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.

Introduction : Le trouble dépressif majeur (TDM) représente un enjeu de Santé Publique. Aujourd’hui, il existe différents médicaments antidépresseurs (AD), mais 60% des patients déprimés ne répondent pas suffisamment à ce type de traitement. La pharmacogénétique (PG) se définit comme l’étude de la variabilité de la réponse aux médicaments associée à des variations génétiques des gènes de la pharmacodynamie ou de la pharmacocinétique. La médecine personnalisée utilise la PG pour améliorer la prise en charge des patients. La venlafaxine (VEN), AD fréquemment utilisé en psychiatrie, est métabolisée par les enzymes du Cytochrome P450 (CYP) 2D6 et 2C19. Elle augmente le turnover des monoamines cérébrales, qui sont catabolisées par la catechol-O-méthyltransférase (COMT). L'objectif de ce travail est d'identifier des biomarqueurs génétiques de réponse à la VEN qui pourraient être utilisés dans la pratique clinique psychiatrique. Ce travail présente deux études de gènes candidats, et une étude de panel de gènes basée sur une revue de la littérature. Méthodes : Deux cent six patients caucasiens souffrant d’un épisode dépressif majeur unipolaire (DSM-IVTR), nécessitant un nouveau traitement AD, issus de la cohorte METADAP et traités par VEN ont été étudiés. METADAP est une cohorte prospective d’une durée de 6 mois, multicentrique, naturaliste, en conditions réelles de prescription en psychiatrie. La dépression a été mesurée avec l’échelle de dépression de Hamilton à l’inclusion et après 1, 3 et 6 mois de traitement antidépresseur, permettant d’évaluer le pourcentage d’amélioration, la réponse et la rémission. Les patients ont été génotypés pour les polymorphismes génétiques ou Single Nucleotide Polymorphisms (SNP) majeurs du CYP2D6 et du CYP2C19 : allèles défectueux entraînant une déficience enzymatique complète (CYP2D6 *3 rs35742686, *4 rs3892097, *6 rs5030655, délétion du gène *5); (CYP2C19 *2 rs4244285, *3 rs4986893, *4 rs28399504, *5 rs56337013), allèles entraînant une diminution de l'activité enzymatique (CYP2D6 *10 rs1065852, CYP2D6*41 rs28371725), allèles associés à un métabolisme accéléré (duplication du gène CYP2D6*2xN) ; (CYP2C19 *17 rs12248560) et pour le polymorphisme de la COMT Val(108/158)Met, rs4680. La technique de discrimination allélique TaqMan a été utilisée. Les patients ont été classés selon le phénotype CYP2D6 et CYP2C19 en métaboliseurs lents, normaux, rapides, intermédiaires et ultrarapides et en 3 génotypes COMT Val(108/158)Met: Val/Val, Val/Met, Met/Met. Par ailleurs, 70 patients ont été séquencés en utilisant les technologies de séquençage à haut débit ou Next Generation Sequencing (NGS) MiSeq Illumina pour un panel de 70 gènes. Résultats : Dans cet échantillon, il n’existe pas d’association entre l’évolution de la dépression sous VEN et les SNPs que nous avons étudiés du CYP2D6, du CYP2C19 et de la COMT. Les données NGS sont en cours d’analyse. D’ores et déjà, la qualité des données a été validée par comparaison aux résultats de la discrimination allélique TaqMan des CYP. Suite à une revue de la littérature mettant en évidence l’importance des transporteurs OCTs (Organic Cation Transporter) et PMATs (Plasma Membrane Monoamine Transporter) dans le transport des monoamines et leur rôle dans la réponse aux AD, ces gènes seront intégrés dans la sélection du panel de gènes pour le NGS. Conclusion : Ce travail ne permet pas de recommander le génotypage des SNPs du CYP2D6, du CYP2C19 et de la COMT Val(108/158)Met en routine clinique psychiatrique chez les patients déprimés traités par VEN. Ce travail se poursuivra par l’analyse NGS qui tentera d’identifier des variants rares ou ultra-rares et pertinents, notamment pour des gènes qui n'ont pas été étudiés dans le TDM comme ceux des OCTs et PMATs. / Introduction: Major Depressive Disorder (MDD) represents an issue of Public Health. Currently, different antidepressant (AD) treatments exist, but 60% of depressed patients do not respond sufficiently to this type of treatment. Pharmacogenetics (PG) represents the study of the variability of response to a treatment associated to genetic variations identified in pharmacokinetic and pharmacodynamic genes. Personalized medicine is using PG to make the best therapeutic choice for a depressed patient. Venlafaxine (VEN), AD frequently used in psychiatry, is metabolized by the enzymes of Cytochromes P450 (CYP) 2D6 and 2C19. VEN increases the turnover of cerebral monoamines, which are catabolized by the cathecol-O-methyltransferase (COMT). The aim of this study is to identify genetic biomarkers of response to VEN that may be used in clinical practice in psychiatry. This work presents two candidate gene studies and a study of panel of genes based on a review of the literature. Methods : Two hundred and six Caucasian patients suffering from a unipolar major depressive episode (DSM-IVTR), requiring a new AD treatment, selected from METADAP cohort, treated by VEN have been studied. The METADAP cohort is a 6-month prospective, multicenter, real-world setting, treatment study in psychiatry. Depression was assessed by the Hamilton scale at the baseline and after 1, 3 and 6 months of AD treatment allowing the evaluation of the percentage of improvement, the response and the remission. Patients were genotyped for the major SNPs (Single Nucleotide Polymorphisms) of CYP2D6 and CYP2C19: loss of function alleles (CYP2D6 *3 rs35742686, *4 rs3892097, *6 rs5030655, the complete gene deletion *5); (CYP2C19 *2 rs4244285, *3 rs4986893, *4 rs28399504, *5 rs56337013); increased function alleles (gene duplication CYP2D6*2xN); (CYP2C19 *17 rs12248560); decreased function alleles (CYP2D6 *10 rs1065852, CYP2D6*41 rs28371725) and COMT Val(108/158)Met, rs4680. The TaqMan allelic discrimination technology was used. Accordingly to the CYP2D6 and CYP2C19 phenotype, the patients were classified in: poor, normal, extensive, intermediate, and ultra-rapid metabolizers and respectively 3 COMT Val(108/158)Met genotypes : Val/Val, Val/Met, Met/Met. Furthermore, 70 patients were sequenced using Next Generation Sequencing (NGS) technologies of MiSeq Illumina for a panel of 70 genes. Results : No association between the evolution of depression of patients treated by VEN and the SNPs of CYP2D6, of CYP2C19 and of COMT was showed in this sample. The NGS data is being analyzed. Le quality of the NGS data has been validated by comparing the results to the TaqMan allelic discrimination of the CYP. Following the review of the literature showing the importance of the OCTs (Organic Cation Transporter) and PMATs (Plasma Membrane Monoamine Transporter) transporters in the transport of monoamines and their role in the AD response, these genes will be integrated in the selection of the panel of genes for the NGS study. Conclusion: This work shows that routine genotyping of the SNPs of CYP2D6, of CYP2C19 and of COMT Val(108/158) Met cannot be recommended in clinical practice in psychiatry for depressed patients treated by VEN. This work will continue with the NGS analyses that will attempt to identify relevant, rare and very rare variants, in particular for genes that have not been studied in a context of MDD such as OCTs and PMATs.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第22009号 / 社医博第95号 / 新制||社医||10(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 中山 健夫, 教授 村井 俊哉, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

The norepinephrine transporter (NET) plays a pivotal role in terminating noradrenergic signaling and conserving norepinephrine (NE) through the process of re-uptake. Recent evidence suggests a close association between NE release and regulation of NET function. The present study evaluated the relationship between release and uptake, and the cellular mechanisms that govern these processes. KCl stimulation of PC12 cells robustly increased [ H]NE uptake via the NET and simultaneously increased [ H]NE release. KCl-stimulated increases in uptake and release were dependent on Ca . Treatment of cells with phorbol-12-myristate-13-acetate (PMA) or okadaic acid decreased [ H]NE uptake but did not block KCl-stimulated increases in [ H]NE uptake. In contrast, PMA increased [ H]NE release and augmented KCl-stimulated release, while okadaic acid had no effects on release. Inhibition of Ca -activated signaling cascades with KN93 (a Ca calmodulin-dependent kinase inhibitor), or ML7 and ML9 (myosin light chain kinase inhibitors), reduced [ H]NE uptake and blocked KCl-stimulated increases in uptake. In contrast, KN93, ML7 and ML9 had no effect on KCl-stimulated [ H]NE release. KCl-stimulated increases in [ H]NE uptake were independent of transporter trafficking to the plasma membrane. While increases in both NE release and uptake mediated by KCl stimulation require Ca , different intracellular mechanisms mediate these two events.

This study was designed to analyze whether the sleep aid eszopiclone may facilitate the efficacy of fluoxetine on social defeat stress (SDS) in the mouse. Subjects were adult male ‘intruder’ C57/B6 mice that that were exposed to a retired ‘resident’ male breeder ICR mouse in this animal’s home cage for a 5 min period for 10 consecutive days. During this interaction, the resident would establish physical dominance of the intruder. After confrontation, the intruder was housed in a cage that allowed sensory contact with the resident mouse but that would not allow physical interaction during the 10-day period. Once the 10 days of interaction were complete, all animals were assigned to one of four drug treatment groups, and treatment was given for up to 18 days: saline treatment, fluoxetine (10 mg/kg) only, eszopiclone only (3 mg/kg), or fluoxetine + eszopiclone. A social interaction test was given on days 1, 5, 10, and 15 of drug treatment. Sucrose preference was also tested during the interaction test. Results showed that eszopiclone facilitated the action of fluoxetine on the interaction test at days 1 and 5, and these two groups were equivalent on days 10 and 15. SDS produced a significant decrease in sucrose preference that was not affected by drug treatment. This study demonstrates that eszopiclone facilitates the action of fluoxetine in the SDS paradigm, paralleling clinical studies that showed facilatory effects of the drug combination in depressed patients. Future work will examine neurochemical mechanisms underlying the effects of this drug combination

The DNA base excision repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), is a multi-functional enzyme and a member of a subfamily of three PARPs that covalently build PAR polymers onto proteins to regulate their function. Drug inhibitors of PARPs have anti-cancer, anti-inflammatory, and neuroprotective effects. Recently, we reported elevated gene expression levels of PARP1 in postmortem brain tissues from donors who had an active major depressive disorder at the time of death. Since PARP1 gene expression is positively correlated with PARP1 activity, these findings indicate that elevated PARP1 activity may contribute to brain pathology associated with depressive behavior. Therefore, we speculated that drug inhibitors of PARP1 may have antidepressant properties. To determine whether a rodent model could be used to evaluate the role of PARP1 in depressive-like behaviors, rats were exposed to repeated psychological stressors (social defeat and chronic unpredictable stress) for 10 days. Anhedonia (estimated by sucrose preference) and brain PARP1 gene expression levels were measured. After stress exposure, rats exhibited significantly reduced sucrose preference and significantly higher levels of brain PARP1 gene expression. To examine potential antidepressant activity of PARP inhibitors, rats were administered PARP inhibitors or saline vehicle and were exposed to the Porsolt swim test or repeated social defeat and chronic unpredictable stress. Two PARP inhibitors were investigated, 3-aminobenzamide (3-AB) and 5-aminoisoquinolinone (5-AIQ). PARP inhibitors produced antidepressant-like effects in the Porsolt swim test similar to the common antidepressant fluoxetine by significantly decreasing immobility time and increasing latency to immobility. PARP1 inhibitors did not significantly affect locomotor activity or swim speeds, suggesting that antidepressant-like actions of these drugs were not secondary to a stimulant effect. Treatment of rats with a combination of 3-AB and fluoxetine, at low doses of these drugs that individually did not have antidepressant-like effects, significantly decreased immobility time and increased latency to immobility in the swim test. Finally, treatment of rats with 3-AB significantly increased sucrose preference and social interaction times relative to vehicle-treated control rats following repeated exposure to combined social defeat and unpredictable stress, exhibiting effects similar to fluoxetine treatment. These findings uncover PARP1 as a unique molecular target for the development of a novel class of antidepressants that could be used alone or in combination with existing antidepressants.

We report on 3 subjects with premenstrual magnification of major depression (PMMD) treated with nefazodone who benefited from a supplement of additional nefazodone premenstrually. During the 6-month study, subjects were given supplements of either additional nefazodone or placebo prior to the expected onset of menses (double-blind crossover design). Symptoms were assessed during the late luteal and follicular phases. All subjects showed significant improvement for the months in which they received nefazodone supplements, but not when given placebo. Premenstrual dose increase is a clinically promising intervention for women who experience PMMD.

Medication compliance/noncompliance was examined in context of: severity of symptoms; medical side effects; medication education; perceived stigma; and effects on family/social support system. A null hypothesis was formulated for each correlate, stating that those patients who reported a high level of an independent variable (IV) would not be any more likely to discontinue their medication than patients who reported a low level of an IV. To obtain data, a medical usage questionnaire and a depression, assessment (OQT"-45.2) were used. Statistical significance was not obtained for any of the hypothesized relationships but trends were consistent with the established literature. The implication points to the efficacy of relational therapy as a conjunct to the medical treatment of depression.

No description available.

BACKGROUND: Major depression is a pervasive condition that affects every aspect of a patient’s life, and many patients are unable to find symptom alleviation with the current available medications. Ketamine has recently shown promise as a rapid-acting antidepressant, yet its mechanisms are not yet well-understood. OBJECTIVE: We sought to understand the change in depression symptom interrelationships, with particular interest in sleep, in the context of ketamine treatment in depression by completing a network analysis. METHODS: 97 patients with treatment-resistant depression were given ketamine over six treatments, and symptoms were examined via the Quick Inventory of Depressive Symptomology (QIDS-SR-16). Two networks were constructed: one prior to the first treatment, and one prior to the sixth treatment. Each symptom of the inventory formed a node, and partial correlations were used to construct the edges of the network. Centrality indices and network structure was then evaluated and compared. RESULTS: Centrality indices measured were unstable, limiting assertions to node strength, but global network structure was revealed to be changed between the networks. CONCLUSION: The data suggests that ketamine may affect the interrelationships between depressive symptoms, by impacting some symptoms more than others.