OBJECTIVES: The aim of our study was to investigate association of norepinephrine transporter gene (SLC6A2) polymorphism and side effects of osmotic-release oral system methylphenidate (OROS MPH) in children with attention-deficit hyperactivity disorder (ADHD). METHODS: We recruited drug naive children with ADHD (N=97). We administered OROS MPH by tolerable dosage. At week 8 of treatment, parents completed the Barkley's side effect rating scale. We analyzed two SLC6A2 single nucleotide polymorphisms (SNPs), rs192303 and rs3785143, with blood of subjects. We compared the frequency and severity of each side effect among SLC6A2 genotypes of 2 SNPs. RESULTS: In the analysis of frequency of each side effect, irritability differed according to rs192303 and rs3785143 genotype. In comparisons of severity, talking less and disinterest differed according to rs192303 genotype. In the case of rs3785143, severities of disinterest and irritability were involved with genotype. CONCLUSION: Side effects of OROS MPH showed an association with SLC6A2 genotype.
Child ; Genotype ; Humans ; Methylphenidate* ; Norepinephrine Plasma Membrane Transport Proteins* ; Parents ; Polymorphism, Single Nucleotide

OBJECTIVES: This study aimed to examine the association between norepinephrine transporter gene (SLC6A2) polymorphisms and attention-deficit hyperactivity disorder (ADHD) and to examine the relationship between the genotypes and allele variants of SLC6A2 and results of the Korean version of the parent ADHD rating scale (K-ARS). METHODS: We examined the association between ADHD and norepinephrine transporter gene polymorphism using DNA from 137 Korean children with ADHD and 120 normal controls. We compared the genotype distributions and allele frequencies of SLC6A2 polymorphism between the control group and the ADHD group. Then, we correlated the children's K-ARS mean totals, inattention scores, and hyperactivity/impulsivity scores with the genotypes and alleles for each SLC6A2 polymorphism. RESULTS: There were no significant differences in genotype and allele distribution for each SLC6A2 polymorphism, as shown by the Chi-square test (p>.01). There was a trend toward a difference in allele frequency in rs 5568, but it was not statistically significant after adjusting for multiple comparisons (p=.048). Also, there were no significant differences in K-ARS scores according to the genotypes and alleles for the SLC6A2 polymorphisms. CONCLUSION: Our study found no significant evidence of an association between SLC6A2 polymorphisms and ADHD.
Alleles ; Case-Control Studies ; Child ; DNA ; Gene Frequency ; Genotype ; Humans ; Norepinephrine ; Norepinephrine Plasma Membrane Transport Proteins ; Parents

In conventional pharmacological research in the field of mental disorders, pharmacological effect and dose have been estimated by ethological approach and in vitro data of affinity to the site of action. In addition, the frequency of administration has been estimated from drug kinetics in blood. However, there is a problem regarding an objective index of drug effects in the living body. Furthermore, the possibility that the concentration of drug in blood does not necessarily reflect the drug kinetics in target organs has been pointed out. Positron emission tomography (PET) techniques have made progress for more than 20 years, and made it possible to measure the distribution and kinetics of small molecule components in living brain. In this article, we focused on rational drug dosing using receptor occupancy and proof-of-concept of drugs in the drug development process using PET.
Brain ; Central Nervous System ; Drug Evaluation ; Electrons ; Kinetics ; Mental Disorders ; Norepinephrine Plasma Membrane Transport Proteins ; Positron-Emission Tomography ; Receptors, Dopamine D2 ; Serotonin Plasma Membrane Transport Proteins

OBJECTIVE: Bupropion is an antidepressant with proven efficacy for smoking cessation, however the response rate is some limited. With this background, the authors investigated the difference of early bupropion response in smoking cessation according to individual genetic polymorphism and temperamental characteristics. METHOD: Subjects were 113 Korean male volunteers who were nicotine dependent and wanted to quit smoking. Authors compared 6 candidate genes (DRD2, DRD4, dopamine transporter, norepinephrine transporter, serotonin transporter, COMT), and Temperament Character Inventory (TCI) between response group and non-response group after 3 weeks bupropion treatment. RESULT: Among 6 candidate genes, DRD2 homozygotes (A2/A2+A1/A1), COMT H/H genotype and H allele carriers showed high rate of smoking cessation by bupropion. NET-8 GG genotype and G allele carriers showed low rate of smoking cessation by bupropion. Persistence score in TCI was significant between two groups. CONCLUSION: DRD2, COMT, NET-8 genetic polymorphisms and some temperamental characteristics could predict success of smoking cessation by early treatment response of bupropion.
Alleles ; Bupropion* ; Dopamine Plasma Membrane Transport Proteins ; Genotype ; Homozygote ; Humans ; Male ; Nicotine ; Norepinephrine Plasma Membrane Transport Proteins ; Polymorphism, Genetic* ; Serotonin Plasma Membrane Transport Proteins ; Smoke* ; Smoking Cessation* ; Smoking* ; Temperament* ; Volunteers

This article is to review neurobiology of attention-deficit/hyperactivity disorder (ADHD) and pharmacological properties of Osmotic-Controlled Release Oral delivery System Methylphenidate (OROS MPH)(Concerta Oros(R)) in celebration of its one-decade clinical experiences in Korea. ADHD is a highly heritable neurodevelopmental disorder, characterized by age-inappropriate inattention, hyperactivity and impulsiveness. The symptoms of ADHD are consistent with dysfunction of the prefrontal cortex (PFC). The PFC functions such as working memory and executive function are powerfully modulated by the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE). Methylphenidate (MPH) is a first line treatment for children and adolescents with ADHD in Korea. MPH improves the PFC functions with the mechanism of action being modulation of DA and NE tones by blocking both dopamine transporter (DAT) and norepinephrine transporter (NET). Stimulation of D1 and NE alpha2 receptors on the postsynaptic neurons may be its main mechanisms of action which improve working memory and behavioral inhibition in patients with ADHD. OROS MPH, one of long-acting MPH, employs an osmotic-releasing oral system (OROS), which has been designed to have 12 hour duration of effect, which permits oncedaily dosing, which has been shown to be as effective as 3-times-a-day immediate-release formulation of MPH (IR MPH). Recently there is growing evidence that OROS MPH has positive effects even on adults with ADHD, in multidimensional aspects; cognitively, emotionally and functionally.
Adolescent ; Adult ; Child ; Dopamine ; Dopamine Plasma Membrane Transport Proteins ; Executive Function ; Humans ; Korea ; Memory, Short-Term ; Methylphenidate ; Neurobiology ; Neurons ; Neuropharmacology ; Neurotransmitter Agents ; Norepinephrine ; Norepinephrine Plasma Membrane Transport Proteins ; Phenazines ; Prefrontal Cortex

This article is to review neurobiology of attention-deficit/hyperactivity disorder (ADHD) and pharmacological properties of Osmotic-Controlled Release Oral delivery System Methylphenidate (OROS MPH)(Concerta Oros(R)) in celebration of its one-decade clinical experiences in Korea. ADHD is a highly heritable neurodevelopmental disorder, characterized by age-inappropriate inattention, hyperactivity and impulsiveness. The symptoms of ADHD are consistent with dysfunction of the prefrontal cortex (PFC). The PFC functions such as working memory and executive function are powerfully modulated by the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE). Methylphenidate (MPH) is a first line treatment for children and adolescents with ADHD in Korea. MPH improves the PFC functions with the mechanism of action being modulation of DA and NE tones by blocking both dopamine transporter (DAT) and norepinephrine transporter (NET). Stimulation of D1 and NE alpha2 receptors on the postsynaptic neurons may be its main mechanisms of action which improve working memory and behavioral inhibition in patients with ADHD. OROS MPH, one of long-acting MPH, employs an osmotic-releasing oral system (OROS), which has been designed to have 12 hour duration of effect, which permits oncedaily dosing, which has been shown to be as effective as 3-times-a-day immediate-release formulation of MPH (IR MPH). Recently there is growing evidence that OROS MPH has positive effects even on adults with ADHD, in multidimensional aspects; cognitively, emotionally and functionally.
Adolescent ; Adult ; Child ; Dopamine ; Dopamine Plasma Membrane Transport Proteins ; Executive Function ; Humans ; Korea ; Memory, Short-Term ; Methylphenidate ; Neurobiology ; Neurons ; Neuropharmacology ; Neurotransmitter Agents ; Norepinephrine ; Norepinephrine Plasma Membrane Transport Proteins ; Phenazines ; Prefrontal Cortex

OBJECTIVE: We aimed to investigate possible associations between three norepinephrine transporter gene (SLC6A2) single nucleotide polymorphisms (T182C, A3081T, and G1287A) and schizophrenia. Also, we investigated the relationships of those polymorphisms with clinical severity and characteristics of schizophrenia. METHODS: Participants were 220 schizophrenia patients in the acute phase and 167 healthy controls. The genotype, allele frequency, and haplotype of each group were analyzed for T182C, A3081T, and G1287A polymorphisms. Of the 220 schizophrenia patients, 163 patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Korean version of the Calgary depression scale for schizophrenia (K-CDSS) at baseline. RESULTS: We found no significant differences between the schizophrenia patient group and the control group in genotype distribution or allele frequency of the three tested polymorphisms. Likewise, we could not find any significant differences in genotype or allele frequency by analyzing according to gender. In the haplotype study, no significant association emerged between specific haplotype combinations and schizophrenia. We also found no association between clinical scales (PANSS and K-CDSS) and the studied polymorphisms. CONCLUSION: Our results suggest that the investigated polymorphisms of the NET gene are not associated with susceptibility to schizophrenia or its clinical features in a Korean population. However, this study remains significant because it is the first haplotype study to investigate associations between NET gene (SLC6A2) single nucleotide polymorphisms and schizophrenia in a Korean population. Future research with a larger sample size and more genetic markers is needed to replicate our results.
Gene Frequency ; Genetic Markers ; Genotype ; Haplotypes ; Humans ; Norepinephrine Plasma Membrane Transport Proteins* ; Norepinephrine* ; Polymorphism, Single Nucleotide ; Sample Size ; Schizophrenia* ; Weights and Measures

OBJECTIVE: Norepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger's theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger's personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model. METHODS: After written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students. RESULTS: A significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms. CONCLUSION: We conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires.
Alleles ; Asian Continental Ancestry Group* ; Extraversion (Psychology) ; Humans ; Informed Consent ; Norepinephrine ; Norepinephrine Plasma Membrane Transport Proteins* ; Polymerase Chain Reaction ; Surveys and Questionnaires ; Reward

OBJECTIVE: Genetic differences may contribute to the inter-individual differences in treatment response to antidepressants among patients suffering from major depression. This study investigated a possible association of various monoamine transporter genetic polymorphisms with treatment response to mirtazapine in major depressive patients in elderly. METHODS: In this study, three genetic polymorphisms were selected: serotonin transporter 5- HTTLPR, serotonin transporter 5-HTT intron 2 VNTR, and norepinephrine transporter NET (G1287A). The patients with major depression diagnosed by DSM-IV were recruited to a 6 week naturalistic mirtazapine treatment study in Samsung Medical Center. Treatment response to mirtazapine was defined as > or =50% decrease in HAMD-17 scores at 6 weeks, and the genotypes in the patients were determined using the polymerase chain reaction. RESULTS: Our results showed that ss allele carriers were included more in responder group (ss allele in responder vs. non responder group; 69.4% vs. 40.0%). In addition, l-allele (sl/ll) carriers were included less in responder group (sl/ll allele in responder vs. non responder group; 30.6% vs. 60.0%). Multiple logistic regression analyses showed the 5-HTTLPR polymorphism as an predictor of the mirtazapine response (5HTTLPR ss allele carrier vs. l-allele (sl/ll) carrier; odds ratio: 3.81; 95% confidence interval [CI], 1.32-11.0; p=0.013). However, 5-HTT intron 2 VNTR l/s (p=0.33 by multiple logistic regression; [OR], 0.53; 95% [CI], 0.15-1.88), and NET (G1287A) G/A (p=0.68 by multiple logistic regression; [OR], 1.25; 95% [CI], 0.44-3.53) showed no statistical significant influences on response rate. CONCLUSION: In conclusion, 5HTTLPR polymorphism may predict treatment response to mirtazapine in major depressive patients in elderly.
Aged ; Alleles ; Antidepressive Agents ; Depression ; Diagnostic and Statistical Manual of Mental Disorders ; Genotype ; Humans ; Introns ; Logistic Models ; Mianserin ; Norepinephrine Plasma Membrane Transport Proteins ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Serotonin Plasma Membrane Transport Proteins ; Stress, Psychological

OBJECTIVETo determine whether the serotonin transporter (5-HTT) and norepinephrine transporter (NET) gene polymorphisms were associated with the susceptibility to depression.

METHODSFive hundred and seventy-nine patients with depression, evaluated using a 17-item Hamilton Depression Rating Scale for Depression (HAMD), and 437 healthy controls, all of Chinese Han origin, were genotyped by polymerase chain reaction.

RESULTSBoth genotype distributions (P=0.033) and allele frequencies (P=0.023, OR = 1.250, 95% CI = 1.031-1.517) of NET-T182C were significantly different between patients and controls, where the T allele was associated with the onset of depression. Both NET-T182C T- and 5- HTTLPR L-carriers had higher baseline HAMD scores (P=0.032 and 0.023, respectively). There was an interaction between NET-T182C and 5-HTTLPR, where the combined genotype distributions were associated with both onset of depression (P=0.006) and the baseline HAMD scores (P=0.007).

CONCLUSIONThis study suggested a positive relationship between the NET-T182C polymorphism and the susceptibility to depression, and a positive relationship between NET-T182C/5-HTTLPR polymorphisms and the severity of depression.

Adult ; Case-Control Studies ; Depression ; genetics ; Disease Susceptibility ; Female ; Genetic Association Studies ; Humans ; Male ; Middle Aged ; Norepinephrine Plasma Membrane Transport Proteins ; genetics ; Polymorphism, Genetic ; Serotonin Plasma Membrane Transport Proteins ; genetics ; Young Adult