The brain serotonin transporter binding in young adults : methodological considerations and association with Bulimia Nervosa and acquired obesity

The neurotransmitter serotonin (5-HT) modulates many functions important for life, e.g., appetite and body temperature, and controls development of the neural system. Disturbed 5-HT function has been implicated in mood, anxiety and eating disorders. The serotonin transporter (SERT) controls the amount of effective 5-HT by removing it from the extracellular space. Radionuclide imaging methods single photon emission tomography (SPET) and positron emission tomography (PET) enable studies on the brain SERTs. This thesis concentrated on both methodological and clinical aspects of the brain SERT imaging using SPET. The first study compared the repeatability of automated and manual methods for definition of volumes of interest (VOIs) in SERT images. The second study investigated within-subject seasonal variation of SERT binding in healthy young adults in two brain regions, the midbrain and thalamus. The third study investigated the association of the midbrain and thalamic SERT binding with Bulimia Nervosa (BN) in female twins. The fourth study investigated the association of the midbrain and hypothalamic/thalamic SERT binding and body mass index (BMI) in monozygotic (MZ) twin pairs. Two radioligands for SERT imaging were used: [123I]ADAM (studies I-III) and [123I]nor-beta-CIT (study IV). Study subjects included young adult MZ and dizygotic (DZ) twins screened from the FinnTwin16 twin cohort (studies I-IV) and healthy young adult men recruited for study II. The first study validated the use of an automated brain template in the analyses of [123I]ADAM images and proved automated VOI definition more reproducible than manual VOI definition. The second study found no systematic within-subject variation in SERT binding between scans done in summer and winter in either of the investigated brain regions. The third study found similar SERT binding between BN women (including purging and non-purging probands), their unaffected female co-twins and other healthy women in both brain regions; in post hoc analyses, a subgroup of purging BN women had significantly higher SERT binding in the midbrain as compared to all healthy women. In the fourth study, MZ twin pairs were divided into twins with higher BMI and co-twins with lower BMI; twins with higher BMI were found to have higher SERT binding in the hypothalamus/thalamus than their leaner co-twins. Our results allow the following conclusions: 1) No systematic seasonal variation exists in the midbrain and thalamus between SERT binding in summer and winter. 2) In a population-based sample, BN does not associate with altered SERT status, but alterations are possible in purging BN women. 3) The higher SERT binding in MZ twins with higher BMIs as compared to their leaner co-twins suggests non-genetic association between acquired obesity and the brain 5-HT system, which may have implications on feeding behavior and satiety.Serotoniini (5-HT) on yksi aivojen välittäjäaineista, ja se osallistuu mm. hermoston kehityksen sekä monien elintärkeiden toimintojen, kuten ruokahalun ja ruumiinlämmön, säätelyyn. Useisiin psykiatrisiin sairauksiin, esimerkiksi masennukseen ja syömishäiriöihin, uskotaan liittyvän 5-HT-järjestelmän häiriö. Serotoniinitransportteri (SERT) on 5-HT:n kuljettajaproteiini, joka poistaa 5-HT:a solunulkoisesta tilasta ja siten säätelee vaikuttavan 5-HT:n määrää. Aivojen serotoniinitransporttereita voidaan kuvantaa käyttämällä yksifotoniemissiotomografiaa (SPET) tai positroniemissiotomografiaa (PET). Väitöskirjatyössä perehdyttiin aivojen serotoniinitransporttereiden SPET-tutkimuksiin eri näkökannoilta. Ensimmäisessä osatyössä verrattiin automatisoidun ja manuaalisen mielenkiintoalueiden rajaustavan toistettavuutta SERT-kuvien analysoinnissa. Toisessa osatyössä tutkittiin fysiologisen vuodenaikavaihtelun esiintymistä keskiaivojen ja talamuksen alueiden SERT-kertymissä tutkimalla samoja terveitä koehenkilöitä sekä kesällä että talvella. Kolmannessa osatyössä verrattiin keskiaivojen ja talamuksen alueiden SERT-kertymiä bulimia nervosaa (BN) sairastavilla naisilla, heidän terveillä kaksossisarillaan ja muilla terveillä kaksosnaisilla. Neljännessä osatyössä tutkittiin keskiaivojen ja hypotalamuksen/talamuksen alueiden SERT-kertymien ja painoindeksin yhteyttä monotsygoottisista kaksosista koostuvassa aineistossa vertaamalla suuremman painoindeksin omaavia kaksosia heidän pienemmän painoindeksin omaaviin kaksossisariinsa. Osatöissä käytettiin kahta eri SERT-kuvantamiseen soveltuvaa merkkiainetta: [123I]ADAM:ia (osatyöt I-III) ja [123I]nor-beta-CIT:ia (osatyö IV). Automatisoituun menetelmään pohjautuva [123I]ADAM-kuvien analysointimenetelmä osoittautui toistettavuudeltaan perinteistä manuaalista mielenkiintoalueiden rajaustapaa paremmaksi. Keskiaivojen ja talamuksen alueiden SERT-kertymissä ei todettu systemaattista vuodenaikaan liittyvää vaihtelua kesällä ja talvella tehtyjen kuvausten kesken. Keskiaivojen ja talamuksen SERT-kertymissä ei todettu merkittäviä eroja verrattaessa kaikkia bulimia nervosaa sairastaneita naisia, heidän terveitä kaksossisariaan ja terveitä naisia. Alaryhmäanalyyseissä vatsantyhjennys-tyyppistä bulimiaa sairastavien naisten alaryhmässä todettiin korkeampi SERT-kertymä keskiaivojen alueella kuin terveillä naisilla. Painoindeksin ja hypotalamuksen/talamuksen alueen SERT-kertymän välillä havaittiin yhteys: suuremman painoindeksin omaavilla kaksosilla todettiin korkeampi talamuksen/hypotalamuksen SERT-kertymä kuin heidän hoikemmilla kaksossisaruksillaan. Tulokset osoittavat, että automatisoitu menetelmä soveltuu aivojen [123I]ADAM-kuvien analysointiin. Keskiaivojen ja talamuksen alueiden SERT-kertymissä ei todettu merkittävää vuodenaikavaihtelua, minkä perusteella vuodenaikaa ei tarvitse huomioida sekoittavana tekijänä näiden alueiden SERT-kertymien kuvantamistutkimuksissa. Bulimia nervosaan ei väestöpohjaisessa aineistossa liity poikkeavaa SERT-kertymää keskiaivojen tai talamuksen alueilla, mutta bulimia nervosan alaryhmät saattavat erota tässä suhteessa toisistaan. Suuremman painoindeksin omaavien kaksosten suurempi SERT-kertymä hypotalamuksen/talamuksen alueella heidän hoikempiin kaksossisaruksiinsa verrattaessa viittaa ympäristötekijöihin liittyvään yhteyteen aivojen 5-HT-järjestelmän ja painoindeksin välillä, millä puolestaan saattaa olla syömiskäyttäytymiseen liittyviä vaikutuksia

The role of serotonergic system at the interface of aggression and suicide

Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies. Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions

Relationship of genetic polymorphisms with smoking behavior in the Malay population in Kelantan

Smoking addiction is a leading cause of diseases and mortality worldwide. However despite the well-known associated risk to health, smoking prevalence is still increasing worldwide. Nicotine is the main addictive substance in cigarettes that is responsible for the development as well as maintenance of smoking addiction. Genetic variables appear to play a key role in every aspect of nicotine addiction. Therefore genes involved in pharmacodynamic and pharmacokinetic of nicotine are logical candidates for nicotine addiction. Among listed candidate genes published for their known association with nicotine, four of them were selected which were nicotinic acetylcholine receptor (nAChR) rs2273502 and rs2236196, serotonin transporter 5HTTLPR and serotonin receptor 5HT2A and their relationships with smoking behavior in the Malays were investigated in this thesis. The study involved 248 Malay male smokers and 248 Malay male nonsmokers. DNA was extracted from leucocytes. The PCR product of nAChR rs2273502 and rs2236196 and 5HT2A were digested with restriction enzymes AfeI, Sau96I and HpaII respectively. The 5HTTLPR genotypes were analyzed by using PCR method and the results were classified as short (S) alleles or long (L) alleles. No mutation of rs2273502 (TT genotype) was detected in the nonsmoker group whilst the frequencies of homozygous CC genotype and heterozygous CT in nonsmokers were 75.8% and 24.2%, respectively. While in smokers, the frequencies were 73.4%, 2.0% and 24.6%, respectively. No significant difference was observed in genotype (χ2=5.106, p=0.078) and allele (χ2=1.064, p=0.302) frequencies among both group. The frequency distribution for rs2236196 polymorphism in smoker group was 80.6% for homozygous AA genotype while in nonsmoker 77.0%. No mutation (GG genotype) was detected in both groups. The AG genotype for smoker group was 19.4% while in nonsmoker group 23.0%. There was no significant difference observed in the genotype (χ2=0.979, p=0.323) and allele frequencies (χ2=0.863, p=0.353) between both groups. The genotype frequencies for 5HT2A polymorphism in smokers are CC= 10.1%, TT= 46.8% and CT=43.1%. While for nonsmokers are CC=8.1%, TT=46.4% and CT=45.6%. There was no significant difference observed in the genotype 5HT2A (χ2=0.724, p=0.696) and allele frequencies (χ2=0.075, p=0.784). On the other hand, for 5HTTLPR polymorphism, the frequencies of variant alleles S, L and heterozygous SL in nonsmokers were 39.1%, 11.3% and 49.6%, respectively. While in smokers, the frequencies of variant alleles S, L and heterozygous SL were 41.1%, 12.9% and 46.0%, respectively. No significant difference in the frequency distribution of alleles was found between smokers and nonsmokers of genotype 5HTTLPR (χ2 = 0.734, p=0.693) and allele frequencies (χ2 = 0.004, p=0.947) for both group studied. In conclusion, the nicotinic acetylcholine receptor (nAChR) rs2273502 and rs2236196, serotonin transporter (5HTTLPR) and serotonin receptor (5HT2A) polymorphisms were not found to be associated with the smoking behavior in Malay male subjects in Kelantan

Neuroendocrine stress responsiveness in human obesity and non-obesity controls

BACKGROUND: Obesity is a leading health burden of the 21st century. Alterations of the individual endocrine stress response and the monoamine system may pathophysiologically contribute to the obesity pandemic and its metabolic and mental complications. OBJECTIVES: (i) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its relation to serum concentrations of the arginine-vasopressin (AVP) surrogate copeptin in subjects with obesity (OB) compared to non-obesity controls (NOC), (ii) to test whether HPA axis responsiveness and copeptin are related to central noradrenaline (NA) transporter (NAT) availability, (iii) to assess brain serotonin transporter (SERT) binding potentials in OB compared to NOC. METHODS: 40 subjects with obesity (BMI > 35kg/m2) were compared to 25 non-obesity controls, matched for age and sex. (i) All individuals underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters were derived, and copeptin was assessed in the 1500h sample. (ii) Positron emission tomography (PET) was applied in 10 OB and 10 NOC using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and associated to curve indicators derived from the dex/CRH test as well as to copeptin. (iii) PET using the SERT selective radiotracer [11C] DASB was performed in 30 OB and 15 NOC for intergroup comparison. RESULTS: (i) OB subjects showed an increased HPA axis responsiveness as measured by cortisol concentrations after CRH stimulation. Correspondingly, the AVP surrogate copeptin was higher in OB along with being significantly associated to HPA axis reactivity. OB subjects had a higher adrenal sensitivity as measured by a lower ACTH/cortisol ratio. (ii) In NOC, the HPA response was related to NAT availability of the amygdala and the orbitofrontal cortex while in OB, this association was located in the hypothalamus. (iii) There were no differences in SERT availability between OB and NOC, but a higher inter-regional SERT connectivity was observed in OB. CONCLUSION: This work supports the notion of an increased endocrine stress response in human obesity, pointing to interacting alterations of the HPA and neurohypophyseal axes. Normally, these stress axes seem to be linked to prefrontal-limbic NA signaling, whereas a loss of this association in favor of a hypothalamic-centered relation is observed in OB. The SERT network pattern is more closely inter-related in OB, albeit central SERT concentrations per se do not differ between OB and NOC.:ABBREVIATIONS 4 LIST OF FIGURES 5 I. BIBLIOGRAPHIC DESCRIPTION 6 II. INTRODUCTION 7 2.1 Obesity as a global health burden 7 2.2 Neurobiology of stress 8 2.3 Stress and obesity 8 2.4 Neuroendocrine correlates of the stress response – The hypothalamic pituitary-adrenaland neurohypophyseal axes 9 2.4.1 Anatomy of the hypothalamic-pituitary-adrenal and neurohypophyseal axes 10 2.4.2 The role of CRH, ACTH and cortisol in the context of metabolism and obesity 11 2.4.3 The role of AVP in the context of metabolism and obesity 12 2.4.4 Measuring HPA axis responsiveness by means of the combined dexamethasonecorticotropin-releasing hormone (dex/CRH) test 12 2.4.5 Measuring AVP secretion by its equally-released surrogate copeptin 14 2.5 The noradrenergic system in the context of obesity and stress axis modulation 14 2.5.1 NA and its influence on feeding behavior16 2.5.2 The association of the noradrenergic system with the HPA and neurohypophyseal axes 16 2.5.3 Monoamine transporters as regulators of neurotransmitter signaling 17 2.5.4 Noradrenaline transporter imaging 18 2.6 The serotonergic system in obesity 19 2.6.1 Role of serotonin in the context of feeding behavior and metabolism 20 2.6.3 5-HTT imaging 21 2.7 Objectives and hypotheses 22 2.8 Study design 23 III. RESULTS 24 3. 1 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity 24 3. 2 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls 34 3. 3 Central serotonin transporter availability in highly obese individuals compared with nonobese controls: A [11C] DASB positron emission tomography study 46 IV. SUMMARY 56 4.1 Subjects with obesity show an enhanced HPA axis responsiveness which correlates to serum concentrations of the AVP surrogate copeptin and abdominal fat distribution 56 4.2 HPA axis responsiveness and copeptin concentrations are differentially related to central NAT availability in subjects with obesity compared to non-obesity controls 58 4.3 Central serotonin transporter availability does not significantly differ in subjects with obesity compared to their non-obesity counterparts 59 4.4 Future direction 61 V. References 62 VI. APPENDICES 79 6.1 Curriculum vitae 79 6.2 Publications 81 6.3 Scientific contribution of the doctoral candidate to the publications 82 6.4 Declaration of the independent writing of this thesis 83 6.5 Acknowledgements 8

Neurotrophins Role in Depression Neurobiology: A Review of Basic and Clinical Evidence

Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis

Neurobiological Correlates of Personality Traits: A Study on Harm Avoidance and Neuroticism

Harm Avoidance and Neuroticism are traits that predispose to mental illnesses. Studying them provides a unique way to study predisposition of mental illnesses. Understanding the biological mechanisms that mediate vulnerability could lead to improvement in treatment and ultimately to pre-emptive psychiatry. These personality traits describe a tendency to feel negative emotions such as fear, shyness and worry. Previous studies suggest these traits are regulated by serotonin and opiate pathways. The aim of this thesis was to test the following hypotheses using personality trait measures and positron emission tomography (PET): 1) Brain serotonin transporter density in vivo is associated with Harm Avoidance and Neuroticism traits. 2) μ-opioid receptor binding is associated with Harm Avoidance. In addition, we developed a methodology for studying neurotransmitter interactions in the brain using the opiate and serotonin pathways. 32 healthy subjects who were consistently in either the highest or lowest quartile of the Harm Avoidance trait were recruited from a population-based cohort. Each subject underwent two PET scans, serotonin transporter binding was measured with [11C] MADAM and μ-opioid receptor binding with [11C]carfentanil. We found that the serotonin transporter is not associated with anxious personality traits. However, Harm Avoidance positively correlated with μ-opioid receptor availability. Particularly the tendency to feel shy and the inability to cope with stress were associated μ-opioid receptor availability. We also demonstrated that serotonin transporter binding correlates with μ-opioid receptor binding, suggesting interplay between the two systems. These findings shed light on the neurobiological correlates of personality and have an impact on etiological considerations of affective disorders.Persoonallisuuden neurobiologiset taustatekijät Turvallisuushakuisuus ja neuroottisuus ovat persoonallisuuden piirteitä, joihin liittyy ahdistustaipumus ja joiden on osoitettu altistavan mielenterveyshäiriöille. Tutkimalla näitä persoonallisuuspiirteitä on mahdollisuus saada ainutlaatuista tietoa myös alttiudesta sairastua mielenterveyshäiriöön. Tällaista tietoa voitaisiin käyttää hyväksi psykiatrisen hoidon ja sairauksien ennaltaehkäisyn kehittämiseen. Turvallisuushakuisuus ja neuroottisuus kuvaavat taipumusta kokea negatiivisia tunteita kuten pelkoa, ujoutta ja huolta. Aikaisempien tutkimusten perusteella aivojen serotoniini ja opioidijärjestelmien ajatellaan olevan yhteydessä näihin persoonallisuuden piirteisiin. Tässä väitöskirjatyössä käytettiin positroniemissiotomografia (PET) –tekniikkaa aivojen välittäjäainejärjestelmien toiminnan mittaamiseen ja persoonallisuuskyselyjä (TCI, NEO) persoonallisuuspiirteiden määrittelyyn. Tutkimuksessa testattiin seuraavia hypoteeseja: serotoniinin takaisinottajaproteiini on yhteydessä turvallisuushakuisuuteen, serotoniinin takaisinottajaproteiini on yhteydessä neuroottisuuteen ja μ-opioidireseptori on yhteydessä turvallisuushakuisuuteen. Lisäksi tutkimuksessa kehitettiin menetelmä välittäjäaineverkoston tutkimiseen PET menetelmällä. Tutkimukseen värvättiin laajasta väestöpohjaisesta kohorttitutkimuksesta 32 tervettä koehenkilöä, jotka olivat toistettujen mittausten perusteella turvallisuushakuisuuden suhteen joko ylimmässä tai alimmassa kvartiilissa. Kaikille koehenkilöille tehtiin kaksi PET-kuvausta saman päivän aikana. Ensimmäisessä kuvauksessa käytettiin [11C]MADAM–merkkiainetta mittaamaan serotoniinin takaisinottajaproteiinisitoutumista. Toisessa kuvauksessa käytettiin [11C]karfentaniili–merkkiainetta mittaamaan μ-opioidireseptorisitoutumista. Tämän tutkimuksen perusteella serotoniinin takaisinottajaproteiini ei ollut yhteydessä turvallisuushakuisuuteen eikä neuroottisuuteen. Tutkimuksessa havaittiin kuitenkin positiivinen korrelaatio turvallisuushakuisuuden ja μ-opioidireseptorin välillä. Erityisesti ujous ja taipumus tuntea itsensä turvattomaksi vieraiden ihmisten seurassa sekä kyky selvitä stressistä olivat yhteydessä μ-opioidireseptoriin. Lisäksi serotoniinin takaisinottajaproteiinin havaittiin olevan yhteydessä μ-opioidireseptoriin tietyillä aivoalueilla, jotka liittyvät mieliala- ja ahdistuneisuushäiriöihin. Näitä löydöksiä voidaan tulevaisuudessa hyödyntää mielenterveyshäiriöiden etiologisessa ja mahdollisesti ennaltaehkäisevässä tutkimuksessa.Siirretty Doriast

Doctor of Philosophy

dissertationDepressive disorders (DD) are a leading cause of disability worldwide and display diverse symptoms including anhedonia, melancholia, decreased concentration, sleep and appetite disturbances, and suicidal thoughts and acts. Current available medications are still ineffective for more than 30% of patients, suggesting DD are multi-faceted heterogeneous disorders. Despite intense research, as yet there are no widely used biological diagnostic tests for DD. Since DD are likely a manifestation of both genetic and environmental factors, gene expression of peripheral blood leukocyte allows for a non-invasive means to evaluate trait- and state-dependent neurophysiological dysregulation. In this dissertation, we employed real-time quantitative polymerase chain reaction (qPCR) to evaluate differences between healthy controls and patients with medication-refractory depression, for a panel of candidate genes previously implicated in depression as well as novel genes implicated in related neurological disorders. Chapter 1 begins with an overview of the multiple domains involved in depression and of previous literature findings evaluating protein and gene expression. Chapter 2 describes one of our studies of gene expression of a small panel of 14 genes involved in the immune and stress response in 19 patients with medication-refractory depression, before and following symptom improvement, compared to 20 healthy controls. We found that patients displayed trait- and state-dependent dysregulation in immune cytokines IL-10 and IL-6, transcription factor NFkB1, the serotonin receptor HTR1D, GABAA modulator DBI, and the adrenergic receptors ADR2A and ADRB1. Furthermore, the dopamine receptor DRD4, the glucocorticoid receptor NR3C1, and SULT1A1 displayed acute changes following treatment, though no differences were observed Pretreatment. In Chapter 3, we describe another gene expression study with results using a larger sample size (42 patients and 38 controls) and an expanded gene panel (46 genes) that includes candidate genes from diverse biological pathways. In this study, we found upregulation of IL-10 and IL-6 as well as dysregulation in the amyloid precursor protein, neuregulin-1, and several ion channels that have roles in anxiety, pain, and fatigue. Finally, Chapter 4 summarizes results from both studies and discusses future research into promising biomarkers and novel mechanisms of depression

Serotonergic modulation of suicidal behaviour : integrating preclinical data with clinical practice and psychotherapy

Many studies have provided important information regarding the anatomy, development and functional organization of the 5-HT system and the alterations in this system that are present within the brain of the suicidal patient. There is also a growing interest in genetic factors associated with suicide, since these may lead to the emergence of personality traits that prove to be long-term predictors of suicidal behaviour. This review will focus on presenting the scientific literature on the role of the serotonergic system in suicidal behaviour as well as dysfunctional attitudes and personality traits associated with the suicidal patient. The association of the serotonin transporter gene, the 5-HT2 receptors and its metabolite 5-hydroxyindoleacetic acid with suicidal behaviour and animal models that may capture the complexity of suicidal behaviour will be discussed. Finally, the relationship between neurobiological models and psychotherapeutic interventions for suicide prevention will be considered with a focus on Schema Therapy (an approach that has shown particular promise in the treatment of suicidal individuals with personality disorders), aiming to invite the reader to integrate some aspects of the neurobiology of human suicidal behaviour into a model of suicide that can be used in a clinical encounter.peer-reviewe

Serotonin Transporter Polymorphism in Relation to Depression

Serotonin is regarded as one of the most important factors in modern psychiatry and a significant amount of research is associated with that neurotransmitter in some way. Serotonin transporter and its various polymorphisms are implied to be connected with various psychiatric disorders, mostly depression and suicide. In light of that fact, this review article will try to address new and current data regarding serotonin transporter polymorphisms and their association with depression. As this area of research in psychiatry is constantly growing and nowadays incorporates various other factors than was the case previously it was necessary to provide a brief overview of those factors. Therefore, data regarding serotonin transporter polymorphisms and its relation with gene-environment interactions, biological stress reactivity and personality traits and their possible combined effects on depression are discussed. No matter how big is the quantum of knowledge and research regarding serotonin, the only constant finding when analyzing the possible association of serotonin transporter polymorphism and depression are inconsistent conclusions. Therefore it can be concluded that molecular and neural mechanisms that underlie the interplay of genes, environmental adversity and personality traits that constitute disease risk remain incompletely understood. Due to these inconsistent conclusions, further genotyping of SLC6A4 and other genes is necessary, as well as studies performed on bigger samples of participants. Factors like life stress and environmental factors, which may contribute to increased vulnerability in susceptible individuals, should also be more extensively addressed as they may prove be the key to timely treatment and effective preventive strategies