Search

The authors reflect on the implications of the neo-Kraepelin framework (NKF) for clinical practice and research. He says that the practice of psychiatry in the 18th and 19th centuries produced a rich literature through clinical descriptions. Frameworks produced by researcher Emile Kraepelin and psychoanalysis founder Sigmund Freud that shaped modern psychiatry are discussed. The repudiation of any theoretical framework of mental illnesses is considered a major theoretical foundation of the NKF.

Background: The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation. Methods: We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter. Results: In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d' = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate-corrected. Risk-allele carriers did not show any regions of reduced white matter volume. Limitations: The sample size is modest given that a low-frequency variant was being examined. Conclusion: The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP. [ABSTRACT FROM AUTHOR]

Background: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association was reported between ADHD and LPHN3 (which codes for latrophilin 3), and replicated in independent samples. Methods: We have examined the association between tag single nucleotide polymorphisms (SNPs) in LPHN3 within the region previously implicated in ADHD. Family based association tests (FBAT) were conducted ( n = 380 families) with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, and response to treatment (given a fixed dose of methylphenidate, 0.5 mg/day). Stratified FBAT analyses, based on maternal smoking and stress during pregnancy, was conducted. Results: Whereas limited association was observed in the total sample, highly significant interaction between four LPHN3 tag SNPs (rs6551665, rs1947274, rs6858066, rs2345039) and maternal stress during pregnancy was noted. Analysis conducted in the sub-group of mothers exposed to minimal stress during pregnancy showed significant associations with ADHD, behavioral and cognitive dimensions related to ADHD, as well as treatment response. Although extensive association was observed with the candidate SNPs, the findings are partially inconsistent with previously published results with the opposite alleles over-transmitted in these studies. Conclusions: These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD. [ABSTRACT FROM AUTHOR]

Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent 'spatial' navigation, which relies on knowledge of the relationship between landmarks in one's environment to build a cognitive map, and habit-based 'response' learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where 'Met' carriers use a response strategy more frequently than individuals homozygous for the 'Val' allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour. [ABSTRACT FROM AUTHOR]

Association between 5-HTTLPR polymorphism and development of acute and persistence of chronic posttraumatic stress disorder (PTSD) was prospectively investigated. DNA was extracted from 41 motor-vehicle accident victims evaluated for development and persistence of PTSD, 1 and 12 months posttrauma. At Time 1, a nonsignificant trend for higher acute PTSD rate in ll homozygotes (82%) was observed compared to those with ss and sl genotypes (50%). At Time 2, higher chronic PTSD rate was found in ll homozygotes (55%) compared to those with ss and sl genotypes (20%), with an odds ratio of 4.8 (95% CI = 1.09–21.22). Contrary to previous findings, these data are suggestive of a protective role for the s allele of 5-HTTLPR in chronic PTSD. [ABSTRACT FROM AUTHOR]

We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3′-untranslated region (3′-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6–12 years) were assessed with regard to the Conners’ Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3′-UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p=0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3′-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.Neuropsychopharmacology (2007) 32, 1370–1376. doi:10.1038/sj.npp.1301240; published online 25 October 2006 [ABSTRACT FROM AUTHOR]

Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score ( r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes ( P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features. [ABSTRACT FROM AUTHOR]

Amphetamine (AMPH)-induced locomotor activity is a rodent behavioral trait that reflects mesolimbic dopaminergic activity. To identify potential quantitative trait loci (QTL) associated with this behavior, we used 34 recombinant congenic strains (RCSs) of mice derived from A/J (A strains) and C57BL/6J (B strains) and measured AMPH-induced total distance traveled (AMPH-TDIST). Two strains in the A panel (A52 and A63) showed significantly elevated AMPH-TDIST compared to the parental A/J strain and behaved similarly to C57BL/6J. Simple sequence length polymorphism (SSLP) markers on chromosomes 1, 2, 3, 5, 6, 8, 9, 10 and 20 were significantly associated with AMPH-TDIST in the A strains. Within the B panel, two strains (B81 and B74) had significantly higher and two strains (B69 and B75) had significantly lower AMPH-TDIST than C57BL/6J. Markers associated with AMPH-TDIST in the B strains appeared on chromosomes 5, 17 and 20. Combining data from this approach and other genetic (mapping data in humans) and functional (cDNA expression) sources may help to identify suitable candidate genes relevant to human disorders where mesolimbic dopamine dysregulation has been postulated. [ABSTRACT FROM AUTHOR]

Background: An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children. Methods: The Val108/158 Met polymorphism of the COMT gene was genotyped in 118 children with ADHD (DSM-IV). The Wisconsin Card Sorting Test (WCST), Tower of London (TOL), and Self-Ordered Pointing Task (SOPT) were employed to evaluate executive functions. Neuropsychological task performance was compared across genotype groups using analysis of variance. Results: ADHD children with the Val/Val, Val/Met and Met/Met genotypes were similar with regard to demographic and clinical characteristics. No genotype effects were observed for WCST standardized perseverative error scores [F2,97 = 0.67; p > 0.05], TOL standardized scores [F2,99 = 0.97; p > 0.05], and SOPT error scores [F2,108 = 0.62; p > 0.05]. Conclusions: Contrary to the observed association between WCST performance and the Val108/ 158 Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We explored interaction effects involving polymorphisms of targeted dopamine system genes and selected forms of childhood abuse (sexual, physical and emotional) acting upon severity of binge-eating and psychopathological symptoms in women with Bulimia-Spectrum Disorders (BSDs). Methods: Women diagnosed with a BSD (n = 216) were assessed for childhood traumata, eating-disorder (ED) symptoms, and selected psychopathological features (sensation seeking, impulsivity, compulsivity and affective instability), and then provided blood samples for genotyping of main polymorphisms of dopamine-2 receptor (DRD2), dopamine transporter (DAT1) and catechol o-methyltransferase (COMT) genes. Results: Sensation Seeking was elevated in carriers of the low-function allele of the DRD2 Taq1A polymorphism who also reported childhood sexual abuse, relative to that in individuals showing other combinations of alleles and abuse exposures. In addition, carriers of a low-function allele of COMT scored higher on compulsivity, lower on impulsivity, and marginally lower on frequency of binge-eating than did individuals in whom the allele was absent. Discussion: Our results suggest that genes acting within the dopamine system may contribute, either directly or indirectly (i.e., in interaction with traumatic childhood experiences), to variations in the presentation of comorbid traits and, possibly, of bulimic symptoms. [Copyright &y& Elsevier]

Abstract: We recently documented a gene-environment interaction suggesting that individuals with Bulimia Nervosa (BN) differed from normal eaters as to the combined presence of the low-function allele of the glucocorticoid receptor polymorphism, BcII, and childhood abuse. The present study examined the extent to which any such interaction effect may have been attributable to behavioral impulsivity, sensation seeking, affective instability or depression. We had 174 bulimic and 130 nonbulimic women provide blood for genetic assays, and measured psychopathological traits and childhood abuse using structured interviews and self-report questionnaires. As expected, we observed a significant BcII × abuse interaction indicating genetic and environmental susceptibilities to co-occur significantly more often in bulimic than in nonbulimic individuals. The BcII × abuse interaction was attenuated when levels of depression were accounted for, but was surprisingly unaffected by controls for motoric impulsivity, sensation seeking or affective instability. Our findings suggest that stress-induced alterations in glucocorticoid sensitivity contribute to BN and depressive disturbances—without being associated with the behavioral/affective dysregulation seen in many BN sufferers. We discuss theoretical and clinical implications of these observations. [Copyright &y& Elsevier]

Summary: Context: For the past two decades, researchers have shown that elevated levels of circulating stress hormones may negatively impact cognitive performance in older adults. As well, genetic polymorphism of the apolipoprotein E gene (APOE) has been found to contribute to impairment in cognitive performance in old age. To date, only one study has reported a relationship between APOE status and cortisol levels, however the relationship was only found to be significant in dementia patients, with a trend observed in healthy controls. Objective: The goal of the present investigation was to examine the acute and long-term relationship between APOE status, cortisol secretion, and declarative memory performance in older adults. Design: Two sample cohorts were assessed. In the first cohort, 24-h basal serum cortisol levels were obtained once a year over eight years to assess changes in basal cortisol levels over time. Declarative memory was also obtained in this group at three time-points over five years. In the second cohort, basal and stress-induced cortisol levels as well as basal declarative memory was tested. Results: In the first cohort, E4 carriers were found to secrete higher serum cortisol levels than non-E4 carriers during the first 24-h visit (p=0.04) to the laboratory. However, this group difference did not remain over subsequent years. Furthermore, declarative memory performance over years did not significantly differ according to APOE status. In the second cohort, no significant group differences were found for basal or reactive cortisol levels (ps>0.05), and no group difference was found for acute declarative memory performance. Conclusion: The findings in this study suggest minimal to no significant effect of APOE status on cortisol secretion or declarative memory in non-demented older adults. [Copyright &y& Elsevier]

Substance abuse is common in individuals with bulimia-spectrum (binge-purge) eating disturbances, a co-occurrence that has been attributed to shared neurobiological substrates--notably alterations in dopaminergic activity. We examined the implications of variations of selected, dopamine-relevant polymorphisms (DRD2 Taq1A, DRD4 7R, and COMT) for risk of substance abuse in women with binge-purge eating syndromes. We genotyped 183 women (66.1% showing full-threshold BN and 33.9% showing sub-syndromic variants), and assessed lifetime presence of alcohol, cannabis, cocaine, and stimulant abuse or dependence using structured interviews. Tests for main and interaction effects of various allele combinations revealed that individuals who carried high function COMT and low-function DRD4 7R alleles (a combination expected to be associated with higher risk) did indeed show more lifetime substance abuse and, specifically, more cannabis abuse. Our findings suggest that a gene combination that, in theory, codes for low levels of dopaminergic neurotransmission coincides with sensitivity to substance abuse in a sample displaying binge-purge eating-disorder variants. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluated the hypothesis that traumatic stress can increase risk of bulimia nervosa (BN) in individuals who are genetically disposed towards lower modulation of physiological stress reactions. We explored the extent to which childhood abuse (physical or sexual), variants of a main glucocorticoid receptor (GR) polymorphism (Bcl1), or their interaction, differentiated women with and without BN. Women seeking treatment for BN (N =129) and non-eating-disordered comparison women (N =98) provided blood samples for assays of the Bcl1 polymorphism, and completed structured interviews assessing eating symptoms, psychiatric symptoms and childhood abuse. Compared to normal-eaters, bulimic women were significantly more likely to carry the low-function Bcl1 C allele (CC or CG genotypes), to report a history of childhood abuse and, more importantly, to be positive for both factors. We interpret our findings as indicating that traumatic stress, when impacting individuals disposed to lower GR modulation, can be etiological for BN. [Copyright &y& Elsevier]

Abstract: Across populations, findings suggest that rates of self-mutilation, suicidal acts, and other self-harming behaviors (SHBs) may be influenced by polymorphisms that code for activity of the serotonin transporter (e.g., 5HTTLPR) and the enzyme, monoamine oxidase A (e.g., MAOAuVNTR). SHBs being common in patients with Eating Disorders (EDs), we evaluated (in a large sample of eating-disordered women) relationships between triallelic 5HTTLPR and MAOAuVNTR variants, on the one hand, and SHBs, on the other. We had 399 eating-disordered women report on eating symptoms and lifetime history of SHBs, and provide blood samples for genotyping. Individuals carrying high-function MAOAuVNTR alleles reported a history of SHBs about twice as often as did carriers of low-function alleles. We obtained no comparable main effect of 5HTTLPR, or MAOAuVNTR×5HTTLPR interaction effect. Genetic variations did not predict severity of eating symptoms. As in other populations, our findings link the MAOAuVNTR high-function alleles with increased risk of self-directed harm in bulimic females. We discuss theoretical and clinical ramifications of our results. [ABSTRACT FROM AUTHOR]

Abstract: Context: Efforts to classify eating-disordered individuals based on concurrent personality traits have consistently converged on a typology encompassing “over-regulated”, “dysregulated”, and “low psychopathology” subgroups. In various populations, evidence has associated personality variations of an “over-regulated/dysregulated” type with differences on serotonin-system indices, and specifically, with different loadings of serotonin transporter promoter regulatory region polymorphism (5HTTLPR) genotypes and alleles. We explored the extent to which an empirical, trait-defined typology of eating-disordered individuals coincided systematically with variations in 5HTTLPR, assayed using biallelic and triallelic models. Method: We tested 185 women with a DSM-IV eating disorder (108 with Bulimia Nervosa, 17 Anorexia Nervosa, and 60 an Eating Disorder Not Otherwise Specified) and 93 with no eating disorder on measures reflecting psychopathological traits and 5HTTLPR (biallelic and triallelic) genotypes and alleles. Results: The highest-function, triallelic (LA/LA) genotype occurred significantly more frequently among eating-disordered individuals than among controls. However, a more fine-grained analysis suggested that this association was attributable to the fact that, among eating-disordered participants, those displaying an “Inhibited/Compulsive” profile (derived using latent class analysis) were more likely than those of a “Dissocial/Impulsive” or a “Low Psychopathology” group to carry the triallelic 5HTTLPR gain-of-function LA allele and to be LA/LA homozygotes. Discussion: This study’s empirically derived classes coincide with interpretable differences on genetic indices—associating an “Inhibited/Compulsive” group with 5HTTLPR gain-of-function genotypes (and alleles) that have elsewhere been linked to trait compulsivity. The findings, furthermore, suggest that 5HTTLPR, by influencing personality-trait manifestations may, in turn, influence eating-disorder risk and symptom expression. [Copyright &y& Elsevier]

Abstract: Objective: Attention-deficit/hyperactivity disorder (ADHD) is often associated with reduced IQ and high levels of externalizing behavior (EB). This study tested if DRD4 7-repeat allele and DAT1 10-repeat allele homzygosity interact in modulating correlations between IQ and EB in affected boys. Methods: Boys (n =130) between 6 and 12 years of age diagnosed with ADHD were included in the study. IQ and EB were assessed by WISC-III and Child Behavioral Checklist, respectively. The 40 bp variable number tandem repeat (VNTR) of the DAT1 gene and the 48 bp VNTR of the DRD4 gene polymorphisms were genotyped and 4 subgroups were defined by the presence/absence of the DRD4 7-repeat allele and by the presence/absence of the DAT1 10/10 genotype. Correlation coefficients were compared using the Fisher''s Z transformation and regression lines by a Potthoff analysis. Results: In the total sample, all correlation coefficients between EB score and IQ were non significant. Also, no differences in IQ were observed between the 4 genotype groups. However, different pattern of correlations between IQ and EB score appeared. In boys carrying no or only one genetic risk, IQ and EB score were uncorrelated while in children carrying both risk factors, negative and significant correlations emerged. Notably, correlation of EB to verbal IQ was strong (r =−0.71) and highly significant (P <0.01) in boys carrying both risk alleles. All pair-wise comparisons of correlation coefficients were significant for EB–verbal IQ correlation. Test of coincidence of regression lines did not show significant differences. Conclusions: A specific domain of IQ, namely the verbal quotient is highly correlated to the level of EB in boys with ADHD carrying both dopaminergic risk genotypes. Further investigations are required to replicate these results and determine specificity to ADHD. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the association between a Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia. Methods: 408 schizophrenic patients and 172 control subjects were compared with regard to their DRD3 Ser9Gly genotypic and allelic frequencies. In addition, we carried out a family-based association study including 183 pedigrees (472 subjects) using the transmission disequilibrium test (TDT). Results: No significant differences of genotype or homozygosity distribution were identified between patients and controls. When patients were stratified according to gender, response to treatment, age at onset, no significant differences were observed. Neither allele A (Ser), or G (Gly) were preferentially transmitted from parents to affected offspring. Conclusion: The hypothesis that the DRD3 Ser9Gly polymorphism plays a predisposing role in schizophrenia is not supported by this study. [Copyright &y& Elsevier]

Objective: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design.Method: Children (n=191) between 6 and 12 years of age who were diagnosed with ADHD were included in the study. Conduct disorder was diagnosed according to DSM-IV criteria based on clinical evaluation and a structured interview (Diagnostic Interview Schedule for Children-IV). The mother's report on the child's birth weight was used in the analysis. Logistic regression analysis, with genotype and birth weight as independent variables and DSM-IV conduct disorder as the dependent variable, was conducted.Results: No significant main effects of genotype and birth weight or interaction effects on conduct disorder were observed.Conclusion: In this sample of children diagnosed with ADHD, we find no association between the COMT ValMet gene variant, birth weight, and conduct disorder. Further investigations are required before using birth weight and COMT genotype as predictors of conduct disorder in children with attention-deficit/hyperactivity disorder, especially given the societal and legal ramifications of conduct disorder. [ABSTRACT FROM AUTHOR]

Abstract: The Nogo gene was putatively implicated in schizophrenia based on gene expression and genetic association data. In this study, we attempt to replicate the possible association of the CAA insertion and a nearby TATC deletion with schizophrenia in 204 complete and incomplete triads and in a sample of 462 unrelated cases and 153 controls, all of Caucasian origin. Our genotyping results indicated that neither the trinucleotide insertion polymorphism (CAAins; 43.4% vs. 41.8%, p>0.5) nor the polymorphism-TATC deletion (TATCdel; 49.8% vs. 49.3%, p>0.1) allele frequency is significantly different in patients compared to controls. The homozygous CAAins frequency is not significantly different between patients and controls either (18.0% vs. 15.0%, χ2=0.985, p>0.1). Furthermore, neither CAAins/TATCdel individually, nor the haplotype carrying both CAAins and TATCdel is preferentially transmitted to affected offspring. [Copyright &y& Elsevier]

Cortico-subcortical circuit dysfunction plays an important role in the manifestation of ADHD symptoms. Dopamine (DA) and Norepinephrine (NE) are major players in the fine regulation of these circuits. Both of these neurotransmitters are major players in maintaining alertness, increasing focus, sustaining thoughts, and facilitating many cognitive functions. Thus, perturbation of either NE, DA (or both) signaling could be implicated in the pathogenesis of ADHD. Hypothesis: Given the dynamic nature of the brain neuromodulation, where any action on one system may reverberate in the other systems, we hypothesize that NE transporter gene could interact with a gene that is essential for the metabolism of DA (COMT Val108/158Met) on modulating ADHD behaviors. 481 children with ADHD (9–12 years old) were included in a 2-week double blind placebo controlled study with methylphenidate. Teachers and parents were asked to evaluate the child's behavior at baseline, placebo, and MPH weeks. Repeated measure ANOVA with between-subject factor of both genes and within-subject factor of experimental conditions (EC) was used. A highly significant 3-way interaction (NET⁎COMT⁎EC) was revealed in three SNPs of the NET gene (rs41154 p= 0.002, rs187714 p= 0.001, and rs2242447 p= 0.006) according to the parents' evaluation. By stratifying the children according to their COMT genotypes, we observe that all children behave in a similar fashion at baseline but respond differently to placebo and MPH. In the Met/Met and Val/Val genotype groups, children who are carrying the AG genotype of rs41154, CT genotype of rs41154, and CT genotype of rs41154 tend to respond poorly compared to patients with the GG, CC, and CT genotypes respectively on placebo and MPH. Taken together, the current results suggest the epistatic interaction between COMT and NET genetic polymorphisms on response to pharmacological probes. Suggesting that complex gene-by-gene interactions may be important. [ABSTRACT FROM AUTHOR]