Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity.

BACKGROUND: A number of important sociological, psychological, and biological predictors of adolescent criminal behavior have been identified during the most recent decades. The aim of this study was to replicate recent findings that interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter region and psychosocial factors might predict male adolescent criminal activity. METHODS: A cross-sectional study with a randomized sample from the total population of 16- and 19-year-olds from the county of V?stmanland, Sweden. Eighty-one male adolescents, who volunteered to participate, were randomly selected from groups representing different degrees of deviant risk behavior. RESULTS: The present study strongly supports the notion that carrying the 3-repeat allele of the MAO-A-gene promoter increases the risk of male adolescent criminal behavior, when interacting with psychosocial factors. No effects at all of the MAO-A genotype on adolescent criminal activity were found when MAO-A genotype was considered alone (i.e., without its psychosocial context). The explained variance of the bio-psychosocial model (controlling for MAO-A) in this study exceeded the psychosocial model by 12%. CONCLUSIONS: The findings support the notion that genotype and psychosocial factors interact to precipitate male adolescent criminal behavior.     

Positron emission tomography quantification of serotonin transporter binding in medication‐free bipolar disorder

Objectives: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5‐HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [¹¹C]DASB, we compared 5‐HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs). Experimental Design: 5‐HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of V_T/f_P (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt. Principal Observations: 5‐HTT binding (V_T/f_P) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BP_F*, BP_P*, and BP_ND*) indicated lower binding in BD compared with HV across these six regions of interest (BP_F*: P = 0.047; BP_P*: P = 0.032; BP_ND*: P = 0.031). 5‐HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder. Conclusions: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [¹¹C]DASB. We do not find evidence of abnormal 5‐HTT binding in bipolar depression using our primary outcome measure, V_T/f_P. However, we did observe lower 5‐HTT binding in BD with alternative outcome measures that are frequently used with [¹¹C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted. Synapse 70:24–32, 2016. . © 2015 Wiley Periodicals, Inc.     

Lack of association between the LPR and VNTR polymorphisms of the serotonin transporter gene and cocaine dependence in a Spanish sample

We genotyped the LPR and VNTR polymorphisms of the serotonin transporter gene in 504 cocaine-dependent patients and 508 controls. No association was detected with either polymorphism or with any haplotype combination. This study provided no evidence that these polymorphisms confer susceptibility to cocaine dependence in our sample.     

(11)C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET

The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.     

Relationships between serotonin transporter promoter polymorphism, platelet serotonin transporter binding and clinical phenotype in suicidal and non-suicidal adolescent inpatients

Summary. Relationships between the serotonin transporter promoter polymorphism (5-HTTLPR), platelet serotonin transporter (SERT) binding and clinical phenotype were examined in 32 suicidal and 28 non-suicidal Ashkenazi Israeli adolescent psychiatric inpatients. The 5-HTTLPR polymorphism was not associated with transporter binding or with suicidality or other clinical phenotypes. However, in the suicidal group, a significant positive correlation between platelet SERT density and anger scores (n=32, r=.40; p=.027) and a negative correlation between platelet count and trait anxiety (n=32, r=–.42; p=.034) were observed.     

Age‐related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence

The S and L_G alleles of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) lower serotonin transporter expression. These low‐expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala–prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces depression that emerges in adolescence, whereas decreased serotonin transporter that occurs later in development ameliorates depression. However, no brain imaging research has yet investigated the moderating influence of human development on the link between 5‐HTTLPR and effect‐related brain function. We investigated the age‐related effect of 5‐HTTLPR on amygdala activation and amygdala–prefrontal cortex connectivity using a well‐replicated probe, an emotional face task, in children and adolescents aged 9–19 years. A significant genotype‐by‐age interaction predicted amygdala activation, such that the low‐expressing genotype (S/S and S/L_G) group showed a greater increase in amygdala activation with age compared to the higher expressing (L_A/L_A and S/L_A) group. Additionally, compared to the higher expressing group, the low‐expressing genotype group exhibited decreased connectivity between the right amygdala and ventromedial prefrontal cortex with age. Findings indicate that low‐expressing genotypes may not result in the corticolimbic profile associated with depression risk until later adolescence. Hum Brain Mapp 35:646–658, 2014. © 2012 Wiley‐Periodicals, Inc.     

Association of the serotonin transporter gene polymorphism with Korean male alcoholics

This study investigated the association between the serotonin transporter polymorphism (5-HTTLPR) and alcoholism in the Korean population. In addition, in order to reduce the clinical heterogeneity, sub-analysis was carried out according to some clinical variables such as a family history of alcoholism, aggressive/violent behavior and the age of onset of alcoholism. One hundred and forty-five patients meeting the DSM-VI criteria for alcohol dependence and 201 healthy controls were examined. Genotyping was performed using a polymerase chain reaction (PCR)-based method. The frequency of the L-allele of 5-HTTLPR was significantly higher in the alcohol dependent patients than in the normal controls (chi(2)=19.11, df=1, p<0.001). Furthermore, there was a significant difference in the allelic distribution between the subgroups defined by a family history of alcoholism (chi(2)=4.005, df=1, p=0.045). This study suggests a putative role of the 5-HTTLPR for alcoholism in the Korean population. However, a replication study with larger different ethnic samples and a refinement of the subtype of alcoholism is needed.     

Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents

OBJECTIVE: To investigate possible associations between serotonin transporter (5-HTT) promoter genotypic variants (l/l, l/s, and s/s) and differential regulation of platelet 5-HTT functionality parameters in a group of drug-naive depressed children and adolescents and healthy controls. METHOD: Children and adolescents with major depression (n = 18) defined by DSM-III-R criteria and normal controls (n = 21) were assessed both for platelet serotonin functionality and for genotypic variants on 5-HTT promoter region. Four parameters were considered: (1) serotonin uptake rate (Vmax); (2) serotonin dissociation constant (K(m)); (3) paroxetine binding and density of site (Bmax); and (4) paroxetine dissociation constant (Kd). RESULTS: Depressed children had lower Vmax and K(m). Control subjects with l/l genotype had significantly higher Vmax than control subjects with l/s and s/s genotype. Control subjects with l/l genotype also had significantly higher Vmax than their depressed homologs. In contrast, Vmax was not significantly different between depressed and nondepressed subjects who carried the other 2 genotypes. The 5-HTT promoter genotype, diagnoses, or their interaction had no effect on the other serotonin parameters. CONCLUSIONS: While showing a significant decrease of Vmax and K(m) in a group of drug-naive depressed children and adolescents, these data suggest that l/l genotype has a substantial effect on the decrease of Vmax during a depressive episode.     

Combined effect of maternal serotonin transporter genotype and prenatal stress in modulating offspring social interaction in mice

Several studies suggest that prenatal stress is a possible risk factor in the development of autism spectrum disorders. However, many children exposed to stress prenatally are born healthy and develop typically, suggesting that other factors must contribute to autism. Genes that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in the adult offspring. One candidate gene linked to increased stress reactivity encodes the serotonin transporter. Specifically, an insertion/deletion (long/short allele) polymorphism upstream of the serotonin transporter gene correlates with differential expression and function of the serotonin transporter and a heightened response to stressors. Heterozygous serotonin transporter knockout mice show reductions in serotonin transporter expression similar to the human short polymorphism. In this study, the role of prenatal stress and maternal serotonin transporter genotype were assessed in mice to determine whether their combined effect produces reductions in social behavior in the adult offspring. Pregnant serotonin transporter heterozygous knockout and wild-type dams were placed in either a control condition or subjected to chronic variable stress. The adult offspring were subsequently assessed for social interaction and anxiety using a three-chamber social approach task, ultrasonic vocalization detection, elevated-plus maze and an open field task. Results indicated that prenatal stress and reduced serotonin transporter expression of the dam may have the combined effect of producing changes in social interaction and social interest in the offspring consistent with those observed in autism spectrum disorder. This data indicates a possible combined effect of maternal serotonin transporter genotype and prenatal stress contributing to the production of autistic-like behaviors in offspring.     

Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome.

BACKGROUND: Fifty-one patients with major depression were classified for 5-HTT promoter region polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and then examined for treatment outcome. METHODS: Dose was stratified from 1.25 mg to 40 mg per day to allow for the possibility that one genotype could express a lower-dose fluoxetine response. A repeated-measures analysis of variance of 24-item Hamilton depression change through baseline, 1-week placebo lead-in, and 6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. RESULTS: Genotype had a significant effect on outcome (F = 4.7, p <.02), with the initial affinity constant (K(m)) (F = 11.9, p =.001), and dose (F = 6.0, p <.02) being significant covariates on outcome as well. The gene effect, however, was complex in that the 5-HTT promoter region insertion showed two effects: both a placebo response effect (F = 4, p <.025), and a drug dose response effect (r =.40, p <.01). The long allele group was more responsive to placebo, as well as more responsive to drug dose than was the short allele group. CONCLUSIONS: This is the first study to examine the antidepressant dose-response relationship to 5-HTT kinetics and genetics. The findings indicate that both the initial affinity and genotype of 5-HTT may contribute in unique ways to the variation in the outcome of depression treatment trials.     

Predictive factors of post-discharge follow-up care among adolescent suicide attempters.

OBJECTIVE: To study short-term compliance with follow-up care in a sample of adolescent suicide attempters. METHOD: One hundred and sixty-seven adolescents, aged from 13-18 years and hospitalized after a suicide attempt, completed a questionnaire that included the CES-Depression Scale and Zung Anxiety Scale. Physicians assessed the hospital care immediately after the attempt, and post-discharge care plans. Three months later, adolescents were contacted by telephone and asked about follow-up care. RESULTS: After 3 months, 91.6% of the adolescents could be contacted: 25.5% never attended any follow-up; 11.1% went only once; 31.4% missed some appointments; and 32.0% went to all their scheduled appointments. Adolescents who complied with follow-up care differed significantly from those who did not: they showed more depression, anxiety and illicit drug use at the time of the attempt; they had more often planned the attempt; they were hospitalized longer; and they met with a psychiatrist more often while hospitalized. Compliance was also better when the follow-up appointment was scheduled before discharge. CONCLUSION: Compliance with post-discharge follow-up care depends upon the adolescent's psychopathology but may also be improved by the type of hospital care and post-discharge plans.     

青少年强迫症与应激等的关系研究

目的：了解青少年强迫症发病与生活事件、应对方式和社会支持的关系.方法：对44例青少年强迫症患者和214名正常对照者进行一般社会人口学资料表、青少年生活事件量表（ASLEC）、特质应对方式问卷（TCSQ）和领悟社会支持量表（PSSS）的测评.结果：与对照组相比,强迫症组在人际关系、学习压力、受惩罚、健康适应、应激总量的得分上均显著较高（P＜0.05）;强迫症组患者较多采用消极应对方式,较少采取积极应对方式,获得较少社会支持,与正常对照者比较差异非常显著（P＜0.01）.结论：青少年强迫症的发病与负性生活事件、不良应对方式和缺乏社会支持有关.     

5‐HT1B autoreceptor regulation of serotonin transporter activity in synaptosomes

Serotonin‐1B (5‐HT_1B) autoreceptors are located in serotonin (5‐HT) terminals, along with serotonin transporters (SERT), and play a critical role in autoregulation of serotonergic neurotransmission and are implicated in disorders of serotonergic function, particularly emotional regulation. SERT modulates serotonergic neurotransmission by high‐affinity reuptake of 5‐HT. Alterations in SERT activity are associated with increased risk for depression and anxiety. Several neurotransmitter receptors are known to regulate SERT K_m and V_max, and previous work suggests that 5‐HT_1B autoreceptors may regulate 5‐HT reuptake, in addition to modulating 5‐HT release and synthesis. We used rotating disk electrode voltammetry to investigate 5‐HT_1B autoreceptor regulation of SERT‐mediated 5‐HT uptake into synaptosomes. The selective 5‐HT_1B antagonist SB224289 decreased SERT activity in synaptosomes prepared from wild‐type but not 5‐HT_1B knockout mice, whereas SERT uptake was enhanced after pretreatment with the selective 5‐HT_1B agonist CP94253. Furthermore, SERT activity varies as a function of 5‐HT_1B receptor expression—specifically, genetic deletion of 5‐HT_1B decreased SERT function, while viral‐mediated overexpression of 5‐HT_1B autoreceptors in rat raphe neurons increased SERT activity in rat hippocampal synaptosomes. Considered collectively, these results provide evidence that 5‐HT_1B autoreceptors regulate SERT activity. Because SERT clearance rate varies as a function of 5‐HT_1B autoreceptor expression levels and is modulated by both activation and inhibition of 5‐HT_1B autoreceptors, this dynamic interaction may be an important mechanism of serotonin autoregulation with therapeutic implications. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Low level of response to alcohol as associated with serotonin transporter genotype and high alcohol intake in adolescents.

BACKGROUND: A low level of response to alcohol has been associated with both the genetic constitution of the regulatory region (SLC6A4) of the human serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) and with future alcohol intake and an increased risk for alcoholism. To date, all studies of relevant polymorphisms have been carried out in populations in the United States. METHODS: Data were extracted from a subset (n = 243) of a cohort of children who have been observed since birth through evaluation of the family history of alcoholism and psychosocial risk influences. At age 16 years, the response to alcohol was assessed with the Self-Rating of the Effects of Alcohol (SRE) questionnaire, and the average amount of alcohol intake per month was assessed during the prior 6 months. Additional variables that were measured included the 5-HTT genotype, externalizing behavior, and sociodemographic variables, such as gender and age. RESULTS: The level of response to alcohol was significantly lower among carriers of two long alleles of the 5-HTT regulatory region compared with carriers of one or two short alleles (Mann-Whitney U = 5225.0, p = .005). In a multiple regression analysis, the level of response to alcohol and externalizing behavior but not psychosocial factors significantly predicted the average amount of alcohol intake per month. CONCLUSIONS: This study demonstrates that, independent of the assessed psychosocial variables, the 5-HTT genotype correlated with the level of response to alcohol and predicted alcohol intake among 16-year-old adolescents.     

Serotonin transporter, 5‐HT1A receptor,and behavior in DBA/2J mice in comparison with four inbred mouse strains

Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5‐HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5‐HT transporter (5‐HTT) mRNA level, 5‐HT_1A receptor mRNA level, and 5‐HT_1A receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5‐HTT mRNA level in the midbrain and a reduced density of 5‐HT_1A receptors in the frontal cortex without significant changes in 5‐HT_1A receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light‐dark box and elevated plus‐maze tests, were found. The results suggested the involvement of decreased 5‐HTT gene expression and 5‐HT_1A receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive‐like behaviors. © 2009 Wiley‐Liss, Inc.     

Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.

BACKGROUND: Mixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample. METHODS: A nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid. RESULTS: A stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype. CONCLUSIONS: Early or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.     

Epigenetic changes of serotonin transporter in the patients with alcohol dependence: methylation of an serotonin transporter promoter CpG island

Objective

Psychiatric disorders such as depression, anxiety and alcohol dependence are associated with serotonin metabolism. We assessed the methylation level of the serotonin transporter (5-HTT) promoter region in control and alcohol dependent patients.

Methods

Twenty seven male patients who met the Diagnostic and Statistical Manual of Mental Disorder IV (DSM-IV) criteria for alcohol dependence were compared with fifteen controls. Polymerase chain reaction (PCR) assays of bisulfate-modified DNA were designed to amplify a part of the CpG island in the 5HTT gene. Pyrosequencing was performed and the methylation level at seven CpG island sites was measured.

Results

We found no differences in the methylation patterns of the serotonin transporter linked promoter region (5-HTTLPR) between alcohol-dependent and control subjects.

Conclusion

Our negative finding may be because 5-HTT epigenetic variation may not affect the expression for 5-HTT or there may be other methylation site critical for its expression. To find out more conclusive result, repeating the study in more methylation sites with a larger number of samples in a well-controlled setting is needed.