Chromosomal microarray analysis-a routine clinical genetic test for patients with schizophrenia.

Aetiological diagnosis for patients with schizophrenia was long thought to be impossible. However, genomic abnormalities with clear causal relevance can now be identified in a consistent minority of cases using chromosomal microarray analysis (CMA; also known as array Comparative Genomic Hybridization or array-CGH). Analogous to a karyotype but with dramatically improved genome-wide resolution, CMA can inform diagnosis and clinical management by identifying sub-microscopic segments of missing (deleted) or additional (duplicated) chromosomal material known as copy number variants (CNVs). CMA is sensitive, reliable, and widely available in clinical laboratories around the world, including major medical centres in the developing world. Costs are competitive with other investigations such as neuroimaging. CMA is now a standard first-line diagnostic test for intellectual disability and autism where 10-20% of affected individuals have a clinically-relevant deletion or duplication (1). Widespread application of CMA testing in these populations has increased confidence in diagnostic interpretation, enhanced the prognostic evidence base, and facilitated research progress (2). In our view, the time has come to translate replicated research findings with proven clinical utility into routine diagnostic practice for patients with schizophrenia

Agreement between primary care and hospital diagnosis of schizophrenia and bipolar disorder : a cross-sectional, observational study using record linkage

Funding: Support for this project was provided by North York General Hospital.People with serious mental illness die 10–25 years sooner than people without these conditions. Multiple challenges to accessing and benefitting from healthcare have been identified amongst this population, including a lack of coordination between mental health services and general health services. It has been identified in other conditions such as diabetes that accurate documentation of diagnosis in the primary care chart is associated with better quality of care. It is suspected that if a patient admitted to the hospital with serious mental illness is then discharged without adequate identification of their diagnosis in the primary care setting, follow up (such as medication management and care coordination) may be more difficult. We identified cohorts of patients with schizophrenia and bipolar disorder who accessed care through the North York Family Health Team (a group of 77 family physicians in Toronto, Canada) and North York General Hospital (a large community hospital) between January 1, 2012 and December 31, 2014. We identified whether labeling for these conditions was concordant between the two settings and explored predictors of concordant labeling. This was a retrospective cross-sectional study using de-identified data from the Health Databank Collaborative, a linked primary care-hospital database. We identified 168 patients with schizophrenia and 370 patients with bipolar disorder. Overall diagnostic concordance between primary care and hospital records was 23.2% for schizophrenia and 15.7% for bipolar disorder. Concordance was higher for those with multiple (2+) inpatient visits (for schizophrenia: OR 2.42; 95% CI 0.64–9.20 and for bipolar disorder: OR 8.38; 95% CI 3.16–22.22). Capture-recapture modeling estimated that 37.4% of patients with schizophrenia (95% CI 20.7–54.1) and 39.6% with bipolar disorder (95% CI 25.7–53.6) had missing labels in both settings when adjusting for patients’ age, sex, income quintiles and co-morbidities. In this sample of patients accessing care at a large family health team and community hospital, concordance of diagnostic information about serious mental illness was low. Interventions should be developed to improve diagnosis and continuity of care across multiple settings.Publisher PDFPeer reviewe

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD

A cognitive decline precedes the onset of psychosis in patients with the 22q11.2 deletion syndrome

Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk for developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities, starting at a young age

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial

Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety

McGarry et al Suicidality in HD Supplementary Material 10.31.18

McGarry et al Suicidality in HD Supplementary Material 10.31.1

Data from: Risk factors for suicidality in Huntington's disease: an analysis of the 2CARE clinical trial

Most suicidality literature in HD is based on natural history studies or retrospective reviews, but reports on risk factors from clinical trials are limited. We analyzed 609 participants from 2CARE, a randomized, double-blind, placebo controlled clinical trial with up to 5 years of follow-up, for risk factors related to suicidality. The primary outcome variable was the time from randomization until the first occurrence of either suicidal ideation or attempt. We also considered time from randomization until the first suicide attempt as a secondary outcome variable. Depression, anxiety, bipolar disorder, antidepressant or anxiolytic use, and prior suicide attempt at baseline were associated with time to ideation or attempt. Baseline employment status, marital status, CAG repeat length, tetrabenazine use, and treatment assignment (coenzyme Q10 or placebo) were not associated with suicidality. Time-dependent variables from the UHDRS Behavioral Assessment were associated with time to suicidal ideation or attempt, driven mainly by items related to depressed mood, low self-esteem/guilt, anxiety, suicidal thoughts, irritability, and compulsions. Variables associated with time to suicide attempt alone were generally similar. These data suggest psychiatric co-morbidities in HD are predictive of suicidal behavior while participating in clinical trials, reinforcing the importance of clinical surveillance and treatment towards lessening risk during participation and perhaps beyond. Designing a composite algorithm for early prediction of suicide attempts in HD may be of value, particularly given anticipated trials aimed at disease modification are likely to be long-term

Feasibility of computerized working memory training in individuals with Huntington disease

<div><p>Objectives</p><p>Huntington disease (HD) is associated with a variety of cognitive deficits, with prominent difficulties in working memory (WM). WM deficits are notably compromised in early-onset and prodromal HD patients. This study aimed to determine the feasibility of a computerized WM training program (Cogmed QM), novel to the HD population.</p><p>Methods</p><p>Nine patients, aged 26–62, with early stage HD underwent a 25-session (5 days/week for 5 weeks) WM training program (Cogmed QM). Training exercises involved the manipulation and storage of verbal and visuospatial information, with difficulty adapted as a function of individual performance. Neuropsychological testing was conducted before and after training, and performance on criterion WM measures (Digit Span and Spatial Span), near-transfer WM measures (Symbol Span and Auditory WM), and control measures were evaluated. Post-training interviews about patient experience were thematically analyzed using NVivo software.</p><p>Results</p><p>Seven of nine patients demonstrated adherence to the training and completed all sessions within the recommended timeframe of 5 weeks. All adherent patients showed improvement on the Cogmed tasks as defined by the Improvement Index (<i>M</i> = 22.17, <i>SD</i> = 8.84, range = 13–36). All adherent patients reported that they found training helpful (<i>n = 7)</i>, and almost all felt that their memory improved (<i>n = 6)</i>. Participants also expressed that the training was difficult, sometimes frustrating, and time consuming.</p><p>Conclusions</p><p>This pilot study provides support for feasibility of computerized WM training in early-stage patients with HD. Results suggest that HD patients perceive benefits of intensive WM training, though a full-scale and controlled intervention project is needed to understand the size of the effect and reliability of changes over time.</p><p>Trial registration</p><p>ClinicalTrials.gov, Registry number <a href="https://clinicaltrials.gov/ct2/show/NCT02926820" target="_blank">NCT02926820</a></p></div