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1.  A five-year randomized parallel and blinded clinical trial of an extended specialized early intervention vs. regular care in the early phase of psychotic disorders: study protocol 
BMC Psychiatry  2015;15:22.
Background
Specialized Early Intervention services (SEI) for first episode psychosis are shown to be effective for the treatment of positive and negative symptoms, medication adherence, rates of relapse, substance abuse disorders, functional outcome and quality of life at two-year treatment follow up. However, it is also reported that these benefits are not maintained when SEI is not sustained. The objective of this trial is to test the efficacy of a 3-year extension of a SEI service (following 2 years of SEI prior to randomization) for the maintenance and consolidation of therapeutic gains as compared to regular care in the community.
Methods
Following an initial 2 years of SEI, patients are randomized to receive either 3-years of continued SEI or regular care. SEI provided at three sites within the McGill network of SEI services, using a model of treatment comprised of: modified assertive case management; psycho education for families; multiple family intervention; cognitive behavioural therapy; and substance abuse treatment and monitoring. Blinded research assistants conduct ongoing evaluation of the outcome variables every three months. The primary outcome measure is remission status measured both as the proportion of patients in complete remission and the mean length of remission achieved following randomization during the additional three years of follow up. Based on preliminary data, it is determined that a total of 212 patients are needed to achieve adequate statistical power. Intent to treat with the last observation carried forward will be the primary method of statistical analysis.
Discussion
The “critical period” hypothesis posits that there is a five year window during which the effects of the nascent psychotic illness can be countered and the impact of the disorder on symptomatic and functional outcomes can be offset through active and sustained treatment. Providing SEI throughout this critical period may solidify the benefits of treatment such that gains may be more sustainable over time as compared to intervention delivered for a shorter period. Findings from this study will have implications for service provision in first episode psychosis.
Trial registration
ISRCTN11889976
doi:10.1186/s12888-015-0404-2
PMCID: PMC4336502
Specialized early intervention; First episode psychosis; Treatment; Critical period; Remission; Case management; Randomized controlled trial
2.  Reduced hippocampal volume and hypothalamus–pituitary–adrenal axis function in first episode psychosis: Evidence for sex differences 
NeuroImage : Clinical  2014;7:195-202.
Background
Hippocampal volume (HV) decline is an important marker of psychosis and has been associated with hypothalamus–pituitary–adrenal (HPA) axis dysregulation in various disorders. Given recent findings of sex differences in HPA axis function in psychosis, the current study investigated differences in HV in male and female first episode psychosis (FEP) patients and controls and the interaction of HV with the cortisol awakening response (CAR) and symptoms.
Methods
Fifty-eight patients with a diagnosis of FEP (39 men, 19 women) and 27 healthy community controls (15 men, 12 women) underwent structural magnetic resonance imaging (MRI) on a 1.5 T scanner. Hippocampal volume was determined using previously established segmentation protocols. Saliva samples for cortisol assessment were collected at 0, 30 and 60 min after awakening. Psychotic symptoms were assessed with the Scale for Assessment of Positive Symptoms (SAPS), the Scale for Assessment of Negative Symptoms (SANS) and the Global Assessment of Functioning (GAF) scale.
Results
Male patients had significantly smaller left and right HVs compared to male controls, which appeared to be secondary to global brain volume differences. However, even when controlling for overall brain size, male patients showed smaller HV compared to female patients. The CAR was significantly lower in male patients compared to male controls and female patients. Only in male patients, smaller left HV was significantly associated with a blunted CAR, and smaller HV bilaterally was related to positive psychotic symptoms and lower levels of functioning.
Conclusions
We propose that reduced hippocampal volume and an attenuated cortisol awakening response are related markers of increased stress vulnerability in male psychosis patients and that both contribute to the unfavorable clinical picture in men.
Highlights
•We examined sex differences in neurobiological markers of stress in psychosis.•Hippocampal volume and cortisol levels to awakening are reduced in male patients.•Male first episode psychosis patients show markers of high stress vulnerability.•Neurobiological deficits relate to poor outcome in male but not female patients.•The neural-diathesis stress model of schizophrenia is particularly valid for men.
doi:10.1016/j.nicl.2014.12.001
PMCID: PMC4300007  PMID: 25610781
First episode psychosis; Hippocampus; Hypothalamus–pituitary–adrenal axis; Cortisol awakening response; Sex differences
3.  Source retrieval is not properly differentiated from object retrieval in early schizophrenia: An fMRI study using virtual reality 
NeuroImage : Clinical  2014;7:336-346.
Source memory, the ability to identify the context in which a memory occurred, is impaired in schizophrenia and has been related to clinical symptoms such as hallucinations. The neurobiological underpinnings of this deficit are not well understood. Twenty-five patients with recent onset schizophrenia (within the first 4.5 years of treatment) and twenty-four healthy controls completed a source memory task. Participants navigated through a 3D virtual city, and had 20 encounters of an object with a person at a place. Functional magnetic resonance imaging was performed during a subsequent forced-choice recognition test. Two objects were presented and participants were asked to either identify which object was seen (new vs. old object recognition), or identify which of the two old objects was associated with either the person or the place being presented (source memory recognition). Source memory was examined by contrasting person or place with object. Both patients and controls demonstrated significant neural activity to source memory relative to object memory, though activity in controls was much more widespread. Group differences were observed in several regions, including the medial parietal and cingulate cortex, lateral frontal lobes and right superior temporal gyrus. Patients with schizophrenia did not differentiate between source and object memory in these regions. Positive correlations with hallucination proneness were observed in the left frontal and right middle temporal cortices and cerebellum. Patients with schizophrenia have a deficit in the neural circuits which facilitate source memory, which may underlie both the deficits in this domain and be related to auditory hallucinations.
doi:10.1016/j.nicl.2014.08.006
PMCID: PMC4297883  PMID: 25610794
Source memory; Schizophrenia; Associative memory; First episode; Virtual reality; Hallucinations
5.  Cortical Thinning in Temporo-Parietal Junction (TPJ) in Non-Affective First-Episode of Psychosis Patients with Persistent Negative Symptoms 
PLoS ONE  2014;9(6):e101372.
Background
Negative symptoms represent an unmet therapeutic need in many patients with schizophrenia. In an extension to our previous voxel-based morphometry findings, we employed a more specific, vertex-based approach to explore cortical thinning in relation to persistent negative symptoms (PNS) in non-affective first-episode of psychosis (FEP) patients to advance our understanding of the pathophysiology of primary negative symptoms.
Methods
This study included 62 non-affective FEP patients and 60 non-clinical controls; 16 patients were identified with PNS (i.e., at least 1 primary negative symptom at moderate or greater severity sustained for at least 6 consecutive months). Using cortical thickness analyses, we explored for differences between PNS and non-PNS patients as well as between each patient group and healthy controls; cut-off threshold was set at p<0.01, corrected for multiple comparisons.
Results
A thinner cortex prominently in the right superior temporal gyrus extending into the temporo-parietal junction (TPJ), right parahippocampal gyrus, and left orbital frontal gyrus was identified in PNS patients vs. non-PNS patients. Compared with healthy controls, PNS patients showed a thinner cortex prominently in the right superior temporal gyrus, right parahippocampal gyrus, and right cingulate; non-PNS patients showed a thinner cortex prominently in the parahippocampal gyrus bi-laterally.
Conclusion
Cortical thinning in the early stages of non-affective psychosis is present in the frontal and temporo-parietal regions in patients with PNS. With these brain regions strongly related to social cognitive functioning, our finding suggests a potential link between primary negative symptoms and social cognitive deficits through common brain etiologies.
doi:10.1371/journal.pone.0101372
PMCID: PMC4076331  PMID: 24979583
7.  Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis 
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.
doi:10.1503/jpn.120242
PMCID: PMC3868663  PMID: 24016415
8.  Adherence to Psychostimulant Medication in Children with Attention-Deficit/Hyperactivity Disorder: The Role of Attitudes 
Objective:
To investigate how attitudes towards psychostimulant medication influence the adherence to psychostimulant treatment in children with Attention-Deficit/Hyperactivity Disorder (ADHD).
Method:
Thirty-three children with ADHD were prospectively recruited to take part in this study. The children and their parents filled questionnaires at both baseline and at a three-month follow-up to assess the severity of ADHD symptoms in the child and attitudes towards psychostimulant medication. Adherence to medication was assessed through standardized interviews of parents.
Results:
Parental perceived psychosocial benefits of psychostimulant medication at the three-month follow-up were found to be positive predictors of adherence to medication. Parental perceived psychosocial benefits of medication at the three-month follow-up was in turn predicted by parental medication acceptability at three months and child’s perceived psychosocial benefits of medication at three-months.
Conclusion:
Improving parents’ awareness of psychosocial benefits of psychostimulant medication may increase adherence to psychostimulant medication in children with ADHD. Age of the child and severity of symptoms did not significantly affect medication adherence.
PMCID: PMC3825473  PMID: 24223052
Attention-Deficit/Hyperactivity Disorder (ADHD); medication adherence; psychostimulants; attitudes; trouble de déficit de l’attention avec hyperactivité (TDAH); observance des médicaments; psychostimulants; attitudes
10.  Sensitivity of Scales to Evaluate Change in Symptomatology with Psychostimulants in Different ADHD Subtypes 
Objective:
To assess the sensitivity of scales (Conners’ Global Index Parent and Teacher form [CGI-P, CGI-T], Clinical Global Impression Scale [CGI], Continuous Performance Test [CPT], and Restricted Academic Situation Scale [RASS]) in evaluating improvement in symptomatology with methylphenidate in different Attention Deficit Hyperactivity Disorder (ADHD) subtypes.
Method:
Four hundred and ninety children (309 with ADHD Combined/Hyperactive [ADHD-CH] and 181 with ADHD Inattentive subtype [ADHD-I]) participated in a two week double-blind placebo-controlled crossover methylphenidate trial.
Results:
CGI-P showed small effect size for ADHD-I and medium effect size for the ADHD-CH subtype. CGI-T showed medium effect size for ADHD-I and large effect size for ADHD-CH subtype. CGI and RASS showed large effect size while CPT showed medium effect size for both subtypes.
Conclusion:
Acute behavioural assessments by clinicians (CGI, RASS) are better at detecting improvement with medication in all subtypes than parent or teacher reports (CGI-P, CGI-T). CGI-T is better than CGI-P for ADHD-I in detecting change in symptomatology as there is a greater demand for attention at school.
PMCID: PMC3647632  PMID: 23667362
Attention Deficit Hyperactivity Disorder; ADHD; Conners’ scales; RASS; CGI; CPT; scales; ADHD subtypes; inattention; hyperactivity; trouble de déficit de l’attention avec hyperactivité; TDAH; échelles de Conners; RASS; CGI; CPT; échelles; sous-types du TDAH; inattention; hyperactivité
11.  Structure of Spike Count Correlations Reveals Functional Interactions between Neurons in Dorsolateral Prefrontal Cortex Area 8a of Behaving Primates 
PLoS ONE  2013;8(4):e61503.
Neurons within the primate dorsolateral prefrontal cortex (dlPFC) are clustered in microcolumns according to their visuospatial tuning. One issue that remains poorly investigated is how this anatomical arrangement influences functional interactions between neurons during behavior. To investigate this question we implanted 4 mm×4 mm multielectrode arrays in two macaques' dlPFC area 8a and measured spike count correlations (rsc) between responses of simultaneously recorded neurons when animals maintained stationary gaze. Positive and negative rsc were significantly higher than predicted by chance across a wide range of inter-neuron distances (from 0.4 to 4 mm). Positive rsc were stronger between neurons with receptive fields (RFs) separated by ≤90° of angular distance and progressively decreased as a function of inter-neuron physical distance. Negative rsc were stronger between neurons with RFs separated by >90° and increased as a function of inter-neuron distance. Our results show that short- and long-range functional interactions between dlPFC neurons depend on the physical distance between them and the relationship between their visuospatial tuning preferences. Neurons with similar visuospatial tuning show positive rsc that decay with inter-neuron distance, suggestive of excitatory interactions within and between adjacent microcolumns. Neurons with dissimilar tuning from spatially segregated microcolumns show negative rsc that increase with inter-neuron distance, suggestive of inhibitory interactions. This pattern of results shows that functional interactions between prefrontal neurons closely follow the pattern of connectivity reported in anatomical studies. Such interactions may be important for the role of the prefrontal cortex in the allocation of attention to targets in the presence of competing distracters.
doi:10.1371/journal.pone.0061503
PMCID: PMC3632589  PMID: 23630595
12.  Investigation of rare variants in LRP1, KPNA1, ALS2CL and ZNF480 genes in schizophrenia patients reflects genetic heterogeneity of the disease 
Background
Schizophrenia is a severe psychiatric disease characterized by a high heritability and a complex genetic architecture. Recent reports based on exome sequencing analyses have highlighted a significant increase of potentially deleterious de novo mutations in different genes in individuals with schizophrenia.
Findings
This report presents the mutation screening results of four candidate genes for which such de novo mutations were previously reported (LRP1, KPNA1, ALS2CL and ZNF480). We have not identified any excess of rare variants in the additional SCZ cases we have screened.
Conclusions
This supports the notion that de novo mutations in these four genes are extremely rare in schizophrenia and further highlights the high degree of genetic heterogeneity of this disease.
doi:10.1186/1744-9081-9-9
PMCID: PMC3599135  PMID: 23425335
Schizophrenia; De novo mutation; LRP1; ALS2CL; KPNA1; ZNF480
13.  Body Weight and ADHD: Examining the Role of Self-Regulation 
PLoS ONE  2013;8(1):e55351.
Objective
Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex and heterogeneous childhood disorder that often coexists with other psychiatric and somatic disorders. Recently, a link between ADHD and body weight dysregulation has been reported and often interpreted as impaired self-regulation that is shared between the two conditions. The objective of this study is to investigate the relation between body weight/BMI and cognitive, emotional and motor characteristics in children with ADHD.
Methods
284 ADHD children were stratified by weight status/BMI according to WHO classification and compared with regard to their neurocognitive characteristics, motivational style, and motor profile as assessed by a comprehensive battery of tests. All comparisons were adjusted for demographic characteristics of relevance including, socioeconomic status (SES).
Results
Both Obese and overweight ADHD children exhibited significantly lower SES compared to normal weight ADHD children. No significant differences were observed between the three groups with regards to their neurocognitive, emotional and motor profile.
Conclusions
Our findings provide evidence that differences in weight/BMI are not accounted for by cognitive, motivational and motor profiles. Socio-economic characteristics are strongly associated with overweight and obesity in ADHD children and may inform strategies aimed at promoting healthier weight.
doi:10.1371/journal.pone.0055351
PMCID: PMC3558419  PMID: 23383165
14.  Identifying persistent negative symptoms in first episode psychosis 
BMC Psychiatry  2012;12:224.
Background
Although persistent negative symptoms (PNS) are known to contribute significantly to poor functional outcome, they remain poorly understood. We examined the heuristic value of various PNS definitions and their respective prevalence in patients with first episode psychosis (FEP). We also contrasted those definitions to the Proxy for the Deficit Syndrome (PDS) to identify deficit syndrome (DS) in the same FEP cohort.
Methods
One hundred and fifty-eight FEP patients were separated into PNS and non-PNS groups based on ratings from the Scale for Assessment of Negative Symptoms (SANS). PNS was defined in the following ways: 1) having a score of 3 or greater on at least 1 global subscale of the SANS (PNS_1); 2) having a score of 3 or more on at least 2 global subscales of the SANS (PNS_2); and 3) having a score of 3 or more on a combination of specific SANS subscales and items (PNS_H). For all three definitions, symptoms had to be present for a minimum of six consecutive months. Negative symptoms were measured upon entry to the program and subsequently at 1,2,3,6,9 and 12 months. Functional outcome was quantified at first assessment and month 12.
Results
PNS prevalence: PNS_1 (27%); PNS_2 (13.2%); PNS_H (13.2%). The prevalence of DS was found to be 3% when applying the PDS. Regardless of the definition being applied, when compared to non-PNS, patients in the PNS group were shown to have significantly worse functioning at month 12. All three PNS definitions showed similar associations with functional outcome at month 12.
Conclusion
Persistent negative symptoms are present in about 27% of FEP patients with both affective and non-affective psychosis. Although there has previously been doubt as to whether PNS represents a separate subdomain of negative symptoms, the current study suggests that PNS may be more applicable to FEP when compared to DS. Although all three PNS definitions were comparable in predicting functional outcome, we suggest that the PNS definition employed is dependent on the clinical or research objective at hand.
doi:10.1186/1471-244X-12-224
PMCID: PMC3566912  PMID: 23217020
First-episode psychosis; Persistent negative symptoms; Negative symptoms; Functional outcome
15.  Comprehensive Phenotype/Genotype Analyses of the Norepinephrine Transporter Gene (SLC6A2) in ADHD: Relation to Maternal Smoking during Pregnancy 
PLoS ONE  2012;7(11):e49616.
Objective
Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.
Methods
Children (6–12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.
Results
A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z = 3.74, P = 0.0002), behavioral assessments by parents (CBCL, P = 0.00008), as well as restless-impulsive subscale scores on Conners’-teachers (P = 0.006) and parents (P = 0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z = 3.28, P = 0.001), parents (Z = 2.62, P = 0.009), as well as evaluation in the simulated academic environment (Z = 3.58, P = 0.0003).
Conclusions
By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information – Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106.
doi:10.1371/journal.pone.0049616
PMCID: PMC3502190  PMID: 23185385
16.  Efficacy of Methylphenidate in ADHD Children across the Normal and the Gifted Intellectual Spectrum 
Objective:
This study evaluates whether attention-deficit/hyperactivity disorder (ADHD) children with a borderline intelligence quotient (IQ) (70≤FSIQ<80), normal IQ (80≤FSIQ<120) and high IQ (FSIQ≥120) respond differently to psychostimulant treatment.
Method:
502 children, aged 6 to 12 years, with an IQ range from 70 to 150 participated in a two-week, double-blind, placebo-controlled, crossover methylphenidate (MPH) trial.
Results:
In addition to differences in socioeconomic background and parental education, higher IQ children were found to present with less severe symptoms. No significant differences were found with regards to treatment response.
Conclusion:
ADHD children within the normal and high levels of intellectual functioning all respond equally to psychostimulant treatment, and that proper medication management is necessary for all children with the disorder.
PMCID: PMC3490529  PMID: 23133462
ADHD; IQ; methylphenidate response; TDAH; QI; réponse au méthylphénidate
17.  Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia 
Human genetics  2011;130(4):563-573.
Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.
doi:10.1007/s00439-011-0975-z
PMCID: PMC3204930  PMID: 21424692
18.  The Structural Neural Substrates of Persistent Negative Symptoms in First-Episode of Non-Affective Psychosis: A Voxel-Based Morphometry Study 
Objectives: An important subset of patients with schizophrenia present clinically significant persistent negative symptoms (PNS). Identifying the neural substrates of PNS could help improve our understanding and treatment of these symptoms. Methods: This study included 64 non-affective first-episode of psychosis (FEP) patients and 60 healthy controls; 16 patients displayed PNS (i.e., at least one primary negative symptom at moderate or worse severity sustained for at least six consecutive months). Using voxel-based morphometry (VBM), we explored for gray matter differences between PNS and non-PNS patients; patient groups were also compared to controls. All comparisons were performed at p < 0.05, corrected for multiple comparisons. Results: PNS patients had smaller gray matter in the right frontal medial–orbital gyrus (extending into the inferior frontal gyrus) and right parahippocampal gyrus (extending into the fusiform gyrus) compared to non-PNS patients. Compared to controls, PNS patients had smaller gray matter in the right parahippocampal gyrus (extending into the fusiform gyrus and superior temporal gyrus); non-PNS patients showed no significant differences to controls. Conclusion: Neural substrates of PNS are evident in FEP patients. A better understanding of the neural etiology of PNS may encourage the search for new medications and/or alternative treatments to better help those affected.
doi:10.3389/fpsyt.2012.00042
PMCID: PMC3346965  PMID: 22586412
first-episode psychosis; persistent negative symptoms; magnetic resonance imaging; voxel-based morphometry; neural substrates; frontal lobe
20.  Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype 
Background
Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD.
Methods
Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT.
Results
A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5′ region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplotype block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2.
Limitations
The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.
Conclusion
The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.
doi:10.1503/jpn.110073
PMCID: PMC3297073  PMID: 22297068
21.  Maternal Stress during Pregnancy, ADHD Symptomatology in Children and Genotype: Gene-Environment Interaction 
Objective
Case control studies suggest a relationship between maternal stress during pregnancy and childhood ADHD. However, maternal smoking, parenting style and parental psychiatric disorder are possible confounding factors. Our objective was to control for these factors by using an intra-familial design, and investigate gene-environment interactions.
Methods
One hundred forty two children, ages 6 to 12, (71 with ADHD, and their 71 non-ADHD siblings) participated in the intra-familial study design. A larger sample of ADHD children (N=305) was genotyped for DAT1 and DRD4 to examine gene-environment interactions. Symptom severity was evaluated using the Child Behavior Checklist (CBCL) and the Conners’ Global Index for Parents (CGI-P). The Kinney Medical and Gynecological Questionnaire was used to report stressful events during pregnancies.
Results
Logistic regression indicated that mothers were more likely to have experienced high stress during pregnancy of their ADHD child compared to that of the unaffected sibling (OR: 6.3, p=.01). In the larger sample, DRD4 7/7 genotype was associated with increased symptom severity in the high stress pregnancy (p=.01).
Conclusions
Maternal stress during pregnancy was associated with the development of ADHD symptomatology after controlling for family history of ADHD and other environmental factors. This association could partly be mediated through the DRD4 genotype.
PMCID: PMC3269259  PMID: 22299010
ADHD; prenatal stress; pregnancy; DRD4; TDAH; stress prénatal; grossesse; DRD4
23.  Relation between therapeutic response and side effects induced by methylphenidate as observed by parents and teachers of children with ADHD 
BMC Psychiatry  2011;11:70.
Background
The desired (therapeutic) and undesired (side) effects of methylphenidate might have underlying correlations. The aim of this study was to explore the strength and the possible sources of these correlations.
Methods
One hundred and fifty-seven children with ADHD (6-12 years) were administered placebo and methylphenidate (0.5 mg/kg in a divided b.i.d. dose), each for a one-week period, in a double-blind, crossover trial. Therapeutic response was assessed using the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers), while side effects were assessed using the Barkley Side Effects Rating Scale (SERS).
Results
The side effect profile as assessed by the SERS was similar to that of previous studies with insomnia, decreased appetite, and headaches showing significant treatment effects (p < 0.005). These "somatic/physical" side effects did not correlate with CGI-Parents or CGI-Teachers. However, the side effects of "irritability", "proneness to crying", and "anxiousness" showed significant relationships with CGI-Parents. These "mood/anxiety" side effects showed no significant correlations with the CGI-Teachers.
Conclusion
The greater "mood/anxiety" side effects on methylphenidate and placebo, the less the parents observe improvement of their children while treated with methylphenidate. This suggests that the correlations between "mood/anxiety" side effects and poor response to treatment may be driven by observer effects rather than biological commonalities between therapeutic and side effects of methylphenidate.
doi:10.1186/1471-244X-11-70
PMCID: PMC3095543  PMID: 21510895
24.  Mutations in SYNGAP1 in Autosomal Nonsyndromic Mental Retardation 
The New England journal of medicine  2009;360(6):599-605.
Summary
Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPase-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation. We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients. In contrast, we observed no de novo or truncating mutations in SYNGAP1 in samples from 142 subjects with autism spectrum disorders, 143 subjects with schizophrenia, and 190 control subjects. These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.
doi:10.1056/NEJMoa0805392
PMCID: PMC2925262  PMID: 19196676
25.  The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD 
BMC Psychiatry  2010;10:50.
Background
Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) and the response of ADHD relevant behaviors with methylphenidate treatment.
Methods
Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.
Results
Mixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (s+lG = s') responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (lA). No genotype main effects on either CGI-Parents or CGI-teachers were observed.
Conclusions
A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the SLC6A4 gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.
Trial Registration
ClinicalTrials.gov NCT00483106
doi:10.1186/1471-244X-10-50
PMCID: PMC2905344  PMID: 20569447

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