Serotonin Transporter 5-HTTLPR Research Articles

Serotonin transporter 5-HTTLPR polymorphism and escitalopram treatment response in patients with major depressive disorder

BackgroundThere is no doubt that genetic factors have the potential to predict the therapeutic outcomes of antidepressants in patients with major depressive disorder (MDD). This study investigated the association between genetic variants involved in serotonin signaling and brain-derived neurotrophic factor (BDNF) with the response to escitalopram treatment in patients with MDD. We focused on examining the influence of 5-HTTLPR (ins/del), HTR2A rs9316233, BDNF rs962369, CYP2C19 and CYP2D6 on the clinical response to escitalopram.MethodsThe patients were recruited from outpatient psychiatric clinics in Košice between 2020 and 2022. Patients received escitalopram for 12 weeks at a fixed dose of 10 mg daily. Clinical assessment was done at baseline and after 4, 8, and 12 weeks using the 21-item Hamilton Depression Rating Scale (HAMD-21).ResultsAt the end of week 12, 57 (65%) patients were defined as responders to escitalopram treatment, while 31 (35%) patients were non-responders. Genotyping revealed that carriers of the short allele (S) of 5-HTTLPR exhibit a significantly lower therapeutic response to escitalopram measured by HAMD-21 than the long allele (L) carriers (p = 0.01). Adjusting for CYP2C19 and CYP2D6 metabolizer genotypes did not modify the observed relationship between 5-HTTLPR and treatment response. No significant associations were found for HTR2A rs9316233 or BDNF rs962369 variants and the treatment response.ConclusionsThese findings underscore the utility of 5-HTTLPR genotyping in guiding escitalopram therapy for MDD patients. Further research with larger cohorts is warranted to validate these results and elucidate additional genetic determinants of antidepressant efficacy.

Developmental cascades from early childhood attachment security to adolescent level of personality functioning among high-risk youth.

This study examines associations between early childhood attachment security and adolescent personality functioning in a high-risk sample within a developmental psychopathology framework. Data from 2,268 children (1165 male; 1103 female) and caregivers participating in Future of Families and Child Well-Being Study (FFCWS) were used to examine (1) effects of genetic polymorphisms of the serotonin transporter (5-HTTLPR) and dopamine D4 receptor (DRD4) genes and adverse childhood experiences (ACEs) on attachment security and emotional and behavioral dysregulation in early childhood and (2) longitudinal associations and transactional relationships among attachment security, dysregulation, negative parenting attitudes and behaviors, social competence, and adolescent personality functioning. Results revealed that ACEs predicted attachment security over and above sex or the genetic risk, and gene × environment interactions did not increment prediction. Results of cascade models showed that greater early childhood attachment security predicted higher adolescent level of personality functioning via pathways through intermediary variables. Limitations and future research directions are discussed.

0064 Sleep Loss Affects Item and Source Memory Differentially as a Function of Serotonin Transporter (5-HTTLPR) Genotype

0064 Sleep Loss Affects Item and Source Memory Differentially as a Function of Serotonin Transporter (5-HTTLPR) Genotype

The Lack of Influence of Homozygous Long Allele of the 5-HTTLPR Gene on the Severity of Alcohol Craving During 6 Weeks of Rehab Hospitalisation in Comparison to Not Homozygous and Homozygous Short Alleles - Preliminary Report.

The aim of this study was to assess changes in the severity of alcohol craving according to allelic variants of the 5-HTTLPR gene polymorphism during hospitalisation and their association with selected clinical variables in alcohol-dependent patients. The study is exploratory. Participants were investigated at the 2nd and 6th week of alcohol-dependence therapy in the addiction treatment unit. Recruitment was conducted among alcohol-dependent patients from several Polish drug treatment centres. The total sample size was 130 persons (12 females and 118 males). Study subjects' mean age was 43.0 years. Patients were investigated twice by using the Penn Alcohol Craving Scale (PACS) and Beck Depression Inventory (BDI), and once by using Short Alcohol Dependence Data Questionnaire (SADD) and taking a swab for genetic testing. The polymorphism of the gene encoding the serotonin transporter 5-HTTLPR (SLC6A4) was determined from isolated DNA and its homozygous variants of short/short or long/long alleles and heterozygous short/long alleles were analysed. At 6th week of the follow-up, there was a decrease in the severity of alcohol craving in half of subjects with the short/short allele (p = 0.033) and in one-fifth of subjects with the long/short allele (p = 0.002) of the 5-HTTLPR gene. In subjects with long/long allele of the 5-HTTLPR gene, there was no change in the severity of alcohol craving between 2nd and 6th weeks of the study (p = 0.242). There was no statistical influence of the homozygous long allele of the 5-HTTLPR gene on severity of alcohol craving during 6 weeks of rehab hospitalisation in comparison to not homozygous and homozygous short alleles. The s-allele was associated with decrease of alcohol craving. It may point on the potential need for differentiated rehabilitation methods depending on the genetic diversity of addicted patients and its role in the severity of alcohol craving.

The Effects of Genetics and Psychosocial Stress on War-Affected Youth

The atrocities of war have a negative impact on those who must witness them. Syrian refugees have gone to Jordan to escape the civil war in their home country. The genetics of the youngest among the refugees plays a role in the development of mental illnesses. The importance of studying the effect of psychosocial stress and genetics on war-affected youth can be seen today when many children are being uprooted from their homes in Ukraine. This study was done using a case-control study. To get DNA, a gender-balanced group of 417 Syrian refugees and 306 Jodanian non-refugees provided buccal samples to the researchers. The male participants were exposed to more traumatic events, but the female participants had higher rates of perceived stress, insecurity, depression and anxiety, and post-traumatic stress disorder symptoms. The serotonin transporter 5-HTTLPR and the protein-coding gene COMT were found to play a role in the response to trauma. 5-HTTLPR was found to be associated with human insecurity and perceived stress. COMT was found to be associated with CRIES-8, also known as PTSD. The results of this study can be used in many ways. They can be used to know which mental health resources should be allocated to those uprooted by wars and the results can be used to advance the study of human behavior.

Associations Between Personality Traits, Perceived Stress and Depressive Symptoms in Gynecological Cancer Patients Characterized by the Short and Long Allele Variant of the 5-HTTLPR Genotype: Preliminary Results.

ObjectiveThe study explored associations between personality traits, perceived stress and symptoms of depression in oncological patients characterized by the two variants of the serotonin transporter (5-HTTLPR) polymorphisms.MethodThe sample was composed of 41 gynecological cancer patients who completed self-reported questionnaires including the NEO Five-Factor Inventory, the dimension of depression-dejection (D/D) of the Profile of Moods State and the Perceived Stress Scale (PSS). The polymerase chain reaction was also employed to identify genotypes in the serotonin (5HTT) polymorphism.ResultsThe one-way ANOVA test, across the 5-HTTLPR genotype groups, showed significant effects of the short variants on neuroticism (p=0.009) and of the long variant on agreeableness (p=0.022), as well as a tendency to a statistical significance of the l/l variant on consciousness (p=0.074). Bivariate correlations showed positive correlations of neuroticism with both psychopathological symptoms (D/D r=0.522; PSS r=0.586) in the combined group S, negative association of agreeableness with depression (D/D r=-0.613) and of consciousness with depression (D/D r=-0.750) and perceived stress (PSS r=-0.702) in the group of the long variant of 5-HT-TLPR genotype.ConclusionsPersonalized medicine should consider the interaction between genotype and phenotype in reducing levels of clinical psychological distress, highlighting how psychotherapeutic processes should improve patients' quality of life.

Prognosis of the functional outcome of schizophrenia using a multigene panel

To compare the groups of schizophrenic patients with different levels of functional outcome and different frequency of risk variants in polymorphic loci of five candidate genes to create a multigene panel and to test its predictive ability for long-term outcome of the disease. According to the proposed typology, the patients included in the studies were divided into three groups, which differed in the level of social functioning. Group 1 was characterized by the highest level, in group 2 this indicator was significantly lower, and in group 3 the lowest. The multigenic panel included genes for serotonin receptor type 2a (5-HTR2A T102C), serotonin transporter (5-HTTLPR), C-reactive protein (CRP -717A>G), angiotensin II receptor type 1 (AGTR1 A1166C), and brain neurotrophic factor (BDNF Val66Met). A multi-gene risk score was calculated for each patient by summing the total number all his/her risk alleles. For each polymorphism, a score of 2 was assigned to homozygous high-risk genotypes, a score of 1 to heterozygous genotypes and a score of 0 to homozygous low-risk genotype. Accordingly, the multi-gene risk score for a patient could vary from 0 to 10 risk alleles. A significant effect of the group on the multi-gene risk score was shown (p<0.0001). Between-group differences were significant as well (p<0.01). In group 1, there were no carriers of ≥6 risk alleles, and the number of carriers of less than 5 alleles exceeded 50%. In group 2, the number of carriers of ≥6 risk alleles was 19.4%, and in group 3 - 31.7%. Moreover, in these groups there were no carriers of 0-2 risk alleles, while in group 1 their number was 20.7%. The multi-gene risk score predicts the level of functional outcome in patients with schizophrenia. In the case of a smaller number of risk alleles (0-4) in an individual, a favorable functional outcome can be predicted with a high probability in the long-term period of the disease.

P.069 Effects of vortioxetine and agomelatine in the Differential Reinforcement of Low Rate (DRL) test in the rat

Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD.We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene.While viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortexSimilar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD.

In search of positive mental health: Personality profiles and genetic polymorphisms.

Individuals vary greatly in their mental health and these differences may play a critical role in stress resistance, risk reduction and illness recovery. Here we ask how these differences may be related to normal variation in personality and genotype. One hundred healthy college students completed measures of mental health (Mental Health Continuum-Short Form [MHC-SF]), personality (NEO Five Factor Inventory) and adverse childhood experiences. Participants also provided saliva samples, genotyped for both the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF), each assayed for naturally occurring polymorphisms, 5-HTTLPR (short/long) and BDNF (valine/methionine). Mental health correlated strongly with the NEO triad of conscientiousness-extraversion-neuroticism, with largest contributions to MHC-SF scores for conscientiousness, followed by extraversion and then neuroticism. The personality trait interaction of extraversion × conscientiousness uniquely accounted for approximately 44.22% 44.62% of the variance in MHC-SF scores. Polygenic comparisons showed a significant gene × gene interaction, with highest mental health for 5-HTTLPR-S, Met carriers. Together these results provided support for distinct yet interacting roles of personality and genetics in the phenotypical expression of mental health.

Socioemotional Mechanisms of Children’s Differential Response to the Effects of Maternal Sensitivity on Child Adjustment

SYNOPSIS Objective . Children differ in the extent to which they reap the benefits of maternal sensitive care or suffer the adverse consequences of insensitive care, and these differences can be accounted for by biological characteristics. However, how susceptible children adapt to maternal sensitivity in ways that either maximize positive development or lead to maladjustment has yet to be determined. Here, we propose a novel model of socioemotional mechanisms by which the joint influences of maternal sensitivity and child biological characteristics influence child adjustment. Design . We propose a theoretical model, in which children’s vagal functioning and polymorphisms in serotonin transporter (5-HTTLPR) and dopamine receptor D4 (DRD4) genes confer susceptibility to the effects of maternal sensitivity on internalizing, externalizing, prosocial and moral behavior via changes in interpersonal strategies for emotion regulation, the threat response system, and empathy. Results . Theoretical and empirical support for the proposed mechanisms are provided. Conclusions . The proposed mechanistic model of susceptibility to maternal sensitivity offers a novel framework of for whom and how children are affected by early maternal care, highlighting multiple reciprocal, interacting influences across genes, physiology, behavior, and the environment.

Highs and lows: Genetic susceptibility to daily events.

Why people differ in their susceptibility to external events is essential to our understanding of personality, human development, and mental disorders. Genes explain a substantial portion of these differences. Specifically, genes influencing the serotonin system are hypothesized to be differential susceptibility factors, determining a person's reactivity to both positive and negative environments. We tested whether genetic variation in the serotonin transporter (5-HTTLPR) is a differential susceptibility factor for daily events. Participants (N = 326, 77% female, mean age = 25, range = 17-36) completed smartphone questionnaires four times a day over four to five days, measuring stressors, uplifts, positive and negative affect. Affect was predicted from environment valence in the previous hour on a within-person level using three-level autoregressive linear mixed models. The 5-HTTLPR fulfilled all criteria of a differential susceptibility factor: Positive affect in carriers of the short allele (S) was less reactive to both uplifts and stressors, compared to homozygous carriers of the long allele (L/L). This pattern might reflect relative affective inflexibility in S-allele carriers. Our study provides insight into the serotonin system's general role in susceptibility and highlights the need to assess the whole spectrum of naturalistic experiences.

Childhood maltreatment, serotonin transporter gene, and risk for callous and unemotional traits: A prospective investigation

Previous studies have reported associations between the serotonin transporter 5-HTTLPR genotype and antisocial and aggressive traits and between child maltreatment and antisocial traits. However, few studies have examined whether 5-HTTLPR moderates the influence of childhood maltreatment on callous and unemotional traits, a hallmark of psychopathy. Using a prospective cohort design, children with documented cases of maltreatment and matched controls were followed up and interviewed in adulthood. DNA was extracted from blood and saliva (N = 414) and callous-unemotional (CU) traits were assessed. Childhood maltreatment predicted higher CU scores in adulthood, whereas the effect of 5-HTTLPR was not significant. The effect of child maltreatment on CU traits did not differ by genetic risk (high or low activity 5-HTTLPR), whereas controls with the LL genotype had higher CU scores than controls with the SS genotype. Similar results were found for females and White, non-Hispanics, but not for males and Blacks. Variations in 5-HTTLPR did not affect the impact of child maltreatment on CU traits in adulthood. Genetic risk had a stronger effect on adults with lower environmental risk (controls). Having a history of child maltreatment or the LL genotype placed participants at risk for higher levels of callous and unemotional trait scores.

Stress-related Genetic Variants Modulate Electrodermal Response To Maximal Exercise

Previous research from our lab established electrodermal activity (EDA) as a valid, surrogate marker of sympathetic nervous system activity during treadmill exercise. We have subsequently reported dose dependent effects of aerobic fitness, combat exposure and blast exposure on the electrodermal response to acute exercise stress. PURPOSE: As an extension of our prior work, this study evaluated the effect of stress related genetic variants on EDA during maximal exercise in specialized military men. METHODS: Sixty-four male (age = 34.2±7.0 yrs) Explosive Ordnance Disposal operators completed a graded exercise test to assess maximal oxygen consumption (VO2max). EDA was recorded at baseline, during exercise and recovery. Percent change from baseline was calculated for stages of 25, 50, 75 and 100% VO2max, and active and seated recovery. Genetic variants of catechol-o-methyltransferase (COMT), brain-derived neurotrophic factor (Val66Met) and serotonin transporter (5HTTLPR) were determined from saliva. Combination groups of 2 (COMT + Val66Met) or 3 (COMT + Val66Met + 5HTTLPR) variants (2 or 3GCOM) were created and divided into “low” and “high” EDA groups. A 2 or 3 (GCOM) x 6 (STAGE) repeated measures ANOVA evaluated EDA changes across stages for 2 or 3GCOM groups, separately. RESULTS: All GCOM groups showed linear increases in EDA percent change throughout exercise. Low 2GCOM response peaked at 75% VO2max and plateaued in recovery. High 2GCOM had a larger change, peaked at 100% VO2max then declined in recovery. There was a borderline main effect of 2GCOM (p=.06, ηp2=.108) and a main effect of STAGE (p<.001, ηp2=.183). Low 3GCOM had a similar pattern as low 2GCOM, but on a smaller scale. High 3GCOM demonstrated the largest change in magnitude, peaked at 100% VO2max and sharply declined in recovery. There was a 3GCOM x STAGE interaction effect (p<.001, ηp2=.352). CONCLUSION: When combined, genetic variants implicated in the human stress response modulate EDA during and after maximal exercise. Influence of COMT was expected, as EDA is a proxy of plasma catecholamine levels during exercise. Val66Met and 5HTTLPR have been shown to modulate exercise responses and cardiovascular reactivity, respectively. Future work will comprehensively evaluate biobehavioral characteristics and genetic variants in this sample.

The Role of Brain-Derived Neurotrophic Factor and Serotonin Polymorphisms in Stress-Related Personality and Psychiatric Symptoms

Background: Diathesis-stress perspectives of cardiovascular (CV) health and disease have long identified the important role of a host of mental health risk and protective factors in both illness course and recovery. Few studies, however, have investigated these factors within the same sample of healthy people. Aims and Objectives: Accordingly, we focused on the inter-relationships among well-established CV mental health risk factors, specifically childhood adversity, stress-related adult personality traits and psychiatric symptoms, and naturally occurring genetic polymorphisms. Materials and Methods: Here 100 college students completed the NEO Five Factor Model of personality in conjunction with measures of childhood adversity, psychiatric symptoms as well as genetic variables derived from assays of the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF). Results: Single gene comparisons pointed to lower CV risk, as reflected in personality and psychiatric symptom measures for BDNF Met versus Val/Val carriers. In addition, polygenic comparisons revealed a significant BDNF x 5-HTTLPR interactional effect, suggesting that this particular allelic combination may moderate the phenotypic expression of key personality traits, namely neuroticism and extraversion, as well as psychiatric symptoms, all linked to cardiovascular health. In fact, the data showed across personality and symptom measures, evidence of stress-resistance, resilience and protection for carriers of the allelic pair, BDNF Met and 5-HTTLPR-S. Conclusions: The findings suggested the Met variant of the BDNF gene had a risk-reducing and health-promoting effect when paired with the short serotonin allele, arguably reversing the commonly reported 5-HTTLPR-S association with stress vulnerability.

Association between the promoter region of serotonin transporter polymorphisms and recurrent aphthous stomatitis: A meta-analysis

ObjectivesTo assess the association between the promoter region of serotonin transporter (5-HTTLPR) gene polymorphism and recurrent aphthous stomatitis (RAS) occurrence. DesignsWe performed the meta-analysis to determine the potential association between 5-HTTLPR polymorphism and RAS. We retrieved revelant studies from the PubMed, Scopus, Embase, Web of Science and Cochrane Library databases up to January 2019. Data were analyzed for odd ratios with 95% confidence intervals using Revman 5.3 software. ResultsThere were 4 studies in the meta-analysis, which included 291 RAS cases and 286 controls. It indicated a substantially augmented threat of RAS with respect to S vs. L (P = 0.005), SS vs. LL+LS (P ＜ 0.0001) and SS vs. LL models (P ＜ 0.00001), respectively. No heterogeneity was found between studies in all comparisons. ConclusionsThe current meta-analysis provides evidence to prove the association between 5-HTTLPR polymorphism and RAS. Further studies should be performed to clarify the biochemical function and pathological role of 5-HTTLPR in the risk of RAS.

Risk and protective effects of serotonin and BDNF genes on stress-related adult psychiatric symptoms

We focused on individual risk by examining childhood adversity and current psychiatric symptoms in a sample of 100 college students genotyped for both the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF). Naturally occurring allelic variation in 5-HTTLPR (short/long) and BDNF (valine/methionine) have been strongly implicated in stress-related psychiatric risk, but the combined effects of these alleles on psychological functioning have yet to be fully elucidated. Univariate analysis revealed gene-environment correlations linking heightened psychiatric risk with past childhood adversity for short but not long 5-HTTLPR allelic carriers and for valine (Val) but not methionine (Met) BDNF allelic carriers. Multivariate analyses revealed a significant gene x gene interaction with results showing that risk varied systematically depending on both 5-HTTLPR and BDNF alleles, independent of childhood adversity. Hierarchical regression analyses indicated that approximately 11% of the variance in symptoms of depression could be specifically accounted for by the epistatic interaction of 5-HTTLPR and BDNF val66Met polymorphisms. Allelic group analyses indicated lowest risk, as measured by depression and anxiety, for allelic carriers of 5-HTTLPR-short and BDNF Met, followed by 5-HTTLPR-long and BDNF-Val, 5-HTTLPR-short and BDNF-Val, and 5-HTTLPR-long and BDNF-Met. Results suggest that protective or risk-enhancing effects on stress-related psychiatric functioning may depend on specific allelic combinations of 5-HTTLPR and BDNF.

The 5-HTTLPR Polymorphism of the Serotonin Transporter Gene and the Intellectual Environment of Work Activity as Factors Associated with Changes to Memory in Aging

The heterogeneity of mental aging is due to the influences of both genetic and environmental factors. Among the latter, an important role is played by intellectual activity. An association was found between the serotonin transporter 5-HTTLPR gene and the efficiency of solving cognitive tasks, and the “adaptive” nature of one of its genotypes provided grounds for studying the associations of this polymorphism with age-related changes in cognitive functions in relation to the intellectual aspect of professional work. The study included young and old scientists (scientific activity, SA, N = 132) and people with no involvement in scientific activity (NSA, N = 157). The efficiency of verbal memory was assessed in terms of reproduction of words from the right and left ears in a dichotic test procedure and recognition of previously presented words; that of imaginal memory was assessed in terms of the recognition of figures. Independently of age, SA subjects had higher measures of verbal memory than NSA. The intellectual aspect of SA was a factor preventing age-related decline in memory for words addressed to the left hemisphere. Independently of other factors, carriers of the S′ (S or LG) alleles of the 5-HTTLPR polymorphism, as compared with carriers of the L′/L′ (LA/La) genotype, demonstrated better measures of imaginal memory. Thus, the initial cognitive potential and cognitive function-stimulating aspect of SA promotes maintenance of the functional activity of the left hemisphere. Measures of right-hemisphere imaginal memory were associated with the genome.

A preliminary association study between serotonin transporter (5-HTTLPR), receptor polymorphisms (5-HTR1A, 5-HTR2A) and depression symptom-clusters in a north Indian population suffering from Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) is a broad heterogeneous diagnostic construct. Previous studies have shown that it can be resolved into several symptom-clusters which are proposed to be associated with single nucleotide polymorphisms (SNPs) of the serotonergic pathway (5-HTTLPR, 5HTR1A, 5-HTR2A). In a cross-sectional study conducted at a tertiary level mental health care set-up in north India, 80 out-patients with MDD were evaluated with Montgomery Asberg Depression Rating Scale (MADRS) and then genotyping was done. The different clinical and genetic variables were compared across the factor structures of MADRS. Also, the comparison of the genetic data of cases was done with the pre-existing database of the non-blood related healthy ethnically-matched controls. There was no significant association between age, gender, other clinical variables, SNPs like 5-HTTLPR SS/SL, rs6295 CC/CG/GG, rs6311GG/GA/AA, rs6313 CC/CT/TT and different factor-structures like 'detachment' consisting of items like concentration difficulty, lassitude, inability to feel; 'psychic anxiety' consisting of suicidal thoughts and inner tension; 'mood-pessimism' consisting of symptoms like apparent sadness, reported sadness, pessimistic thoughts and 'vegetative symptoms' like decreased sleep, poor appetite. Neither there was any association between genotype of the cases compared with the controls. No significant association was obtained between the four-factor structures of depression in MADRS and serotonin transporter and receptor SNPs in a study with a small sample size. This study evaluates whether depression symptom-clusters have distinct genotypic determinants and necessitates more comprehensive studies for unravelling the genetic determinants of depression.

Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder.

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.

Association of TPH1 and serotonin transporter genotypes with treatment response for suicidal ideation: a preliminary study.

Variants in three genes coding for components of the serotonergic system, the tryptophan hydroxylase 1 (TPH1) rs1799913, serotonin transporter (SLC6A4) 5-HTTLPR, and serotonin receptor 2A (HTR2A) rs6311, were evaluated for association with suicidal ideation (SI) and with recovery from SI in a psychiatric inpatient population. Five hundred and eighty-two adult inpatients, including 390 patients who had SI, collected from December 2012 to April 2016 were assessed. SI recovery, calculated as change in SI between the first two-week period after admission and weeks 5 and 6, was appraised for association with the three variants. In this preliminary study, both TPH1 and 5-HTTLPR genotypes were associated with recovery (TPH1: recessive model, increased recovery with AC genotype, P = 0.026; additive model, increased recovery with AC genotype, P = 0.037; 5-HTTLPR: recessive model, increased recovery with AC, P = 0.043). When patients with comorbid alcohol use disorder (AUD) were removed, given that TPH1 has been associated with alcoholism, the associations of those recovered from SI with TPH1 rs1799913 remained significant for the additive (increased recovery with AC, P = 0.045) and recessive (increased recovery with C-carriers, P = 0.008) models, and with 5-HTTLPR using the dominant model (increased recovery with S'S', P = 0.016). In females, an association of SI recovery with TPH1 rs1799913 was found using a recessive model (increased recovery with C-carriers, P = 0.031), with 5-HTTLPR using additive (increased recovery with L'S', P = 0.048) and recessive (increased recovery with S'S', P = 0.042) models. Additionally, an association of SI with TPH1 rs1799913 was found in females using both additive (increased risk in AC, P = 0.033) and recessive (increased risk in C-carriers, P = 0.043) models, and with 5-HTTLPR using a recessive model (increased risk in S'S', P = 0.030). This study provides evidence that variation in the TPH1 and serotonin transporter genes play key roles in moderating recovery from SI during treatment in an inpatient psychiatric clinic.