiomer. CITA is metabolized by CYP2C19, CYP2D6 and CYP3A to demethylcitalopram (DCITA) and by CYP2D6 to didemethylcitalopram. The present study investigated the influence of enzyme inhibitors on the enantioselective metabolism of CITA in rats and healthy volunteers. Male Wistar rats (n=6 for each group) received a single dose of 20 mg/kg CITA (control group) or were pretreated with 80 mg/kg quinidine (quinidine group), 10 mg/kg fluvoxamine (fluvoxamine group), or 50 mg/kg ketoconazole (ketoconazole group). Blood samples were collected from the animals up to 20 h after the administration of CITA. Healthy volunteers phenotyped as extensive metabolizers of CYP2C19 (omeprazole as marker drug) and of CYP2D6 (debrisoquine as marker drug) and those with normal CYP3A activity (midazolam as marker drug) received a single oral dose of 20 mg racemic CITA combined or not with omeprazole (20 mg/day for 18 days). The CITA and DCITA enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R chiral column and a mobile phase of acetonitrile:methanol:water (30:30:40, v/v/v) containing 0.05% diethylamine. The method was linear in the concentration range of 0.1-20 ng of each CITA and DCITA enantiomer/mL human plasma and of 0.1-500 ng of each CITA and DCITA enantiomer/mL rat plasma. Accuracy and precision were below the acceptance limits of 15% for human and rat plasma. The kinetic disposition of CITA was enantioselective in rats of the control (AUCS/R ratio = 0.4), quinidine (AUCS/R ratio = 0.5) and ketoconazole (AUCS/R ratio = 0.8) groups. The inhibition of CYP2D by quinidine resulted in the non-enantioselective inhibition of the metabolism of CITA and DCITA. The inhibition of CYP2C by fluvoxamine and of CYP3A by ketoconazole only inhibited the metabolism of (+)-(S)-CITA. The kinetic disposition of CITA in healthy volunteers was enantioselective in the absence of treatment with omeprazole, with the observation of a higher plasma proportion of the (-)-(R)-CITA enantiomer. The AUCS/R ratio was 0.56 for CITA and 1.06 for the DCITA metabolite. The administration of racemic CITA to healthy volunteers treated with omeprazole showed a loss of enantioselectivity in the pharmacokinetics of CITA. The AUCS/R ratio was 0.96 for CITA and 0.92 for DCITA. The administration of multiple doses of omeprazole to healthy volunteers enantioselectively inhibited the metabolism of the (+)-(S)-CITA eutomer, with an approximately 140% increase of plasma concentrations

O citalopram (CITA), inibidor seletivo da recaptação da serotonina, é disponível na clínica como mistura racêmica dos enantiômeros (+)-(S) e (-)-(R) ou como enantiômero puro (+)-(S)-CITA. O CITA é metabolizado pelo CYP2C19, CYP2D6 e CYP3A ao desmetilcitalopram (DCITA) e pelo CYP2D6 ao didesmetilcitalopram. O estudo investiga a influência de inibidores enzimáticos no metabolismo enantiosseletivo do CITA em ratos e em voluntários sadios. Os ratos machos Wistar (n=6 para cada grupo) foram tratados com dose única de 20 mg/Kg de CITA (grupo controle) ou pré-tratados com 80 mg/Kg de quinidina (grupo quinidina), 10 mg/Kg de fluvoxamina (grupo fluvoxamina) ou 50 mg/Kg de cetoconazol (grupo cetoconazol). As amostras de sangue foram colhidas dos ratos até 20 h após a administração do CITA. Os voluntários sadios fenotipados como metabolizadores extensivos (EM) do CYP2C19 (omeprazol como fármaco marcador), EM do CYP2D6 (debrisoquina como fármaco marcador) e com atividade normal do CYP3A (midazolam como fármaco marcador) receberam dose única p.o. de 20 mg de CITA racêmico associado ou não ao omeprazol (20 mg/dia durante 18 dias). Os enantiômeros do CITA e do DCITA foram analisados no sistema LC-MS/MS, com a coluna quiral Chiralcel OD-R e fase móvel constituída por acetonitrila:metanol:água (30:30:40 v/v/v) contendo 0,05 % de dietilamina. O método foi linear no intervalo de concentrações de 0,1 20 ng de cada enantiômero do CITA e DCITA/mL de plasma humano e de de 0,1 500 ng de cada enantiômero do CITA e DCITA/mL de plasma de rato. Os coeficientes de variação obtidos nos estudos da precisão e a inexatidão foram inferiores a 15 % para plasma humano e plasma de ratos. A disposição cinética do CITA é enantiosseletiva nos ratos dos grupos controle (razão de AUCS/R de 0,4), quinidina (razão de AUCS/R de 0,5) e cetoconazol (razão de AUCS/R de 0,8). A inibição do CYP2D pela quinidina resultou em inibição do metabolismo do CITA e do DCITA de maneira não enantiosseletiva. A inibição do CYP2C pela fluvoxamina e do CYP3A pelo cetoconazol resultou em inibição somente do metabolismo do (+)-(S)-CITA. A disposição cinética do CITA em voluntários sadios é enantiosseletiva na ausência de tratamento com o omeprazol com observação de maior proporção plasmática do enantiômero (-)-(R)-CITA. A razão de AUCS/R obtida para o CITA foi de 0,56 e para o metabólito DCITA foi de 1,06. A administração de CITA racêmico a voluntários sadios em tratamento com o omeprazol exibe perda da enantiosseletividade na farmacocinética do CITA. A razão de AUCS/R foi de 0,96 para o CITA e de 0,92 para o DCITA. A administração de omeprazol em doses múltiplas a voluntários sadios inibe de maneira enantiosseletiva o metabolismo do eutômero (+)-(S)-CITA com aumento das concentrações plasmáticas em aproximadamente 140%. / Citalopram (CITA), a selective serotonin reuptake inhibitor, is available for clinical use as a racemic mixture of the (+)-(S) and (-)-(R) enantiomers or as the pure (+)-(S)-CITA enantiomer. CITA is metabolized by CYP2C19, CYP2D6 and CYP3A to demethylcitalopram (DCITA) and by CYP2D6 to didemethylcitalopram. The present study investigated the influence of enzyme inhibitors on the enantioselective metabolism of CITA in rats and healthy volunteers. Male Wistar rats (n=6 for each group) received a single dose of 20 mg/kg CITA (control group) or were pretreated with 80 mg/kg quinidine (quinidine group), 10 mg/kg fluvoxamine (fluvoxamine group), or 50 mg/kg ketoconazole (ketoconazole group). Blood samples were collected from the animals up to 20 h after the administration of CITA. Healthy volunteers phenotyped as extensive metabolizers of CYP2C19 (omeprazole as marker drug) and of CYP2D6 (debrisoquine as marker drug) and those with normal CYP3A activity (midazolam as marker drug) received a single oral dose of 20 mg racemic CITA combined or not with omeprazole (20 mg/day for 18 days). The CITA and DCITA enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R chiral column and a mobile phase of acetonitrile:methanol:water (30:30:40, v/v/v) containing 0.05% diethylamine. The method was linear in the concentration range of 0.1-20 ng of each CITA and DCITA enantiomer/mL human plasma and of 0.1-500 ng of each CITA and DCITA enantiomer/mL rat plasma. Accuracy and precision were below the acceptance limits of 15% for human and rat plasma. The kinetic disposition of CITA was enantioselective in rats of the control (AUCS/R ratio = 0.4), quinidine (AUCS/R ratio = 0.5) and ketoconazole (AUCS/R ratio = 0.8) groups. The inhibition of CYP2D by quinidine resulted in the non-enantioselective inhibition of the metabolism of CITA and DCITA. The inhibition of CYP2C by fluvoxamine and of CYP3A by ketoconazole only inhibited the metabolism of (+)-(S)-CITA. The kinetic disposition of CITA in healthy volunteers was enantioselective in the absence of treatment with omeprazole, with the observation of a higher plasma proportion of the (-)-(R)-CITA enantiomer. The AUCS/R ratio was 0.56 for CITA and 1.06 for the DCITA metabolite. The administration of racemic CITA to healthy volunteers treated with omeprazole showed a loss of enantioselectivity in the pharmacokinetics of CITA. The AUCS/R ratio was 0.96 for CITA and 0.92 for DCITA. The administration of multiple doses of omeprazole to healthy volunteers enantioselectively inhibited the metabolism of the (+)-(S)-CITA eutomer, with an approximately 140% increase of plasma concentrations

Objective: To determine whether genotype at the catechol-O-methyltransferase rs4680, dopamine D2 receptor rs1800497, serotonin receptor 1A rs6295 or serotonin transporter 5-HTTLPR single nucleotide polymorphisms is associated with response to citalopram and escitalopram treatment in patients with major depressive disorder and generalized anxiety disorder. Methods: Twenty one patients with depression or anxiety who were treated with citalopram or escitalopram for greater than one year, and who stopped the medication for a period of time during which their symptoms returned, and upon re-commencing the medication their symptoms were again reduced, were classified as responders. Patients were assessed using the Sheehan Disability Scale and the Quick Inventory of Depressive Symptomology- self report. The control group consisted of 146 healthy participants. Genotype was determined at each of the candidate genes studied: catechol-O-methyltransferase, dopamine D2 receptor, serotonin receptor 1A and serotonin transporter. Chi squared tests were used to compare genotypic and allele frequencies between responders and controls. Results: There was no significant difference in genotypic or allele frequencies between responders and controls at each of the genes analyzed. Conclusions: This pilot study suggests that genotype at the catechol-O-methyltransferase, dopamine D2 receptor, serotonin receptor 1A and serotonin transporter genes is not associated with response to citalopram and escitalopram treatment in patients with depression and anxiety. A larger sample size, along with a genome-wide scan are needed to identify genetic variants that predict medication response in future patients. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-08-31 12:26:21.402

Ph.d.

Hyponatriämie, definiert als Serum-Natrium < 135 mmol/l, ist ein potentiell lebensbedrohender Zustand und wird häufig bei älteren und psychiatrischen Patienten beobachtet. In den letzten Jahren wurden viele Case reports über SSRI- und SNRI- induzierte Hyponatriämien publiziert. Kardiale Veränderungen, insbesondere eine verlängerte QT-Zeit oder erhöhte Herzfrequenz, werden auch als häufig beobachtete Nebenwirkungen unter Therapie mit Antidepressiva beschrieben. Dies konnte bislang insbesondere während der Einnahme von trizyklischen Antidepressiva beobachtet werden. Oft kann der beobachtete Effekt in Zusammenhang mit der verabreichten Dosis gebracht werden. Bei der SSRI- bzw. SNRI-induzierten Hyponatriämie konnte dies bislang nicht gezeigt werden. In der Literatur lassen sich im Allgemeinen kaum Studien finden, die einen Zusammenhang der Serumkonzentration von SSRI und SNRI auf potentiell auftretende Nebenwirkungen untersucht haben. Ziel der vorliegenden Studie war zu zeigen, ob höhere Serumkonzentrationen von Citalopram, Escitalopram, Sertralin, Venlafaxin oder Duloxetin häufiger zu Hyponatriämien bzw. Verlängerungen der QT-Zeit führen. / Hyponatremia, defined as a serum sodium below 135 mmol/L, is a potentially life-threatening condition and was shown to be more frequent in elderly and psychiatric patients. In the last years numerous case reports on SSRI- and SNRI-induced hyponatremia were published indicating a higher incidence than previously thought. Cardiac side effects, especially QT-interval prolongation, are also reported as a common side effect under therapy with antidepressants in general. While QT-interval prolongation seems to be dose-dependent, SSRI-induced hyponatremia was shown not to correlate with dose. There were hardly studies, who investigate a correlation between plasma levels of SSRI and SNRI and potentially occuring side effects. Aim of this study was to show, if there is a higher incidence of hyponatremia and QT-interval prolongation under increasing plasma levels of Citalopram, Escitalopram, Sertralin, Venlafaxin and Duloxetin.

In der Pathophysiologie der Depression könnte das Zusammenspiel von Immun- und Nervensystem eine zentrale Rolle spielen. In den Krankheitsepisoden zeigen depressive Patienten eine gesteigerte Produktion pro-inflammatorischer Zytokine wie z. B. Interleukin (IL)-1β und dem Tumornekrosefaktor (TNF)-α. Es gibt nur begrenzte Informationen bezüglich der Effekte von Antidepressiva auf Zytokine. Die meisten Studien berichten nur über die Veränderungen einzelner Zytokine und keine hat bis jetzt über Effekte von Antidepressiva auf IL-22 berichtet. Wir haben systematisch die Wirkung von drei Antidepressiva, nämlich Citalopram, Escitalopram und Mirtazapin auf die Sekretion der Zytokine IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 und TNF-α in einem Vollblutverfahren in-vitro untersucht. Als Immunstimulanzien wurden der gegen humanes CD3 gerichtete monoklonale Antikörper OKT3 und der gegen CD40 gerichtete monoklonale Antikörper 5C3 verwendet. Es zeigte sich, dass es unter Citalopram zu einer erhöhten IL-1β, I-6, IL-22 und TNF-α-Produktion und unter Mirtazapin zu einer erhöhten Produktion von IL-1β, IL-22 und TNF-α gegenüber der Kontrollbedingung, in der keine Antidepressiva zugesetzt wurden, kam. Unter Escitalopram kam es zu einer gegenüber der Kontrollbedingung verringerten IL-17-Produktion. Der Einfluss der Antidepressiva auf IL-2 und IL-4 war für alle drei Psychopharmaka nicht signifikant. Verglichen mit Escitalopram führte Citalopram zu höheren IL-1β-, IL-6-, IL-17- und IL-22-Konzentrationen und Mirtazapin führte zu einer höheren IL-1β-, IL-17-, IL-22- und TNF-α-Produktion. Möglicherweise besteht ein Bezug zwischen dem Profil der Zytokinproduktion eines Antidepressivums und seinen therapeutischen Effekten, Nebenwirkungen und seinem Rückfallrisiko. Zur Überprüfung dieser Hypothese sind jedoch in-vivo Studien notwendig. / The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively.Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.

ithium is an important psychopharmacologi- cal agent for the treatment of unipolar as well as bipolar affective disorders. Lithium has a number of side effects such as hypothyroidism and aggravation of psoriasis. On the other hand, lithium has pro-inflammatory effects, which appear beneficial in some disorders associated with immunological deficits, such as human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE). Therefore, immunological characteristics of lithium may be an important consideration in individualized ther- apeutic decisions. We measured the levels of the cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-22, IL-17 and tumour necrosis factor (TNF)-a in the stimulated blood of thirty healthy subjects supplemented with lithium alone, the antidepressants citalopram, escitalopram or mirtazapine alone, the combination of each antidepressant with lithium, and a no drug control. These drugs were tested under three blood stimulant conditions: murine anti-human CD3 monoclonal antibody OKT3 and the 5C3 monoclonal antibody (OKT3/5C3), phytohemagglutinin (PHA), and unstimulated blood. Lithium, alone and in combination with any of the tested antidepressants, led to a consistent increase of IL-1ß, IL-6 and TNF-a levels in the unstimulated as well as the stimulated blood. In the OKT3/ 5C3- and PHA-stimulated blood, IL-17 production was significantly enhanced by lithium. Lithium additionally increased IL-2 concentrations significantly in PHA-stimu- lated blood. The data support the view that lithium has pro- inflammatory properties. These immunological character- istics may contribute to side effects of lithium, but may also explain its beneficial effects in patients suffering from HIV infection or SLE.

La toxicité des antidépresseurs inhibiteurs de recapture de la sérotonine (IRS) dont le citalopram est le représentant le plus sélectif, est réputée faible. Or les IRS ont été rendus responsables de syndromes sérotoninergiques, de convulsions, d’anomalies électrocardiographiques, voire de troubles respiratoires et de décès. L’implication de cette classe pharmacologique au cours des intoxications médicamenteuses volontaires (IMV) apparait peu documentée par des données récentes en France. Ainsi, la morbidité des IMV impliquant un IRS aux urgences (SAU) et les symptômes les plus fréquemment observés à la suite d’une exposition toxique aux IRS sont peu décrits. De même, les mécanismes toxiques impliqués dans les décès ne sont clairs. Objectifs : Nous avons mené ces travaux dans le but de : 1- mieux connaitre l’épidémiologie des IMV dans un SAU et y préciser l’implication des IRS ; 2- explorer une éventuelle sur-morbidité liée aux IRS dans les IMV polymédicamenteuses ; 3-comprendre les mécanismes de décès induits par de fortes doses de citalopram et les moyens de les prévenir. Méthodes: Nous avons conduit une étude observationnelle des IMV admises au SAU durant 4 ans, avec appariement des patients ayant ingéré un IRS versus des patients intoxiqués non exposés à un IRS. Nous avons également mené une étude expérimentale chez le rat Sprague-Dawley pour connaitre la dose létale médiane (MLD) du citalopram et explorer la toxicité neurologique, respiratoire et systémique impliquée dans le décès consécutif à l’administration de citalopram. Des dosages de sérotonine plasmatiques et plaquettaires ont été effectués afin de caractériser le rôle de la toxicité sérotoninergique. Résultats : Les IRS étaient impliqués dans 16% des IMV au SAU, soit en 2e position après les benzodiazépines. L’attribution des symptômes observés aux effets sérotoninergiques était rarement faite (dans environ un cas sur cinq) par les médecins urgentistes en charge des patients. La survenue d’un syndrome sérotoninergique et de convulsions était plus fréquente dans le groupe de patients intoxiqués par IRS que chez les témoins appariés. Un allongement du QT a été noté chez un patient et aucune toxicité respiratoire n’a été décelée. Le recours à la ventilation mécanique était plus important du fait de troubles de la conscience, sans augmentation pour autant du nombre d’admission en réanimation en comparaison aux témoins. L’étude expérimentale nous a permis de montrer que les décès induits par le citalopram étaient toujours précédés de convulsions, et que la prévalence des convulsions étaient dose-dépendante, significativement plus fréquente pour les fortes doses de citalopram (80 et 120% de la MLD) comparativement aux autres groupes (60% de la MLD et témoins). De même, le citalopram induisait une baisse dose-dépendante de la sérotonine plaquettaire et une élévation dose-dépendante de la sérotonine plasmatique. L’incidence du syndrome sérotoninergique était, par contre, comparable. Le citalopram n’induisait ni hypoxémie, ni hypercapnie, ni hyperlactatémie ; mais il était responsable d’un allongement du temps inspiratoire et d’un « braking expiratoire » mimant un phénomène adaptatif à l’hypoxémie. Par ailleurs, le prétraitement par diazépam ou cyproheptadine des rats intoxiqués avec une dose létale de citalopram prévenait les convulsions et le décès. Conclusions : La toxicité des IRS et du citalopram en particulier, semble essentiellement neurologique, tant chez l’homme que chez l’animal. Le syndrome sérotoninergique et les convulsions devraient être rassemblés en marqueurs de la toxicité sérotoninergique. Il est nécessaire de sensibiliser les médecins urgentistes à cette toxicité, en utilisant les critères de Hunter, plus simples et probablement plus spécifique. La place des antidotes restent à définir, mais, selon notre modèle expérimental, ils pourraient être efficaces pour réduire cette toxicité spécifique. / Toxicity of the serotonin-reuptake inhibitors (SRI) including citalopram, the most selective one, is considered as relatively low. However SRI may be responsible for serotonin syndrome, seizures, electrocardiographic abnormalities, respiratory failure, and even death. Implication of SRI in deliberate drug poisonings has not been assessed by recent data in France. Morbidity of SRI-related poisonings as well as the most common resulting presentations in the emergency department (ED) remains poorly described. Moreover, mechanisms of SRI-attributed death remain unclear. Objectives: We conducted these clinical and experimental studies: 1-to better understand the epidemiology of drug poisonings in one ED in Paris area and analyze SRI involvement; 2- to investigate a possible over-morbidity related to SRI in multidrug poisonings and describe the most common SRI-related complications; 3- to understand mechanisms of death induced by elevated doses of citalopram and its possible prevention. Methods: We conducted an observational study during 4 years in an ED matching patients who ingested at least one IRS with patients who did not. We also conducted an experimental study in the Sprague-Dawley rat to determine the median lethal dose (MLD) of citalopram and investigate citalopram-related neurological, respiratory, and systemic toxicity as well as mechanisms of citalopram-induced death. Platelet and plasma serotonin were measured to ensure the serotoninergic mechanism. Results: SRI were involved in 16% of the drug poisonings admitted to the ED, ranking at the second place after the benzodiazepines. Attribution of the observed signs and symptoms to the serotonin toxicity was rarely performed by the emergency physicians in charge, in only one out of five cases. Onset of serotonin syndrome and seizures were more frequent in SRI-exposed patients than in their matched controls. QT prolongation was observed in one patient while no direct respiratory toxicity was reported. Mechanical ventilation was more frequently used in SRI-exposed patients due to impaired consciousness, despite no resulting increased admission rate to the intensive care unit in comparison to the controls. Based on our rat study, citalopram-induced death always occurred after seizures which were dose-dependent, with a greater prevalence at the two highest doses of citalopram (80 and 120% of the MLD) than in the other groups (60% of control and the MLD). Citalopram-induced decrease in platelet serotonin and increase in plasma serotonin were dose-dependent. However, incidence of serotonin syndrome appears similar in all the groups. Citalopram did not induce hypoxemia, hypercapnia or hyperlactacidemia, but resulted in a slight prolongation in the inspiratory time and an "expiratory braking" that could be attributed to an adaptive phenomenon to hypoxemia. Pretreatment with diazepam and cyproheptadine prevented rats treated with lethal-doses of citalopram from seizures and death. Conclusions: SRI and citalopram in particular are mainly responsible for neurological toxicity, both in humans and rats. Serotonin syndrome and seizures should be grouped as markers of serotonin toxicity. Emergency physicians should become more aware of this specific toxicity. Using the simpler and probably more specific Hunter criteria may be useful in the ED. The exact indications of antidotes remain to be defined, but our experimental model seems to support their effectiveness to prevent IRS-related specific serotonin toxicity.

Introduction Citalopram is a preferred medication used for the treatment of depression and belongs to a group known as selective serotonin reuptake inhibitors (SSRI). When used on a long-term basis, it leads to a significant decrease of serotonin in thrombocytes. Citalopram-treated patients often display haemorrhagia that is explained by its anti-platelet effect, which is also - more or less - the case for other medications from the SSRI group. Aim of the Thesis The aim of the thesis was to find out: a) Whether citalopram treatment (2 weeks) has influence on the plasma concentration of thromboxane B2; b) Whether there is a relation between the expected decrease of thromboxane B2 levels and the plasma concentration of citalopram. Methods and Patient Population We carried out clinical and laboratory tests on a study population consisting of elderly and polymorbid patients who underwent a 14-day citalopram treatment with daily doses of 20mg. Among other tests, we observed the plasma concentration of thromboxane and citalopram. Out of 160 patients examined, 78 patients were assessed. Results Our study has proved that even a short-term citalopram treatment results to a significant increase in the plasma concentration of thromboxane B2 and the suppression rate of thromboxane B2 correlates with the higher...