Dual Antidepressant Consumption in the Czech Republic Author: Kristýna Čiháková Supervisor: PharmDr. Pavel Horký, Ph.D. Consultant: PharmDr. Kateřina Malá, Ph.D. Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Introduction: Antidepressants are widely used in many indications. Dual antidepressants are prescribed in treatment of depressive disorder, anxiety disorder, in pain therapy and insomnia. Besides that, there are trials to prove the efficacy of dual antidepressants in different indications. Generally, antidepressant consumption in the Czech Republic is increasing. The question is, what the real proportion of dual antidepressant consumption is. Objective: As the objective, dual antidepressant consumption was analysed. Methods: The consumption of antidepressants venlafaxine, duloxetine, mirtazapine and mianserin was performed in the period from 1 January 2008 to 31 December 2018. The State Institute for Drug Control (SÚKL) database was used. The data were described by descriptive statistics. The drug consumption in Defined Daily Doses (DDD) was converted into Defined Daily Dose/1,000 inhabitants/day (DID). In addition, comparison of use of particular dual antidepressant doses was made. Results: Overall, the relative consumption of dual...

SSRI antidepressant consumption in Czech republic Author: Júlia Behrová Supervisor: PharmDr. Pavel Horký, PhD. Consultant: PharmDr. Eva Zimčíková, Ph.D Introduction: Selective serotonin reuptake inhibitors increase the available amount of neurotransmitter serotonin in synapses, resulting in their antidepressant and anxiolytic effect. Objective: The objective of this diploma thesis was to evaluate the consumption of SSRI antidepressants in the Czech Republic in the period from 01. 01. 2008 - 31. 12. 2018, based on the data on consumption from the State Institute of Drug Control (SIDC). Methods: The research consisted of a retrospective analysis of the SIDC database. The study included all approved SSRI in the Czech Republic. Drug Utilization Review was used in the thesis as a methodology. Drug consumption is calculated as the number of defined daily doses per thousand inhabitants per day (DID). The data on the number of residents was acquired from the Czech Statistical Office. Descriptive statistics and ATC/DDD methodology were applied. Results: The consumption of sertraline and escitalopram increased significantly during the period under review. For sertraline, the DID increased from an initial 8.623 to 15.513, increasing consumption by 1.8 fold. The greatest increase in consumption was observed...

For many years, the norepinephrine transporter (NET) was considered a 'static' protein that contributed to the termination of the action of norepinephrine in the synapse of noradrenergic neurons. The concept that the NET is dynamically regulated, adjusting noradrenergic transmission by changing its function and/or expression, was considered initially in the mid 1980s. Since that time, a plethora of studies demonstrate that the NET is regulated by several intracellular and extracellular signaling molecules, and that phosphorylation of the NET is a major pathway regulating its cell surface expression and thereby its function. The NET is a target of action of a number of drugs that are used long-term therapeutically or abused chronically. This has driven numerous investigations of how the NET and its function are regulated by long-term exposure to drugs. While repeated exposure to many drugs has been shown to affect NET function and expression, the intracellular mechanisms for these effects remains elusive.

It is documented that stress activates the locus coeruleus-norepinephrine system. However, there are far few reports regarding effects of stress on the expression of dopamine β-hydroxylase, a hallmark enzyme of the noradrenergic neuron. In the present study, adult Fischer 344 rats were subjected to chronic social defeat for 4 weeks. Dopamine β-hydroxylase expressional levels in the locus coeruleus and its terminal regions were measured by in situ hybridization and western blotting. The results showed that immediately following chronic social defeat there are significantly increased mRNA and protein levels of dopamine β-hydroxylase in the locus coeruleus, and dopamine β-hydroxylase protein levels in the hippocampus, frontal cortex and amygdala, compared with those in the control. This chronic social defeat-induced upregulation of dopamine β-hydroxylase was completely abolished by adrenalectomy, and/or by treatment with corticosteroid receptor antagonists, mifepristone and spironolactone, either alone or in combination. Furthermore, treatment with desipramine, an antidepressant with specific inhibitory effects on norepinephrine transport, prevented an increased dopamine β-hydroxylase expression by chronic social defeat in the locus coeruleus and its main terminal regions such as the hippocampus, frontal cortex and amygdala. However, treatment with fluoxetine, an antidepressant with specific inhibition for serotonin transport, only selectively blocked increased dopamine β-hydroxylase protein levels in the hippocampus caused by CSD. The present findings indicate that chronic social defeat activates the locus coeruleus-norepinephrine system by upregulating the expression of dopamine β-hydroxylase, which may increase norepinephrine synthesis. This chronic social defeat induced upregulation of DBH expression was mediated through corticosterone and corticosteroid receptors, with possible interference from antidepressants.

It is documented that stress activates the locus coeruleus-norepinephrine system. However, there are far few reports regarding effects of stress on the expression of dopamine β-hydroxylase, a hallmark enzyme of the noradrenergic neuron. In the present study, adult Fischer 344 rats were subjected to chronic social defeat for 4 weeks. Dopamine β-hydroxylase expressional levels in the locus coeruleus and its terminal regions were measured by in situ hybridization and western blotting. The results showed that immediately following chronic social defeat there are significantly increased mRNA and protein levels of dopamine β-hydroxylase in the locus coeruleus, and dopamine β-hydroxylase protein levels in the hippocampus, frontal cortex and amygdala, compared with those in the control. This chronic social defeat-induced upregulation of dopamine β-hydroxylase was completely abolished by adrenalectomy, and/or by treatment with corticosteroid receptor antagonists, mifepristone and spironolactone, either alone or in combination. Furthermore, treatment with desipramine, an antidepressant with specific inhibitory effects on norepinephrine transport, prevented an increased dopamine β-hydroxylase expression by chronic social defeat in the locus coeruleus and its main terminal regions such as the hippocampus, frontal cortex and amygdala. However, treatment with fluoxetine, an antidepressant with specific inhibition for serotonin transport, only selectively blocked increased dopamine β-hydroxylase protein levels in the hippocampus caused by CSD. The present findings indicate that chronic social defeat activates the locus coeruleus-norepinephrine system by upregulating the expression of dopamine β-hydroxylase, which may increase norepinephrine synthesis. This chronic social defeat induced upregulation of DBH expression was mediated through corticosterone and corticosteroid receptors, with possible interference from antidepressants.

DNA damage is a form of cell stress and injury. Increased systemic DNA damage is related to the pathogenic development of neurodegenerative diseases. Depression occurs in a relatively high percentage of patients suffering from degenerative diseases, for whom antidepressants are often used to relieve depressive symptoms. However, few studies have attempted to elucidate why different groups of antidepressants have similar effects on relieving symptoms of depression. Previously, we demonstrated that neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)- and camptothecin (CPT) induced the DNA damage response in SH-SY5Y cells, and DSP4 caused cell cycle arrest which was predominately in the S-phase. The present study shows that CPT treatment also resulted in similar cell cycle arrest. Some classic antidepressants could reduce the DNA damage response induced by DSP4 or CPT in SH-SY5Y cells. Cell viability examination demonstrated that both DSP4 and CPT caused cell death, which was prevented by spontaneous administration of some tested antidepressants. Flow cytometric analysis demonstrated that a majority of the tested antidepressants protect cells from being arrested in S-phase. These results suggest that blocking the DNA damage response may be an important pharmacologic characteristic of antidepressants. Exploring the underlying mechanisms may allow for advances in the effort to improve therapeutic strategies for depression appearing in degenerative and psychiatric diseases.

Bien que l’effet psychotrope des antidépresseurs soit bien connu, afin de corriger les conséquences du stress et de renforcer la confiance en soi, de nombreux autres effets pharmacologiques, notamment périphériques, doivent encore être approfondis. Les antidépresseurs inhibiteurs de la recapture de la sérotonine (ISRS) peuvent avoir un effet bénéfique sur la performance physique en participant à une réparation et à une croissance plus rapides des muscles. Il a récemment été démontré que la sérotonine était impliquée dans la récupération de la force musculaire chez un modèle murin de myopathie de Duchenne (Gurel et al., 2015). Les antidépresseurs tels que les inhibiteurs sélectifs de la recapture de la sérotonine (ISRS) sont largement utilisés pour traiter divers troubles de la santé mentale, tels que la dépression modérée à sévère et l’anxiété. Les deux symptômes contribuent à l’insomnie, à la perte d’appétit, au manque de motivation et à une fatigue physique accrue. Ces symptômes peuvent nuire aux performances physiques des athlètes, en particulier de ceux qui développent des habiletés et des techniques spécifiques à un sport, reçoivent des volumes d’entraînement plus importants à différentes intensités et participent à des compétitions plus fréquentes. Par conséquent, les athlètes peuvent utiliser des médicaments qui renforcent la motivation et / ou améliorent la condition physique générale en réduisant les symptômes dépressifs. L'utilisation d'antidépresseurs n'est pas encore interdite dans les sports d'élite. Des rapports récents sur le dopage associé aux ISRS montrent une tendance croissante de son utilisation chez les athlètes en bonne santé. La consommation d'antidépresseurs chez les athlètes a augmenté dans différents sports au cours de la dernière décennie, notamment les sports d'endurance.. Notre projet doit donc permettre de caractériser les conséquences d'un traitement chronique par ISRS sur les performances physiques chez la souris et de mettre en évidence le ou les mécanismes impliqués, en particulier la variation du shunt métabolique sérotonine / kynurénine, ainsi que les modifications de biomarqueurs, variations potentiellement utilisables chez l'homme dans la lutte contre le dopage.Nous aimerions élucider notre travail de recherche dans les articles suivants:Article 1: Nous avons étudié les effets de l'exercice et de la fluoxétine seuls ou en association avec un traitement prolongé à la fluoxétine (18 mg / kg / jour) et un exercice physique d'endurance (six semaines) chez la souris mâle BalbC / j, sur tapis roulant. Nous avons ensuite évalué l'activité neurocomportementale, les marqueurs musculaires du stress oxydatif et les modifications du métabolisme du tryptophane dans les tissus plasmatiques, musculaires et cérébraux des souris BalbC / J. En général, nous nous sommes concentrés sur la vitesse aérobie la plus élevée, le temps d’endurance jusqu’à l’épuisement, la force musculaire des membres antérieurs en saisissant un mesureur de force, des tests neurocomportementaux tels que le test en champ ouvert et élevé et le labyrinthe, l’activité enzymatique mitochondriale (activité du citrate synthase et du cytochrome C oxydase) dans le muscle gastrocnémien. , marqueur de stress oxydant tel que le test DHE (Dihydroéthidium) et DCF-DA (Dichlorofluorscine diacétate).Article 2: Nous avons étudié les effets de l’exercice et de la fluoxétine seule ou les effets combinés d’un traitement prolongé à la fluoxétine (18 mg / kg / jour) et d’un exercice d’endurance physique (six semaines) chez la souris mâle BalbC / j, sur tapis roulant. / As much as the psychotropic effect of antidepressants is well known, correcting the consequences of stress and boosting self-confidence, so many other pharmacological effects, peripheral in particular, remain to be deepened. Serotonin reuptake inhibitor antidepressants (SSRIs) may have a beneficial effect on physical performance by participating in faster muscle repair and growth. It has recently been shown that serotonin was involved in the recovery of muscle strength in a mouse model of Duchenne myopathy (Gurel et al., 2015).Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely used to treat various mental health disorders, such as moderate-to-severe depression and anxiety. Both symptoms contribute to insomnia, loss of appetite, lack of motivation and increased physical fatigue. These symptoms can impair physical performances for athletes, more specifically for those who develop sport-specific skills and techniques, receive higher training volumes at various intensities, and participate in more frequent competitions. Therefore athletes may use drugs that enhance motivation and/or improve overall fitness by reducing depressive symptoms. The use of antidepressants is not yet forbidden in elite sports. Recent reports on doping associated with SSRIs show an increasing trend of its usage among healthy athletes. The antidepressants intake among athletes has increased in different sports over the last decade, especially endurance sports. The antidepressants Bupropion and Amineptine were removed from the list of banned substances.Our project must therefore make it possible to characterize the consequences of chronic treatment with SSRIs on the physical performance in mice and to highlight the mechanism (s) involved, in particular the variation of the serotonin / kynurenine metabolic shunt, as well as the modifications of biomarkers, potentially usable variations in humans in the fight against doping.We would like to elucidate our research work in the following articles:Article 1: We studied the effects of exercise and fluoxetine alone or in combination of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. Subsequently we evaluated neurobehavioral activity, muscle markers of oxidative stress, and changes in tryptophan metabolism in plasma, muscle and brain tissues in the BalbC/J mice. Generally we focused on the highest aerobic velocity, endurance time until exhaustion, forelimb muscle strength by gripping strength meter, neurobehavioral tests such as open field and elevated plus maze test, mitochondrial enzyme activity (Citrate synthase and cytochrome-C oxidase activity) in gastrocnemius muscle, oxidative stress marker such as DHE (Dihydroethidium) and DCF-DA (Dichlorofluorscine di-acetate)test.Article 2: We studied the effects of exercise and fluoxetine alone or combinative effects of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. After the mentioned exercise protocol we focused on changes in tryptophan (TRP) metabolism in plasma, muscle and brain tissues in the BalbC/J mice. To confirm the metabolomic, we also studied the KP related enzyme related genes and proteins by the modern required materials and methods. We correlated the result of article1 with the metabolites level of kynurenine pathway of tryptophan metabolism. We studied the expression of transcriptor factor PGC1α level in muscle which is induced by physical exercise(Agudelo et al., 2014). PGC1α subsequently induce the expression of kynurenine aminotransferase 1 and 2 (KAT1 and KAT2) in skeletal muscles, which convert kynurenine (KYN) to kynurenic acid (KYNA). Conversion of kynurenine to kynurenic acid decrease the level of kynurenine and quinolinic acid an NMDA receptor agonist and a neurotoxic compound.

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Following decades of research on stress and its impact on behaviour, it is now widely accepted that selective psycho-pathologies, in particular clinical depression are more prevalent in humans with prior history of life-stress events. Interest in stress has led to questions about how it might affect the physiology and behaviour of animals exposed indirectly during gestational development. Not unexpectedly gestational stress has been shown to affect the offspring in several ways: endocrine responses to stress are elevated, fear, arousal and affective disturbances are all subject to vary if the pregnant animal is subjected to periods of aversive stimulation. Beginning in 1997, Michael Meaney of McGill University produced a series of publications suggesting that peri-natal events influence offspring and infant development, not via physical discomfort or physiological disturbance, but does so through modifications of maternal behaviour. Highly nurturant mothers (those who engage in active arched-back nursing (ABN), and spend more time licking and grooming (L/G) their pups), programme their offspring with improved cognitive abilities, decreased anxiety and fear, and reduced HPA axis hormone secretion. Low-nurturant mothers, who engage in less ABN and less L/G, tend to programme the opposite responses in their offspring. Our initial foray into this field was to investigate if gestational stress might also produce responses in the offspring via changes in maternal behaviour, and indeed ABN and L/G were reduced in dams which were subjected to gestational stress. We queried why stressed Dams would be less maternal towards their infants, and tested gestationally-stressed Dams in the Porsolt test for depressive-like behaviour. Our results suggested that these stressed Dams were actually depressed and this resulted in less maternal behaviour. Human mothers with depression are also less maternal and have been shown to divest themselves of infant care much like our prenatally-stressed Dams. On this basis we have proposed that gestational stress induced decrements in maternal behaviour represent a novel rat model for postnatal depression with face and construct validities. In the present work we have attempted to replicate the findings of Smythe¿s group (Smith et al., 2004), and have investigated the potential for antidepressants to alter the influence of gestational stress on maternal behaviours and depressive-like response, and whether or not the offspring¿ are modified by maternal treatment with ant-depressants. Approximately 140 time-mated, lister hooded rats were generated in house, and subjected to gestational stress on days 10-20 (1hr restraint/day) or remained undisturbed in their home cages. Following birth, cohorts of control and stressed Dams were administered vehicle or an antidepressant (imipramine 15mg/kg; or sertraline 10mg/kg) once daily until postnatal day 10. We assessed maternal Porsolt activity, nurturance (ABN, L/G, nest building) and anxiety-like behaviour in the elevated plus maze (EPM). Representative offspring of each Dam¿s treatment conditions were maintained post weaning and assessed in the Porsolt and EPM to determine if any changes in maternal behaviour elicited by the antidepressants altered their behavioural programming. Our findings confirm that Dams show depressive-like symptoms following gestational stress, and that administration of antidepressants to the Dams reduces depressive-like behaviour and increased maternal care. We propose that rat gestational stress is a putative model for human postnatal depression. Prenatal stress effects on maternal behaviour in the rat Dam represent a novel, and innovative model for human postnatal depression. / Ministry of Defence, Prince Sultan Military College of Health Sciences and the Saudi Culture Bureau

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