This study assessed the in vivo effects of various serotonin (5-HT) receptor modulators on 5-HT neurotransmission in the rat hippocampus. Vortioxetine, humanized-vortioxetine, and escitalopram blocked the 5-HT transporter, but similar to ipsapirone did not dampen the sensitivity of postsynaptic 5-HT1A receptors. Long-term administration of all treatments increased the tonic activation of postsynaptic 5-HT1A heteroreceptors, an effect common to all antidepressants. Vortioxetine decreased the function of the terminal 5-HT1B autoreceptor under high but not a low degree of activation, thus showing that its partial agonism led to increased 5-HT release and that long-term administration results in the desensitization of terminal 5-HT1B autoreceptors. Vortioxetine overcame the effects of 5-HT1B and 5-HT3 receptor agonists. This study was unable to determine the involvement of 5-HT7 receptor antagonism exerted by vortioxetine affects 5-HT neurotransmission. Therefore, vortioxetine would appear to exert different actions, via transporter and receptor activity, on the serotonergic system in the hippocampus, consistent with its unique pharmacological profile.

This study assessed the in vivo effects of various serotonin (5-HT) receptor modulators on 5-HT neurotransmission in the rat hippocampus. Vortioxetine, humanized-vortioxetine, and escitalopram blocked the 5-HT transporter, but similar to ipsapirone did not dampen the sensitivity of postsynaptic 5-HT1A receptors. Long-term administration of all treatments increased the tonic activation of postsynaptic 5-HT1A heteroreceptors, an effect common to all antidepressants. Vortioxetine decreased the function of the terminal 5-HT1B autoreceptor under high but not a low degree of activation, thus showing that its partial agonism led to increased 5-HT release and that long-term administration results in the desensitization of terminal 5-HT1B autoreceptors. Vortioxetine overcame the effects of 5-HT1B and 5-HT3 receptor agonists. This study was unable to determine the involvement of 5-HT7 receptor antagonism exerted by vortioxetine affects 5-HT neurotransmission. Therefore, vortioxetine would appear to exert different actions, via transporter and receptor activity, on the serotonergic system in the hippocampus, consistent with its unique pharmacological profile.

Les traitements actuels de la dépression présentent une efficacité partielle et nécessitent une administration pendant plusieurs semaines avant d’obtenir un effet thérapeutique. Il est donc urgent de trouver de nouvelles stratégies antidépressives. La vortioxetine (Lu AA21004) est un nouvel antidépresseur en cours de développement. À la différence des inhibiteurs sélectifs de recapture de la sérotonine (ISRS), il est multi-cibles. Il bloque non seulement le transporteur de la sérotonine (SERT) mais aussi les récepteurs 5-HT3. Afin de caractériser les effets de ce composé et d’évaluer l'implication du blocage des récepteurs 5-HT3 dans son mécanisme d’action, plusieurs marqueurs précliniques de la réponse antidépressive ont été évalués. Nous avons utilisé des approches électrophysiologiques, immunohistochimiques, comportementales et de microdialyse chez le rat. La vortioxetine augmente la prolifération cellulaire hippocampique et induit une désensibilisation des autorécepteurs 5-HT1A dès 3 jours contre 2 à 3 semaines pour les antidépresseurs classiques. Elle induit également une importante libération de sérotonine malgré une occupation partielle du SERT. Ces effets sont liés, au moins en partie, au blocage des récepteurs 5-HT3. Nous avons ensuite montré qu’un antagoniste des récepteurs 5-HT3, l’ondansetron, à très faible dose, potentialisait l’effet d’un ISRS, la paroxetine. L’ensemble de nos données in vivo et ex vivo prouvent que le blocage des récepteurs 5-HT3 participe à l’efficacité pseudo-antidépressive de la vortioxetine. Les récepteurs 5-HT3 sont donc une cible intéressante pour améliorer l’efficacité des antidépresseurs et raccourcir leur délai d’action / Therapeutic effects of current antidepressant drugs only appear after several weeks of treatment and a significant number of patients do not respond to any treatment. Thus, more effective treatments for major depression are still needed. Vortioxetine (Lu AA21004), a novel antidepressant in development, displays effective properties in human. To the difference of selective serotonin reuptake inhibitors (SSRIs), it is a multimodal serotoninergic agent. Not only does it block the 5-HT transporter but it is also a potent 5-HT3 receptor antagonist. This current study was undertaken to characterize the effects of this compound and the role of 5-HT3 blockade. Using electrophysiological, immunohistochemical, autoradiography and behavioral approaches in rats, several pre-clinical markers of antidepressant-like response were assessed. Vortioxetine increased hippocampal cell proliferation and desensitized 5-HT1A autoreceptors from 1-3 days versus 2-3 weeks for classical antidepressants. In contrast to SSRIs, it also increased 5-HT hippocampal release with an incomplete SERT occupancy. Later effects are at least partly due to 5-HT3 receptors blockade. In parallel, we also showed that the 5-HT3 receptor antagonist ondansetron potentiated the effect of the SSRI paroxetine. Taken together, our in and ex vivo findings highlight the crucial role of 5-HT3 receptor blockade in the antidepressant-like efficacy of vortioxetine. Thus, we propose that the 5-HT3 receptors are an interesting target to improve antidepressant efficacy and reduce the therapeutic delay

In this master thesis, the formation of supramolecular complexes between vortioxetine active substance and cyclodextrins (α, β, γ) is examined and the stability constants of these complexes are determined. The stoichiometric ratios of cyclodextrin and vortioxetine 1:1 and 2:1 are considered. The results suggest that the 1:1 ratio of cyclodextrin and vortioxetine is more accurate for each of used cyclodextrins and that the strongest interaction is between vortioxetine and β-cyclodextrin. Further, a method for vortioxetine assay in a tablet is developed by using non-aqueous capillary electrophoresis technique. The precision, accuracy, and robustness are validated and the values of detection and quantification limits are determined. This method can be used as a verification method for the results obtained by HPLC as the separation principle is different in capillary electrophoresis. Also, the stability of vortioxetine as a pure powder and as a mixture with excipients is examined under the conditions of elevated temperature and humidity.

Irritable bowel syndrome (IBS) är en av de vanligaste diagnostiserade GI-tillstånden idag och är en störning av gastrointestinalkanalen (GI-kanalen). Det finns inget botemedel mot IBS på grund av att patogenesen är oklar och därför är fokusen symtomlindring vid behandling.  De vanligaste symtom som förekommer är buksmärta, obehag i buk, uppblåsthet, utspänd buk och förändring av avföringens konsistens och frekvens. Patofysiologin är inte fullt klarlagd men en rubbning i tarm-hjärn-axeln kan leda till förändring i GI-rörelser. Neurotransmittorerna noradrenalin och serotonin (5-HT) är troligen viktiga faktorer för patofysiologin kopplad till tarm-hjärn-axeln. Syftet var att undersöka effektiviteten och säkerheten för de antidepressiva läkemedlen vid behandling av IBS. De antidepressiva som undersöktes i arbetet var tianeptin, amitriptylin, escitalopram, venlafaxin, vortioxetin och mirtazapin. De fem artiklarna som användes i detta arbete upptäcktes med hjälp av databaserna Pubmed och Onesearch. Sökord som användes var ”IBS” AND ”antidepressants” och ”IBS” AND ”SSRI”.  Alla antidepressiva visade en signifikant förbättring för livskvalitén hos deltagarna i studierna. Tianeptin, amitriptylin, escitalopram, venlafaxin och mirtazapin undersökte förändring av buksmärta och alla hade en signifikant förbättring förutom escitalopram. Escitalopram jämfördes mot rektal ballongutvidgning vid behandling hos IBS med förstoppning (IBS-C). Ballongutvidgningen visade bättre resultat än escitalopram och denna jämförelse gör det svårt att dra någon slutsats om escitalopram i arbetet. Amitriptylin, tianeptin och mirtazapin undersökte förändring av avföringskonsistensesn och frekvensen och visade en signifikant förbättring hos IBS med diarré (IBS-D). Venlafaxin visade signifikant förbättring för både lös och hård avföringsfrekvens och studerade ingen specifik IBS-grupp. Vortioxetin undersökte alla IBS-grupper och endast förändring av livskvalitén, depression och ångest vilket också gör det svårt att dra slutsats om effekt hos IBS. Det var inga av de depressiva medlen som gav allvarliga biverkningar, dock kan vissa biverkningar tolkas som mer obehagliga än andra. För vissa antidepressiva var det deltagare som avslutade studien på grund av biverkningar. Amitriptylin, tianeptin, venlafaxin vortioxetin och mirtazapin visade alla god effekt och säkerhet. Om effektiviteten ock säkerheten jämförs bland dessa har tianeptin det bästa resultatet. / Irritable bowel syndrome (IBS) is one of the most diagnosed conditions in the gastrointestinal (GI) tract today and is a disorder of the GI tract. There is no cure for IBS, which is probably due to the fact that the pathogenesis is unclear, and therefore the focus has been a symptom-relieving treatment. The most common symptoms that occur are abdominal pain, abdominal discomfort, bloating, distension of the abdomen, and change in the consistency and frequency of the stool. The pathophysiology is not fully understood, but a disorder of the gut-brain axis can lead to a change in GI movements. The neurotransmitters norepinephrine and serotonin (5-HT) are probably important factors for pathophysiology and linked to the gut-brain axis.  The aim was to investigate the effectiveness and safety of antidepressants used in IBS treatment. The antidepressants examined in this literature were tianeptine, amitriptyline, escitalopram, venlafaxine, vortioxetine, and mirtazapine. The five articles on which current litter tour work is based were obtained using the PubMed and OneSearch databases. Keywords used were "IBS" AND "antidepressants" and "IBS" AND "SSRI."  All the antidepressants examined showed a significant improvement in the participants' quality of life in the studies. The studies also examined changes in abdominal pain using tianeptine, amitriptyline, escitalopram, venlafaxine, and mirtazapine. All participants showed a significant improvement and reduced abdominal pain except when ingesting escitalopram. Intake of escitalopram was compared against rectal balloon enlargement as a treatment for IBS with constipation (IBS-C). The balloon expansion showed better results than escitalopram, and this comparison makes it difficult to draw any conclusion about escitalopram and its actual effect in different types of IBS. Amitriptyline, tianeptine, and mirtazapine investigated stool consistency and stool frequency changes and showed a significant improvement in these symptoms in IBS with diarrhea (IBS-D). Venlafaxine showed significant improvement for both loose and hard stool frequency; however, no specific IBS group was studied in this study. When ingesting vortioxetine, all different IBS groups and changes in quality of life, depression, and anxiety were examined, making it difficult to conclude about the effect of the drug in IBS. None of the antidepressant medicines produced severe side effects. However, some side effects can be interpreted as more unpleasant than others, and hence there was some loss during some studies.  Amitriptyline, tianeptine, venlafaxine vortioxetine, and mirtazapine showed good efficacy and safety. If the effectiveness and safety were to be compared between these drugs, tianeptine would be the first choice in treating IBS.