Polimorfna regija vezana za gen serotoninskog transportera u bolesnika s posttraumatskim stresnim poremećajem

Kovačić, Zrnka (2010) Polimorfna regija vezana za gen serotoninskog transportera u bolesnika s posttraumatskim stresnim poremećajem. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Posttraumatic stress disorder (PTSD) is characterized by neurobiological and psychophysiological alterations and psychological symptoms. The clinical picture of PTSD is often complicated by different comorbid psychiatric disorders and suicidal behaviour. Complex interactions among traumatic experience, neurobiological, genetic, and environmental factors and early traumatic experience are assumed to lead to PTSD. Although the role of central 5-hydroxytryptamine (5-HT, serotonin) in the pathophysiology of PTSD is still unclear, it is believed that 5-HT and related genes are critical for the development of PTSD symptoms, primarily due to the role of 5-HT in the mood regulation, arousal, and sleep cycle. It has been shown that serotonin transporter gene polymorphism (5-HTTLPR) influences the development of depression induced by various life stressors, whereas its possible role in the development of PTSD has not been completely elucidated. Only a few studies reported the association between 5-HTTLPR and PTSD, bun none was performed in a homogenous veteran population of the same ethnicity, sex, and matched traumatic experience. Since platelet and brain serotonin are structurally identical and coded by the same gene, and platelet 5-HT concentration is altered in particular psychopathological conditions and symptoms, we investigated the concentration of platelet 5-HT and 5-HTTLPR in war veterans with or without PTSD, comorbid disorders, and suicidal behaviour. The overall aim of the study was to evaluate the association between SS, LS, and LL genotypes of the 5-HTTLPR and development of PTSD, and to determine if the concentration of platelet 5-HT in patients with PTSD might be used as a possible biochemical marker of more severe (psychotic or depressive) forms of PTSD, or suicidal behaviour which occurs in PTSD. The study was performed in a sample of 608 war veterans randomly selected from a clinical population in the Referral Center for Stress-related Disorders of the University Hospital Dubrava and Polyclinic Neuron of the Croatian Institute for Brain Research, 115 healthy male volunteers undergoing a regular systematic health examination at the Department of Aviation Medicine, Dubrava University Hospital, Zagreb, Croatia. For data collection, we used Sociodemographic questionnaire; Structured anamnestic pretraumatic, traumatic (combat-related) and posttraumatic experience questionnaire; and Mini International Neuropsychiatric Interview (MINI); as well as the Clinician Administered PTSD Scale (CAPS), Positive and Negative Syndrome Scale (PANSS), Hamilton Rating Scale for Depression (HAMD), and Hamilton Anxiety Scale (HAMA). Differences between the scores on these scales and platelet 5-HT concentrations were analyzed with one-way analysis of variance (ANOVA) and Tukey’s test. Differences in the allele and genotype frequencies of the 5-HTTLPR were analyzed with a χ2-test. The level of significance was set at 5%. Psychotic and anxiety symptoms were more intense, and PTSD symptoms more severe, in war veterans with psychotic PTSD than in those with PTSD, war veterans with PTSD and comorbid depression, war veterans with PTSD and other comorbid disorders. War veterans with psychotic PTSD had significantly increased platelet 5-HT concentration, whereas war veterans with suicidal tendencies had significantly decreased platelet 5-HT concentration compared to all other study groups. These differences indicated that PTSD with psychotic symptoms could be a separate clinical entity. Research results showed that platelet 5-HT could be used as a peripheral biological marker of particular symptoms and behaviour (e.g., psychotic symptoms and suicidal behaviour) in war veterans with PTSD. Since no differences were found in the frequency of alleles and genotypes of the 5HTTLPR between war veterans with PTSD, war veterans with PTSD and comorbid depression, war veterans with psychotic PTSD, war veterans with PTSD and other comorbid disorders, war veterans without PTSD and healthy subjects, or between war veterans with PTSD with or without suicidal tendencies, our study did not confirm the hypothesis that the presence of the SS genotype of the 5-HTTLPR was associated with higher likelihood of development of PTSD and/or suicidal behaviour. Since numerous biological mechanisms are involved in the development of PTSD and/or suicidal behaviour, a single gene may only have a mild influence on these complex behaviours or disorders. Our results did not confirm the significant association between the genotypes or alleles for the 5-HTTLPR and development of PTSD or suicidal behaviour in PTSD. Therefore, a prospective study in a larger sample of subjects with more pronounced suicidal behaviour, such as attempted suicide, should be performed to verify our results.

Abstract in Croatian

PTSP je obilježen neurobiološkim i psihofiziološkim promjenama te psihološkim simptomima, a klinička slika je često komplicirana pojavom različitih komorbidnih psihijatrijskih poremećaja i samoubilačkim porivima. Pretpostavlja se da kompleksne interakcije između doživljaja traume, neurobioloških i genetskih čimbenika, čimbenika iz okoline i ranog traumatskog iskustva dovode do razvoja PTSP-a. Premda je uloga središnjeg 5-HT-a u patofiziologiji PTSP-a još uvijek nejasna, smatra se da su 5-HT i pripadajući geni ključni za razvoj PTSP simptoma, i to radi uloge 5-HT-a u nadzoru raspoloženja, pobudljivosti i spavanja. Pokazano je da varijante gena za serotoninski transporter s obzirom na 5-HTTLPR utječu na razvoj depresije povezane sa životnim stresorima, dok njihova moguća uloga u razvoju PTSP-a nije potpuno istražena. U literaturi do sada postoji samo nekoliko istraživanja o povezanosti 5-HTTLPR-a i PTSP-a, no niti jedno nije bilo provedeno na populaciji veterana koja je bila homogena s obzirom na rasu, spol i traumatsko iskustvo. Budući da su trombocitni i moždani 5-HT strukturalno identični i kodirani istim genom, a koncentracija trombocitnog 5-HT-a je promijenjena u određenim psihopatološkim stanjima i simptomima, istražili smo koncentraciju trombocitnog 5-HT-a i varijante gena za serotoninski transporter s obzirom na 5-HTTLPR u ratnih veterana s PTSP-om ili bez njega, s komorbidnim poremećajima ili bez njih i sa samoubilačkim porivima ili bez njih. Opći cilj rada bio je istražiti povezanost SS, LS i LL genotipova gena za serotoninski transporter s obzirom na 5-HTTLPR i pojave PTSP-a te odrediti koncentraciju trombocitnog 5-HT-a u bolesnika s PTSP-om kao mogućeg biokemijskog pokazatelja u prepoznavanju težih (psihotičnih ili depresivnih) oblika PTSP-a te samoubilačkih poriva koji se javljaju u PTSP-u. Istraživanje je provedeno metodom slučajnog uzorka na 608 ratnih veterana iz kliničke populacije Referentnog centra za poremećaje uzrokovane stresom Kliničke bolnice Dubrava i Poliklinike Neuron Hrvatskog instituta za istraživanje mozga, 115 zdravih dobrovoljaca muškog spola, koji su bili podvrgnuti redovitom sistematskom pregledu na Odjelu zrakoplovne medicine KB Dubrava. Primijenjen je Upitnik za sociodemografske podatke, Strukturirani anamnestički upitnik za pretraumatska, traumatska (borbena) i posttraumatska iskustva, Međunarodni neuropsihijatrijski intervju (MINI), te sljedeće skale: Klinička skala za posttraumatski stresni poremećaj (CAPS), Skala pozitivnih i negativnih psihotičnih simptoma (PANSS), Hamiltonova skala za depresiju (HAMD) i anksioznost (HAMA). Razlike u broju bodova na kliničkim skalama i koncentraciji trombocitnog 5-HT-a analizirane su jednosmjernom analizom varijance (ANOVA-e) i Tukeyjevim testom. Razlike u učestalosti pojedinih alela ili genotipova 5-HTTLPR-a analizirane su χ2-testom. Rezultati su interpretirani na razini značajnosti od 5%. Opažen je veći intenzitet psihotične i anksiozne simptomatike te veća težina simptoma iz kruga PTSP-a kod ratnih veterana s psihotičnim PTSP-om prema veteranima s PTSP-om, ratnim veteranima s PTSP-om i komorbidnom depresijom, te ratnim veteranima s PTSP-om i drugim komorbidnim poremećajima. Ratni veterani s psihotičnim PTSP-om imali su značajno povišenu koncentraciju trombocitnog 5-HT-a, a ratni veterani sa samoubilačkim porivima značajno sniženu koncentraciju trombocitnog 5-HT-a prema svim ostalim istraživanim skupinama. Navedene razlike upućuju da bi PTSP s psihotičnim simptomima mogao biti zaseban klinički entitet. Rezultati istraživanja upućuju na to da bi se trombocitni 5-HT mogao koristiti kao periferni biološki pokazatelj određenih simptoma i ponašanja (npr. psihotičnih simptoma ili samoubilačkih poriva) kod ratnih veterana s PTSP-om. Budući da nisu pronađene značajne razlike u frekvenciji pojavljivanja varijanti gena za serotoninski transporter s obzirom na 5-HTTLPR između ratnih veterana s PTSP-om, ratnih veterana s PTSP-om i komorbidnom depresijom, ratnih veterana s psihotičnim PTSP-om, ratnih veterana s PTSP-om i drugim komorbidnim poremećajima, ratnih veterana bez PTSP-a ili zdravih ispitanika, kao ni između ratnih veterana s PTSP-om sa samoubilačkim porivima ili bez njih, ti rezultati nisu potvrdili hipotezu da je prisutnost SS genotipa gena za serotoninski transporter s obzirom na 5-HTTLPR povezana s većom vjerojatnošću pojave PTSP-a i/ili samoubilačkih poriva. Budući da su mnogobrojni biološki mehanizmi uključeni u nastanak PTSP-a i/ili samoubilačkih poriva, jedan gen može imati vrlo mali učinak na ta kompleksna ponašanja ili poremećaje. Naši podatci nisu potvrdili značajnu povezanost između genotipova ili alela gena za serotoninski transporter s obzirom na 5-HTTLPR i razvoj PTSP-a ili samoubilačkih poriva u PTSP-u, pa ove rezultate treba potvrditi prospektivnim istraživanjem na većem uzorku ispitanika, s teže izraženim samoubilačkim ponašanjem, kao što su pokušaji samoubojstva.

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