Search

Suicidal Behavior (SB) is the second leading cause of death among youths worldwide and the tenth among all age groups. Inherited genetic differences have a role in suicidality with heritability ranging from 30 to 55%. The SLC6A4 5-HTTLPR gene variant has been largely investigated for association with SB, with controversial results. In this work, we sought to determine whether the results of previous meta-analyses were confirmed or modified subsequent to the inclusion of more recent literature data. An electronic literature search was performed to identify relevant studies published until July 2018. Data were analysed through RevMan v5.3. Subgroup and sensitivity meta-analyses were performed considering different SB sub-phenotypes, ethnicity, gender and psychiatric diagnostic categories. Our literature search yielded 1186 articles; among these, we identified 45 pertinent case-control studies (15,341 subjects). No association was found between low-expressing alleles or genotypes (S + LG alleles or S′ carrier genotypes) and SB in the primary analyses. However, low-expressing alleles (S + LG) were associated with an increased risk of Violent Suicide Attempt (OR = 1.44, C.I. 1.17–1.78, p = .0007). An effect of the same alleles on SB was found in a subpopulation of substance abusers, but this result was not confirmed after the exclusion of healthy subjects from the control group. The other sensitivity meta-analyses did not show any significant effect. Our findings contribute to clarify the conflicting previous evidence by suggesting an association between the 5-HTTLPR and Violent SB. Nonetheless, many other modulators, including environmental factors and epigenetic mechanisms may act to further increase the level of complexity.

The COVID-19 pandemic represents a collective trauma that may have enduring stress effects during sensitive periods, such as pregnancy. Prenatal stress may result in epigenetic signatures of stress-related genes (e.g., the serotonin transporter gene, SLC6A4) that may in turn influence infants’ behavioral development. In April 2020, we launched a longitudinal cohort study to assess the behavioral and epigenetic vestiges of COVID-19-related prenatal stress exposure in mothers and infants. COVID-19-related prenatal stress was retrospectively assessed at birth. SLC6A4 methylation was assessed in thirteen CpG sites in mothers and infants’ buccal cells. Infants’ temperament was assessed at 3-month-age. Complete data were available from 108 mother-infant dyads. Greater COVID-19-related prenatal stress was significantly associated with higher infants’ SLC6A4 methylation in seven CpG sites. SLC6A4 methylation at these sites predicted infants’ temperament at 3 months.

Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this system, and especially of the SLC6A4 gene, may be associated with psychiatric disorders. In this study we aimed to evaluate the pleiotropic nature of SLC6A4 alterations and their association with the overall risk of brain diseases rather than disorder-specific. SLC6A4 variants, namely 5HTTLPR, STin2, rs2066713, rs25531, rs4251417, rs6354 and rs7224199 were investigated in 4 independent cohorts of subjects with specific psychiatric disorders, including Alcohol dependence disorder (ALC), Alzheimer disease (ALZ), Schizophrenia (SCZ) and Bipolar disorder (BPD). Other variables (biochemical parameters and Psychiatric scales scores) were also tested for association. SLC6A4 polymorphisms are not associated with the risk of developing major psychiatric disorders (SCZ and BPD); however some signals were detected in ALC (HTTLPR pd = 9.25 × 10−03, pr = 7.24 × 10−03; rs2066713 pd = 6.35 × 10−08; rs25531 pd = 2.95 × 10−02; rs4251417 pd = 2.46 × 10−03), and ALZ (rs6354 pr = 1.22 × 10−02; rs7224199 pd = 1.00 × 10−08, pr = 2.65 × 10−02) cohorts. Some associations were also observed on exploratory analyses. Our findings did not reveal any major influence on SCZ and BPD development; On the other hand, some alteration of the SLC6A4 sequence were associated with an increased risk of ALC and ALZ disorders, suggesting common pathways. The results of this study should be carefully interpreted since it suffers of some inherent limitations (e.g. cohort size, slight ethnic heterogeneity). Further analyses may provide better detail on the molecular processes behind SLC6A4 alterations.

Resilience is the ability to cope with critical situations through the use of personal and socially mediated resources. Since a lack of resilience increases the risk of developing stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), a better understanding of the biological background is of great value to provide better prevention and treatment options. Resilience is undeniably influenced by genetic factors, but very little is known about the exact underlying mechanisms. A recently published genome-wide association study (GWAS) on resilience has identified three new susceptibility loci, DCLK2, KLHL36, and SLC15A5. Further interesting results can be found in association analyses of gene variants of the stress response system, which is closely related to resilience, and PTSD and MDD. Several promising genes, such as the COMT (catechol-O-methyltransferase) gene, the serotonin transporter gene (SLC6A4), and neuropeptide Y (NPY) suggest gene × environment interaction between genetic variants, childhood adversity, and the occurrence of PTSD and MDD, indicating an impact of these genes on resilience. GWAS on PTSD and MDD provide another approach to identifying new disease-associated loci and, although the functional significance for disease development for most of these risk genes is still unknown, they are potential candidates due to the overlap of stress-related psychiatric disorders and resilience. In the future, it will be important for genetic studies to focus more on resilience than on pathological phenotypes, to develop reasonable concepts for measuring resilience, and to establish international cooperations to generate sufficiently large samples.

Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRI) are commonly used for treating major depression. Regretfully, significant heterogeneity exists regarding the benefits of SSRI/SNRI in individual cases. We previously reported that a polymorphism located in the serotonin transporter linked promoter region (5-HTT LPR) is associated with an interindividual difference in SSRI treatment efficacy. However, this explains only a small part of the variation of this complex phenotype. Other 5-HTT variants in the coding regions, 3' untranslated region (3' UTR), and introns adjacent to each exon could also contribute to treatment response. Therefore, we performed a sequencing analysis of the SLC6A4 gene (coding for 5-HTT) and investigated the association between variants detected in this study and the antidepressant response to SSRI/SNRI in 201 Japanese depressive patients. Seventeen novel mutations were identified by sequencing analysis. We found that the polymorphism G2563T (rs3813034) as a tag single-nucleotide polymorphism of IVS9 A-90G (rs140701), G2356T (rs1042173), and A3641C (rs7224199) is associated with interindividual variability of SSRI/SNRI efficacy at week 6, independent from clinical variables and effect of 5-HTT LPR (P < 0.001 by multiple regression analysis). This polymorphism could help determine individualized SSRI/SNRI treatments for depressive patients in combination with 5-HTT LPR.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.44.

Aim: The identification of antidepressant drugs (ADs) response biomarkers in depression is of high clinical importance. We explored CHL1 and ITGB3 expression as tentative response biomarkers. Materials & methods: In vitro sensitivity to ADs, as well as gene expression and genetic variants of the candidate genes CHL1, ITGB3 and SLC6A4 were measured in lymphoblastoid cell lines (LCLs) of 58 depressed patients. Results: An association between the clinical remission of depression and the basal expression of CHL1 and ITGB3 was discovered. Individuals whose LCLs expressed higher levels of CHL1 or ITGB3 showed a significantly better remission upon AD treatment. In addition individuals with the CHL1 rs1516338 TT genotype showed a significantly better remission after 5 weeks AD treatment than those carrying a CC genotype. No association between the in vitro sensitivity of LCLs toward AD and the clinical remission could be detected. Conclusion: CHL1 expression in patient-derived LCLs correlated with the clinical outcome. Thus, it could be a valid biomarker to predict the success of an antidepressant therapy. Original submitted 8 December 2014; Revision submitted 2 March 2015

Visual Abstract, Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2fl°x conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following reestablishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.

Background: Social adjustment is impaired in depressed patients. The difficulty to adjust to social circumstances has been hypothesized to be one of the causes of depression, as well as a consequence of the disorder. Genetic variation in the serotonin transporter gene has been previously associated with social adjustment levels in patients with mood disorders. Methods: We investigated whether variations on the HTR1A (rs6295) and HTR2A (rs7997012) genes were associated with levels of social adjustment using the Social Adjustment Scale in two samples of depressed patients (total n=156). Results: Patients carrying the GG genotype of the HTR2A-rs7997012 showed better social adjustment in areas of work and family unit bonding. Limitations: These findings did not survive correction for multiple testing and should be interpreted with caution. Conclusion: Our finding is in line with previous observations that have associated the G allele of the HTR2A-rs7997012 with higher rate of antidepressant response. The HTR2A-rs7997012 is worthy of further investigation in studies examining factors that are related to depression course and outcome. (C) 2013 Elsevier B.V. All rights reserved

Background: Serotonin transporter-linked polymorphic region (5-HTTLPR) variants have been extensively studied in psychiatric disorders. Although gender effects have been reported, they have not been comprehensively reviewed. The aim of our study was to summarize literature findings on 5-HTTLPR and gender differences in affective disorders. Methods: A systematic search of PubMed, ISI Web of Knowledge, and PsycINFO databases was performed for dates until January 2015. The included articles (n=78) analyzed the association between 5-HTTLPR and affective spectrum disorders, taking into account gender. The quality of each study was assessed through STROBE and CONSORT. Results: 5-HTTLPR modulation of affective disorders varied by gender. The S allele (or SS genotype) seemed to be differently associated with an increased risk of depression, depressive symptoms, anxiety traits and symptoms, and symptoms of internalizing behavior among women and an increased risk of aggressiveness, conduct disorder and symptom counts of externalizing behavior among men. Moreover, the presence of stressful life events reinforced the association. Interestingly, these differences seemed to begin with adolescence and were not consistent among the elderly, suggesting a plausible role of hormonal fluctuations. Limitations: The review is limited by the small number of included papers, due to the paucity of information in the literature regarding 5-HTTLPR and gender. Conclusions: 5-HTTLPR variants may exert a differential modulation on a number of features depending on gender. Further studies are needed to more deeply investigate the effect of 5-HTTLPR x gender on the modulation of affective disorders. (C) 2015 Elsevier B.V. All rights reserved. Background Serotonin transporter-linked polymorphic region (5-HTTLPR) variants have been extensively studied in psychiatric disorders. Although gender effects have been reported, they have not been comprehensively reviewed. The aim of our study was to summarize literature findings on 5-HTTLPR and gender differences in affective disorders. Methods A systematic search of PubMed, ISI Web of Knowledge, and PsycINFO databases was performed for dates until January 2015. The included articles (n=78) analyzed the association between 5-HTTLPR and affective spectrum disorders, taking into account gender. The quality of each study was assessed through STROBE and CONSORT. Results 5-HTTLPR modulation of affective disorders varied by gender. The S allele (or SS genotype) seemed to be differently associated with an increased risk of depression, depressive symptoms, anxiety traits and symptoms, and symptoms of internalizing behavior among women and an increased risk of aggressiveness, conduct disorder and symptom counts of externalizing behavior among men. Moreover, the presence of stressful life events reinforced the association. Interestingly, these differences seemed to begin with adolescence and were not consistent among the elderly, suggesting a plausible role of hormonal fluctuations. Limitations The review is limited by the small number of included papers, due to the paucity of information in the literature regarding 5-HTTLPR and gender. Conclusions 5-HTTLPR variants may exert a differential modulation on a number of features depending on gender. Further studies are needed to more deeply investigate the effect of 5-HTTLPR×gender on the modulation of affective disorders.

Mucosal immune activation and altered serotonin metabolism participate in the pathophysiology of irritable bowel syndrome (IBS). However, the reciprocal interplay between these two systems remains unknown. We evaluated the expression and release of interferon (IFN)-γ from the colonic mucosa of patients with IBS and its impact on serotonin reuptake transporter ( SERT) gene expression in Caco-2 cells. qPCR was used to evaluate IFN-γ gene expression in colonic mucosal biopsies, whereas IFN-γ protein amount was assessed by ELISA. Colonic T box expressed in T cells (T-bet) and phosphorylated signal transducer and activator of transcription 4 protein amount were evaluated by Western blot. The impact of colonic mucosal mediators on SERT gene expression was evaluated in Caco-2 cells using qPCR. IFN-γ receptor was silenced in Caco-2 cells to determine the effect of IFN-γ released by mucosal biopsies. Compared with asymptomatic controls (ACs), the expression of IFN-γ gene and its transcription factor T-bet were markedly increased in the colonic mucosa of patients with IBS. Compared with ACs, IFN-γ protein tissue levels and its release by mucosal biopsies were significantly increased in IBS. The exposure of Caco-2 cells to IBS supernatants induced a significant decrease in SERT gene expression, independently of IBS subtypes, compared with AC mucosal supernatants. In Caco-2 cells, IFN-γ receptor silencing reversed the reduction of SERT expression evoked by IBS supernatants vs. nonsilenced cell lines. IFN-γ gene, its transcription factor T-bet, IFN-γ protein expression, and its release are increased in the colonic mucosa of patients with IBS and downregulate SERT gene expression in vitro. These results suggest that IFN-γ downregulates SERT expression, hence likely playing a role in altered serotonin metabolism of patients with IBS.

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder characterized by behavioral and language disturbances. We performed a case-control association study in the Italian population to assess the relevance for FTLD genetic susceptibility of the serotonin (5-HT) transporter gene-linked polymorphic region [rs4795541, alias short (S)/long (L)] an in/del polymorphism of the promoter region of the gene coding for the 5-HT transporter (SLC6A4). This functional polymorphism was reported to influence the SLC6A4 transcription rate, with the S-allele having a two-fold reduced efficiency. We collected 225 independent subjects (74 sporadic FTLD and 151 age-matched healthy controls, CT) that were genotyped for the rs4795541, the SLC6A4 single nucleotide polymorphisms (SNP) rs25531 and rs6354, and the apolipoprotein E (APOE) allelic variants. A significant correlation [P = 0.018, OR (95% CI): 2.1 (1.1-3.9)] between rs4795541 S-allele presence and FTLD susceptibility was found. In summary, the rs4795541 might be important for FTLD susceptibility in the Italian population. © 2008 The Japan Society of Human Genetics and Springer.

The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are SLC6A4, HTR2A, BDNF, GNB3, FKBP5, ABCB1, and cytochrome P450 genes (CYP2D6 and CYP2C19). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of SLC6A4, HTR2A, ABCB1, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications.

Several gene variants have been related to major depressive disorder (MDD) treatment outcomes; however, few studies have investigated a possible different effect on pharmacotherapy and brief psychotherapy response. A total of 137 MDD patients were randomized to either interpersonal counseling (IPC; n = 40) or antidepressant pharmacological treatment (n = 97). Outcomes were remission, response, and symptom improvement at week 8. Five genetic variants were investigated (5HTR2A rs6314, BDNF rs6265, SLC6A4 rs8076005, CREB1 rs2253206, and TPH2 rs11179023) as possible modulators of outcomes. The LC6A4 rs8076005 AA genotype and A allele were associated with response rate in the antidepressant group (p = 0.015 and 0.005, respectively) and in the whole sample (p = 0.03 and 0.02, respectively). In the IPC group a non-significant trend in the same direction was observed. The TPH2 rs11179023 A allele showed a marginal association with symptom improvement in the IPC group only. Other gene variants did not impact on outcomes in any treatment group. Our study suggests that rs8076005 in the SLC6A4 gene may be a modulator of antidepressant response, especially when pharmacological treatment is used.

Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel-based morphometry and Freesurfer) in 138 healthy individuals categorized into 'no anxiety' and 'subclinical anxiety' groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours.

Antipsychotics-induced weight gain is a complex phenomenon with a relevant underlying genetic basis. Polymorphisms of serotonin receptors and related proteins were genotyped in 139 schizophrenia patients and incorporated as covariates in a mixture regression model of weight gain in combination with clinical covariates. The HTR1D rs6300 polymorphism was showing a slight significance conferring risk for obesity (heavy weight gain group) under additive model. After correcting for multiple testing all the genetic predictors were non-significant, however the clinical predictors were associated with the risk of heavy weight gain. These findings suggest a role of ethnicity and olanzapine in increasing the risk for obesity in the heavy weight gain group and haloperidol protecting against heavy weight gain. The mixture regression model appears to be a useful strategy to highlight different weight gain subgroups that are affected differently by clinical and genetic predictors. © 2012 Elsevier B.V. and ECNP.

The density of the serotonin transporter in the plasma membranes of blood platelets was evaluated by labelled paroxetine binding in three different groups. These groups were: normal controls, epileptic patients having undergone a recent seizure (less than 4 days before) and patients who equally recently presented psychogenic non-epileptic seizures (pseudoseizures). Real seizures resulted in a significant decrease of membrane serotonin transporter density. In the instances of pseudoseizures, its membrane density was undistinguishable from that of normal controls. These data lend further support to the idea that down regulation of serotonin transporter may play a homeostatic role in the cessation of epileptic seizures.

Background: Establishing the short-term prognosis in Frontotemporal Lobar Degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. No reliable neuropsychological assessment balancing all FTLD aspects is available yet, thus no clear-cut follow-up study has been performed. Objective: To evaluate the rate of progression and the predictors of worsening in FTLD patients. Methods: One-hundred twenty-seven FTLD patients entered the study and were re-evaluated at 1-year follow-up. A statistical driven approach on wide neuropsychological, behavioral, and functional data was applied to identify homogeneous groups both at baseline and at follow-up within FTLD. Three set of predictors on disease progression were considered: (i) the demographic characteristics, (ii) the genetic background, i.e. Apolipoprotein E (APOE) genotype, Tau haplotype, and functional polymorphisms affecting serotonin and dopamine pathways, and (iii) the clinical phenotype. Results: Among FTLD, two groups of patients were recognized on the basis of the overall assessment, thus termed for different disease severity as "good performers" and "bad performers". At 1-year follow-up, almost 30% of FTLD patients progressed from "good" to "bad" performances, whilst 70% maintained stable "good" performances. APOE ε4 allele, Tau H2 haplotype and behavioral variant FTD phenotype were associated with worse prognosis over time. Conclusions: This preliminary study proposed genetic and clinical predictors in FTLD progression. The identification of disease-modifying predictors of prognosis opens a new avenue in studying FTLD, and may contribute to define outcomes and to monitor pharmacological targets. © 2008 Elsevier Inc. All rights reserved.

Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper, we investigated early partial improvement (EPI) defined as 20% or more improvement by rating scales 2weeks after treatment, in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder. Two randomized controlled trials with 168 Japanese depressed patients were used. A stepwise multiple linear regression model with HAM-D score change at week 6 as the dependent variable and genotypes, EPI, baseline HAM-D score, age and sex as independent variables was performed in paroxetine, fluvoxamine and milnacipran, respectively, to estimate the prediction of HAM-D change at week 6. In the paroxetine sample, only EPI (P

The definition of a genetic liability profile for specific antidepressant treatment will soon be available offering considerable help in early detection of effective therapy in affective disorders. The search for genetic factors predisposing to drug response or side-effects in affective disorders started only in the last few years. The efficacy of antidepressant action was associated with several polymorphisms, located on coding genes of proteins thought to be involved in the different mechanisms of action of antidepressant treatments. Among these, gene variants in sequences of serotonin pathway proteins were candidate, both for the well known evidence of its involvement in the development of depressive symptomathology and for the wide-world use of selective serotonin reuptake inhibitors as first choice treatment of depression. A polymorphism in the promoter region of the serotonin transporter (SERTPR) was independently associated with efficacy for a range of treatments, other polymorphism located on the tryptophan hydroxylase gene, 5-HT2a receptor and G-protein beta 3 showed some association, while other candidate genes were not associated with treatment efficacy. Possible liability genes controlling at least to some extent both acute and long-term treatment were identified, and the further objective is to identify other candidate genes in order to define individualized treatments according to genetic profile in a future. The present paper reviews the pharmacogenetic studies published to date, focusing the attention on the serotonergic pathway. © 2005 Elsevier Inc. All rights reserved.