103 research outputs found
Association between the COMT gene and rumination in a Hungarian sample.
Introduction: Rumination is a multidimensional trait which is a
proven risk factor in the vulnerability to depression. The aim
to identify the main risk genes for depression in addition to
the gene-environment interactions pointed to the importance of
intermediate phenotypes, like rumination, to improve our
understanding of the biological mechanisms of depression.
Catechol-O-Methyltransferase (COMT) gene is extensively
investigated in depression with contradictory results but its
association with rumination, as an intermediate phenotype in
depression, has not been investigated yet. Methods: In our
study, four tagging SNPs in the COMT gene (rs933271, rs740603,
rs4680, rs4646316) were genotyped in a nonclinical Hungarian
sample (n=939). We investigated the association between the COMT
gene and rumination scores measured by the Ruminative Response
Scale using haplotype trend regression. Results: We found a
significant association between COMT haplotypes and rumination
scores (p=0.013) but no significant association was apparent
between the functional Val158Met polymorphism (rs4680) and
rumination in any genetic model. Discussion: Variations in the
COMT gene exert complex effects on susceptibility to depression
involving intermediate phenotypes, such as rumination and also
impulsivity, as we previously demonstrated. Both rumination and
impulsivity represent maladaptive cognitive styles that can lead
to depressive state by influencing the response to negative life
events and life stressors. In conclusion, our findings provide
evidence that in addition to other genes, COMT also has a
significant role in the development of depression, and
demonstrate that analysing the complex phenotype associations of
genes by haplotype tagging is a powerful method
A kis „n”, nagy „P” probléma a neuropszichofarmakológiában, avagy hogyan kontrolláljuk a hamis felfedezések arányát
Számos korszerű neuropszichofarmakolĂłgiai vizsgálati mĂłdszer jellegzetessĂ©ge, hogy aránylag kevĂ©s vizsgálati egyĂ©nrĹ‘l (n) nagyon sok adatot (paramĂ©tert, P) gyűjt. PĂ©ldakĂ©ppen emlĂthetjĂĽk a kĂ©palkotĂł mĂłdszereket (pl. funkcionális mágneses rezonancia Ă©s egyĂ©b kĂ©palkotĂł eljárásokat), az elektroenkefalográfiát (EEG), vagy a genomikai vizsgálatokat. Egyetlen microarray chip pĂ©ldául több ezer prĂłbát tartalmazhat, azaz a P ezres nagyságrendekkel haladhatja meg az n-t. Az ilyen elrendezĂ©sű vizsgálatok elemzĂ©se komoly statisztikai problĂ©mákat vet fel, amit a statisztikai szakirodalomban kis "n" nagy "P" problĂ©mának neveznek. A többszörös tesztelĂ©s problĂ©mája akkor lĂ©p fel, ha kĂ©t vagy több csoportba tartozĂł egyĂ©neket hasonlĂtunk össze a mĂ©rt P számĂş jellemzĹ‘ alapján. Amennyiben az összehasonlĂtás az egyes jellemzĹ‘k alapján törtĂ©nik, akkor akár több ezer statisztikai hipotĂ©zisvizsgálat elvĂ©gzĂ©se is szĂĽksĂ©gessĂ© válhat. Amennyiben a többszörös tesztelĂ©s okozta megnövekedett klasszifikáciĂłs hibát nem vesszĂĽk figyelembe, akkor számos statisztikailag szignifikáns kĂĽlönbsĂ©get fedezhetĂĽnk fel a vizsgálati csoportok között. Azonban ezeknek a felfedezĂ©seknek egy rĂ©sze valĂłjában a vĂ©letlen műve Ă©s ezek a kĂsĂ©rleti eredmĂ©nyek általában nem reprodukálhatĂłak. A problĂ©mára több megoldás is szĂĽletett. Ezek közĂĽl cikkĂĽnkben a klaszter szintű összehasonlĂtást, valamint a hamis találati arányon alapulĂł statisztikai tesztet mutatjuk be
A new clinical evidence-based gene-environment interaction model of depression.
In our current understanding of mood disorders, the role of
genes is diverse including the mediation of the effects of
provoking and protective factors. Different or partially
overlapping gene sets play a major role in the development of
personality traits including also affective temperaments, in the
mediation of the effects of environmental factors, and in the
interaction of these elements in the development of depression.
Certain genes are associated with personality traits and
temperaments including e.g., neuroticism, impulsivity, openness,
rumination and extroversion. Environmental factors consist of
external (early and provoking life events, seasonal changes,
social support etc.) and internal factors (hormones, biological
rhythm generators, comorbid disorders etc). Some of these
environmental factors, such as early life events and some
prenatal events directly influence the development of
personality traits and temperaments. In the NEWMOOD cohort
polymorphisms of the genes of the serotonin transporter, 5-HT1A,
5-HT1B and 5-HT2A and endocannabinoid CB1 receptors, tryptophan
hydroxylase, CREB1, BDNF and GIRK provide evidence for the
involvement of these genes in the development of depression.
Based on their role in this process they could be assigned to
different gene sets. The role of certain genes, such as promoter
polymorphisms of the serotonin transporter (5-HTTLPR) and CB1
receptor has been shown in more than one of the above factors.
Furthermore, gene-gene interactions of these promoters
associated with anxiety suggest the application of these
polymorphisms in personalized medicine. In this review we
introduce a new model including environmental factors, genes,
trait and temperament markers based on human genetic studies
Further evidence for the involvement of 5-HT2C receptors in the pentylenetetrazole model of epilepsy
Antidepresszivumok, stresszorok es a szerotonin 1A receptor.
5-HT1A receptor is a receptor of surprises. Buspirone, an anxiolytic drug with a then yet unidentified mechanism of action had been marketed for years when it was discovered that it is a 5-HT1A partial agonist. Several more years had to pass before it was accepted that this receptor plays the key role in the action mechanism of buspirone. This was followed by further surprises. It was discovered that in spite of its anxiolytic effect buspirone activates the hypothalamic-pituitary-adrenal (HPA) stress axis, furthermore, it increases peripheral noradrenaline and adrenaline concentration via a central mechanism. Thus activation of this receptor leads to ACTH/corticosterone and catecholamine release and also increases beta-endorphine, oxytocin and prolactin secretion while decreasing body temperature, increasing food uptake, eliciting characteristic behavioural responses in rodents and also playing a role in the development of certain types of epilepsy. Human genetic studies revealed the role of 5-HT1A receptors in cognitive processes playing a role in the development of depression such as impulsiveness or response to environmental stress. This exceptionally wide spectrum of effects is attributable to the presence of 5-HT1A receptors in serotonergic as well as other, for example glutamatergic, cholinergic, dopaminergic and noradrenergic neurons. The majority of the effects of 5-HT1A receptors is manifested via the mediation of Gi proteins through the hyperpolarisation or inhibition of the neuron carrying the receptor. 5-HT1A receptors on serotonergic neurons can be found in the somatodendritic area and play a significant role in delaying the effects of antidepressants which is an obvious disadvantage. Therefore the newest serotonergic antidepressants including vilazodone and vortioxetine have been designed to possess 5-HT1A receptor partial agonist properties. In the present paper we focus primarily on the role of 5-HT1A receptors in stress and antidepressant response
Pharmaco- and therapygenetic aspects in the treatment of anxiety disorders beyond the serotonergic system: a brief review
A szezonális depresszió etiopatologiája és terápiás lehetóségei
To understand the etiology of seasonal affective disorder (SAD) heterogeneous biological, psychological and environmental mechanisms needs to be considered. The aim of our study was to review theoretical hypotheses and therapeutic possibilities for seasonal affective disorder, which focus on alterations of circadian rhythms and monoaminergic neurotransmitter function as well as the role of vitamin D3 and possible implications of the cognitive-behavioral model. These discrepant hypotheses are insufficient alone to interpret the pathophysiology of SAD, but the integrative dual vulnerability hypothesis is an option to explain emergence of seasonal affective disorder. In addition to summarizing theoretical approaches we also review and evaluate the therapeutic possibilities derive form these hypotheses. In practice the most effective treatment for SAD is the combination of light therapy, antidepressants and psychotherapy. Keywords: seasonal affective disorder, depression, circadian rhythm, pharmacotherapy, light therapy, D3 vitamin Correspondence: Eszter Molnar, e-mail: [email protected] Full text: www.mppt.hu
Genetically reduced FAAH activity may be a risk for the development of anxiety and depression in persons with repetitive childhood trauma
Fatty acid amide hydrolase (FAAH) inhibitors are addressed for promising anxiolytics, but human studies on genetically reduced FAAH activity, stress and affective phenotypes are scarce. We investigated the effect of a functional polymorphism of FAAH (FAAH C385A or rs324420; low FAAH activity and high anandamide concentration are associated with the A allele) together with childhood adversity on the anxious and depressive phenotypes in 858 subjects from the general population. Phenotypes were measured by the Zung Self-Rating Depression Scale (ZSDS), the depression and anxiety subscales of the Brief Symptom Inventory (BSI-DEP, BSI-ANX) and the State-Trait Anxiety scales (STAI-S, STAI-T). Childhood Adversity Questionnaire (CHA) was used to assess early life traumas. Frequency of the A allele was greater among subjects with high ZSDS scores compared to the CC genotype. Furthermore, FAAH C385A and the CHA have shown a robust gene-environment interaction, namely, significantly higher anxiety and depression scores were exhibited by individuals carrying the A allele if they had high CHA scores compared to CC carriers. These data provided preliminary evidence that genetically reduced FAAH activity and repetitive stress in the childhood are associated with increased vulnerability for anxiety and depression in later life. Our results together with earlier experimental data suggest that permanently elevated anandamide level together with early life stress may cause a lifelong damage on stress response probably via the downregulation of CB1R during the neurodevelopment in the brain. It may also point to pharmacogenomic consequences, namely ineffectiveness or adverse effects of FAAH inhibitors in this subpopulation
Nem pszichiátriai gyógyszerek szorongást és depressziót kiváltó mellékhatásai
Annak ellenére, hogy számos szomatikus betegség kezelésére alkalmazott – például daganatellenes, antimikrobás,
immunmoduláns, neurolĂłgiai, illetve hormonháztartásra hatĂł – gyĂłgyszer hathat negatĂv irányban a hangulatra,
ezt egészen a rimonabant 2008-ban emiatt történt visszavonásáig nem kezelték jelentőségének megfelelően. A szerzők
a teljes gyógyszerpalettát áttekintve tárgyalják a szorongást és a depressziót, mint gyógyszer-mellékhatásokat.
A gyógyszerválasztásnál minden esetben fi gyelembe kell venni, ha a betegeknél magas a depresszió kialakulásának
a kockázata, például, ha már korábban előfordult vagy jelenleg is fennáll a depressziós epizód vagy betegség, ha a
családi anamnézisben előfordul depresszió, illetve ha a betegnél olyan neurotikus személyiségvonások állnak fenn,
amelyek következtĂ©ben sĂ©rĂĽlĂ©kenyebb a depressziĂłt kiváltĂł hatásokkal szemben. A veszĂ©lyt jelentĹ‘ gyĂłgyszerek felĂrása
elĹ‘tt emellett cĂ©lszerű fi gyelembe venni az alkalmazni kĂvánt szer hatĂ©konyságát, a rendelkezĂ©sre állĂł alternatĂv
gyĂłgyszeres Ă©s nem gyĂłgyszeres terápiás lehetĹ‘sĂ©geket, Ă©s minden esetben biztosĂtani kell a beteg monitorozását a
kezelés során az esetleges depressziós vagy szorongásos tünetek mihamarabbi észlelése érdekében
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