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Background: A history of childhood symptoms of inattention-hyperactivity is often reported in first episode psychosis (FEP) as is cannabis use. In the general population childhood ADHD predicts future cannabis use but the relationship has not been tested in FEP.Method: Parents of patients with a first episode of psychosis (n=75) retrospectively assessed their affected child for symptoms of early-life disorders, namely, attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD) using the Child Behaviour Checklist (CBCL). Assessments were made prospectively of cannabis use over two years following a FEP and of SCID diagnosis of cannabis-use disorder.Results: Childhood hyperactivity-inattention symptoms predicted inability to maintain abstinence from cannabis following treatment (Wald=8.4, p=.004) and lifetime cannabis-use diagnosis (Wald=5.3, p=.022) in a logistic regression controlling for relevant covariates including symptoms of CD and ODD from ages 12 to 18. When the symptom of inattention was considered in place of the hyperactivity-inattention syndrome it predicted cannabis-use diagnosis (Wald=6.4, p=.011) and persistent abstinence from cannabis (Wald=5.3, p=.021). Symptoms of CD and ODD did not predict cannabis use when hyperactivity-inattention symptoms were controlled for.Conclusions: Symptoms of childhood inattention-hyperactivity predict subsequent cannabis use in FEP. [ABSTRACT FROM AUTHOR]

It is now well established that genetic factors play an important role in the pathogenesis of autism disorder and converging lines of evidence suggest the implication of the X chromosome. Using a sample of subjects diagnosed with autism spectrum disorders, exclusively composed of males from French-Canadian (FC) origin, we tested markers covering the entire X chromosome using a family-based association study. Our initial analysis revealed the presence of association at two loci: DXS6789 (P=0.026) and DXS8043 (P=0.0101). In a second step, we added support to the association at DXS8043 using additional markers, additional subjects and a haplotype-based analysis (best obtained P-value=0.00001). These results provide support for the existence of a locus on the X chromosome that predisposes the FC to autism spectrum disorders.Molecular Psychiatry (2006) 11, 206–213. doi:10.1038/sj.mp.4001756; published online 1 November 2005 [ABSTRACT FROM AUTHOR]

BACKGROUND: A short (s) allele in the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (5HTTLPR) has been associated with low transcription of the 5-HT transporter protein, and with clinical manifestations including impulsivity, affective disorder, and bulimia nervosa. METHODS: We studied implications of the 5HTTLPR s allele for eating symptoms, psychopathologic traits, and platelet [3H-] paroxetine binding in 59 women with bulimia spectrum syndromes. RESULTS: Compared with those without it, carriers of the s allele of 5HTTLPR showed significantly more affective instability, behavioral impulsivity, interpersonal insecurity, comorbid borderline personality disorder (BPD), and lower density (Bmax) of paroxetine-binding sites. CONCLUSIONS: Our results suggest that proneness to impulsivity, affective dysregulation, and reduced central 5-HT reuptake may (in part) be codetermined by the 5HTTLPR polymorphism. However, given inconsistent 5HTTLPR expression in different populations, we speculate that we may be observing a phenotype (i.e., eating disorder)-dependent manifestation. 2004 by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Tourette syndrome (TS) is a genetically complex disorder for which no causative genes have been unequivocally identified. Nevertheless, a number of molecular genetic studies have investigated several candidate genes, particularly those implicated in dopamine modulation. The results of these studies were inconclusive, which may be due, at least in part, to the variable ethnicity of the patients included in different studies and the chosen research design. In this study, we used a family-based association approach to investigate the implication of dopamine-related candidate genes, which had been previously reported as possibly associated with TS [genes that encode for the dopamine receptors DRD2, DRD3 and DRD4, the dopamine transporter 1 (SLC6A3) and the monoamine oxidase-A (MAO-A). The studied group was composed of 110 TS patients. These patients were selected from the French Canadian population, which displays a founder effect. Excess transmission of the 7-repeat allele of the DRD4 exon-3 VNTR polymorphism (?2 TDT =4.93, 1 df, P=0.026) and the putative ‘high-activity’ alleles of the MAO-A promoter VNTR polymorphism (?2 TDT =7.124, 1 df P=0.0076) were observed. These results were confirmed in a subgroup of patients with no attention deficit/hyperactivity or obsessive compulsive comorbid disorders. Haplotype analysis using one or two supplemental polymorphism in each of these genes confirmed these associations and allowed one to identify risk haplotypes. No associations were found for DRD2, DRD3 or SLC6A3. These data support the notion that DRD4 and MOA-A genes may confer an increased risk for developing TS in the French Canadian population.Molecular Psychiatry (2004) 9, 272-277. doi:10.1038/sj.mp.4001411 [ABSTRACT FROM AUTHOR]

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better longterm outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional5 and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome. [ABSTRACT FROM AUTHOR]

Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamineexpanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab lC2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]

Help-seeking and treatment delays are increasingly critical areas of study in mental health services. The duration of untreated psychosis (DUP), or the time between illness onset and initiation of treatment, is a predictor of symptom remission and functioning for a first episode of psychosis (FEP). The World Health Organization recommends that specialized treatment for psychosis be initiated within the first three months of FEP onset. As a result, research has focused on factors that are associated with threshold-level DUP, while the experience of subthreshold psychotic symptoms (STPS) prior to a FEP may also complicate and present barriers to accessing care for young people. We therefore examine the possibility that STPS can impact DUP and its components. Using a follow-back cross-sectional design, we sought to describe duration of untreated illness, length of prodrome, DUP, help-seeking delay, referral delay, and number of help-seeking contacts among FEP patients who did and did not have STPS prior to psychosis onset. We found that patients who experienced STPS had a longer median duration of untreated illness, prodrome length, DUP, and help-seeking delay compared to patients who did not have such symptoms. Referral delay did not differ substantially between the two groups. Importantly, treatment delays were extremely lengthy for many participants. Pre-onset STPS are associated with help-seeking delays along the pathway to care even during a FEP. Examining early signs and symptoms may help to improve and tailor interventions aimed at reducing treatment delays and ultimately providing timely care when the need arises. [ABSTRACT FROM AUTHOR]

Examines the involvement of polyglutamine tract expansion on the onset of schizophrenia. Level of protein expression; Polyglutamine expansion signals; Glutamine repeat acidic protein.

Background: Delay in treatment of psychosis is associated with poor clinical and social outcome and is measured as the duration of untreated psychosis (DUP) prior to treatment of the first episode. It has been suggested that this may be mediated through toxic effects of psychosis on the structure and function of the brain. Equivocal evidence exists regarding association between longer DUP and neuro-anatomical changes such as, reduced grey matter volume in specific regions in the brain and deficits in neurocognitive functions.Objective: To examine if duration of untreated psychosis (DUP) preceding treatment of a first episode of psychosis is associated with structural brain abnormalities and deficits in neurocognitive functions.Method: We investigated the relationship between DUP and grey matter volume using voxel-based morphometry techniques and with multiple domains of cognition. Eighty patients with a first episode of psychosis were separated into two equal sized groups based on a median split (18 weeks) of their DUP.Results: Compared to the short-DUP group (mean DUP 7.9 weeks ± 5.6), the long-DUP group (mean 113.7 weeks ± 170 .4) showed significant grey matter volume reductions in orbital-frontal regions (bilateral medial frontal gyrus and bilateral rectal gyrus, BA 11) and parietal regions (postcentral gyrus and superior parietal lobule) as well as a significant reduction in whole brain grey matter volume (p<0.04). For schizophrenia spectrum cases only these findings were confined to left rectal gyrus. There were no differences in white matter or cerebral spinal fluid volumes or on cognitive functions. Results are controlled for antipsychotic medication exposure.Limitations: The inherent difficulty in separating slow and insidious onset from long-DUP may limit the interpretation of our results and there may be an overlap between DUP and duration of illness (including the prodrome).Conclusion: Patients with a longer delay in treatment of psychosis show a significant reduction in overall grey matter volume with specific reductions in the inferior-orbital region. These results provide some support to a possible neurotoxic effect of prolonged untreated psychosis. [ABSTRACT FROM AUTHOR]

Abstract: Previous work on chronic psychosis patients has suggested that low self-reflectiveness and overconfidence in judgments may be associated with delusions. In the present study we evaluated whether this extends to a first-episode psychosis sample. Thirteen actively delusional and 53 non-delusional participants with a first-episode psychosis completed the Beck Cognitive Insight Scale. Relative to non-delusional participants, delusional participants endorsed greater self-reflectiveness, though their confidence in their judgments was the same as non-delusional participants. These results suggest that the capacity to self-reflect and refrain from overconfidence may interact with delusions differentially across multiple phases of psychosis. The cognitive system involved in self-reflectiveness may be important for delusional thinking during a first-episode psychosis. [Copyright &y& Elsevier]

BACKGROUND: Low-function alleles of the serotonin transporter promoter polymorphism (5HTTLPR) have been linked to various psychopathological entities, especially in individuals exposed to prior stressors. In women with bulimic syndromes, we explored associations with personality pathology of 5HTTLPR and prior sexual or physical maltreatment. METHODS: Ninety-two women with bulimic syndromes were genotyped for 5HTTLPR short (S) and long (L(G) and L(A)) alleles and were then assessed for eating symptoms, dimensional personality disturbances, history of sexual or physical abuse and borderline personality disorder (BPD). RESULTS: With a classification based on a biallelic model of 5HTTLPR (i.e., presence or absence of at least 1 S-allele copy), multiple regression analyses indicated significant proportions of variance in stimulus seeking and insecure attachment to be explained by abuse x genotype interaction effects, with greater psychopathology always occurring in S-allele carriers who had been abused. Likewise, a logistic regression analysis linked BPD to significant main effects of genotype and abuse. Analyses that aggregated carriers according to a triallelic model of 5HTTLPR (i.e., presence or absence of at least 1 copy of a presumably low-function S or LG allele) produced similar patterns but no statistically significant effects. CONCLUSIONS: Traits such as sensation seeking and insecure attachment are, on average, elevated in 5HTTLPR S-allele carriers with bulimic syndromes who report prior physical or sexual maltreatment. These results add to the literature associating pronounced psychopathological manifestations, with conjoint effects of stress and the 5HTTLPR polymorphism. [ABSTRACT FROM AUTHOR]

This paper describes a research program intended to provide a better understanding of the influence of several putative risk factors for schizophrenia on child development and psychosis. Two related components of the overall program are described: the retrospective EnviroGen projects, which use a variety of putative risk factors to explain variance in several dimensions of schizophrenia and in psychotic symptoms in community controls, and Project Ice Storm, which prospectively examines the effects of prenatal maternal stress in the children of women who were exposed to the 1998 Quebec ice storm during their pregnancies. The EnviroGen projects have been successful in explaining variance in several dimensions of illness, including premorbid adjustment and severity of dissociative symptoms. Project Ice Storm has demonstrated the noxious effects of prenatal stress on cognitive and language development in children. We have also found that 'ice storm children' exposed in specific weeks of gestation show greater dermatoglyphic asymmetry, as has been reported for samples of patients with schizophrenia. In both studies, prenatal maternal stress has been associated with more severe childhood behaviour problems. The combination of retrospective and prospective studies is a rich source of triangulated results providing information about developmental psychopathology. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To review the results of genetic studies investigating dopamine-related genes in attention-deficit hyperactivity disorder (ADHD). DATA SOURCES: Papers (association/linkage, meta-analyses and animal model studies) were identified through searches of the PubMed database and systematically reviewed. DATA SYNTHESIS: Consistent results from molecular genetic studies are pointing strongly to the possible link between 2 specific genes, the dopamine transporter (SLC3A6) and the dopamine receptor 4 (DRD4), and ADHD. CONCLUSIONS: The implication of SLC6A3 and DRD4 genes in ADHD appears to be one of the most replicated in psychiatric genetics and strongly suggests the involvement of the brain dopamine systems in the pathogenesis of ADHD. However, more work is required to further these findings by genotype-to-phenotype correlations and identify the functional allelic variants/mutations that are responsible for these associations. The role of other dopamine genes, which may have smaller effects than SLC6A3 and DRD4, needs also to be determined. [ABSTRACT FROM AUTHOR]

Objective: To test whether duration of untreated psychosis (DUP) < 3 months, recommended by the World Health Organization/International Early Psychosis Association, enhances the effects of an extended early intervention service (EEIS) on symptom remission. Method: We examined data from a randomized controlled trial in which patients who received 2 years of treatment in EIS for psychosis were subsequently randomized to either 3 years of EEIS or 3 years of regular care (RC). Using a DUP cut‐off ≤ 12 weeks (approximately < 3 months), patients were split into two groups. Length of positive, negative and total symptom remission were the outcomes. Results: Patients (N = 217) were mostly male (68%) with schizophrenia spectrum disorder (65%); 108 (50%) received EEIS (58 had DUP ≤12 weeks; 50 had DUP >12 weeks). Interaction between treatment condition (EEIS vs. RC) and DUP cut‐off ≤ 12 weeks was only significant in multiple linear regression model examining length of negative symptom remission as the outcome (adjusted β = 36.88 [SE = 15.88], t = 2.32, P = 0.02). EEIS patients with DUP ≤12 weeks achieved 25 more weeks of negative symptom remission than EEIS patients with DUP >12 weeks. Conclusion: Having a short DUP may be critical in deriving long‐term benefits from EIS for psychosis, including EEIS settings. This work empirically supports policy recommendations of reducing DUP <3 months. [ABSTRACT FROM AUTHOR]

Objective: The experience of pre‐onset subthreshold psychotic symptoms (STPS, signifying a clinical high‐risk state) in first episode psychosis (FEP) predicts poorer outcomes during treatment, possibly through differential adherence to medication. We explored whether adherence differs between FEP patients with and without pre‐onset STPS. Methods: Antipsychotic medication adherence was compared in 263 STPS+ and 158 STPS− subjects in a specialized early intervention program for FEP. Data were gathered from a larger observational study conducted between 2003 and 2016. STPS status, sociodemographic, and baseline clinical variables were tested as predictors of non‐adherence using univariate and multivariate logistic regressions. Time to onset of non‐adherence was analyzed using Kaplan–Meier curves. The same predictors were tested as predictors of time to onset of non‐adherence using Cox regression models. Results: Medication non‐adherence was higher in STPS+ participants (78.9% vs. 68.9%). STPS status (OR 1.709), substance use disorder (OR 1.767), and milder positive symptoms (OR 0.972) were significant baseline predictors of non‐adherence. Substance use disorder (HR 1.410), milder positive symptoms (HR 0.990), and lack of contact between the clinical team and relatives (HR 1.356) were significant baseline predictors of time to non‐adherence. Conclusion: FEP patients who experience pre‐onset STPS are more likely to be non‐adherent to antipsychotic medication over 2 years of intervention. FEP programs should routinely evaluate pre‐onset symptomatology to deliver more personalized treatments, with emphasis on engaging both patients and family members from the beginning of care. [ABSTRACT FROM AUTHOR]

BackgroundAltered hypothalamus-pituitary-adrenal (HPA) axis function and reduced hippocampal volume (HV) are established correlates of stress vulnerability. We have previously shown an attenuated cortisol awakening response (CAR) and associations with HV specifically in male first-episode psychosis patients. Findings in individuals at ultra-high risk (UHR) for psychosis regarding these neurobiological markers are inconsistent, and assessment of their interplay, accounting for sex differences, could explain incongruent results.MethodStudy participants were 42 antipsychotic-naive UHR subjects (24 men) and 46 healthy community controls (23 men). Saliva samples for the assessment of CAR were collected at 0, 30 and 60 min after awakening. HV was determined from high-resolution structural magnetic resonance imaging scans using a semi-automatic segmentation protocol.ResultsCortisol measures and HV were not significantly different between UHR subjects and controls in total, but repeated-measures multivariate regression analyses revealed reduced cortisol levels 60 min after awakening and smaller left HV in male UHR individuals. In UHR participants only, smaller left and right HV was significantly correlated with a smaller total CAR (ρ = 0.42, p = 0.036 and ρ = 0.44, p = 0.029, respectively), corresponding to 18% and 19% of shared variance (medium effect size).ConclusionsOur findings suggest that HV reduction in individuals at UHR for psychosis is specific to men and linked to reduced post-awakening cortisol concentrations. Abnormalities in the neuroendocrine circuitry modulating stress vulnerability specifically in male UHR subjects might explain increased psychosis risk and disadvantageous illness outcomes in men compared to women. [ABSTRACT FROM AUTHOR]

Schizophrenia is a highly heritable neurodevelopmental disorder associated with alterations in synaptic connectivity. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, plays a pivotal role in organizing neuronal circuitry by guiding growing axons and dendrites to their correct targets and by influencing synaptic connectivity. Results from experiments we previously conducted in dcc-heterozygous mice show that DCC plays a critical role in the developmental organization of the mesocorticolimbic dopamine (DA) circuitry. Furthermore we have shown that reduced expression of DCC during development and/or throughout life confers resilience to the development of schizophrenia-like DA and behavioural abnormalities. Importantly, this "protective" phenotype only emerges after puberty. Here we assess whether DCC may contribute to the risk of schizophrenia. We examined single nucleotide polymorphisms (SNPs) located in the DCC gene for association with schizophrenia using a case-control sample consisting of 556 unrelated schizophrenic patients and 208 healthy controls. We found one SNP, rs2270954, to be nominally associated with schizophrenia; patients were less likely to be heterozygous at this locus and more likely to be homozygous for the minor allele (χ(2)=9.84, df=2, nominal p=0.0071). Intriguingly, this SNP is located within the 3' untranslated region, an area known to contain a number of regulatory sequences that determine the stability and translation efficacy of mRNA. These results, together with our previous findings from studies in rodents, point at DCC as a promising novel candidate gene that may contribute to the genetic basis behind individual differences in susceptibility to schizophrenia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cognitive deficits in schizophrenia are well established and are known to be present during the first episode of a psychotic disorder. In addition, consistent heterogeneity within these impairments remains unexplained. One potential source of variability may be the level of pre-morbid adjustment prior to the onset of first-episode psychosis (FEP). METHOD: Ninety-four FEP patients and 32 healthy controls were assessed at baseline on several neuropsychological tests comprising six cognitive domains (verbal memory, visual memory, working memory, processing speed, reasoning/problem-solving and attention) and an abbreviated version of the full IQ. A global neurocognitive domain was also computed. Pre-morbid adjustment patterns were divided into three distinct groups: stable-poor, stable-good and deteriorating course. RESULTS: Based on a cut-off of 0.8 for effect size, the stable-poor pre-morbid adjustment group was significantly more impaired on most cognitive domains and full IQ compared to the deteriorating group, who were more severely impaired on all measures compared to the stable-good group. The type of cognitive deficit within each subgroup did not differ and the results indicate that a global neurocognition measure may reliably reflect the severity of cognitive impairment within each subgroup. CONCLUSIONS: Pre-morbid adjustment patterns prior to onset of psychosis are associated with severity but not type of cognitive impairment. Patients in the stable-poor group are generally more impaired compared to the deteriorating group, who are, in turn, more impaired than the stable-good group. [ABSTRACT FROM AUTHOR]

Background. Cognitive deficits in schizophrenia are well established and are known to be present during the first episode of a psychotic disorder. In addition, consistent heterogeneity within these impairments remains unexplained. One potential source of variability may be the level of pre-morbid adjustment prior to the onset of first-episode psychosis (FEP). Method. Ninety-four FEP patients and 32 healthy controls were assessed at baseline on several neuropsychological tests comprising six cognitive domains (verbal memory, visual memory, working memory, processing speed, reasoning/problem-solving and attention) and an abbreviated version of the full IQ. A global neurocognitive domain was also computed. Pre-morbid adjustment patterns were divided into three distinct groups: stable-poor, stable-good and deteriorating course. Results. Based on a cut-off of 0.8 for effect size, the stable-poor pre-morbid adjustment group was significantly more impaired on most cognitive domains and full IQ compared to the deteriorating group, who were more severely impaired on all measures compared to the stable-good group. The type of cognitive deficit within each subgroup did not differ and the results indicate that a global neurocognition measure may reliably reflect the severity of cognitive impairment within each subgroup. Conclusions. Pre-morbid adjustment patterns prior to onset of psychosis are associated with severity but not type of cognitive impairment. Patients in the stable-poor group are generally more impaired compared to the deteriorating group, who are, in turn, more impaired than the stable-good group. [ABSTRACT FROM AUTHOR]

Objective: To determine to what extent the clinical response to methylphenidate (MPH) is affected by psychiatric comorbidities in children diagnosed with attention-deficit hyperactivity disorder (ADHD).Methods: Children (n = 267) aged 6 to 12 years diagnosed with ADHD participated in a double-blind, placebo-controlled, 2-week medication trial of MPH. Children were assessed using parent and teacher ratings and laboratory measures. Clinical response to MPH was determined by integrating all obtained measures.Results: Meeting criteria for conduct disorder (CD) was 27.7% of children, 40.8% for oppositional defiant (ODD), 47.2% for anxiety, and 7.9% for depressive disorders. The presence of CD or ODD was associated with good response to MPH. In contrast, children diagnosed with only comorbid anxiety were more likely to receive poor response rating independent of age, sex, or socioeconomic status. Low family income was found to be predictive of good response to MPH.Conclusions: The response to MPH in children with ADHD may be dependent on the type of comorbid disorder present.Clinical Trial Registration Number: NCT00483106. [ABSTRACT FROM AUTHOR]

Summary: Background: Patients with schizophrenia may differ from healthy controls by having dysregulated physiological responses to stress. Our objective was to determine the extent to which cortisol reaction can discriminate between controls and schizophrenia patients while controlling for symptom severity, personality, body mass index (BMI) and smoking. Method: 30 chronic schizophrenia patients and 30 matched controls underwent a modified version of the Trier Social Stress Test (TSST), consisting of public speaking and mental arithmetic. Heart rate, blood pressure, and salivary cortisol were measured repeatedly throughout the TSST. In addition, participants completed the NEO Personality Inventory (NEO-FFI), and were interviewed with the Brief Psychiatric Rating Scale (BPRS). Results: Both groups had a significant increase in heart rate and mean arterial pressure following the TSST. Results of a logistic regression suggests that patients can be discriminated from controls with a smaller change in cortisol between baseline and 15min post-TSST, controlling for BMI and severity of positive symptoms. There was a trend for lower overall cortisol secretion in patients. Conclusions: Despite demonstrable effects of the stressor on cardiac measures, schizophrenia patients tend to have smaller acute cortisol reaction to psychosocial stress. The significance of this conclusion for vulnerability-stress models of schizophrenia is discussed. [Copyright &y& Elsevier]

Abstract: The present study examined the influence of genetic polymorphisms in the apolipoprotein (APOE) and the butyrylcholinesterase (BCHE) gene on GC secretion, cognition and personality in 66 healthy older adults. These particular variables were chosen given that they have been shown to be associated with human stress (i.e.stress markers). Measures included basal serum GC levels and cognitive scores on declarative memory obtained annually over 3 years. Also, self-esteem, neuroticism and depression were evaluated. Results showed that participants with the APOE E4–BCHE K variant (E4–K group) present increased basal levels of GCs and poorer cognitive performance when compared to non-carriers of these variants. In addition, the E4–K group reported lower self-esteem and higher levels of depression. These findings may indicate a genotype effect on markers of stress and cognitive integrity years before symptoms of dementia are apparent. [Copyright &y& Elsevier]

Background: We reviewed systematically the results of genetic studies investigating associations between putative susceptibility genes for attention-deficit hyperactivity disorder (ADHD) and neuropsychological traits relevant for this disorder. Methods: We identified papers for review through the PubMed database. Results: Twenty-nine studies examined 10 genes (DRD4, DAT1, COMT, DBH, MAOA, DRD5, ADRA2A, GRIN2A, BDNF and TPH2) in relation to neuropsychological traits relevant for ADHD. For DRD4, the continuous performance test (CPT) and derived tasks were the most used tests. Association of high reaction time variability with the 7-repeat allele absence appears to be the most consistent result and seems to be specific to ADHD. Speed of processing, set-shifting and cognitive impulsiveness were less frequently investigated but seem to be altered in the 7-repeat allele carriers. No effect of genotype was found on response inhibition (the stop and go/no-go tasks). For DAT1, 4 studies provide conflicting results in relation to omission and commission errors from CPT and derived tasks. High reaction time variability seems to be the most replicated cognitive marker associated with the 10-repeat homozygosity. The other genes have attracted fewer studies, and the reported findings need to be replicated. Limitations: Although we aimed to perform a formal meta-analysis, this was not possible because the number of studies using the same neurocognitive endophenotypes was limited. We referred only minimally to the various theoretical frameworks in this field of research; more detail would have been beyond the scope of our systematic review. Finally, sample sizes in most of the studies we reviewed were small. Thus, some negative findings could be attributed to a lack of statistical power, and positive results should be considered preliminary until they are replicated in extended samples. Conclusion: Several methodological issues, including measurement errors, developmental changes in cognitive abilities, sex, psychostimulant effects and presence of comorbid conditions, represent confounding factors and may explain conflicting results. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few studies have examined the underlying factor structure of signs and symptoms occurring before the first psychotic episode. Our objective was to determine whether factors derived from early signs and symptoms are differentially associated with non-affective versus affective psychosis.MethodA principal components factor analysis was performed on early signs and symptoms reported by 128 individuals with first-episode psychosis. Factor scores were examined for their associations with duration of untreated illness, drug abuse prior to onset of psychosis, and diagnosis (schizophrenia versus affective psychosis). RESULTS: Of the 27 early signs and symptoms reported by patients, depression and anxiety were the most frequent. Five factors were identified based on these early signs and symptoms: depression, disorganization/mania, positive symptoms, negative symptoms and social withdrawal. Longer duration of untreated illness was associated with higher levels of depression and social withdrawal. Individuals with a history of drug abuse prior to the onset of psychosis scored higher on pre-psychotic depression and negative symptoms. The two mood-related factors, depression and disorganization/mania, distinguished the eventual first-episode diagnosis of affective psychosis from schizophrenia. Individuals with affective psychosis were also more likely to have a 'mood-related' sign and symptom as their first psychiatric change than individuals later diagnosed with schizophrenia. CONCLUSIONS: Factors derived from early signs and symptoms reported by a full diagnostic spectrum sample of psychosis can have implications for future diagnostic trajectories. The findings are a step forward in the process of understanding and characterizing clinically important phenomena to be observed prior to the onset of psychosis. [ABSTRACT FROM AUTHOR]

BackgroundFew studies have examined the underlying factor structure of signs and symptoms occurring before the first psychotic episode. Our objective was to determine whether factors derived from early signs and symptoms are differentially associated with non-affective versusaffective psychosis.MethodA principal components factor analysis was performed on early signs and symptoms reported by 128 individuals with first-episode psychosis. Factor scores were examined for their associations with duration of untreated illness, drug abuse prior to onset of psychosis, and diagnosis (schizophrenia versusaffective psychosis).ResultsOf the 27 early signs and symptoms reported by patients, depression and anxiety were the most frequent. Five factors were identified based on these early signs and symptoms: depression, disorganization/mania, positive symptoms, negative symptoms and social withdrawal. Longer duration of untreated illness was associated with higher levels of depression and social withdrawal. Individuals with a history of drug abuse prior to the onset of psychosis scored higher on pre-psychotic depression and negative symptoms. The two mood-related factors, depression and disorganization/mania, distinguished the eventual first-episode diagnosis of affective psychosis from schizophrenia. Individuals with affective psychosis were also more likely to have a ?mood-related? sign and symptom as their first psychiatric change than individuals later diagnosed with schizophrenia.ConclusionsFactors derived from early signs and symptoms reported by a full diagnostic spectrum sample of psychosis can have implications for future diagnostic trajectories. The findings are a step forward in the process of understanding and characterizing clinically important phenomena to be observed prior to the onset of psychosis. [ABSTRACT FROM AUTHOR]

Objective: To compare glucose and lipid metabolism parameters between drug-naïve first-episode psychosis (FEP) patients with a diagnosis of schizophrenia spectrum disorder and healthy controls matched for age, ethnicity, and gender.Method: Baseline evaluations of fasting glucose and lipid metabolism parameters and the oral glucose tolerance test were performed with FEP patients (n=38), having no more than 10 days of cumulative exposure to antipsychotic medication, and normal community controls (n=36). Analysis of variance (ANOVA) was conducted to examine between group differences.Results: FEP patients did not show a higher prevalence of the precursors to diabetes (impaired fasting glucose, impaired glucose tolerance, insulin resistance), and no significant difference in beta-cell function or lipid profile measures, compared to healthy controls. FEP patients showed a higher waist to hip ratio compared to controls.Conclusions: FEP patients having a schizophrenia spectrum disorder do not differ from healthy controls, in their baseline measures of glucose and lipid metabolites, nor in the prevalence of diabetes or its precursors, before (or close to) the onset of antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Left–right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.Molecular Psychiatry (2007) 12, 1129–1139; doi:10.1038/sj.mp.4002053; published online 31 July 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether children with attention-deficit hyperactivity disorder (ADHD) and learning disabilities respond differently to methylphenidate (MPH) compared with children with ADHD only. METHODS: We conducted a prospective, double-blind, placebo-controlled, randomized, 2-week crossover trial of MPH, during which response to MPH was assessed. Learning ability was appraised using the Wide Range Achievement Test, Revised (WRAT-R), for English-speaking students and the Test de rendement pour francophones for French-speaking students. The study was conducted at the Douglas Hospital, a McGill University-affiliated teaching hospital in Montréal. Ninety-five children, aged 6-12 years, who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria for ADHD participated in the study, which ran from 2001 to 2004. The outcome measure used was the Consensus Clinical Response, an indicator of the degree of clinical improvement shown when taking MPH. RESULTS: The proportion of children with learning disabilities who responded to MPH (55%) was significantly smaller (chi(2)1 = 4.5, p = 0.034) than the proportion of children without learning disabilities who responded adequately to MPH (75%). This difference was mainly because of children with mathematics disability being particularly unresponsive to MPH (chi(2)1 = 4.5, p = 0.034). Children with reading disability did not show this pattern of poor response (chi(2)1 = 1.0, p = 0.33). CONCLUSION: Children with ADHD and comorbid learning disability tended to respond more poorly to MPH. In particular, children with disability in mathematics responded less to MPH than those without disability in mathematics. Additional therapy may be indicated for this group of patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Genetic and nonshared environmental factors (experienced by 1 family member to the exclusion of the others) have been strongly implicated in the causes of attention-deficit hyperactivity disorder (ADHD). Pregnancy, labour/delivery and neonatal complications (PLDNC) have often been associated with ADHD; however, no investigations aimed at delineating the shared or nonshared nature of these factors have been reported. We aimed to identify those elements of the PLDNC that are more likely to be of a nonshared nature. METHODS: We used an intrafamily study design, comparing the history of PLDNC between children diagnosed with ADHD, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and their unaffected siblings. Children with ADHD were recruited from the outpatient, day-treatment program of the Child Psychiatry Department, Douglas Hospital, Montreal. The unaffected sibling closest in age to the child with ADHD was used as a control. The history of PLDNC was assessed using the Kinney Medical and Gynecological Questionnaire and the McNeil-Sjostrom Scale for both children with ADHD and their siblings. Seventy children with ADHD along with 50 of their unaffected siblings agreed to participate in the study. Child Behavior Checklist (CBCL), Continuous Performance Test (CPT) and Restricted Academic Situation Scale (RASS) scores were also used as measures of ADHD symptoms in children with ADHD. RESULTS: The children with ADHD had significantly higher rates of neonatal complications compared with their unaffected siblings (F4,196 = 3.67, p < 0.006). Furthermore, neonatal complications in the children with ADHD were associated with worse CBCL total and externalizing scores and with poorer performance on the CPT. CONCLUSIONS: These results suggest that neonatal complications are probably a nonshared environmental risk factor that may be pathogenic in children with ADHD. [ABSTRACT FROM AUTHOR]

Investigates the link between tryptophan hydroxylase (TPH) and suicide completion. Association between the gene that codes TPH and suicidal behavior; Genotyping of a sample of suicide completers; Public-health problem of suicidal behavior; Evidence that subjects with suicidal behavior have reduced serotonergic neuro-transmission.

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stablize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a γ-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 ± 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (χ² = 8.09; empirical P=0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD=1.45; empirical P=0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is impli- cated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined. [ABSTRACT FROM AUTHOR]

Individuals with sub-threshold psychotic symptoms (STPS) are considered at clinical high risk for psychosis (CHR). Imaging studies comparing CHR and patients shortly after a first episode of psychosis (FEP) support progressive cortical thinning by illness stage. However, at least 30% of FEP patients deny pre-onset STPS, suggesting no history of CHR. This calls into question the generalizability of previous imaging findings. To better understand the physiology of early psychosis symptomology, we investigated the relationship between pre-onset STPS and cortical thickness (CT) among FEP patients, examining regional CT and structural covariance (SC). Patients (N = 93) were recruited from PEPP-Montreal, a FEP clinic at the Douglas Mental Health University Institute. The Circumstances of Onset and Relapse Schedule was administered to retrospectively identify patients who recalled at least one of nine expert-selected STPS prior to their FEP (STPS+, N = 67) and to identify those who did not (STPS-, N = 26). Age and sex-matched healthy controls (HC) were recruited (N = 84) for comparison. Participants were scanned between one and three times over the course of two years. CT values of 320 scans (143 HC, 123 STPS+, 54 STPS-) that passed quality control were extracted for group analysis. Linear mixed effects models accounting for effects of age, sex, education, and mean thickness were applied for vertex-wise, group comparisons of cortical thickness and SC. Multiple comparison corrections were applied with Random Field Theory (p-cluster = 0.001). Compared to controls, only STPS- patients exhibited significantly reduced CT in a cluster of the right ventral lateral prefrontal cortex. The vertex with the highest t-statistic within this cluster was employed as a seed in the subsequent SC analysis. After RFT-correction, STPS+ patients exhibited significantly stronger SC between the seed and right pars orbitalis compared to STPS- patients, and HC exhibited significantly stronger SC between the seed and right middle temporal gyrus compared to STPS- patients. Our results revealed patterns of SC that differentiated patient subgroups and patterns of cortical thinning unique to STPS- patients. Our study demonstrates that the early course of sub-threshold psychotic symptoms holds significance in predicting patterns of CT during FEP. • Whether patients in a first episode of psychosis had prior subthreshold psychotic symptoms (STPS) predicted neural trends. • Pre-onset STPS is associated with greater structural covariance in regions within the right prefrontal cortex (rPFC). • Compared to controls, patients without prior STPS had increased rPFC cortical thinning while those with prior STPS did not. [ABSTRACT FROM AUTHOR]

Focuses on the role of polyglutamine in bipolar disorder. Response to lithium; Use of the repeat expansion detection technique.

An image of LRRTM1 protein is presented.