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Purpose: Cross-cultural psychosis research has typically focused on a limited number of outcomes (generally symptom-related). It is unknown if the purported superior outcomes for psychosis in some low- and middle-income countries extend to fundamental treatment processes like trust. Addressing this gap, we studied two similar first-episode psychosis programs in Montreal, Canada, and Chennai, India. We hypothesized higher trust in healthcare institutions and providers among patients and families in Chennai at baseline and over follow-up. Methods: Upon treatment entry and at months 3, 12 and 24, trust in healthcare providers was measured using the Wake Forest Trust scale and trust in the healthcare and mental healthcare systems using two single items. Nonparametric tests were performed to compare trust levels across sites and mixed-effects linear regression models to investigate predictors of trust in healthcare providers. Results: The study included 333 patients (Montreal = 165, Chennai = 168) and 324 family members (Montreal = 128, Chennai = 168). Across all timepoints, Chennai patients and families had higher trust in healthcare providers and the healthcare and mental healthcare systems. The effect of site on trust in healthcare providers was significant after controlling for sociodemographic characteristics known to impact trust. Patients' trust in doctors increased over follow-up. Conclusion: This study uniquely focuses on trust as an outcome in psychosis, via a comparative longitudinal analysis of different trust dimensions and predictors, across two geographical settings. The consistent differences in trust levels between sites may be attributable to local cultural values and institutional structures and processes and underpin cross-cultural variations in treatment engagement and outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Although extensively studied in high-income countries (HICs) and less so in low- and middle-income countries (LMICs), pathways to care and treatment delays in early psychosis have not been compared across contexts. We compared pathways to early intervention for psychosis in an HIC (Montreal, Canada) and an LMIC (Chennai, India). We hypothesised that the duration of untreated psychosis (DUP) would be longer in Chennai. Methods: The number of contacts preceding early intervention, referral sources, first contacts, and DUP and its referral and help-seeking components of first-episode psychosis patients at both sites were similarly measured and compared using chi-square analyses and t tests/one-way ANOVAs. Results: Overall and help-seeking DUPs of Chennai (N = 168) and Montreal (N = 165) participants were not significantly different. However, Chennai patients had shorter referral DUPs [mean = 12.0 ± 34.1 weeks vs. Montreal mean = 13.2 ± 28.7 weeks; t(302.57) = 4.40; p < 0.001] as the early intervention service was the first contact for 44% of them (vs. 5% in Montreal). Faith healers comprised 25% of first contacts in Chennai. Those seeing faith healers had significantly shorter help-seeking but longer referral DUPs. As predicted, most (93%) Montreal referrals came from medical sources. Those seeing psychologists/counsellors/social workers as their first contact had longer DUPs. Conclusion: Differences in cultural views about mental illnesses and organizational structures shape pathways to care and their associations with treatment delays across contexts. Both formal and informal sources need to be targeted to reduce delays. Early intervention services being the first portal where help is sought can reduce DUP especially if accessed early on in the illness course. [ABSTRACT FROM AUTHOR]

Psychotic disorders are highly heterogeneous. Understanding relationships between symptoms will be relevant to their underlying pathophysiology. We apply dimensionality-reduction methods across two unique samples to characterize the patterns of symptom organization. We analyzed publicly-available data from 153 participants diagnosed with schizophrenia or schizoaffective disorder (fBIRN Data Repository and the Consortium for Neuropsychiatric Phenomics), as well as 636 first-episode psychosis (FEP) participants from the Prevention and Early Intervention Program for Psychosis (PEPP-Montreal). In all participants, the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were collected. Multidimensional scaling (MDS) combined with cluster analysis was applied to SAPS and SANS scores across these two groups of participants. MDS revealed relationships between items of SAPS and SANS. Our application of cluster analysis to these results identified: 1 cluster of disorganization symptoms, 2 clusters of hallucinations/delusions, and 2 SANS clusters (asocial and apathy, speech and affect). Those reality distortion items which were furthest from auditory hallucinations had very weak to no relationship with hallucination severity. Despite being at an earlier stage of illness, symptoms in FEP presentations were similarly organized. While hallucinations and delusions commonly co-occur, we found that their specific themes and content sometimes travel together and sometimes do not. This has important implications, not only for treatment, but also for research—particularly efforts to understand the neurocomputational and pathophysiological mechanism underlying delusions and hallucinations. [ABSTRACT FROM AUTHOR]

Purpose: While the prevalence of delusional themes appears to be consistent across geographic contexts, little is known about the relative prevalence of such themes within a given setting over periods of time. We therefore investigated delusional themes across 12 years of presentation to a catchment-based early intervention service for first episode psychosis (FEP). Methods: Systematically collected data from 500 patients at an early intervention service for FEP were analyzed. Four cohorts of 3 years each, from 2006 to 2017, were used to compare the frequency of delusion themes across cohorts. We also integrated into the analysis baseline sociodemographic factors such as gender, age, and highest level of education and clinical factors such as anxiety, depression, suicidality, hallucinations, and primary diagnosis (affective or non-affective psychosis). Results: Sex and education level were stable across cohorts, while patient age varied (p = 0.047). Clinical anxiety, depression, and suicidality at entry were also stable. Across cohorts, the proportion of patients with affective versus non-affective diagnosis differed (p = 0.050), with no differences in global rating of delusion severity or theme prevalence except for delusions of guilt or sin (p = 0.001). This single theme difference was not correlated with age or diagnosis. Conclusion: Our study suggests relatively stable prevalence of delusion themes across cohorts of individuals experiencing FEP. This demonstrates the potential utility of studying thematic content both for understanding delusions in clinical populations and in research. Future explorations of the relationships between delusion themes and across individual patient episodes should be conducted. [ABSTRACT FROM AUTHOR]

Purpose: To study the impact of supervised antipsychotic medication discontinuation on clinical and functional outcomes in first-episode psychosis (FEP) in two different cultural environments. Method: FEP patients(N = 253), treated in two early intervention services (Montreal, Canada and Chennai, India) for 2 years, were assessed for medication use, positive and negative symptom remission and social–occupational functioning at regular intervals. Results: Between months 4 and 24 of treatment, 107 patients discontinued medication ('Off'group) as compared to 146 who stayed on medication ('On'group). Medication discontinuation was higher in Chennai as compared to Montreal (n = 80, 49.07% vs n = 27, 16.87%; χ2 37.80, p < 0.001), with no difference in time to discontinuation [Means(SDs) = 10.64(6.82) and 10.04(5.43), respectively, p = 0.71). At month 24 (N = 235), there were no differences in the rate of positive symptom remission between the on and Off groups (81.5 vs 88.0%, respectively) at both sites. The rate of negative symptom remission was lower among patients in the On compared to the Off group (63.2 vs 87.9%, respectively, χ2 = 17.91, p < 0.001), but only in Montreal (55.4% vs 80.0%, respectively, χ2 = 4.12, p < 0.05). Social and Occupational Functioning Assessment Scale scores were equally high in both Off and On medication groups in Chennai [Means (SDs) = 79.43(12.95) and 73.59(17.63), respectively] but higher in the Off compared to the On group in Montreal Means (SDs) = 77.47(14.97) and 64.94(19.02), respectively; Time × site interaction F = 3.96(1,217), p < 0.05]. Medication status (On–Off) had no impact on the outcomes, independent of other variables known to influence outcomes. Conclusion: Certain cultural environments and patient characteristics may facilitate supervised discontinuation of antipsychotic medication following treatment of an FEP without negative consequences. [ABSTRACT FROM AUTHOR]

Background: This study aims at characterizing the extent of correlation of treatment response (TR) obtained in various observation settings (home, school, clinic) by different observers (parents, teachers, clinicians). Methods: Children with attention deficit hyperactivity disorder (ADHD) underwent a 2-week double-blind, randomized, cross-over clinical trial with methylphenidate and placebo, and various measures were obtained during the 2 weeks. Interrelationships of TR were examined using Pearson's correlation coefficients. Results: The study included 526 children (420 male, 106 female) with ADHD. TR between different observers shows a variable correlation between parents and teachers. No correlation is seen between parents/teacher evaluation of TR and laboratory-based measures (Continuous Performance Task; Restricted Academic Situation Scale). Conclusion: The results firmly support the need to synthesize information from many sources in evaluating TR in ADHD. [ABSTRACT FROM AUTHOR]

Purpose: The early phases of psychosis, including the prodrome, often feature educational/occupational difficulties and various symptoms and signs, that can render or keep youths "Not in Employment, Education or Training" (NEET). Conversely, NEET status itself may increase risk for illness progression and impaired functioning, and impede access to appropriate services for psychosis. As these issues have not been investigated, we aimed to examine differences in the illness and care pathways and characteristics of youths with psychosis who are NEET and non-NEET.Methods: Youths entering a catchment-based Canadian early intervention service for psychosis (N = 416) were assessed as being NEET or non-NEET and compared on symptomatology, premorbid adjustment, prodrome and duration of untreated psychosis (DUP).Results: Thirty-nine percent of the sample was NEET. Compared to non-NEET youths, NEET youths had 34% higher negative symptoms scores, longer prodromes (median of 52 weeks vs. 24 weeks), and were more often continuously ill after their first psychiatric change until the onset of psychosis (62% vs. 45%). Both groups had similar premorbid adjustment scores until late adolescence when scores were significantly worse for NEET youths. Accounting for other predictors, NEET youths had 23% longer DUPs on average, despite having made more help-seeking attempts.Conclusions: Despite being more narrowly defined, NEET status was thrice as prevalent in our sample as in the Canadian population. The NEET group followed a distinct trajectory of persistent symptoms and functional decline before presenting with a psychotic disorder. The systemic delays that NEET youths encountered indicate a need for better-targeted early identification efforts. [ABSTRACT FROM AUTHOR]

Results of candidate gene investigations in ADHD have been difficult to replicate. The complexity of the phenotypes and their underlying determinants, and the relatively small effect sizes of genetic variants may, in part, be contributing to these inconsistencies. The objective of this study is to conduct an exploratory analysis using a comprehensive approach to investigate the role of candidate genes. This approach combines a dimensional behavioural approach akin to Research Domain Criteria (RDoC), a pharmaco-dynamic evaluation of behaviours relevant to ADHD, together with association and linkage testing in a large sample of children with ADHD. Parents, teachers, and research staff evaluated children with ADHD under three experimental conditions (EC): 1 week of baseline observation, followed by 1 week of methylphenidate (MPH) and 1 week of placebo, administered in a double-blind crossover order. Several quantitative behavioural and cognitive dimensions relevant for ADHD were also assessed. We combined family-based (FBAT) and quantitative trait genetic analyses (n = 575 probands with members of their nuclear families) to investigate the role of DRD3 (Ser-9-Gly) in ADHD and its relevant behavioural dimensions. Comparing the behaviours of children with different genotypes under the three EC showed a nominal association between the T allele and poorer behavioural scores during the MPH week (as assessed by teachers), particularly in boys. With the family-based analysis, the T allele showed a nominal association with increased risk for ADHD, response to placebo and MPH as assessed by research staff, and the modulation of other behavioural and cognitive dimensions. These results provide convergent, albeit preliminary evidence for the implication of the DRD3 (Ser-9-Gly) polymorphism in the aetiology of ADHD and the modulation of its various behavioural dimensions, including RDoC cognitive constructs and response to pharmacological probes. This illustrative example suggests that this research paradigm might help to reliably uncover the role of other candidate genes in ADHD. [ABSTRACT FROM AUTHOR]

Purpose: To explore the unintended impact of a targeted case identification (TCI) campaign for first episode psychosis (FEP) on people not experiencing FEP ("non-cases") with respect to referral patterns and reasons for being a non-case.Methods: Sources of referral, reasons for being a non-case, and subsequent referral destinations of non-cases were examined before and after a TCI.Results: Following the TCI, a greater proportion of non-cases lived outside the study catchment area. A smaller proportion was referred by the parent hospital's emergency room or had a substance-induced psychosis.Conclusions: TCIs for FEP may have unintended effects, with implications for early case identification and early intervention services. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this review is to report on recent developments in youth mental health incorporating all levels of severity of mental disorders encouraged by progress in the field of early intervention in psychotic disorders, research in deficiencies in the current system and social advocacy.Methods: The authors have briefly reviewed the relevant current state of knowledge, challenges and the service and research response across four countries (Australia, Ireland, the UK and Canada) currently active in the youth mental health field.Results: Here we present information on response to principal challenges associated with improving youth mental services in each country. Australia has developed a model comprised of a distinct front-line youth mental health service (Headspace) to be implemented across the country and initially stimulated by success in early intervention in psychosis; in Ireland, Headstrong has been driven primarily through advocacy and philanthropy resulting in front-line services (Jigsaw) which are being implemented across different jurisdictions; in the UK, a limited regional response has addressed mostly problems with transition from child-adolescent to adult mental health services; and in Canada, a national multi-site research initiative involving transformation of youth mental health services has been launched with public and philanthropic funding, with the expectation that results of this study will inform implementation of a transformed model of service across the country including indigenous peoples.Conclusions: There is evidence that several countries are now engaged in transformation of youth mental health services and in evaluation of these initiatives. [ABSTRACT FROM AUTHOR]

Purpose: Interventions aimed at influencing specific pathways to care may reduce the duration of untreated psychosis (DUP). The purpose of this study was to reduce delay in referral to an early intervention service following first contact for help seeking for psychosis in a defined urban catchment area. Methods: Using a historical control design, we conducted a targeted intervention comprised of intensive training and education regarding first onset of psychosis and benefits of early intervention with all potential points of contact in pathways to care in a defined catchment area of a specialized early intervention (EI) service. Data collected on different components of DUP [help seeking (H-DUP) and referral (R-DUP)] and demographic and clinical characteristics on patients seeking treatment of first episode of a psychotic (FEP) disorder accepted in the EI service for 3 years before and 3 years after the intervention were contrasted. No other systemic changes occurred in this catchment area during this period. Results: There was a significant increase in the number of cases of FEP referred to the EI service post-intervention from hospitals other than the parent institute, in the proportion with a diagnosis of affective psychosis and proportion of patients from a lower socioeconomic status (SES). Although largest proportion of patients continued to make their first contact with community services, the latter failed to refer cases of psychosis to the EI service despite making a large number of mostly non-cases (for psychosis). The intervention had no direct effect on total DUP, R-DUP or H-DUP. After controlling for diagnosis and SES, post-intervention, R-DUP remained significantly lower for patients making first contact with the emergency service of the parent institute. Conclusions: The intervention failed to reduce R-DUP for patients making contact with or referred from community services and most patients still used hospital resources to enter treatment at the EI service. [ABSTRACT FROM AUTHOR]

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [11C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87±8.65) and 18 healthy male controls (age: 25.44±6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [11C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [11C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity. [ABSTRACT FROM AUTHOR]

Exposure to stressors results in a spectrum of autonomic, endocrine, and behavioral responses. A key pathway in this response to stress is the hypothalamic-pituitary-adrenal (HPA) axis, which results in a transient increase in circulating cortisol, which exerts its effects through the two related ligand-activated transcription factors: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Genetic polymorphisms in these receptors have been shown to influence HPA axis reactivity, and chronic dysregulation of the HPA axis has been associated with the development of several psychiatric disorders. The objective of the study was to test the association between four functional polymorphisms in NR3C1 (encoding GR: ER22/23EK-rs6189, N363S-rs6195, BclI-rs41423247, A3669G-rs6198) and two in NR3C2 (encoding MR: 215G/C-rs2070951, I180 V-rs5522) with childhood ADHD. Family-based association tests (FBAT) were conducted with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, as well as with treatment response assessed in a 2-week, double-blind, placebo-controlled trial with methylphenidate. A specific haplotype (G:A:G:G; ER22/23EK- N363S- BclI- A3669G) of NR3C1 showed a significant association with behaviors related to ADHD (particularly thought and attention problems, aggressive behavior), comorbidity with oppositional defiant disorder, and executive function domains. An association was also observed with treatment response (assessed by the Conners'-Teachers and Restricted Academic Situation Scale). In contrast, MR gene polymorphisms were not associated with any of the variables tested. To the best of our knowledge, this is the first report showing an association between functional polymorphisms in NR3C1 and ADHD, providing genetic evidence for involvement of the HPA axis in the disorder and treatment response. [ABSTRACT FROM AUTHOR]

As a relatively large body of research has been published up to now, it may be informative to explore whether the use of endophenotypes has produced consistent findings in attention-deficit hyperactivity disorder (ADHD). We reviewed the results of genetic studies investigating associations between putative susceptibility genes for ADHD and neuropsychological traits relevant for this disorder. A PubMed database search identified 47 studies. Most of them ( n = 36) examined a single candidate gene, while seven studies examined two or three genes and only four studies examined 10 genes or more. The most investigated genes were DRD4, DAT1, COMT, MAOA, and DBH. Regarding DRD4, association of high reaction time variability with the 7-R allele absence appears to be the most consistent result. Speed of processing, set shifting, and cognitive impulsiveness were less frequently investigated, but seem to be altered in the 7-R allele carriers. Regarding DAT1, majority of studies reported negative results indicating that this gene may have a modulating effect rather than direct influence on cognitive functioning. The other genes were investigated in fewer studies, and the reported findings need to be replicated. The principal methodological issues that could represent confounding factors and may explain conflicting results are discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe psychiatric disorder that profoundly affects cognitive, behavioral and emotional processes. The wide spectrum of symptoms and clinical variability in schizophrenia suggest a complex genetic etiology, which is consistent with the numerous loci thus far identified by linkage, copy number variation and association studies. Although schizophrenia heritability may be as high as ?80%, the genes responsible for much of this heritability remain to be identified. Here we sequenced the exomes of 14 schizophrenia probands and their parents. We identified 15 de novo mutations (DNMs) in eight probands, which is significantly more than expected considering the previously reported DNM rate. In addition, 4 of the 15 identified DNMs are nonsense mutations, which is more than what is expected by chance. Our study supports the notion that DNMs may account for some of the heritability reported for schizophrenia while providing a list of genes possibly involved in disease pathogenesis. [ABSTRACT FROM AUTHOR]

It has been suggested that the symptoms of attention-deficit/hyperactivity disorder (ADHD), including inattention and/or hyperactivity/impulsivity, translate into deficits in task-oriented behavior or problem-focused activity. The frontosubcortical dopamine pathway has been implicated in ADHD. One of the key modulators of extracellular dopamine levels in the prefrontal cortex is catechol-O-methyltransferase (COMT). The objective of this study was to examine the association of the COMT Val108/158Met polymorphism with (1) task-oriented behavior in children with ADHD, and (2) response of this behavior given methylphenidate (MPH) treatment. Children of Caucasian ethnicity, having ADHD (n=188), were assessed using the Restricted Academic Situation Scale (RASS). The RASS uses a simulated academic environment within the research clinic, to assess the child's ability for independent, sustained orientation to an assignment of math problems. Each child was administered placebo and MPH (0.5 mg/kg in a divided b.i.d. dose), each for a 1-week period, in a randomized, double-blind, crossover trial. On day 3 of the respective treatment week, the child was administered placebo/MPH in the clinic, and the acute change in behavior (before and 1 h after treatment) was evaluated on the RASS. Analysis was carried out using mixed model analysis of variance. Significant main effects of COMT genotype (F2,184=5.12, p=0.007) and treatment (F1,184=44.26, p<0.001) on task-oriented behavior were observed. However, no genotype by treatment interaction was observed. These results suggest that the COMT Val108/158Met polymorphism modulates task-oriented behavior, but it does not modulate the response of this behavior with MPH treatment.Neuropsychopharmacology (2008) 33, 3069–3077; doi:10.1038/npp.2008.85; published online 25 June 2008 [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the fundamental movement skills of 22 children with attention-deficit hyperactivity disorder (ADHD), from 6 to 12 years of age, to gender- and age-matched peers without ADHD and assess the effects of stimulant medication on the movement skill performance of the children with ADHD. Repeated measures analyses revealed significant skill differences between children with and without ADHD (p

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]

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]

Reduced brain serotonin (5-hydroxytryptamine: 5-HT) transporter activity has been associated with susceptibility to various forms of psychopathology, including bulimia nervosa (BN) and related syndromes characterized by appetitive or behavioural dysregulation. We applied density (Bmax) of platelet [3H-]paroxetine binding as a proxy for central 5-HT reuptake activity in two groups of women (33 with BN-spectrum disorders and 19 with no apparent eating or psychiatric disorders), most of these individuals' mothers (31 and 18, respectively), and a small sampling of their sisters (seven and eight, respectively). Hierarchical linear modeling techniques were used to account for nesting of individuals within families and diagnostic groupings. Bulimic probands, their mothers, and their sisters all displayed significantly lower density (Bmax) of platelet-paroxetine binding than did ‘control’ probands, mothers, or sisters—even when relatives showing apparent eating or psychiatric disturbances were excluded. In addition, in bulimic probands and mothers, significant within-family correlations were obtained on Bmax. These findings imply a heritable trait (or endophenotype), linked to 5-HT activity, and carried by BN sufferers and their first-degree relatives (even when asymptomatic). We propose that, under conducive circumstances, such a trait may increase risk of binge-eating behavior, or associated symptoms of affective or behavioral dysregulation.Neuropsychopharmacology (2006) 31, 1785–1792. doi:10.1038/sj.npp.1301011; published online 11 January 2006 [ABSTRACT FROM AUTHOR]

Rationale. Schizophrenia is a heterogeneous syndrome both at the etiological and clinical levels. In particular, patients with schizophrenia exhibit important variability in their therapeutic and metabolic responses to clozapine, an antipsychotic medication. Objective. Here, we determine whether two mouse strains show differing clozapine responses with respect to weight gain, enhancement of prepulse inhibition of acoustic startle, and reversal of amphetamine-induced locomotion. Observed between-strain differences may be partly due to genetic factors that can be subsequently mapped using quantitative genetic approaches. Methods. We treated the A/J and C57BL/6J inbred mouse strains with clozapine for 22 days. Prepulse inhibition and amphetamine-induced locomotion were measured after 3–4 days of clozapine treatment and again after 21–22 days of treatment. Weight gain was also monitored during treatment. Results. Three-day treatment with clozapine increased prepulse inhibition in both strains. Four-day clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain. Long-term (21–22 days) clozapine treatment did not affect these behaviors in either strain. After an initial weight loss during the first 5 days, clozapine (4 mg/kg) induced a significant weight gain in both strains. Conclusions. The reversal of schizophrenia-related behaviors after short-term, but not long-term, clozapine treatment is consistent with other rodent studies. Although short-term clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain, strain differences in amphetamine responses confound the interpretation of these results; therefore, quantitative genetic approaches may be difficult to carry out with this trait. In contrast, enhancement of prepulse inhibition after three days of clozapine treatment and weight gain induced by clozapine are relatively straightforward to quantify, making these trait more amenable to quantitative genetic approaches. [ABSTRACT FROM AUTHOR]

Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating, defined as an inhibition of the startle response when a low intensity stimulus, the prepulse, precedes the startling stimulus. Deficits in PPI have been reported in schizophrenia and other psychiatric/neurological disorders, and correlate with symptom severity in schizophrenia, suggesting that deficient PPI per se or abnormalities in neural circuits regulating PPI may cause some symptoms of schizophrenia. If so, then genes conferring reduced PPI may contribute toward genetic vulnerability to schizophrenia. Studies with selectively bred rodent strains indicate that PPI is under genetic control; however, the identity of the relevant genes is unknown. The current study used recombinant congenic mouse strains derived from C57BL/6J and A/J parents to assess genetic variability in PPI and in ASR and to identify provisional quantitative trait loci (QTLs) modulating these phenotypes. Significant between-strain differences in ASR and in PPI at each of several prepulse intensities (75, 80, 85, 90, 95 dB) were found. Correlations between PPI at the various prepulse intensities were highly significant, suggesting appreciable overlap in genetic regulation of PPI across prepulse intensities. Five QTLs (chromosomes 3, 5, 7, 16) associated with PPI across all prepulse intensities, but not with ASR, were identified. Two additional QTLs (chromosomes 2, 11) associated with both PPI and ASR were found. Fifteen QTLs were associated with ASR alone. Data on genotypes of informative congenic strains were used to support probable involvement of loci modulating PPI and to narrow the probable chromosomal location of QTLs. If confirmed, these QTLs may suggest candidate genes directing novel mechanisms for regulation of PPI [Copyright &y& Elsevier]

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental psychiatric disorder. Genome-wide association studies (GWAS) have identified several loci associated with ADHD. However, understanding the biological relevance of these genetic loci has proven to be difficult. Here, we conduct an ADHD transcriptome-wide association study (TWAS) consisting of 19,099 cases and 34,194 controls and identify 9 transcriptome-wide significant hits, of which 6 genes were not implicated in the original GWAS. We demonstrate that two of the previous GWAS hits can be largely explained by expression regulation. Probabilistic causal fine-mapping of TWAS signals prioritizes KAT2B with a posterior probability of 0.467 in the dorsolateral prefrontal cortex and TMEM161B with a posterior probability of 0.838 in the amygdala. Furthermore, pathway enrichment identifies dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Overall, our findings highlight the power of TWAS to identify and prioritize putatively causal genes. A recent GWAS reported 12 genetic loci for attention deficit/hyperactivity disorder (ADHD). Here, Liao et al. perform transcriptomic imputation using these data and 12 brain-relevant tissues from GTEx and CMC to identify 9 genes associated with ADHD by TWAS, 3 of which had not yet been reported for ADHD. [ABSTRACT FROM AUTHOR]

Purpose: High rates of Not in Education, Employment or Training (NEET) are seen in people with first episode of psychosis (FEP). Sociodemographic and clinical factors were reported to be associated with NEET status in FEP patients. This study follows Intersectionality to examine the independent and additive effects, and most importantly the intersections of sociodemographic and clinical variables concerning NEET status in FEP patients. It was hypothesized that NEET status in FEP patients would be described by the intersection between at least two predictor variables.Secondary analyses with chi-square tests, multiple logistic regression and Chi-squared Automatic Interaction Detection (CHAID) analyses were performed on 440 participants with FEP.Chi-square tests indicated that patient socioeconomic status and negative symptom severity were significantly and independently associated with their NEET status. Multiple logistic regression suggested additive effects of age (odds ratio = 1.61), patient socioeconomic status (odds ratio = 1.55) and negative symptom severity (odds ratio = 1.75) in predicting patients’ NEET status. CHAID detected an intersection between patients’ negative symptom severity and socioeconomic status in shaping their NEET status.This study explored how the NEET status of patients with FEP was explained not only by the separate effects of negative symptom severity and socioeconomic status but also by the unique intersections of their clinical and social identities. Findings indicated that functional outcomes of patients appear co-constructed by the intersections of multiple identities. Crucial clinical implications of complementing care for negative symptom severity with vocational resources to improve functional outcomes of patients are discussed.Methods: High rates of Not in Education, Employment or Training (NEET) are seen in people with first episode of psychosis (FEP). Sociodemographic and clinical factors were reported to be associated with NEET status in FEP patients. This study follows Intersectionality to examine the independent and additive effects, and most importantly the intersections of sociodemographic and clinical variables concerning NEET status in FEP patients. It was hypothesized that NEET status in FEP patients would be described by the intersection between at least two predictor variables.Secondary analyses with chi-square tests, multiple logistic regression and Chi-squared Automatic Interaction Detection (CHAID) analyses were performed on 440 participants with FEP.Chi-square tests indicated that patient socioeconomic status and negative symptom severity were significantly and independently associated with their NEET status. Multiple logistic regression suggested additive effects of age (odds ratio = 1.61), patient socioeconomic status (odds ratio = 1.55) and negative symptom severity (odds ratio = 1.75) in predicting patients’ NEET status. CHAID detected an intersection between patients’ negative symptom severity and socioeconomic status in shaping their NEET status.This study explored how the NEET status of patients with FEP was explained not only by the separate effects of negative symptom severity and socioeconomic status but also by the unique intersections of their clinical and social identities. Findings indicated that functional outcomes of patients appear co-constructed by the intersections of multiple identities. Crucial clinical implications of complementing care for negative symptom severity with vocational resources to improve functional outcomes of patients are discussed.Results: High rates of Not in Education, Employment or Training (NEET) are seen in people with first episode of psychosis (FEP). Sociodemographic and clinical factors were reported to be associated with NEET status in FEP patients. This study follows Intersectionality to examine the independent and additive effects, and most importantly the intersections of sociodemographic and clinical variables concerning NEET status in FEP patients. It was hypothesized that NEET status in FEP patients would be described by the intersection between at least two predictor variables.Secondary analyses with chi-square tests, multiple logistic regression and Chi-squared Automatic Interaction Detection (CHAID) analyses were performed on 440 participants with FEP.Chi-square tests indicated that patient socioeconomic status and negative symptom severity were significantly and independently associated with their NEET status. Multiple logistic regression suggested additive effects of age (odds ratio = 1.61), patient socioeconomic status (odds ratio = 1.55) and negative symptom severity (odds ratio = 1.75) in predicting patients’ NEET status. CHAID detected an intersection between patients’ negative symptom severity and socioeconomic status in shaping their NEET status.This study explored how the NEET status of patients with FEP was explained not only by the separate effects of negative symptom severity and socioeconomic status but also by the unique intersections of their clinical and social identities. Findings indicated that functional outcomes of patients appear co-constructed by the intersections of multiple identities. Crucial clinical implications of complementing care for negative symptom severity with vocational resources to improve functional outcomes of patients are discussed.Conclusion: High rates of Not in Education, Employment or Training (NEET) are seen in people with first episode of psychosis (FEP). Sociodemographic and clinical factors were reported to be associated with NEET status in FEP patients. This study follows Intersectionality to examine the independent and additive effects, and most importantly the intersections of sociodemographic and clinical variables concerning NEET status in FEP patients. It was hypothesized that NEET status in FEP patients would be described by the intersection between at least two predictor variables.Secondary analyses with chi-square tests, multiple logistic regression and Chi-squared Automatic Interaction Detection (CHAID) analyses were performed on 440 participants with FEP.Chi-square tests indicated that patient socioeconomic status and negative symptom severity were significantly and independently associated with their NEET status. Multiple logistic regression suggested additive effects of age (odds ratio = 1.61), patient socioeconomic status (odds ratio = 1.55) and negative symptom severity (odds ratio = 1.75) in predicting patients’ NEET status. CHAID detected an intersection between patients’ negative symptom severity and socioeconomic status in shaping their NEET status.This study explored how the NEET status of patients with FEP was explained not only by the separate effects of negative symptom severity and socioeconomic status but also by the unique intersections of their clinical and social identities. Findings indicated that functional outcomes of patients appear co-constructed by the intersections of multiple identities. Crucial clinical implications of complementing care for negative symptom severity with vocational resources to improve functional outcomes of patients are discussed. [ABSTRACT FROM AUTHOR]