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Objective: Cognitive insight represents the capacity to self-reflect and consider external feedback when re-evaluating faulty beliefs. It is associated with specific cognitive capacities such as verbal memory, of which there is substantial evidence for sex differences in psychotic disorders. Like more general cognitive capacities, cognitive insight might too be modulated by sex differences.Method: One hundred and seventy-one first episode psychosis (FEP; 123 males, 48 females), and 203 multiple episode psychosis (MEP; 147 males, 56 females) participants completed the Beck Cognitive Insight Scale (BCIS). A two-way MANOVA was conducted on the three BCIS measures (self-reflectiveness, self-certainty, composite index) with sex (male, female) and illness stage (FEP, MEP) as factors, followed by two-way ANOVAs and a post hoc test of simple effects.Results: The only significant interaction to emerge was between sex and illness stage in self-certainty (F(1, 373) = 5.88, p = .016). A test of simple effects revealed that self-certainty group means were significantly different for males and females in FEP, where females had lower self-certainty than males (p = .053) but not during MEP (p = .119).Conclusion: Sex differences do not modulate cognitive insight in MEP, which may be attributable to females having greater positive symptom severity than males. In FEP however, results revealed that females were significantly less self-certain than males. Lower self-certainty relative to self-reflectiveness predicts treatment response in psychological interventions, and as such future FEP studies should explore sex differences in psychological interventions. [ABSTRACT FROM AUTHOR]

Introduction: Discontinuation of the initial oral antipsychotic prescribed for a first episode of psychosis (FEP) can derail outcome. Our objective was to examine the rate of and time to all-cause discontinuation of the first antipsychotic prescribed and the factors influencing such discontinuation.Methods: In a sample of 390 FEP patients, we estimated the rate of and time to discontinuation of the initial antipsychotic over a one-year period. The effects of a number of putative predictors of discontinuation were estimated using regression analyses.Results: Rate of discontinuation of the first antipsychotic was 72%, with no difference between the 3 investigated antipsychotics (olanzapine (73%), risperidone (68%) and aripiprazole (75%)), (χ2 (2) = 1.89, p = 0.388). Mean time to discontinuation was 7.2 (4.6) months and was not different among the three antipsychotics (Log-rank χ2 (2) = 0.257, p = 0.879). Binary logistic regression showed that higher positive and negative symptoms remission and baseline functioning were associated with lower rates of discontinuation (Nagelkerke R2 = 0.36, χ2 (10) = 66.9, p < 0.001). Multiple linear regression showed the same predictors, in addition to male gender and less weight gain per month of exposure to the initial antipsychotic, to be associated with longer time to discontinuation (adjusted R2 = 0.336, F (9, 219) = 13.8, p < 0.001).Conclusion: Discontinuation of the initial antipsychotic is a major concern in the course of treating FEP. Symptom relief, better functioning and lower side effects appear to be the major factors associated with continuing an antipsychotic medication. [ABSTRACT FROM AUTHOR]

Attention Deficit/Hyperactivity Disorder (ADHD) has been associated with atypical patterns of neural activity measured by electroencephalography (EEG). However, the identification of EEG diagnostic biomarkers has been complicated by the disorder's heterogeneity. The objective of this review was to synthesize the literature investigating EEG variation in patients diagnosed with ADHD, addressing the following questions: 1) Are the diagnostic ADHD subtypes associated with different EEG characteristics? 2) Are EEG measures correlated with ADHD traits and/or symptom severity? and 3) Do classification techniques using EEG measures reveal different clinical presentations of ADHD? Outcomes highlight the potential for electrophysiological measures to provide meaningful insights into the heterogeneity of ADHD, although direct translation of EEG biomarkers for diagnostic purposes is not yet supported. Key measures that show promise for the discrimination of existing ADHD subtypes and symptomatology include: resting state and task-related modulation of alpha, beta and theta power, and the event-related N2 and P3 components. Prescriptions are discussed for future studies that may help to bridge the gap between research and clinical application. • Electrophysiology provides meaningful insight into the heterogeneity of ADHD. • Attentional, inhibitory control, and resting tasks are compared in ADHD subtypes. • Power spectrum and event-related potential analyses are related to ADHD symptoms. • EEG shows promise for the discovery of novel subgroups of ADHD. [ABSTRACT FROM AUTHOR]

The article presents a study conducted by the authors on impact of environmental factors over hyperactivity disorder. Topics discussed include information on studies conducted over DNA methylation and histone acetylation; impact of hyper methylation and hypo methylation over gene expression; and positive impact of chromatin remodeling.

Abstract: Objective: Previous findings indicate that women with Bulimia Nervosa (BN), when compared to women with no eating disorder (NED), tend to display elevated methylation in the promoter region of the DRD2 gene. The preceding would be compatible with evidence of generally reduced dopamine activity in people with BN. However, altered DNA methylation has also been associated with adverse environmental exposures (such as to childhood abuse) and with psychiatric disturbances (such as Borderline Personality Disorder: BPD). In this study, we examined the extent to which DRD2 methylation was associated with the presence or absence of a bulimic eating disorder, to childhood abuse exposure, or to comorbid BPD. Method: Women with a bulimia-spectrum disorder (BSD) and women with NED were assessed for childhood traumata, eating-disorder symptoms and BPD, and provided blood samples for methylation analyzes. Results: BSD and NED groups did not differ as to mean percent DRD2 promoter methylation. However, among the women with a BSD, those with BPD showed small, but significant increases in DRD2 methylation levels compared to women with NED (as indicated by Hochberg's post-hoc tests). Similarly, women with a BSD who reported a history of childhood sexual abuse showed a trend-level elevation of DRD2 methylation compared to our NED group. Discussion: Our findings imply that, in people with a BSD, increased methylation of the DRD2 gene promoter may be more strongly characteristic of comorbid psychopathology than it is a global correlate of the eating disorder per se. We discuss theoretical implications of our findings. [Copyright &y& Elsevier]

Abstract: Both medication non-adherence and co-morbid cannabis abuse are associated with poor clinical outcome in first episode psychosis (FEP). The nature of interaction between adherence to medication and continued cannabis use remains unexplored. The objectives of this study were to examine variation in medication adherence associated with cessation or continuation of cannabis use, and to determine the impact of interaction between cannabis use and adherence to medication on symptom outcome at 12months. From a consecutive patient cohort (N=192) with a DSM-IV diagnosis of a FEP, 62 patients who met DSM-IV criteria for a currently active cannabis abuse disorder were followed up for one year. Complete data on repeated measures of medication adherence, symptoms, and cannabis use were available for 48 of the 62 patients. Twenty-eight patients (58.7%) continued while 20 (41.2%) stopped cannabis use after entering treatment. While both groups were relatively non-adherent at six months, 25/28 (92%) of the former group became adherent compared to 8/20 (40%) of those who stopped cannabis use (p <.01). While there was no overall effect of continued cannabis use on symptom levels at 12months, after controlling for medication adherence patients with continuous cannabis use had significantly higher level of symptoms (F(1,30)=2.74, p =0.03). FEP patients with an active cannabis use disorder may make a choice of either stopping cannabis and not taking medications or continuing cannabis but becoming more adherent to medications, adherence to medication appears to help both groups but continuous users remain at higher risk of poor symptom outcome even while on medication. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Summary: The present study assessed the modulating effect of education level on cortisol reactivity to the Trier Social Stress Test (TSST) in a sample of 101 middle-aged adults (22 males, 79 females) between the ages of 50 and 65. The TSST involves a public speech and mental arithmetic task in front of an audience. No previous studies have assessed whether education level can have an impact on cortisol reactivity to this psychosocial stressor. It is plausible that greater exposure to academia may impact how one perceives and responds to the demands of the speech and arithmetic task. Should education have an impact on cortisol reactivity to the TSST, future studies will be required to control for this factor in order to reduce both statistical error and false interpretations. In addition to completing the TSST, participants were administered a battery of neurocognitive tests and personality questionnaires, including a report on education level (i.e. number of years total and degree: High School, Junior College, Technical, University). Results showed that adults with post-secondary education above Junior College tended to secrete higher cortisol levels overall, as measured by total area under the curve. However, it was the group with lower educational attainment who showed a greater stress response specific to the TSST, as measured by percentage increase in cortisol from pre- to post-TSST. Analyses also found that higher educated adults performed better than their less educated peers on verbal fluency. Considering that the TSST is an oral task, it is suggested that middle-aged individuals with a lower level of education may find the TSST more stressful due to lower verbal capacity, which may lead to an increased cortisol response to the TSST when compared to individuals with a higher level of education. [Copyright &y& Elsevier]

Objective: It is suggested that schizophrenic patients who respond to neuroleptic medication and those who do not might differ with respect to their pathogenesis. In particular, it has been proposed that genetic factors may contribute to treatment response and/or outcome. In order to test this hypothesis, we compared the pattern of familial aggregation of schizophrenia related disorders in schizophrenic patients who are either responders (R) or nonresponders (NR) to typical neuroleptics.Method: R (n=36) or NR (n=35) patients to typical neuroleptics and healthy controls (n=63) were recruited. At least one key informant relative of each proband was interviewed blind as to the status of the proband using the Family Interview for Genetic Studies. Morbid risk for schizophrenia and cluster A personality disorders and family loading score for schizophrenia were examined in first- and second-degree relatives of these probands.Results: First-degree relatives of NR patients were at a significantly higher risk for schizophrenia (MR=8.84), compared, respectively, to relatives of controls (MR=1.52) or relatives of R patients (MR=2.45). The same pattern was observed in second-degree relatives. Family loading score for schizophrenia in first- and second-degree relatives was significantly higher in NR compared to R patients.Conclusions: Schizophrenic patients who do not respond to typical neuroleptics may suffer from a more familial form of schizophrenia compared to patients who are responders. [ABSTRACT FROM AUTHOR]

An increased incidence of schizophrenia has been associated with several perinatal insults, most notably maternal infection during pregnancy and perinatal hypoxia. This study used a rat model to directly test if maternal exposure to bacterial endotoxin (lipopolysaccharide, LPS) during pregnancy alters behaviors relevant to schizophrenia, in offspring at adulthood. The study also tested if postnatal anoxia interacted with gestational LPS exposure to affect behavior. At adulthood, offspring from dams administered LPS on days 18 and 19 of pregnancy showed significantly increased amphetamine-induced locomotion, compared to offspring from saline-treated dams. A period of anoxia on postnatal day 7 had no effect on amphetamine-induced locomotion and there was no interaction between effects of gestational LPS and postnatal anoxia on this behavior. Offspring from LPS-treated dams also showed enhanced acoustic startle responses as adults, compared to offspring from saline-treated dams. In offspring tested for pre-pulse inhibition (PPI) of acoustic startle and for apomorphine modulation of PPI, no effects of either gestational LPS or of postnatal anoxia and no interactions between LPS and anoxia were observed. It is concluded that maternal LPS exposure during pregnancy in the rat may be a useful model to study mechanisms responsible for effects of maternal infection on behaviors relevant to schizophrenia, in offspring. [Copyright &y& Elsevier]

To determine whether two groups of schizophrenic patients representing the two extremes of the neuroleptic response-spectrum (consistent responders vs. consistent nonresponders) differ with respect to their neuropsychological profile. Neuroleptic-responder (R; n=36) and -nonresponder (NR; n=39) schizophrenic patients were recruited according to a priori defined criteria of responsiveness to typical neuroleptics. Seven neuropsychological domains were assessed and compared between groups: attention-vigilance, abstraction-flexibility, spatial organization, visual-motor processing, visual memory, verbal abilities, and verbal memory and learning. All measures were standardized using the scores of 36 healthy volunteers. NR schizophrenic patients performed worse in all neuropsychological domains compared to normal controls and R schizophrenic patients. However, only performances on visual memory, verbal abilities, and verbal memory and learning were significantly poorer in NR compared to R patients. Only the latter domain significantly differentiated NR patients from the other two groups. R patients performed at an intermediate level in all domains. This report of differences in neuropsychological profile between neuroleptic-responder and -nonresponder schizophrenic patients adds to the growing evidence supporting the value of distinguishing schizophrenic patients on the basis of their therapeutic response to neuroleptics. [ABSTRACT FROM AUTHOR]

Persistent negative symptoms (PNS) are linked to poor functional outcomes and may be primary or caused by secondary factors. Although several studies have examined PNS in first-episode psychosis (FEP), a comparison with a data-driven approach is lacking. Here, we compared clinically defined PNS subgroups with class trajectories identified through latent growth modeling (LGM). Patients admitted to an early intervention service (N = 392) were classified as PNS (n = 105), secondary PNS (sPNS; n = 74), or non-PNS (n = 213) based on longitudinal data collected six to twelve months after admission. LGM was used to stratify patients based on similar negative symptom course over the same time period. Using multiple linear regression, we assessed the utility of both approaches in predicting Social and Occupational Functioning Assessment Scale (SOFAS) scores at two-year follow-up. Three negative symptom trajectories were identified: low and remitting (LR; n = 158), moderate and improving (MI; n = 163) and delayed partial response (DR; n = 71). Most non-PNS patients followed the LR trajectory, while patients with PNS or sPNS were generally divided between MI and DR. Both PNS classification and trajectory membership were significant predictors of two-year functional outcomes; the DR and MI trajectories predicted greater increases in SOFAS scores (DR: b = -19.14; MI: b = -11.54) than either sPNS (b = -9.19) or PNS (b = -6.46). These findings demonstrate that combining PNS and symptom-based stratification can predict functional outcomes more accurately than either taxonomy alone. Such a combined approach could yield significant advances in developing more targeted interventions for patients at risk for poor functional outcomes. [ABSTRACT FROM AUTHOR]

Hallucinations are a core feature of psychosis, and their severity during the acute phase of illness is associated with a range of poor outcomes. Various clinical and sociodemographic factors may predict hallucinations and other positive psychotic symptoms in first episode psychosis (FEP). Despite this, the precise factors associated with hallucinations at first presentation to an early intervention service have not been extensively researched. Through detailed interviews and chart reviews, we investigated sociodemographic and clinical predictors in 636 minimally-medicated patients who entered PEPP-Montréal, an early intervention service for FEP, between 2003 and 2018. Hallucinations were measured using the Scale for the Assessment of Positive Symptoms (SAPS), while negative symptoms were assessed using the Scale for the Assessment of Negative symptoms (SANS). Depressive symptoms were evaluated through the Calgary Depression Scale for Schizophrenia (CDSS), and anxiety symptoms via the Hamilton Rating Scale for Anxiety (HAS). A majority (n = 381, 59.9 %) of the sample presented with clinically significant hallucinations (SAPS global hallucinations score ≥ 3) at program entry. These patients had an earlier age at onset, fewer years of education, and a higher severity of delusions, depression and negative symptoms than those without clinical-level hallucinations. These results suggest that individuals with clinically significant hallucinations at admission tend to be younger and have a greater overall symptom burden. This makes it especially important to monitor hallucinations alongside delusions, depression and negative symptoms in order to identify who might benefit from targeted interventions. The implications of these findings for early intervention and person-centered care are discussed. [ABSTRACT FROM AUTHOR]

Despite their acknowledged value, patient-reported outcome measures (PROMs) are infrequently used in psychosis, particularly in low-and middle-income countries. We compared ratings on two single-item PROMs, Self-Rated Health (SRH) and Self-Rated Mental Health (SRMH), of persons receiving similar early psychosis services in Chennai, India and Montreal, Canada. We hypothesized greater improvements in SRH and SRMH in the Chennai (compared to the Montreal) sample. Participants (Chennai N = 159/168 who participated in the larger study; Montreal N = 74/165 who participated in the larger study) completed the SRH and SRMH during at least two out of three timepoints (entry, months 12 and 24). Repeated measures proportional odds logistic regressions examined the effects of time (baseline to month 24), site, and relevant baseline (e.g., gender) and time-varying covariates (i.e., symptoms) on SRH and SRMH scores. SRH (but not SRMH) scores significantly differed between the sites at baseline, with Chennai patients reporting poorer health (OR: 0.33; CI: 0.18, 0.63). While Chennai patients reported similar significant improvements in their SRH (OR: 7.03; CI: 3.13; 15.78) and SRMH (OR: 2.29, CI: 1.03, 5.11) over time, Montreal patients only reported significant improvements in their SRMH. Women in Chennai (but not Montreal) reported lower mental health than men. Higher anxiety and longer durations of untreated psychosis were associated with poorer SRH and SRMH, while negative symptoms were associated with SRH. As hypothesized, Chennai patients reported greater improvements in health and mental health. The marked differences between health and mental health in Montreal, in contrast to the overlap between the two in Chennai, aligns with previous findings of clearer distinctions between mind and body in Western societies. Cross-context (e.g., anxiety) and context-specific (e.g., gender) factors influence patients' health perceptions. Our results highlight the value of integrating simple PROMs in early psychosis. [ABSTRACT FROM AUTHOR]

Preventing relapse in schizophrenia improves long-term health outcomes. Repeated episodes of psychotic symptoms shape the trajectory of this illness and can be a detriment to functional recovery. Despite early intervention programs, high relapse rates persist, calling for alternative approaches in relapse prevention. Predicting imminent relapse at an individual level is critical for effective intervention. While clinical profiles are often used to foresee relapse, they lack the specificity and sensitivity needed for timely prediction. Here, we review the use of speech through Natural Language Processing (NLP) to predict a recurrent psychotic episode. Recent advancements in NLP of speech have shown the ability to detect linguistic markers related to thought disorder and other language disruptions within 2–4 weeks preceding a relapse. This approach has shown to be able to capture individual speech patterns, showing promise in its use as a prediction tool. We outline current developments in remote monitoring for psychotic relapses, discuss the challenges and limitations and present the speech-NLP based approach as an alternative to detect relapses with sufficient accuracy, construct validity and lead time to generate clinical actions towards prevention. [ABSTRACT FROM AUTHOR]

Background: The influence of socioeconomic deprivation on the cardiovascular health of patients with psychosis-spectrum disorders (PSD) has not been investigated despite the growing recognition of social factors as determinants of health, and the disproportionate rates of cardiovascular mortality observed in PSD. Discordant results have been documented when studying dyslipidemia -a core cardiovascular risk factor- in first-episode psychosis (FEP), before chronic exposure to antipsychotic medications. The objective of the present study is to determine the extent to which socioeconomic deprivation affects blood lipids in patients with FEP, and examine its implications for cardiovascular risk in PSD.Methods: Linear regression models, controlling for age, sex, exposure to pharmacotherapy, and physical anergia, were used to test the association between area-based measures of material and social deprivation and blood lipid levels in a sample of FEP patients (n = 208).Results: Social, but not material deprivation, was associated with lower levels of total and HDL cholesterol. This effect was statistically significant in patients with affective psychoses, but not in schizophrenia-spectrum disorders.Conclusions: Contrary to other reports from the literature, the relationship between socioeconomic disadvantage and blood lipid levels was contingent on the social rather than the material aspects of deprivation. Furthermore, this association also depended on the main diagnostic category of psychosis, suggesting a complex interaction between the environment, psychopathology, and physical health. Future studies exploring health issues in psychosis might benefit from taking these associations into consideration. A better understanding of the biology of blood lipids in this context is necessary. [ABSTRACT FROM AUTHOR]

Identifying risk factors for suicidal ideation and attempt among first-episode psychosis patients is essential to prevent suicide in this high-risk population. We investigated risk factors at admission for suicidal ideation and attempt during a 2-year early intervention program. Our sample included patients aged 18–35 years who were consecutively admitted to an early intervention program (2003–2017). Sociodemographic and clinical variables were obtained from a longitudinal study, while data on suicidal ideation and attempt were collected via systematic file review. Univariable and multivariable logistic regressions assessed the association of these variables with suicide ideation and attempt. Of 446 participants, 35 (7.8 %) attempted suicide during the 2-year follow up, including two resulting in death (0.45 %), and 168 (37.7 %) reported solely suicidal ideation. Multivariable analyses indicated living alone (OR = 4.01, CI = 2.11–7.63), affective psychosis (OR = 1.95, CI = 1.22–3.14) and depressive symptomatology (OR = 1.45, CI = 1.13–1.86) were associated with increased risk for suicidal ideation. Attempting suicide close to admission (OR = 10.29, CI = 3.63–29.22), living alone (OR = 4.17, CI = 1.40–12.35), and depressive (OR = 1.67, CI = 1.06–2.63) and positive symptomatology (OR = 1.60, CI = 1.02–2.50) were associated with increased risk for suicide attempt. Attempting suicide close to admission (OR = 11.65, CI = 4.08–33.30), being part of an ethnic minority (OR = 3.71, CI = 1.59–8.63), and presenting lower anxiety (OR = 0.58, CI = 0.36–0.94) were the only factors specifically associated with suicide attempt compared to ideation. Close monitoring of patients who recently attempted suicide, live alone, are part of an ethnic minority, and present with affective and positive symptomatology may help reduce the risk of suicide-related outcomes during early intervention programs. [ABSTRACT FROM AUTHOR]

Highlights • Compared to patients who recently experienced a first-episode of psychosis (FEP), a larger proportion of patients who have had multiple episodes of psychosis (MEP) present with severe and widespread cognitive impairment. • Multiplicity of psychotic episodes may have a detrimental influence on cognitive impairment. • The increased risk of cognitive impairment in more domains as the illness progresses may be explained in part by the fact that illness chronicity is associated with a lack of educational and vocational opportunities. • It may be beneficial to adapt the content of cognitive remediation therapy to patients' cognitive profiles as well, rather than to stage of illness only. Abstract Cognitive impairments in psychotic disorders (PD) present heterogeneously across patients. Between 2 and 5 clusters have been identified in previous studies with first-episode (FEP) and multiple-episodes of psychosis (MEP) patients suggesting different profiles of impairment. Past findings suggest there are differences between FEP and MEP patients regarding severity and number of affected cognitive domains. Heterogeneity of cognitive deficits in PD has perhaps hindered our understanding of their course. The present study compared non-affective FEP and MEP patients to assess whether illness chronicity could influence cognitive impairment profiles. We analyzed cognitive data, collected with the Cogstate Schizophrenia Battery, of FEP and MEP patients using cluster analysis. We compared clustering methods to obtain a more robust solution. For FEP patients, data were collected at their entry to a specialized clinic; the MEP group consisted of in- and outpatients. Results suggested cognitive heterogeneity was similar in FEP and MEP samples, although in different proportions. Three clusters were identified as the most stable solution and comprised groups of patients with either 1- no cognitive impairment (over-representation of FEP), 2- generalized deficits (over-representation of MEP), or 3- intermediate impairments. These findings encourage early interventions adapted to the profile of impairment. [ABSTRACT FROM AUTHOR]

Diagnostic criteria used in autism research have undergone a shift towards the inclusion of a larger population, paralleled by increasing, but variable, estimates of autism prevalence across clinical settings and continents. A categorical diagnosis of autism spectrum disorder is now consistent with large variations in language, intelligence, comorbidity, and severity, leading to a heterogeneous sample of individuals, increasingly distant from the initial prototypical descriptions. We review the history of autism diagnosis and subtyping, and the evidence of heterogeneity in autism at the cognitive, neurological, and genetic levels. We describe two strategies to address the problem of heterogeneity: clustering, and truncated-compartmentalized enrollment strategy based on prototype recognition. The advances made using clustering methods have been modest. We present an alternative, new strategy for dissecting autism heterogeneity, emphasizing incorporation of prototypical samples in research cohorts, comparison of subgroups defined by specific ranges of values for the clinical specifiers, and retesting the generality of neurobiological results considered to be acquired from the entire autism spectrum on prototypical cohorts defined by narrow specifiers values. • Autistic people involved in research are increasingly distant from initial descriptions of autism. • The subgrouping of the autism spectrum using cluster methods leads to inconsistent results. • Research may benefit from focusing on cohorts truncated based on prototypicality. • Autism subgroups defined by narrow specifiers values should be studied separately. • Delivering or not services to autistic people should not be influenced by their prototypicality. [ABSTRACT FROM AUTHOR]

Differences in subjective quality of life among persons receiving early intervention for psychosis in varying geo-sociocultural contexts have rarely been examined. Our prospective longitudinal study compared the quality of life of persons with first-episode psychosis receiving two years of similar early intervention in Chennai, India and Montreal, Canada. We hypothesized that general life satisfaction would be higher in Chennai compared to Montreal, and that social relations (a specific quality of life component) would also be higher in Chennai and positively contribute to general life satisfaction. Participants completed the general satisfaction and social relations domains of the Wisconsin Quality of Life Index at baseline, months 12 and 24. Baseline weighted mean general satisfaction and social relations scores were in the low to moderate range. Generalized estimating equation analyses showed that general satisfaction scores increased with time [Wald χ2 (1) = 125.28, p < 0.001] and were higher in Chennai than in Montreal [Wald χ2 (1) = 7.50, p = 0.006]. Social relations scores showed the highest association with general satisfaction scores (B = 0.52), followed by positive symptom remission (B = 0.24) and gender (B = 0.18) with Chennai males having the highest general satisfaction scores. Social relations weighted mean scores increased with time [Wald χ2 (1) = 87.30, p < 0.001] and were positively associated with years of education [Wald χ2 (1) = 4.76, p = 0.029] and early negative symptom remission [Wald χ2 (1) = 7.38, p = 0.007]. Our results suggest that subjective quality of life may improve following early intervention for psychosis across contexts. Our findings advance knowledge about the role of sociocultural (e.g., gender) and clinical factors in influencing subjective outcomes in psychosis, and point to social support networks and symptom remission as avenues to boost quality of life. [ABSTRACT FROM AUTHOR]

Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway. [ABSTRACT FROM AUTHOR]

Verbal memory (VM) dysfunction is prevalent in first-episode psychosis (FEP) and has major impacts on long-term functional and clinical outcomes. Nevertheless, a substantial proportion of FEP patients have VM performance in the norm, called normal-range (NR) VM, and only a few studies have explored its relation to outcomes. Moreover, probable decrements between estimated premorbid and current cognitive performance could confuse the relationship between VM and clinical or functional outcomes in FEP patients. These potential interactions have not yet been considered in FEP, thus, we examined 1) the longitudinal relationship between VM performance (NR vs. below NR (BNR)) in FEP and clinical and functional outcomes over 24 months following admission to treatment, and 2) compared the clinical and functional status of NR patients with and without cognitive decrement at baseline and 12 months. A total of 271 patients (BNR = 114, NR = 157; 81 out of 105 NR with decrement) completed measures of psychosocial functioning and clinical symptoms at baseline, month 12, and month 24. Generalized Estimating Equations and unpaired t-tests were used to address the first and second aim, respectively. NR demonstrated better functioning and fewer negative symptoms when compared to BNR. Interestingly, NR patients with decrement reported significantly more negative symptoms at baseline compared to their counterparts without decrement. These findings document that a large proportion (57.9 %) of FEP patients have NR VM that appear to be functionally advantageous but that NR VM is nuanced by the presence or absence of a potential decrement early in the developmental course of the disorder. [ABSTRACT FROM AUTHOR]

Objective: Adolescent-onset psychosis has traditionally been characterized as a more severe form of psychosis with a poorer prognosis. However, it is still unclear if patients with an adolescent-onset have worse symptom remission outcomes. Symptom remission is the principal clinical outcome known to predict quality of life and social functioning in the long term. The goal of this study is to clarify the influence of age of onset of psychosis on symptom remission in a sample of first-episode psychosis patients.Method: A total of 246 first-episode psychosis patients were recruited from a specialized early intervention program serving a defined epidemiological catchment area. Age of onset of psychosis (adolescence vs. adulthood) was used as the main predictor, and duration of untreated psychosis (DUP), baseline symptoms, baseline functioning, substance abuse diagnosis, medication adherence and gender were used as covariates in hierarchical regression models predicting the following positive and negative symptom remission outcomes: maximum continuous months in remission and early remission (i.e., occurring in the first three months of follow-up).Results: After controlling for other variables, onset of psychosis in adulthood and shorter DUP predicted early remission of positive symptoms. This effect was stronger in patients with a diagnosis of a schizophrenia-spectrum disorder. Remission of negative symptoms did not depend on age of onset, and was only predicted by baseline negative symptoms.Conclusion: Patients with onset of psychosis during adulthood are more likely to achieve early positive symptom remission than those with adolescent onset. This effect might be stronger in patients with a diagnosis of a schizophrenia-spectrum disorder. [ABSTRACT FROM AUTHOR]

In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self-Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self-Reflectiveness in FES. [ABSTRACT FROM AUTHOR]

Hippocampal circuitry and related cortical connections are altered in first episode psychosis (FEP) and are associated with verbal memory deficits, as well as positive and negative symptoms. There are robust sex differences in the clinical presentation of psychosis, including poorer verbal memory in male patients. Consideration of sex differences in hippocampal-cortical circuitry and their associations with different behavioral dimensions may be useful for understanding the underlying pathophysiology of verbal memory deficits and related symptomatology in psychosis. Here, we use a data-driven approach to simultaneously capture the complex links between sex, verbal memory, symptoms, and cortical-hippocampal brain metrics in FEP. Structural magnetic resonance imaging and behavioral data were acquired from 100 FEP patients (75 males, 25 females) and 87 controls (55 males, 32 females). Multivariate brain-behavior associations were examined in FEP using partial least squares to map sociodemographic, verbal memory, and clinical data onto brain morphometry. The analysis identified two sex-dependent patterns of verbal memory, symptoms, and brain structure. In male patients, verbal memory deficits and core psychotic symptoms were associated with both increased and decreased frontal and temporal cortical thickness and reductions in CA2/3 hippocampal subfield and fornix volumes. In female patients, fewer negative/depressive symptoms were associated with a more attenuated cortical thickness pattern and more diffuse reductions in hippocampal white matter regions. Taken together, the results contribute towards better understanding the underlying pathophysiology of psychosis by highlighting the unique contribution of specific hippocampal subfields and surrounding white matter and their connections with broader cortical networks in a sex-dependent manner. [Display omitted] • Sex-dependent brain alterations may subserve sex differences in psychosis pathology. • A data-driven approach links brain-behavior associations in early psychosis. • Greater cortical alterations and psychosis symptoms in male-dependent pattern. • Greater hippocampal subfield reductions and less severe pathology in female pattern. • Integrating sex in neuroimaging and clinical research in psychosis is crucial. [ABSTRACT FROM AUTHOR]

Adherence to therapeutic guidelines in psychiatry is anchored and facilitated by rating scales. However, they are rarely used in routine care, particularly for psychotic disorders. Consequently, adherence to treatment guidelines are not ideal and patient outcomes are often sub-optimal. In this study, we used the clinician-rated Clinical Global Impressions Scale (CGI) to implement a measurement-based care (MBC) approach and derive indices of quality of care at a first episode psychosis (FEP) program. At the individual level, an algorithm was created using CGI scores and their changes over time to define the concept of Patient Requiring Clinical Attention (PRCA) that encompasses several categories (e.g. episode of severity , treatment inertia , or treatment resistance). At the service level, CGI scores were used to derive several indices of quality of care: severity of illness and its change over time, conformity to the use of low doses of antipsychotic medications, and clozapine offer index. 135 Patients were included in this study of whom 19 patients were identified as PRCA. Of these, 12 (63%) received timely medication, and 7 (37%) were suspected cases of therapeutic inertia. Additionally, 15 patients met criteria for treatment resistance of whom 7 were offered clozapine (47%). At the service level, the average CGI improved by 2 points from baseline to month 1 and average doses of antipsychotic medications prescribed were in line with prescription guidelines for FEP patients. The proposed CGI-based treatment algorithm and service evaluation strategy can help to optimize quality care and services for patients. • Measurement-based care integration strategy for first episode psychosis. • Operationalization of antipsychotic treatment response, resistance & inertia. • Derivation of indices of quality of care and evaluation of psychiatric services. • Creation and application of treatment quality detection algorithm for clinicians. • Novel criteria for clozapine prescription in first-episode psychosis. [ABSTRACT FROM AUTHOR]

Introduction: Measurement-based care (MBC) is an evidence-based practice wherein clinical decisions are informed by patient data collected throughout treatment. MBC has yielded superior patient outcomes compared to standard care. However, the implementation of MBC in the day-to-day practice, particularly in psychotic disorders, poses several challenges. This study evaluates the clinician-rated Clinical Global Impressions Scale of Severity (CGI-S), for MBC implementation at a first-episode psychosis program.Methods: The CGI-S was evaluated in the context of routine care on fidelity to practice, inter-rater reliability among psychiatrists and concurrent validity with scales measuring different domains of psychopathology (SAPS, SANS, GAF, BPRS, PANSS-6).Results: A high fidelity to practice (67%) and inter-rater reliability was found (rwg = 0.92). CGI-S correlations were significant and strongest with BPRS (r = 0.55; p < 0.01), GAF (r = 0.53; p < 0.01), SAPS (r = 0.52, p < 0.01), and PANSS-6 (r = 0.41; p < 0.05) scores. However, correlations with SANS and PANSS-6 Negative sub-scale were weak.Conclusion: Findings suggest the CGI may be used to overcome important barriers towards MBC implementation within the context of first episode psychosis. However, as suggested by data, further improvements in capturing negative symptoms by rating clinicians are needed.Twitter: A novel strategy for measurement-based care to optimize treatment for individuals with first episode psychosis and related psychotic disorders. [ABSTRACT FROM AUTHOR]

DNA methylation allows for the environmental regulation of gene expression and is believed to link environmental stressors to such mental-illness phenotypes as eating disorders. Numerous studies have shown an association between bulimia nervosa (BN) and variations in brain-derived neurotrophic factor (BDNF). BDNF has also been linked to borderline personality disorder (BPD) and to such traits as reward dependence. We examined the extent to which BDNF methylation corresponded to bulimic or normal-eater status, and also to the presence of comorbid borderline personality disorder (BPD) and childhood abuse. Our sample consisted of 64 women with BN and 32 normal-eater (NE) control women. Participants were assessed for eating-disorder symptoms, comorbid psychopathology, and childhood trauma, and then they were required to provide blood samples for methylation analyses. We observed a significant site×group (BN vs. NE) interaction indicating that women with BN showed increases in methylation at specific regions of the BDNF promoter. Furthermore, examining effects of childhood abuse and BPD, we observed significant site×group interactions such that groups composed of individuals with childhood abuse or BPD had particularly high levels of methylation at selected CpG sites. Our findings suggest that BN, especially when co-occurring with childhood abuse or BPD, is associated with a propensity towards elevated methylation at specific BDNF promoter region sites. These findings imply that hypermethylation of the BDNF gene may be related to eating disorder status, developmental stress exposure, and comorbid psychopathology. [ABSTRACT FROM AUTHOR]

Ownership of cats in childhood has been inconsistently associated with psychosis in adulthood. Parasitic exposure, the putative mechanism of this association, may be more common with rodent-hunting cats, and its association with psychosis may depend on other environmental exposures. We examined the conditional associations between childhood cat ownership and the frequency of psychotic experiences in adulthood. Adults (n = 2206) were recruited in downtown Montreal to complete a survey about childhood cat ownership (non-hunting or rodent-hunting), winter birth, residential moves in childhood, head trauma history, and tobacco smoking. The frequency of psychotic experiences (PE) was measured with the 15-item positive subscale of the Community Assessment of Psychic Experiences. Associations between exposures and PE were examined in linear regressions adjusted for age and sex. Interactions among variables were explored using a conditional inference tree. Rodent-hunting cat ownership was associated with higher PE scores in male participants (vs. non-hunting or no cat ownership: SMD = 0.57; 95% CI: 0.27, 0.86), but not in female participants (SMD = 0.10; 95% CI: −0.18, 0.38). In the conditional inference tree, the highest mean PE score was in the class comprised of non-smokers with >1 residential move, head trauma history, and rodent-hunting cat ownership (n = 22; mean standard score = 0.96). The interaction between rodent-hunting cat ownership and head trauma history was supported by a post-hoc linear regression model. Our findings suggest childhood cat ownership has conditional associations with psychotic experiences in adulthood. [ABSTRACT FROM AUTHOR]

• While maternal smoking during pregnancy (MSDP) is established as a risk factor for ADHD, the mechanisms underlying this association are not well understood. • We investigated the effect of MSDP on cortical brain structures in children with ADHD. • A significant effect of MSDP on structural MRI parameters was detected when using an epigenetic signature instead of maternal recall. Maternal smoking during pregnancy (MSDP) is considered a risk factor for ADHD. While the mechanisms underlying this association are not well understood, MSDP may impact the developing brain in ways that lead to ADHD. Here, we investigated the effect of prenatal smoking exposure on cortical brain structures in children with ADHD using two methods of assessing prenatal exposure: maternal recall and epigenetic typing. Exposure groups were defined according to: (1) maternal recall (+MSDP: n = 24; −MSDP: n = 85) and (2) epigenetic markers (EM) (+EM: n = 14 −EM: n = 21). CIVET-1.1.12 and RMINC were used to acquire cortical brain measurements and perform statistical analyses, respectively. The vertex with highest significance was tested for association with Continuous Performance Test (CPT) dimensions. While no differences of brain structures were identified between +MSDP and –MSDP, +EM children (n = 10) had significantly smaller surface area in the right orbitofrontal cortex (ROFc), middle temporal cortex (RTc) and parahippocampal gyrus (RPHg) (15% FDR) compared to -EM children (n = 20). Cortical surface area in the RPHg significantly correlated with CPT commission errors T-scores. This study suggests that molecular markers may better define exposure to environmental risks, as compared to human recall. [ABSTRACT FROM AUTHOR]

Abstract: Negative symptoms are present early on during the first episode of psychosis (FEP). The severity of these symptoms has been linked to cognitive deficits, including memory; however, its relationship with persistent negative symptoms (PNS) remains unclear. Thus, the goals of the current paper were to explore memory profiles in FEP patients identified as having PNS and to delineate this relationship in PNS over a 1-year period. Patients diagnosed as having a first episode of psychosis were segregated into groups of patients who met the criteria for PNS (N=39) and patients who did not, or non-PNS (N=97). At an initial assessment, all subjects were administered neurocognitive tests for three memory domains including verbal, visual and working memory. In addition, in FEP patients, clinical symptoms including negative, positive and depressive symptoms were also measured at the initial assessment as well as months 1, 2, 3, 6, 9, and 12. A significant interaction of memory×group was observed (F=4.997, d.f.=1,181, P=0.002), with post hoc comparisons indicating that the PNS group performed more poorly than non-PNS only in the verbal memory domain. All three-memory domains remained stable over time. Hence, in comparison to non-PNS patients, FEP patients with PNS appear to have greater (selective) verbal memory impairments throughout the first year of treatment. [Copyright &y& Elsevier]

Summary: Early life adversity has been associated with an increased risk for the development of mental health problems, including psychotic disorders, perhaps mediated by a changed regulation of the Hypothalamic Pituitary Adrenal (HPA) axis. Aim of the present study was to confirm our previous finding of an attenuated cortisol awakening response (CAR) in men with first episode psychosis (FEP) and to explore a possible link between a blunted CAR and early adversity as indicated by perceived parental bonding. Fifty-eight patients (38 men, 20 women; mean age 23.25±3.86) with a FEP and 33 healthy community controls (16 men, 17 women; mean age 22.91±3.64) participated in the study. Saliva samples for assessment of the CAR were collected immediately, 30 and 60min after awakening. Complete cortisol samples were available in a reduced sample of 56 patients (37 men) and 30 controls (13 men). Parental bonding during the first 16 years of life was assessed retrospectively with the Parental Bonding Inventory. Results showed a significantly blunted CAR in male compared to female patients, confirming our previously reported findings. We also found a lower CAR in the total FEP group compared to controls, which failed to reach significance after controlling for time of awakening. A significantly lower percentage of patients than controls reported optimal maternal parenting. Within the patient group, significantly fewer male than female patients reported optimal maternal and paternal parenting. Only in patients, unfavorable paternal parenting was related to a blunted CAR. Dysregulation of the HPA axis in male patients might be a consequence of non-optimal parenting and contribute to the less favorable course of psychosis in men compared to women. [ABSTRACT FROM AUTHOR]

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

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

Abstract: Using voxel-based morphometry (VBM), our laboratory recently identified significantly lower grey matter concentration in the parahippocampal gyrus bilaterally in non-remitted patients with a first episode of psychosis (FEP) compared with remitted FEP patients. These results identified a localized difference but did not reveal which cortex (entorhinal, perirhinal, or parahippocampal), if any, was predominantly affected. So, the parahippocampal gyrus was manually segmented and grey matter volumes from the three cortices were compared between 42 non-remitted and 17 remitted patients with a first episode of schizophrenia (FES). Remission was defined as mild or less on eight key symptoms and maintained for 6 consecutive months following the 2005 consensus definition. The non-remitted patients displayed smaller volumes in the parahippocampal cortex – trend-level difference on the left [mm3, mean (S.D.): non-remitted=2486 (413); remitted=2775 (593)] and significant difference on the right [mm3, mean (S.D.): non-remitted=2546 (463); remitted=2926 (525)]. No notable differences were found in the entorhinal or perirhinal cortices. This result supported our VBM finding of reduced parahippocampal grey matter bilaterally in non-remitted patients and further suggested differences may be selectively limited to the parahippocampal cortex. A smaller parahippocampal cortex may represent a neural marker in FES patients who do not achieve remission after 1 year of treatment. [Copyright &y& Elsevier]

Abstract: 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 (18weeks) of their DUP. Results: Compared to the short-DUP group (mean DUP 7.9weeks±5.6), the long-DUP group (mean 113.7weeks±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. [Copyright &y& Elsevier]

Abstract: Alterations of the fornix in chronic patients with psychosis are well established, but its integrity in the early stage of schizophrenia remains unknown. Thirty-two patients experiencing first-episode schizophrenia (FES) and 25 matched controls completed a DTI scan. DTI-tractography was used to estimate fractional anisotropy (FA) in bilateral fornices. The analysis showed significant overall FA reductions in the fornix in FES patients relative to controls. No significant correlations were found between FA values and clinical and sociodemographic data in FES patients. These findings revealed slight alterations along the fornix in early stage of schizophrenia. [Copyright &y& Elsevier]

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

While chronic forms of psychosis, like schizophrenia, are more explored, accurately identifying individuals at early stages of psychosis and determining who will progress to schizophrenia remains a challenge. So far, there are no specific biomarkers available. Genetic factors have shown promises in predicting clinical outcomes. Polygenic risk scores have been investigated but rare variants have not been explored in ultra-high risk patients or in first episodes of psychosis. We have decided to turn our attention to overlooked variants which were historically challenging to study, such as tandem repeats (TRs). TRs are sequences of DNA bases repeated multiple times in a head-to-tail manner. They constitute 6% of the human genome and play a role in many biological processes, including brain function and behavior. Investigating TRs, especially the rare ones, could contribute to understanding the etiology of psychosis, and potentially serve as future biomarkers and drug targets. This study aimed to investigate TRs in early stages of psychosis and to explore their characteristics, and potential functional implications. The investigation began with a French/Quebecker cohort consisting of 318 first-episodes of psychosis/ultra-high risk patients and 78 help seekers who did not convert to psychosis. The samples were sequenced using Illumina Seq and the genome-wide TR identification was done by Expansion Hunter de novo (EHdn). The quality control was done by Expansion Hunter to ensure unbiased calls. Outliers were identified using EHdn, and only the expanded TRs with a z-score greater than 2 were selected for further analysis. The identified TRs were then characterized in terms of their size, base, and region distribution. We use the 1000 Genomes Project samples to filter the TRs based on their frequency. The potential functional implications of the exonic TRs were assessed using enrichment analysis, gene-set confrontation analysis, pathway analysis, and functional enrichment analysis. We identified 7798 rare TRs. They were enriched in cytosine and exhibiting abnormal motif size distributions. Among them, a subset of 302 TRs located in the exonic regions was chosen for subsequent analysis. Functional enrichment analysis revealed that theseTRs were associated with genes involved in neuronal communication, neurotransmitter regulation, and the construction and maintenance of neuronal membranes. Enrichment clusters related to lipids, including phospholipids, sphingolipids, and cholesterol, highlighted the significance of TRs in the structural integrity and fluidity of neuronal membranes. Moreover, the TRs were implicated in key processes such as synaptic catecholamine uptake, coupled glutamate signaling, and neuron projection axonogenesis. Additionally, we observed that TRs within exonic regions exhibited upregulation during critical periods of neurodevelopment, including late prenatal development, early infancy, and adolescence. This study provides valuable insights into the potential correlation between TRs and the early phases of psychosis. The unique characteristics of the identified TRs, their association with genes involved in neuronal communication, and their temporal alignment with critical neurodevelopmental periods support their role in the pathogenesis of psychosis. However, further analysis is necessary to gain a deeper understanding of the precise role of TRs and to demonstrate their pathogenicity in the context of psychosis. [ABSTRACT FROM AUTHOR]

Negative symptoms are present at the onset of psychosis and their persistence is significantly associated with poor psychosocial functioning and lower quality of life. Persistent negative symptoms (PNS) may be idiopathic or secondary to other factors such as depression, positive symptoms, and medication side-effects. Several studies have examined neurocognitive functions in early psychosis patients with PNS relative to non-PNS, but have not systematically controlled for secondary PNS (sPNS). The latter may have a distinct neurocognitive profile that could obscure differences between PNS and non-PNS. Using a large (n = 425) sample, we examined neurocognitive functions in PNS, sPNS, and non-PNS and hypothesized that PNS would be associated with greater impairments relative to non-PNS. Following admission to an early intervention program, a neurocognitive battery was administered after at least 3 months of treatment, and symptom data collected during a subsequent 6-month period were used to classify patients as PNS, sPNS and non-PNS. At month 12, both PNS and sPNS groups had significantly lower level of functioning relative to the non-PNS group but the sPNS group experienced higher levels of depressive and positive symptoms and were on a higher dose of antipsychotics. Relative to non-PNS, PNS patients exhibited significant impairments in verbal memory and working memory, whereas sPNS patients exhibited a trend towards greater impairments in verbal memory. This study confirms that the presence of PNS or sPNS negatively influences functioning with more selective cognitive impairments found in PNS, providing evidence that these groups of patients could benefit from different personalised interventions. [ABSTRACT FROM AUTHOR]

Objective: Early life adversity is suspected to play an important role for onset and course of psychosis, but its relationship with longer-term clinical outcome is not entirely clear. In this longitudinal study, we investigated the impact of childhood trauma (CT) on positive and negative symptom remission in first episode psychosis (FEP) patients over two years.Methods: A total of 210 FEP patients were assessed with the Childhood Trauma Questionnaire. Patients reporting moderate to severe trauma (CT; N = 114; 54.3%) were compared to those without trauma (N-CT; N = 96; 45.7%). Positive (PSR) and negative symptom remission (NSR) were determined monthly over 24 months following established criteria using the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms. Global Functioning was evaluated at baseline and 24 months of follow-up.Results: Compared to N-CT patients, CT patients had achieved significantly lower rates of PSR at 12 months and significantly lower rates of NSR at 24 months. A dose-response relationship was observed between the number of trauma categories fulfilled and the number of patients not achieving PSR and NSR at these time points. Higher trauma scores were significantly associated with poor functioning and higher positive and negative symptom severity at 24 months, but not at baseline and 12 months of follow-up.Conclusion: Differential effects of CT on clinical outcome may not be apparent at psychosis onset, but only become evident through poor symptomatic remission and general functioning over time. Targeted diagnostic and therapeutic efforts after illness onset might limit these detrimental consequences. [ABSTRACT FROM AUTHOR]

COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD. Two hundred and thirty children with ADHD (6–12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex. Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = −0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = −0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response. These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD. clinicaltrials.gov, number NCT00483106. [ABSTRACT FROM AUTHOR]

• First episode psychosis patients show reduced baseline cortisol levels during the TSST. • Cortisol increase following the TSST is intact in first episode psychosis patients. • Lower cortisol levels during the TSST are associated with poor self-esteem and active coping skills. • Cortisol non-responders to the TSST had experienced more physical neglect during childhood. Psychosis has been associated with abnormalities in hypothalamic-pituitary-adrenal axis functioning, which may emerge through heightened stress sensitivity following early life adversity – ultimately resulting in illness onset and progression. The present study assessed cortisol levels during an established psychosocial stress task and their association with current stress perception, putative protective factors and adverse childhood experiences in patients with a first episode of psychosis (FEP). A total of 100 volunteers participated in the study, 57 of whom were patients with a FEP (mean age 23.9 ± 3.8) and 43 healthy community controls (mean age 23.2 ± 3.9). Salivary cortisol, heart rate and blood pressure were measured at eight time points before and after the Trier Social Stress Test. Subjective stress and protective factors were assessed with the Perceived Stress Scale, the Self-Esteem Rating Scale and the Brief COPE. Early life adversity was assessed with the Childhood Trauma Questionnaire. Patients compared to controls showed significantly lower cortisol levels (F = 7.38; p =.008) throughout the afternoon testing period, but no difference in the cortisol response to the TSST. Heart rate was elevated and protective factors were lower in patients compared to controls. Attenuated cortisol levels were associated with higher levels of perceived stress, poor protective factors and more physical neglect during childhood. Our results suggest that attenuated baseline cortisol levels and not a blunted response during an acute stress task might be an indicator of heightened stress vulnerability and poor resilience in psychosis. The possible influence of childhood adversity and antipsychotic medication is discussed. [ABSTRACT FROM AUTHOR]

Background: Lack of insight is a frequent characteristic of psychotic disorders, both in patients who recently experienced a first episode of psychosis (FEP) and those who experience recurrent multiple episodes (MEP). Insight is a multifaceted construct: its clinical form notably includes the unawareness of being ill, of symptoms, and of the need for treatment. Cognitive capacity is among the key determinants of insight into symptoms, but less is known about whether stage of illness (FEP vs. MEP) moderates this association.Methods: Our aim is to evaluate the association between cognitive capacity and symptom unawareness using structural equation modeling and moderated multiple regression. A total of 193 FEP and MEP patients were assessed using the CogState battery and the Scale to Assess Unawareness of Mental Disorder.Results: Analyses suggest that cognitive capacity accounts for a relatively small proportion of the total variation in symptom unawareness (6.4%). There was no evidence to suggest a moderating effect of stage of illness on this association.Conclusions: The effect of general cognitive capacity on symptom unawareness is relatively small, and this basic relation was unrelated to stage of illness. It is possible that stage of illness could moderate this association only for certain facets of insight not assessed in this study (e.g., unawareness of the need for treatment). [ABSTRACT FROM AUTHOR]

Early life adversity is associated with increased risk for psychosis onset and poor clinical outcome. Male compared to female patients often show a more severe course of psychotic illness. The aim of the present study was to investigate gender differences in childhood trauma (CT) and their impact on symptomatic and functional outcome following psychosis onset. The study included 210 patients (144 men, 66 women) diagnosed with a first-episode of psychosis (FEP). Early adversity was assessed with the Childhood Trauma Questionnaire. Psychotic symptoms and general functioning were rated with the Brief Psychiatric Rating Scale and Global Assessment of Functioning scale at baseline, 12 and 24 months of follow-up in an established early intervention service. Male patients reported higher rates of physical or emotional neglect, whereas female patients indicated significantly higher rates of emotional abuse. More severe CT was related to higher levels of depression in women and to negative symptoms in men. Distinct CT effects were observed on positive and negative symptom severity and global functioning in male patients at 24 months. Emotional abuse was the strongest predictor of depression in both genders. In male patients only, emotional abuse predicted positive symptom severity and impaired global functioning, whereas emotional neglect predicted more severe negative symptoms. Our results suggest differences in CT experiences in male and female FEP patients, with a more pronounced impact on longer-term outcome in male patients. The findings support the notion that sex differences in stress vulnerability account for the relatively poor illness course in male psychosis patients. [ABSTRACT FROM AUTHOR]

Highlights • There is evidence that neurodevelopmental disorders overlap. Yet it is unclear how etiological pathways intersect. • SNPs identified in non-ADHD GWAS showed association with multiple dimensions related to ADHD. • Here we attempt to tease apart the heterogeneity in the phenotype, and understand its genetic underpinnings. • Results are presented as preliminary findings as they provide insight into cross-disorder associations. Abstract Several epidemiological and genetic studies have provided evidence of an overlap between neurodevelopmental disorders. However, the details of the etiological pathways remain to be elucidated. In this study, we garnered the findings of previous GWAS, conducted with schizophrenia and bipolar disorder. We conducted an exploratory study to examine the association between these SNPs and quantitative clinical/ behavioural/ cognitive/ structural brain parameters, as well as response to treatment with a fixed dose of methylphenidate, in a relatively large sample of children with ADHD. Family-based association tests were conducted with nine tag SNPs with 602 nuclear families. In addition, structural magnetic resonance imaging (sMRI) was conducted in a subset of children with ADHD (n = 76). Of the 9 tag SNPs examined, rs1602565 showed a significant association with ADHD, several dimensional measures and response to treatment. An association was also observed between rs1006737 (CACNA1C) and performance IQ. In addition, significant reductions in cortical thickness measurements were observed with the risk allele in rs1006737. These results provide preliminary evidence for putative shared genetic vulnerability between childhood ADHD and other neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Among individuals with psychosis, those with poor cognitive insight (lower Self-Reflectiveness, higher Self-Certainty) show volumetric reductions in cortical structure. We evaluated whether changes in cognitive insight are associated with progressive changes in cortical structure in first-episode psychosis (FEP) and control subjects. Beck Cognitive Insight Scale ratings and magnetic resonance imaging scans were acquired at baseline for 130 FEP and 52 controls, 59 FEP and 28 controls at 1-year, and 53 FEP and 20 controls at 2-years. Cortical thickness was computed across scans and analyzed with linear mixed models. At baseline, groups did not differ on Self-Reflectiveness or Self-Certainty. At baseline, higher Self-Reflectiveness significantly correlated with thinner right occipital cortex in FEP, and higher Self-Certainty was significantly negatively correlated with cortical thickness in left posterior cingulate in controls. Longitudinal analysis showed that Self-Reflectiveness and Self-Certainty did not change over time in either group. Interestingly, the lack of change in cognitive insight aligned with longitudinal cortical thickness results, where no interaction effects were seen with cortical thickness between time and either Self-Reflectiveness or Self-Certainty. Exploratory analyses with a reduced threshold found that in FEP, across all time-points, higher Self-Certainty associated with thinner cortex in left posterior cingulate/precuneus. Results suggest that the posterior cingulate may be a common neural correlate for Self-Certainty in FEP and non-clinical subjects. [ABSTRACT FROM AUTHOR]

Objective: Although early intervention (EI) programs for psychosis invest in clients remaining engaged in treatment, disengagement remains a concern. It is not entirely clear whether immigrants are likelier to disengage. The rates and predictors of disengagement for immigrant vis-à-vis non-immigrant clients in a Canadian EI setting were analyzed.Method: 297 clients were included in a time-to-event analysis with Cox Proportional Hazards regression models. Immigrant status (first- or second-generation immigrant or non-immigrant), age, gender, education, substance abuse, family contact, social and material deprivation and medication non-adherence were tested as predictors of service disengagement.Results: 24.2% (n=72) of the clients disengaged from services before completing two years. Disengagement rates did not differ between first-generation immigrants (23.3%), second-generation immigrants (22.7%) and non-immigrants (25.3%). For all clients, only medication non-adherence predicted disengagement (HR=3.81, 95% CI 2.37-6.14). For first-generation immigrants, age (HR=1.17, 95% CI 1.02-1.34) and medication non-adherence (HR=2.92, 95% CI 1.09-7.85) were significant predictors. For second-generation immigrants, material deprivation (HR=1.03, 95% CI 1.00-1.05) and medication non-adherence (HR=11.07, 95% CI 3.20-38.22) were significant.Conclusion: Disengagement rates may be similar between immigrants and non-immigrants, but their reasons for disengagement may differ. Medication adherence was an important predictor for all, but the role of various sociodemographic factors differed by group. Sustaining all clients' engagement in EI programs may therefore require multi-pronged approaches. [ABSTRACT FROM AUTHOR]

Maternal smoking during pregnancy is the most commonly cited risk factor for ADHD. While the causal relation between this factor and ADHD is debated, several lines of evidence suggest that it modulates the severity of ADHD, particularly through higher association with conduct disorder (CD). We hypothesized that maternal smoking during pregnancy may be associated with differential methylation in selected genes in children with ADHD. DNA extracted from peripheral blood was used to examine methylation between 25 children exposed, and 22 children not exposed to maternal smoking during pregnancy. Three genes ( AHRR , CYP1A1 , GFI 1) were selected based on previous results observed in the general population. Regression analysis was conducted between methylation levels in these candidate genes and: (a) total number of ADHD and CD symptoms; (b) birth weight. Significant differences in methylation were observed in each of the candidate genes between children exposed and not exposed to maternal smoking during pregnancy. Methylation at the selected sites showed significant association with specific phenotypes. Significant correlations were observed between methylation within AHRR and number of CD symptoms; GFI 1 and number of ADHD symptoms and GFI 1 and birth weight. These initial results may have important clinical implications if confirmed in a larger independent sample. [ABSTRACT FROM AUTHOR]