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This study aimed to examine the predictors of cognitive performance in patients with pediatric mild traumatic brain injury (pmTBI) and to determine whether group differences in cognitive performance on a computerized test battery could be observed between pmTBI patients and healthy controls (HC) in the sub-acute (SA) and the early chronic (EC) phases of injury.
203 pmTBI patients recruited from emergency settings and 159 age- and sex-matched HC aged 8–18 rated their ongoing post-concussive symptoms (PCS) on the Post-Concussion Symptom Inventory and completed the Cogstate brief battery in the SA (1–11 days) phase of injury. A subset (156 pmTBI patients; 144 HC) completed testing in the EC (∼4 months) phase.
Within the SA phase, a group difference was only observed for the visual learning task (One-Card Learning), with pmTBI patients being less accurate relative to HC. Follow-up analyses indicated higher ongoing PCS and higher 5P clinical risk scores were significant predictors of lower One-Card Learning accuracy within SA phase, while premorbid variables (estimates of intellectual functioning, parental education, and presence of learning disabilities or attention-deficit/hyperactivity disorder) were not.
The absence of group differences at EC phase is supportive of cognitive recovery by 4 months post-injury. While the severity of ongoing PCS and the 5P score were better overall predictors of cognitive performance on the Cogstate at SA relative to premorbid variables, the full regression model explained only 4.1% of the variance, highlighting the need for future work on predictors of cognitive outcomes.
This chapter comprises the following sections: names, taxonomy, subspecies and distribution, descriptive notes, habitat, movements and home range, activity patterns, feeding ecology, reproduction and growth, behavior, parasites and diseases, status in the wild, and status in captivity.
Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia.
To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability.
We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores.
Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015–0.017), with carriers being 7.5–7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder.
This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.
It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies.
Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes.
The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses.
Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population.
Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.
We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.
Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.
Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.
To evaluate the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in bipolar mania.
Completers of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to monotherapy were followed up over 46-weeks on open-label aripiprazole plus lithium (ARI+LI) or valproate (ARI+VAL).
283 (ARI+LI n=108; ARI+VAL n=175) patients entered and 146 (ARI+LI n=55; ARI+VAL n=91) completed the 46-week extension. Safety results for both combinations were consistent with the known tolerability profile of aripiprazole, lithium and valproate. No clinically significant changes in lipids or glucose were observed with either ARI+LI or ARI+VAL. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI+LI and 2.0 (0.4) kg with ARI+VAL. Temporal analysis of the time of first onset of adverse events showed that akathisia and insomnia tended to occur early in treatment, with few new cases in patients previously treated with aripiprazole during the 6-week study.
Significant improvements from baseline in YMRS total score and MADRS total score were sustained over the 52 weeks with both ARI+LI and ARI+VAL treatment.
Mean reduction from baseline at Week 52 LOCF[95%CI], p value vs baseline
YMRS total score
-16.5 [-18.1; -14.8], p<0.001
-17.6 [-18.9; -16.3] p<0.001
MADRS total score
-1.7 [-3.3; -0.1] p<0.05
-2.7 [-4.0; -1.4] p<0.001
Long-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well-tolerated. Improvements in manic and depressive symptoms observed during the first 6 weeks of treatment were maintained.
To evaluate the efficacy of aripiprazole as adjunctive treatment in patients with major depressive disorder (MDD) without psychotic features and an inadequate response to standard antidepressant therapy (ADT).
Data were collected from three identical, short-term, double-blind, placebo-controlled studies (CN138-139, CN138-163, CN138-165). After a single-blind prospective phase with placebo plus ADT, patients with inadequate response were randomized to 6-weeks’ treatment with adjunctive aripiprazole or placebo. The primary efficacy endpoint was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score during the double-blind phase. Secondary endpoints were response (≥50% reduction in MADRS total score), remission (MADRS total score ≤10 and ≥50% reduction in MADRS total score), and mean change in Hamilton Depression Rating Scale (HAM-D17) total score.
In all three studies, adjunctive aripiprazole was associated with a significantly greater reduction in MADRS total score than adjunctive placebo, with a treatment difference ranging between -3.73 and -2.84 (p≤0.001 in each study). Response and remission rates with adjunctive aripiprazole (32.4-46.6% and 25.4-36.8%, respectively) were also significantly higher than with adjunctive placebo (17.4-26.6% [p< 0.05 in each study] and 15.2-18.9% [p< 0.05 in each study]). Mean change in HAM-D17 total score ranged from -7.64 to -6.77 with adjunctive aripiprazole and from -5.12 to -4.41 with adjunctive placebo (p< 0.001 for each study).
Results of the three studies indicate that treatment with adjunctive aripiprazole and ADT is effective in improving the symptoms of MDD in patients who have had an inadequate response to ADT.
To conduct a subgroup analysis of the efficacy of adjunctive aripiprazole as treatment in patients with major depressive disorder (MDD) who demonstrated an inadequate response to standard antidepressant therapy (ADT).
Data were pooled from three identical, short-term, double-blind, placebo-controlled studies (CN138-139, CN138-163, CN138-165) with an 8-week phase of placebo plus ADT and a 6-week double-blind phase with ADT plus adjunctive placebo or aripiprazole. Only MDD patients without psychotic features were eligible for entry. The primary efficacy endpoint was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score in the double-blind phase. Subgroup analyses of the primary efficacy endpoint were performed for age, race, ethnicity, MADRS response, number and choice of previous ADTs, episode duration, and use of selective serotonin re-uptake inhibitors (SSRI).
Compared with the adjunctive placebo group, adjunctive aripiprazole was associated with greater reductions in MADRS total score in all subgroups. Mean change in MADRS total score ranged from -10.71 to -5.89 with adjunctive aripiprazole and -7.57 to -4.10 with adjunctive placebo. No statistically significant treatment-by-subgroup interaction effects were observed for any subgroup except gender (p=0.039). This difference is, however, primarily because of results from study CN138-139 results; consistent results between men and women were reported in CN138-163 and CN138-165.
Pooled data indicate that in patient populations with similar baseline characteristics, treatment with adjunctive aripiprazole and ADT is efficacious in improving the symptoms of MDD in subgroups of patients having an inadequate response to ADT.
Metabolic syndrome - a significant risk factor for cardiovascular morbidity and mortality - is twice as prevalent among psychiatric patients (21-63%) as general populations (20-24%). Although there is an inherent illness-associated metabolic risk, medications do contribute. Atypicals vary in metabolic risk from high (clozapine, olanzapine), moderate (risperidone, quetiapine) to low (aripiprazole, ziprasidone) (ADA, 2004). Few studies have comprehensively measured cardiovascular risk or directly compared antipsychotics. Limited controlled data show that antipsychotic-induced metabolic abnormalities may be reversible, rationalizing the switch to a lower-risk agent (DeNayer, 2004). Non-HDL-cholesterol encompasses all atherogenic cholesterols and provides a marker of CV risk: an increase of 29ng/dL in diabetics is associated with 50% increased risk (Jiang, 2004). Non-HDL-cholesterol is independently associated with increased risk of non-fatal myocardial infarction and angina.
This study will provide cross-European data from 13 countries on MS rates in schizophrenia and will assess antipsychotic metabolic profiles and benefits of antipsychotic switching.
In this ongoing, 16-week, open-label, European multicentre study, 258 schizophrenia patients treated for ≥3 months with olanzapine, risperidone or quetiapine and who have MS will be randomized to switch to aripiprazole (Week 1: 5mg/day; Week 2: 10mg/day; flexible 10-30mg/day after Week 2) or continue with previous antipsychotic. the primary objective is to demonstrate superiority of aripiprazole versus atypicals on mean percentage change of fasting non-HDL-cholesterol from baseline to Week 16.
This study will provide the first direct and comprehensive comparison of metabolic risk with various atypicals in Europe and should impact the future management of schizophrenia.
To evaluate dyslipidaemia risk among patients with schizophrenia treated with aripiprazole or olanzapine.
Pooled analysis of the aripiprazole clinical database, including studies of ≥7 days with at least an oral aripiprazole monotherapy arm. Mean changes from baseline to endpoint and shifts from normal to abnormal lipid levels were calculated.
Seventeen placebo- and five olanzapine-controlled studies (3 weeks->3 years) of adult patients (≥18 years) were included. Mean changes (LOCF) in lipids were similar between aripiprazole and placebo for all lipid parameters; aripiprazole showed significant improvements versus olanzapine (p≤0.01). the incidence (OC) of switching to abnormal lipid levels from baseline normal was similar between placebo and aripiprazole, and significantly lower with aripiprazole than olanzapine for most measures.
Despite limitations inherent to pooled analyses, these findings lend further support to the differential profile of atypicals, with aripiprazole showing effects on lipids comparable with placebo.
Optimal management of schizophrenia in adolescents is limited by the lack of available therapies. The efficacy and tolerability of aripiprazole was investigated in this patient population.
This 6-week, randomized, double-blind, placebo controlled trial was conducted at 101 international centers, with a safety monitoring board. 13-17 year-olds with a DSM-IV diagnosis of schizophrenia were randomized to placebo, or a fixed dose of aripiprazole 10 mg or 30 mg reached after a 5 or 11 day titration, respectively. The primary endpoint was mean change from baseline on the PANSS Total score at week 6. Secondary endpoints included the PANSS Positive and Negative subscales, and CGI Improvement score. Tolerabilility assessements included frequency and severity of adverse events, as well as blood chemistries, metabolic parameters and weight gain.
Over 85% of 302 patients completed this study. Both 10 mg and 30 mg doses were superior to placebo on the primary endpoint (PANSS total), with significant differences observed as early as Week 1 (30mg). Both doses showed significant improvement on the PANSS Positive and CGI-I scales; and the 10 mg dose group was superior on PANSS Negative score. Approximately 5% of aripiprazole patients discontinued due to AEs. Weight gain and changes in prolactin were minimal.
10mg and 30mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. Aripiprazole was well tolerated, in general, with few discontinuations due to AEs. EPS was the most common AE. Change in body weight was similar to placebo.
This pilot study tested the feasibility, acceptability, and effect-sizes of a multimodal, individual intervention designed to optimize antipsychotic medication use in patients ≥40 years of age with schizophrenia or schizoaffective disorder.
We randomized 40 patients into two groups: usual care (UC) or a nine-session, manualized, antipsychotic adherence intervention (AAI). the AAI attempted to improve adherence by combining three psychosocial techniques:
b. skills training, and
c. alliance building.
Sessions employed a semi-structured format to facilitate open communication. the primary outcome was antipsychotic adherence at study end. We obtained qualitative data regarding patient preferences for the duration and modality for receiving the adherence intervention.
Compared to the UC group, a greater proportion of the AAI group was adherent post-intervention based on medication possession ratio, a commonly used measure of medication adherence (85% vs. 66.6%; OR=2.64), a difference that was statistically not significant. the entire AAI group reported that they intended to take medications, and 75% were satisfied with the intervention.
The AAI was feasible and acceptable. Preliminary data on its effectiveness warrant a larger study. Qualitative data shows that patients prefer brief adherence interventions and accept telephone strategies.
Akathisia remains a challenge in routine psychiatric practice, despite the widespread use of second generation antipsychotics (SGAs). This analysis was performed to quantify and qualify clinical characteristics of akathisia in schizophrenia or schizoaffective disorder patients experiencing an acute relapse who were randomized to receive aripiprazole, or placebo in 5 pooled short term trials.
A post hoc analysis of the safety dataset was conducted to assess clinical aspects of akathisia in five 4- or 6-week, double-blind, randomized trials comparing aripiprazole (2, 5, 10, 15, 20, 30 mg/day) to placebo.
A total of 1,635 patients was included in this analysis (aripiprazole: n=1170; placebo: n=465). Akathisia was reported by 9% of the aripiprazole-treated patients and 6% of those receiving placebo. Among those reporting akathisia, more patients receiving aripiprazole (83%, n=86) reported this AE within the first 2 weeks of the trials when compared to placebo (69%, n=20). The mean and median duration of akathisia was generally low in both groups (Mean: aripiprazole=12.5 days and placebo=4.2 days; Median, aripiprazole=5.0 days and placebo=1.5 days). The percentage of patients reporting akathisia at endpoint (BARS Item 4≥2) was similar between aripiprazole- (16%) and placebo-treated patients (14%).
In the aripiprazole and placebo groups, akathisia appeared to occur early in treatment, was time-limited, and was associated with high rates of concomitant benzodiazepine usage. Additionally, most cases of akathisia were reported as mild to moderate and rarely associated with treatment discontinuation.
There is limited published data from long-term pediatric bipolar clinical trials with which to guide appropriate treatment decisions. Long-term efficacy and safety of aripiprazole was investigated in this patient population.
296 youths, ages 10-17 year-old with a DSM-IV diagnosis of bipolar I disorder were randomized to receive either placebo or aripiprazole (10mg or 30mg) in a 4-week double-blind trial. Completers continued assigned treatments for an additional 26 weeks (double-blind). Efficacy endpoints included mean change from baseline to week 4 and week 30 on the Young Mania Rating Scale; Children's Global Assessment Scale, Clinical Global Impressions-Bipolar version severity scale, General Behavior Inventory, Attention Deficit Hyperactivity Disorders Rating Scale, and time to discontinuation. Tolerability/safety assessments included incidence and severity of AEs, blood chemistries and metabolic parameters.
Over the 30-week course of double-blind treatment, aripiprazole (10 mg and 30 mg) was superior to placebo as early as week 1 (p< 0.002) and at all scheduled visits from week 2 through week 30 on mean change from baseline in the Y-MRS total score (p<.0001; all visits). Significant improvements were observed on multiple endpoints including the CGAS, GBI, CGI-BP, ADHD-RS-IV total score, time to discontinuation, and response and remission rates. The 3 most common AEs were somnolence, extrapyramidal disorder, and fatigue. Mean change in body weight z-scores over 30 weeks was not clinically significant.
Over 30-weeks of treatment, both doses of aripiprazole were superior to placebo in the long term treatment of pediatric bipolar patients. Aripiprazole was generally well tolerated.
Recent genetic findings suggest shared genetic risk between autism, epilepsy and schizophrenia. A sodium channel subunit gene, SCN2A, exhibits de novo stop-codon mutations in individuals with autism and a stop-codon mutation in an individual with a seizure disorder. Our recent exome-sequencing study of schizophrenia cases identified a de novo splicesite mutation at SCN2A and further mutations may exist.
To examine a role for rare, protein damaging mutations at SCN2A in the aetiology of schizophrenia.
We aim to show an excess of coding sequence mutations in schizophrenia cases when compared to controls.
Mutation screening of the coding sequence of SCN2A in 993 Caucasian individuals with DSM-IV schizophrenia. We employed High-Resolution Melt Analysis(LightScanner™), followed by dye- terminator sequencing to confirm allele carriers. We compared our results to an exome-sequencing dataset of 4300 Caucasian individuals (NHLBI Exome Sequencing Project).
34 variants were identified; 15 intronic, 13 synonymous and 7 non-synonymous. One of the non-synonymous variants introduces a stop codon at amino acid 169 (169 E>X). No stop-codon variants were identified in the control dataset. Burden analysis did not show an excess of protein damaging changes in the UK dataset when compared to controls.
A total of 4 stop-codon mutations have been identified at SCN2A; all in individuals with a neuropsychiatric disorder. Our data do not suggest a general role for protein coding mutations at SCN2A in the pathogenesis of schizophrenia; however there may be a role for very damaging alleles at SCN2A in several neuropsychiatric disorders.