Comparative effect of antipsychotics on risk of self-harm among patients with schizophrenia.

OBJECTIVE: To investigate the association of different antipsychotic treatments with hospitalization due to self-harm among patients with schizophrenia. METHOD: This retrospective cohort study was based on Taiwan's universal health insurance database. Patients aged 15-45 years with a newly diagnosed schizophrenic disorder in 2001-2012 were included. The study outcome was the first hospitalization due to self-harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time-dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD). RESULTS: Among 70 380 patients with a follow-up of 500 355 person-years, 2272 self-harm hospitalization episodes were identified. Compared with none or former use, current use of several second-generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self-harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15-0.47). CONCLUSION: The protective effect on self-harm may vary across different antipsychotics. Further studies are needed to replicate the findings.

ARHGEF10 knockout inhibits platelet aggregation and protects mice from thrombus formation.

Essentials ARHGEF10 single-nucleotide polymorphism provides risk of ischemic and atherothrombotic stroke. The role of ARHGEF10 in platelet function was examined using ARHGEF10 knockout mice. ARHGEF10 deficiency inhibits platelet function and arterial thrombus formation. ARHGEF10 knockout protects mice from stroke-induced infarction. SUMMARY: Background ARHGEF10, a member of the Rho guanine nucleotide exchange factor (GEF) family, stimulates Rho GTPases. Rho GTPases have been reported to regulate a variety of cellular behaviors, such as cell polarity, cytoskeletal organization, and gene transcription. ARHGEF10 single-nucleotide polymorphisms are linked to the risk of ischemic stroke. However, the role of ARHGEF10 in platelet function remains unknown. Objective To examine the role of ARHGEF10 in platelet function. Methods ARHGEF10-/- were generated. We examined the in vitro and in vivo effects of ARHGEF10 knockout on platelet function and arterial thrombosis formation. Results ARHGEF10-/- mice had normal platelet counts, but showed altered aggregation in response to thrombin, collagen, ADP, protease-activated receptor-4 peptide, and U46619 stimulation. ARHGEF10 knockout influenced platelet spreading on fibrinogen-coated surfaces, and caused the platelets to show less lamellipodia-like extension than wild-type platelets. ARHGEF10 knockout also inhibited platelet clot retraction induced by thrombin stimulation. ARHGEF10 knockout resulted in prolonged tail bleeding time and inhibited the stable thrombus formation induced by FeCl3 in the carotid artery. Conclusions ARHGEF10 serves as an important regulator in platelet shape change, spreading, and aggregation. Moreover, ARHGEF10 also plays an important role in arterial thrombosis formation.

Shared atypical brain anatomy and intrinsic functional architecture in male youth with autism spectrum disorder and their unaffected brothers.

BACKGROUND: Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, yet the search for definite genetic etiologies remains elusive. Delineating ASD endophenotypes can boost the statistical power to identify the genetic etiologies and pathophysiology of ASD. We aimed to test for endophenotypes of neuroanatomy and associated intrinsic functional connectivity (iFC) via contrasting male youth with ASD, their unaffected brothers and typically developing (TD) males. METHOD: The 94 participants (aged 9-19 years) - 20 male youth with ASD, 20 unaffected brothers and 54 TD males - received clinical assessments, and undertook structural and resting-state functional magnetic resonance imaging scans. Voxel-based morphometry was performed to obtain regional gray and white matter volumes. A seed-based approach, with seeds defined by the regions demonstrating atypical neuroanatomy shared by youth with ASD and unaffected brothers, was implemented to derive iFC. General linear models were used to compare brain structures and iFC among the three groups. Assessment of familiality was investigated by permutation tests for variance of the within-family pair difference. RESULTS: We found that atypical gray matter volume in the mid-cingulate cortex was shared between male youth with ASD and their unaffected brothers as compared with TD males. Moreover, reduced iFC between the mid-cingulate cortex and the right inferior frontal gyrus, and increased iFC between the mid-cingulate cortex and bilateral middle occipital gyrus were the shared features of male ASD youth and unaffected brothers. CONCLUSIONS: Atypical neuroanatomy and iFC surrounding the mid-cingulate cortex may be a potential endophenotypic marker for ASD in males.

Different neural substrates for executive functions in youths with ADHD: a diffusion spectrum imaging tractography study.

BACKGROUND: The relationship between white-matter tracts and executive functions (EF) in attention deficit hyperactivity disorder (ADHD) has not been well studied and previous studies mainly focused on frontostriatal (FS) tracts. The authors explored the microstructural property of several fibre tracts hypothesized to be involved in EF, to correlate their microstructural property with EF, and to explore whether such associations differ between ADHD and typically developing (TD) youths. METHOD: We assessed 45 youths with ADHD and 45 individually matched TD youths with a computerized test battery for multiple dimensions of EF. From magnetic resonance imaging, FS tract, superior longitudinal fasciculus (SLF), arcuate fasciculus (AF) and cingulum bundle (CB) were reconstructed by diffusion spectrum imaging tractography. The generalized fractional anisotropy (GFA) values of white-matter tracts were computed to present microstructural property of each tract. RESULTS: We found lower GFA in the left FS tract, left SLF, left AF and right CB, and poorer performance in set-shifting, sustained attention, cognitive inhibition and visuospatial planning in ADHD than TD. The ADHD and TD groups demonstrated different association patterns between EF and fibre tract microstructural property. Most of the EF were associated with microstructural integrity of the FS tract and CB in TD youths, while with that of the FS tract, SLF and AF in youths with ADHD. CONCLUSIONS: Our findings support that the SLF, AF and CB also involve in a wide range of EF and that the main fibre tracts involved in EF are different in youths with ADHD.

Visual memory and sustained attention impairment in youths with autism spectrum disorders.

BACKGROUND: An uneven neurocognitive profile is a hallmark of autism spectrum disorder (ASD). Studies focusing on the visual memory performance in ASD have shown controversial results. We investigated visual memory and sustained attention in youths with ASD and typically developing (TD) youths. METHOD: We recruited 143 pairs of youths with ASD (males 93.7%; mean age 13.1, s.d. 3.5 years) and age- and sex-matched TD youths. The ASD group consisted of 67 youths with autistic disorder (autism) and 76 with Asperger's disorder (AS) based on the DSM-IV criteria. They were assessed using the Cambridge Neuropsychological Test Automated Battery involving the visual memory [spatial recognition memory (SRM), delayed matching to sample (DMS), paired associates learning (PAL)] and sustained attention (rapid visual information processing; RVP). RESULTS: Youths with ASD performed significantly worse than TD youths on most of the tasks; the significance disappeared in the superior intelligence quotient (IQ) subgroup. The response latency on the tasks did not differ between the ASD and TD groups. Age had significant main effects on SRM, DMS, RVP and part of PAL tasks and had an interaction with diagnosis in DMS and RVP performance. There was no significant difference between autism and AS on visual tasks. CONCLUSIONS: Our findings implied that youths with ASD had a wide range of visual memory and sustained attention impairment that was moderated by age and IQ, which supports temporal and frontal lobe dysfunction in ASD. The lack of difference between autism and AS implies that visual memory and sustained attention cannot distinguish these two ASD subtypes, which supports DSM-5 ASD criteria.

Intra-individual reaction time variability based on ex-Gaussian distribution as a potential endophenotype for attention-deficit/hyperactivity disorder.

OBJECTIVE: Intra-individual variability in reaction time (IIV-RT), defined by standard deviation of RT (RTSD), is considered as an endophenotype for attention-deficit/hyperactivity disorder (ADHD). Ex-Gaussian distributions of RT, rather than RTSD, could better characterize moment-to-moment fluctuations in neuropsychological performance. However, data of response variability based on ex-Gaussian parameters as an endophenotypic candidate for ADHD are lacking. METHOD: We assessed 411 adolescents with clinically diagnosed ADHD based on the DSM-IV-TR criteria as probands, 138 unaffected siblings, and 138 healthy controls. The output parameters, mu, sigma, and tau, of an ex-Gaussian RT distribution were derived from the Conners' continuous performance test. Multi-level models controlling for sex, age, comorbidity, and use of methylphenidate were applied. RESULTS: Compared with unaffected siblings and controls, ADHD probands had elevated sigma value, omissions, commissions, and mean RT. Unaffected siblings formed an intermediate group in-between probands and controls in terms of tau value and RTSD. There was no between-group difference in mu value. Conforming to a context-dependent nature, unaffected siblings still had an intermediate tau value in-between probands and controls across different interstimulus intervals. CONCLUSION: Our findings suggest IIV-RT represented by tau may be a potential endophenotype for inquiry into genetic underpinnings of ADHD in the context of heterogeneity.

Neural correlates of inhibitory control and visual processing in youths with attention deficit hyperactivity disorder: a counting Stroop functional MRI study.

BACKGROUND: Despite evidence of inhibitory control and visual processing impairment in attention deficit hyperactivity disorder (ADHD), knowledge about its corresponding alterations in the brain is still evolving. The current study used counting Stroop functional MRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to investigate if brain activation of inhibitory control and visual processing would differ in youths with ADHD relative to neurotypical youths. METHOD: We assessed 25 youths with ADHD [mean age 10.9 (s.d.=2.2) years] and 23 age-, gender- and IQ-matched neurotypical youths [mean age 11.2 (s.d.=2.9) years]. The participants were assessed by using the Wechsler Intelligence Scale for Children, third edition, and two tests from the CANTAB: rapid visual information processing (RVP) and pattern recognition memory (PRM) outside the scanner. RESULTS: Youths with ADHD showed more activation than neurotypical youths in the right inferior frontal gyrus [Brodmann area (BA) 45] and anterior cingulate cortex, which were correlated with poorer performance on the RVP test in the CANTAB. In contrast, youths with ADHD showed less activation than neurotypical youths in the left superior parietal lobule (BA 5/7), which was correlated with the percentage of correct responses on the PRM test in the CANTAB. CONCLUSIONS: Our findings suggest that youths with ADHD might need more inhibitory control to suppress interference between number and meaning and may involve less visual processing to process the numbers in the counting Stroop task than neurotypical youths.

Rapid visual information processing as a cognitive endophenotype of attention deficit hyperactivity disorder.

BACKGROUND: Deficits in sustained attention and reaction time are core features of attention deficit hyperactivity disorder (ADHD). However, little is known about attention performance in unaffected siblings. Hence, we examined sustained attention and reaction time in youths with ADHD, unaffected siblings and controls to test whether impaired performance in attention tasks can be a potential endophenotype of ADHD. METHOD: We recruited 438 probands with clinical diagnosis of ADHD according to DSM-IV criteria, 180 unaffected siblings, and 173 healthy controls without lifetime ADHD. They were assessed using psychiatric interviews, Conners' Continuous Performance Test, and the tasks involving attention performance of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Rapid Visual Information Processing (RVP), Reaction Time (RTI) and Match to Sample Visual Search (MTS). Multi-level models were used for data analysis. RESULTS: Compared with the controls, probands with ADHD and unaffected siblings had significantly higher total misses, lower probability of hits in the RVP task and probands with ADHD performed worse in the RTI and MTS tasks after controlling for sex, age, co-morbidity, parental educational levels and IQ. The duration of methylphenidate use and IQ but not psychiatric co-morbidity or current use of methylphenidate were associated with deficits in sustained attention in probands with ADHD. CONCLUSIONS: Our findings suggest that attention performance assessed by the RVP task, but not the RTI or MTS tasks, of the CANTAB may be a useful cognitive endophenotype for ADHD genetic studies.

Neural substrates of behavioral variability in attention deficit hyperactivity disorder: based on ex-Gaussian reaction time distribution and diffusion spectrum imaging tractography.

BACKGROUND: Increased intra-individual variability (IIV) in reaction time (RT) across various tasks is one ubiquitous neuropsychological finding in attention deficit hyperactivity disorder (ADHD). However, neurobiological underpinnings of IIV in individuals with ADHD have not yet been fully delineated. The ex-Gaussian distribution has been proved to capture IIV in RT. The authors explored the three parameters [µ (mu), σ (sigma), τ (tau)] of an ex-Gaussian RT distribution derived from the Conners' continuous performance test (CCPT) and their correlations with the microstructural integrity of the frontostriatal-caudate tracts and the cingulum bundles. METHOD: We assessed 28 youths with ADHD (8-17 years; 25 males) and 28 age-, sex-, IQ- and handedness-matched typically developing (TD) youths using the CCPT, Wechsler Intelligence Scale for Children, 3rd edition and magnetic resonance imaging (MRI). Microstructural integrity, indexed by generalized fractional anisotropy (GFA), was measured by diffusion spectrum imaging tractrography on a 3-T MRI system. RESULTS: Youths with ADHD had larger σ (s.d. of Gaussian distribution) and τ (mean of exponential distribution) and reduced GFA in four bilateral frontostriatal tracts. With increased inter-stimulus intervals of CCPT, the magnitude of greater τ in ADHD than TD increased. In ADHD youths, the cingulum bundles and frontostriatal integrity were associated with three ex-Gaussian parameters and with µ (mean of Gaussian distribution) and τ, respectively; while only frontostriatal GFA was associated with µ and τ in TD youths. CONCLUSIONS: Our findings suggest the crucial role of the integrity of the cingulum bundles in accounting for IIV in ADHD. Involvement of different brain systems in mediating IIV may relate to a distinctive pathophysiological processing and/or adaptive compensatory mechanism.

Risperidone and olanzapine versus another first generation antipsychotic in patients with schizophrenia inadequately responsive to first generation antipsychotics.

OBJECTIVE: This study compares the efficacy of risperidone and olanzapine to that of first-generation antipsychotics (FGAs) in patients with schizophrenia, who failed to show a response to initial trials of FGAs. METHOD: This study was an 8-week treatment, randomized, rater-blind, active-control study with 3 treatment arms. 48 patients, who showed inadequate response to 1 FGA, were enrolled and randomized into risperidone, olanzapine, or FGA (haloperidol or trifluoperazine) groups. They were blindly assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale-Severity, and the Extrapyramidal Symptom Rating Scale (ESRS) at baseline and biweekly. RESULTS: All 3 groups demonstrated a significant decrease in the PANSS total, positive, and general scores from baseline to endpoint (p-values range from 0.003 to 0.021). There were no significant differences among the 3 groups in score changes. The olanzapine group had significant score reductions than the risperidone and FGAs groups in terms of the ESRS subjective total score and did not experience a significant increase in the dose of anticholinergics. The FGA group demonstrated that extrapyramidal syndrome (EPS) worsened under an increased dosage of anti-EPS drugs. Olanzapine was associated with significant body weight gain (2.69 ± 4.0 kg, p=0.026), but there were no significant group differences on weight gain. CONCLUSIONS: Haloperidol or trifluoperazine demonstrated similar efficacy as risperidone or olanzapine for patients with schizophrenia who had failed their first trial with a FGA. Related double-blind, fixed dose studies with a larger sample size are needed to confirm the results of our study.

Identification and molecular characterization of two novel chromosomal deletions associated with autism.

Autism is a childhood-onset neurodevelopmental disorder with a strong genetic basis in its etiology. Conventional karyotype analysis has revealed that chromosomal structural aberrations such as translocation, inversion, deletion, and duplication play a role in causing autism spectrum disorders (ASD). In addition, recent array-based comparative genomic hybridization (array CGH) studies discovered that submicroscopic deletion and duplication of DNA segments also contributed significantly to the genetic etiology of ASD. Together, these studies indicate that genomic rearrangement is an important genetic mechanism of ASD. Using karyotyping analysis and array CGH technology, we identified a subtelomeric deletion of approximately 6.8 Mb at 4q35.1-35.2 and a terminal deletion of approximately 2.4 Mb at 8p23.2-pter in two autistic boys, respectively. These two deletions were further validated using fluorescent in situ hybridization and real-time quantitative polymerase chain reaction, and their breakpoints were delineated using high-resolution array CGH. The 4q deletion is a rare de novo mutation, while the transmission of 8p deletion is unknown, because the father of the patient was unavailable for study. These two deletions are rare mutations and were not found in the additional 282 patients with ASD and in the 300 control subjects in our population. The identification of these two chromosomal deletions contribute to our understanding of the genetic basis of ASD, and the haploinsufficiency of several genes located at the deleted regions of chromosome 8p and 4q may contribute to the clinical phenotypes of autism.