The influence of the serotonin transporter gene 5-HTTLPR polymorphism on suicidal behaviors: a meta-analysis

Fanelli, Giuseppe; Serretti, Alessandro

doi:10.1016/j.pnpbp.2018.08.007

Cited by 42 publications

(39 citation statements)

References 143 publications

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“…Furthermore, distal (predisposing) factors interact with proximal (precipitating) factors in determining suicidal event, i.e., genetic predisposition/vulnerability, early adversities and associated epigenetic modifications, and together may modulate suicidal behaviour and personality traits associated to suicide in MDD. 49 Early life adversity is considered one of the strongest risk factor for SA, i.e., exposure to maltreatment during the early phases of a person's development increases the risk of SB thought the lifespan within 2-to 5-fold times. 50 In fact, these events may epigenetically regulate key emotional and behavioural systems which in turns may contribute to the development of MDD and suicide behaviour, mainly by inducing a DNA methylation.…”

Section: Genetic Vulnerability and Epigenetic Modulationmentioning

confidence: 99%

Understanding the Complex of Suicide in Depression: from Research to Clinics

Orsolini

Latini²,

Pompili³

et al. 2020

Psychiatry Investig

239

167

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Objective Amongst psychiatric disorders, major depressive disorder (MDD) is the most prevalent, by affecting approximately 15–17% of the population and showing a high suicide risk rate equivalent to around 15%. The present comprehensive overview aims at evaluating main research studies in the field of MDD at suicide risk, by proposing as well as a schematic suicide risk stratification and useful flow-chart for planning suicide preventive and therapeutic interventions for clinicians.Methods A broad and comprehensive overview has been here conducted by using PubMed/Medline, combining the search strategy of free text terms and exploded MESH headings for the topics of ‘Major Depressive Disorder’ and ‘Suicide’ as following: ((<i>suicide</i> [Title/Abstract]) AND (<i>major depressive disorder</i> [Title/Abstract])). All articles published in English through May 31, 2019 were summarized in a comprehensive way.Results Despite possible pathophysiological factors which may explain the complexity of suicide in MDD, scientific evidence supposed the synergic role of genetics, exogenous and endogenous stressors (i.e., interpersonal, professional, financial, as well as psychiatric disorders), epigenetic, the hypothalamic-pituitary-adrenal stress-response system, the involvement of the monoaminergic neurotransmitter systems, particularly the serotonergic ones, the lipid profile, neuro-immunological biomarkers, the Brain-derived neurotrophic factor and other neuromodulators.Conclusion The present overview reported that suicide is a highly complex and multifaceted phenomenon in which a large plethora of mechanisms could be variable implicated, particularly amongst MDD subjects. Beyond these consideration, modern psychiatry needs a better interpretation of suicide risk with a more careful assessment of suicide risk stratification and planning of clinical and treatment interventions.

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Section: Genetic Vulnerability and Epigenetic Modulationmentioning

confidence: 99%

Understanding the Complex of Suicide in Depression: from Research to Clinics

Orsolini

Latini²,

Pompili³

et al. 2020

Psychiatry Investig

239

167

View full text Add to dashboard Cite

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“…To date, numerous studies on genetic predisposition to SB have demonstrated association of SB risk with serotonergic system genes such as serotonin transporter (SLC6A4), tryptophan hydroxylase (TPH), and serotonin receptor 1A (5-HT1A) (Bach, Arango, 2012). In 2018, a meta-analysis of 45 studies was conducted, confirming the association of a low-expressing S allele in the serotonin transporter gene (SLC6A4) with an increased risk of developing SB (Fanelli, Serretti, 2018).…”

Section: The Role Of Genetic Factors In the Development Of Suicidal Bmentioning

confidence: 94%

“…Suicidal behavior (SB) is a generic term used to denote risk, attempts and committed suicide (Bani-Fatemi et al, 2015). SB is the second cause of death among individuals of young age and takes the 10th place in all age groups worldwide Fanelli, Serretti, 2018). For example, a longitudinal study of adolescents aged 13-18 revealed that 12.1 % of American adolescents had suicidal thoughts, 4 % were planning suicides, and 4.1 % committed suicide (Nock et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Epigenetics of suicidal behavior

et al. 2019

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Suicide is the second leading cause of death among young people and therefore being a serious global problem worldwide. The study of genetic and epigenetic factors in the development of suicidal behavior plays an important role in the development of advanced methods of diagnosis and treatment of this pathology. The role of hereditary factors in the development of suicidal behavior is estimated at 30–55 %, with a pronounced comorbidity with other psychopathologies. The study of genetic liability to suicidal behavior is based on molecular-genetic methods including association and linkage analyses, chip gene expression arrays, and genome-wide association studies. Published data identified multiple genes including those involved in the functioning of serotonergic (SLC6A4, TPH, 5-HT1A), hypothalamic-pituitary-adrenal systems (FKBP5) and polyamines (SAT and OATL1) associated with suicidal behavior. However, the diversity of interacting genetic loci complicates the interpretation of the development of a complex phenotype of pathology and prevents the association from being detected. To solve this problem and interpret the missing relationship between the environment and the genome, promising results were obtained from a study of epigenetic factors, which affected the expression of a number of candidate genes involved in brain functioning in suicidal behavior. The analysis of a brain obtained from suicide victims, representing a unique tool for the analysis of modified genomic processes, revealed a wide range of reprogramming patterns of DNA methylation in promoters of the genes of polyamine (OAZ1, OAZ2, AMD1, ARG2, SKA2), serotonergic (SLC6A4) and GABAergic (GABRA1) systems, HPA-axis (GR, NR3C1), tyrosine kinase (TrkB) receptors, brain-derived neurotrophic factor (BDNF). The role of histone modifications in distinct genes (Cx30, Cx43, TrkB.T1) and the expression of specific long noncoding RNAs and microRNAs in the development of suicidal behavior, which is promising for the development of diagnostic algorithms and target therapy, is discussed.

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“…The human SERT, encoded by the SLC6A4 gene, presents a functional polymorphism in the promoter region (5-HTTLPR) generating a short and a long allele variant of the serotonin transporter (Murphy et al, 2008). The short allelic variant induces a decrease in the SERT transcription in comparison to the long allelic variant (Lesch et al, 1996), and it is linked to increased risk for depression and suicidal behavior (Bleys et al, 2018;Caspi et al, 2003;Fanelli and Serretti, 2019;Homberg et al, 2014). Additionally, the short allele variant appears to be associated with insufficient response to SSRIs (Kroeze et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

BDNF overexpression in the ventral hippocampus promotes antidepressant- and anxiolytic-like activity in serotonin transporter knockout rats

Diniz¹,

Calabrese

Brivio

et al. 2020

Preprint

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AbstractBrain-derived neurotrophic factor is one of the most studied proteins playing a pivotal role in neuroplasticity events and vulnerability and resilience to stress-related disorders. Most importantly, BDNF is decreased in depressive patients, and increased after antidepressant treatment. Additionally, BDNF was found to be reduced in a genetic subset of depression susceptible patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT-/-) is one of the animal models used to investigate the underlying molecular mechanisms behind the genetic susceptibility to depression in humans. SERT-/- rats present decreased BDNF levels, especially BDNF exon IV, in the prefrontal cortex (PFC) and ventral hippocampus (vHIP), and display anxiety- and depression-like behavior. To investigate whether upregulating BDNF in the vHIP would meliorate the phenotype of SERT-/- rats, we overexpressed BDNF locally into the rat brain by means of stereotaxic surgery and submitted the animals to behavioral challenges, including the sucrose consumption, the open field, and forced swim tests. Additionally, we measured hypothalamus-pituitary-adrenal (HPA)-axis reactivity. The results showed that lentivirus-induced BDNF IV overexpression in the vHIP of SERT-/- rats promoted higher sucrose preference and sucrose intake, on the first day of the sucrose consumption test, indicative for decreased anhedonia-like behavior. Moreover, it decreased immobility time in the forced swim test, suggesting adaptive passive coping. Additionally, BDNF upregulation increased the time spent in the center of a novel environment, implying decreased novel-induced anxiety-like behavior. Finally, it promoted a stronger decrease in plasma corticosterone levels 60 minutes after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT-/- rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential candidate for the development new therapeutic approaches targeting the improvement of depressive symptoms.

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The influence of the serotonin transporter gene 5-HTTLPR polymorphism on suicidal behaviors: a meta-analysis

Cited by 42 publications

References 143 publications

Understanding the Complex of Suicide in Depression: from Research to Clinics

Understanding the Complex of Suicide in Depression: from Research to Clinics

Epigenetics of suicidal behavior

BDNF overexpression in the ventral hippocampus promotes antidepressant- and anxiolytic-like activity in serotonin transporter knockout rats

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