Public support for the implementation of personalised medicine policies (PMPs) within routine care is important owing to the high financial costs involved and the potential for redirection of resources from other services.

We aimed to determine the attributes of a PMP most likely to elicit public support for implementation. We also aimed to determine whether such support differed between a depression PMP and one for cystic fibrosis.

In a discrete-choice experiment, paired vignettes illustrating both the current model of care (CMoC) and a hypothetical PMP for either depression or cystic fibrosis were presented to a representative sample of the UK public (n = 2804). Each vignette integrated varying attributes, including anticipated therapeutic benefit over CMoC, and the annual cost to the taxpayer. Respondents were invited to express their preference for either the PMP or CMoC within each pair.

The financial cost was the most important attribute influencing public support for PMPs. Respondents favoured PMP implementation where it benefited a higher proportion of patients or was anticipated to be more effective than CMoC. A reduction in services for non-eligible patients reduced the likelihood of support for PMPs. Respondents were more willing to fund PMPs for cystic fibrosis than for depression.

Cost is a significant factor in the public's support for PMPs, but essential caveats, such as protection for services available to PMP-ineligible patients, may also apply. Further research should explore the factors contributing to condition-specific nuances in public support for PMPs.

The approval of the esketamine nasal spray for treatment-resistant depression in March 2019 by the Food and Drug Administration (FDA), and few months later by the European Medicine Agency, triggered a vivid debate and many concerns, mainly because of the lack of convincing evidence on its efficacy and safety, based on the development programs, approval trials and few post-marketing trials.

We aimed to detect and characterize safety signals for esketamine, by analyzing relevant adverse events (AEs) reports in the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020).

We performed disproportionality analysis through the case/non-case approach: reporting odds ratios (ROR) and information components (IC) with 95% confidence intervals (95%CI) were estimated for esketamine-related AEs with at least four counts. We compared serious and non-serious AEs using non-parametrical tests.

The FAERS database registered 962 reports of esketamine-related AEs in one year. Signals (i.e., statistically significant disproportionality) were detected for several AEs, such as dissociation, sedation, feeling drunk, suicidal ideation and completed suicide. Signals for suicidal ideation, but not suicide attempt and completed suicide, remained significant when comparing esketamine to venlafaxine. The comparison of patients with serious vs. non-serious esketamine AEs revealed that females, patients receiving antidepressant polypharmacy, co-medication with antipsychotics, mood stabilizers, benzodiazepines or somatic medications were more likely to suffer from serious AEs.

This real-world pharmacovigilance analysis detected signals of serious unexpected esketamine-related AEs, thus reinforcing current worries regarding esketamine safety/acceptability. Further real-world studies are urgently needed to unravel the safety profile of esketamine.

No significant relationships.

Lurasidone is an atypical antipsychotic approved for the treatment of patients with schizophrenia. We report on a meta-analysis focusing on both the efficacy and safety/tolerability of lurasidone in the treatment of patients with schizophrenia.

To obtain pooled estimates from placebo-controlled clinical trials on the efficacy and safety/tolerability of lurasidone in schizophrenia.

We selected acute, randomized placebo-controlled trials of lurasidone for schizophrenia. Primary outcome for efficacy was the Positive and Negative Syndrome Scale (PANSS) change and for “acceptability” was all-cause discontinuation. Secondary outcomes included specific adverse events, body weight change, ≥7% weight gain, and glucose and lipid parameter change.

Across 10 RCTs (n=3,963, age=40.5±2.3 years, males=64.7 %, trial duration=6.0 weeks), lurasidone outperformed placebo regarding the PANSS total score (N=10, n=3,354, SMD=-0.34, 95% CI: -0.47−-0.21, p<0.001). Stratifying the analysis by dose, lurasidone significantly outperformed placebo at doses 40-160 mg/day. Lurasidone was associated with significantly lower all-cause discontinuation than placebo (N=10, n=3,410, RR=0.87, 95% CI: 0.78−0.97, p=0.014). Lurasidone had significantly higher body weight change compared with placebo (N=10, n=3,359, SMD=0.17, 95% CI: 0.09−0.24, p<0.001), but without significant differences regarding ≥7% body weight gain (N=9, n=3,186, p=0.112). Lurasidone did not differ from placebo in total cholesterol (N=10, n=3,140, p=0.439), LDL-cholesterol (N=7, n=2,414, p=0.849), triglycerides (N=10, n=3,140, p=0.238), and fasting glucose change (N=10, n=3,112, p=0.633).

In short-term trials, lurasidone was efficacious, acceptable and safe, having minimal effect on body weight gain and glucose and lipid metabolism.

K. Hagi is a full time employee of Sumitomo Dainippon Phrma Co., Ltd.

During the COVID-19 pandemic, the use of telemedicine as a way to reduce COVID-19 infections was noted and consequently deregulated. However, the degree of telemedicine regulation varies from country to country, which may alter the widespread use of telemedicine. This study aimed to clarify the telepsychiatry regulations for each collaborating country/region before and during the COVID-19 pandemic.

We used snowball sampling within a global network of international telepsychiatry experts. Thirty collaborators from 17 different countries/regions responded to a questionnaire on barriers to the use and implementation of telepsychiatric care, including policy factors such as regulations and reimbursement at the end of 2019 and as of May 2020.

Thirteen of 17 regions reported a relaxation of regulations due to the pandemic; consequently, all regions surveyed stated that telepsychiatry was now possible within their public healthcare systems. In some regions, restrictions on prescription medications allowed via telepsychiatry were eased, but in 11 of the 17 regions, there were still restrictions on prescribing medications via telepsychiatry. Lower insurance reimbursement amounts for telepsychiatry consultations v. in-person consultations were reevaluated in four regions, and consequently, in 15 regions telepsychiatry services were reimbursed at the same rate (or higher) than in-person consultations during the COVID-19 pandemic.

Our results confirm that, due to COVID-19, the majority of countries surveyed are altering telemedicine regulations that had previously restricted the spread of telemedicine. These findings provide information that could guide future policy and regulatory decisions, which facilitate greater scale and spread of telepsychiatry globally.

Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series.

This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences.

We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions.

The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs.

Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.

Recent studies have identified DAAO as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders.

The present investigation examined the impact of DAAO genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers.

We tested the hypotheses that the high-risk variant of DAAO would be associated with altered prefrontal function and functional connectivity in schizophrenic and bipolar patients.

We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 121 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 48 healthy volunteers. We then used statistical parametric mapping (SPM) and psycho-physiological interaction (PPI) analyses to estimate the main effects of diagnostic group, the main effect of genotype and their interaction on brain activation and functional connectivity.

In schizophrenic patients relative to bipolar patients and controls, the high-risk variant of DAAO was associated with lower deactivation in the left precuneus and greater activation in the right calcarine and posterior cingulate gyrus during task performance. In addiction, these areas expressed altered functional connectivity with the rest of the brain in schizophrenic patients relative to bipolar patients and controls.

Our results suggest that genetic variation in DAAO has a significant impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in specific brain regions.

Whether the modest QTc-prolonging effect of ziprasidone increases cardiovascular event risk is unknown.

The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC), an open-label, randomized, postmarketing study, enrolled patients with schizophrenia from routine clinical practice settings in 18 countries. The primary outcome was non-suicide mortality in the year after initiation of assigned treatment. A total of 18,154 subjects were randomized to ziprasidone or olanzapine, dosed according to enrolling physician's clinical judgment. A physician-administered baseline questionnaire collected information on demographics, medical and psychiatric history, and concomitant medication use. Brief follow-up questionnaires elicited hospitalization data since the last study visit, vital status, study medication continuation, and concomitant antipsychotic medication(s) use. ZODIAC study subjects reflected the general population of patients with schizophrenia.

The incidence of nonsuicide mortality within one year of initiating therapy was 0.91% for the ziprasidone group and 0.90% for the olanzapine group (both n = 9,077), relative risk (95% confidence interval [CI]) of 1.01 (0.75, 1.37). This finding was robust in numerous secondary and sensitivity analyses. Regarding secondary endpoints, the risk of all-cause mortality or cardiovascular mortality was similar among ziprasidone and olanzapine users; the incidence of all-cause hospitalizations was higher among ziprasidone users. The proportion of patients remaining on treatment at 6 months was lower for the ziprasidone group.

ZODIAC is one of the largest randomized studies conducted to date of patients with schizophrenia. With substantial statistical power, the study found no difference in risk of nonsuicide death associated with the use of ziprasidone vs. olanzapine.

The rate-corrected Q-T interval (QTc) prolongation is a risk factor for sudden death and may be produced by antipsychotic drugs.

To determined the frequency and psychopharmacological correlates of baseline prolongation of QTc in a large pediatric cohort.

The QTc was measured on the electrocardiograms obtained on 811 children and adolescents (404 males and 407 females, mean age: 15.5 ± 2.4 years) consecutively evaluated in the admissions unit of a psychiatric hospital. Each patient with QTc > 440 msec was age- and gender-matched with 5 patients with QTc< 420 msec. The psychiatric diagnoses and psychotropic treatment of patients with prolonged QTc and control subjects were compared in univariate and logistic analyses.

QTc duration was > 440 msec (mean 454 ± 10 msec, range 442–481 msec) in 16 patients (1.97%; 95% confidence interval (CI): 1.17%–3.25%). The 80 control subjects had a mean QTc of 391 ± 21 msec. The groups were similar with regard to the proportion of patients on antipsychotics (43.8% vs. 40.8%, p = 0.78) and chlorpromazine equivalents (165.5 ± 109.7 mg vs. 167.6 ± 217.8 mg, p = 0.98). Logistic regression identified schizophrenia as the only psychiatric predictor of baseline QTc prolongation (odds-ratio: 6.17, 95% CI: 1.24–30.69, p = 0.042).

In a large cohort of children and adolescents with psychiatric disorders, baseline QTc prolongation was infrequent and, at most, of moderate severity. The findings argue against performing electrocardiograms prior to the initiation of antipsychotics in all patients from this age group.

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.

Studies using death certificates have indicated an excess of sudden cardiac deaths among users of antipsychotic drugs compared to the general population, but may have underestimated the presence of other known causes of sudden and unexpected death.

To assess the cause and risk factors for sudden death discovered by contemporaneous investigation of all deaths occurring over a 26-year period (1984–2009) in adult patients registered for care in one large psychiatric hospital in New York.

Circumstances of death, psychiatric diagnoses, psychotropic drugs and past medical history were extracted from the root cause analyses of sudden unexpected deaths. After the exclusion of suicides, homicides and drug overdoses, explained and unexplained cases were compared regarding clinical variables and the utilization of antipsychotics.

One hundred cases of sudden death were identified among of 119, 500 patient-years. The death remained unexplained in 52 cases. The incidence of unexplained sudden death was 125/100,000 (95% CI 88.9–175.1/100,000) patient-years in 2005–2009, 53/100,000 (95% CI 31.7–88.5/100,000) patient-years in 1999–2004 and 7/100,000 (95% CI 3.7–19.4/100,000) patient-years in 1984–1998. Explained and unexplained cases were similar regarding psychiatric diagnoses and treatment with any psychotropic class, including first- and second-generation antipsychotics. Dyslipidemia (p = 0.012), diabetes (p = 0.055) and co-morbid dyslipidemia and diabetes (p = 0.008) were more common in the unexplained than in the explained cases.

In a consecutive cohort of psychiatric patients, the unexplained sudden deaths were associated with known risk factors for coronary artery disease, but not with higher utilization of first- or second-generation antipsychotics.

Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.

Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed.

710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p< 0.0001, log-rank test). Discontinuations due to treatment-emergent adverse events (AEs) were: Phase 1, 3.8% (n=24/632); Phase 2, 3.0% (n=21/709); Phase 3, 4.9% (n=28/576); Phase 4, 7.1% (n=19/269). Most AEs were mild or moderate. Insomnia was the only AE >5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders.

ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia1.

Controlled data on optimization of dosing regimen for antipsychotics in schizophrenia is an unmet medical need.

To evaluate the efficacy of low dose lurasidone in schizophrenia; and to determine optimal dosing for patients not achieving improvement in Positive and Negative Syndrome Scale (PANSS) total score by week 2 of standard dosing.

Patients with schizophrenia were randomized to double-blind treatment with fixed daily doses of lurasidone 18.5 mg (for 6 wks; N=101), 74 mg (for 2 wks; N=198), or placebo (for 6 wks; N=112). After 2 weeks of treatment, patients in the 74 mg group with <20% PANSS improvement were re-randomized to continue on the 74 mg dose, or increase to a dose of 148 mg, for the next 4 wks.

Lurasidone 18.5 mg did not demonstrate significant improvement vs. placebo at Week 6 (−17.6 vs −14.5; P=0.25). In the group with <20% PANSS improvement after 2 weeks (N=95), titration to lurasidone 148 mg resulted in significantly greater improvement in PANSS total score at Week 6 compared with 4 additional weeks of treatment at the 74 mg dose (−16.6 vs. −8.9; p=0.023).

This trial supports the 37 mg/d dose of lurasidone as minimally effective dose in patients with acute schizophrenia consistent with evidence from previous studies. Increasing the dose of lurasidone to 148 mg/d after 2 weeks of nonresponse at 74 mg/d resulted in a significant efficacy advantage with important potential implications for clinical practice.

NCT01821378.

Sponsored by Sunovion Pharmaceuticals Inc.

To evaluate the initial (3 months) all-cause discontinuation and safety of aripiprazole once-monthly 400mg (AOM-400mg), an extended release injectable suspension of aripiprazole, stratified by previous treatment.

These two studies (NCT00705783 & NCT00706654) were double-blind, placebo- or active-controlled assessing the efficacy and safety of AOM-400mg. Detailed study designs have been reported previously (1, 2). This analysis was conducted on the pooled population in the first 3 months after initiating AOM-400mg treatment, on patients who received at least one dose of AOM-400mg. Outcome measures are reported for groups stratified by prior treatment.

During the first 3 months of treatment, discontinuation due to all-causes (except for those who discontinued due to the sponsor stopping the NCT00705783 study early after pre-specified efficacy parameters were met) as well as due to adverse events are presented in Table 1. The rates of insomnia and akathisia are shown in Table 1

Aripiprazole once-monthly 400mg appeared equally safe and effective (as measured by all cause discontinuation) in the first 3 months after initiation, regardless of treatment prior to entering trials.

Evaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.

Detailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening.

710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p< 0.0001). Mean changes in PSP Total scale scores showed improvement during Phase 2 (3.0) and Phase 3 (2.6). Mean change in PSP scores during Phase 4 showed greater functional stability with ARI-OM (−1.7) compared with placebo-OM (−6.2) (p=0.0002 vs. placebo-OM).

Improvements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.

There is a need for accurate and efficient assessment tools that cover a range of mental health and psychosocial problems. Existing, lengthy self-report assessments may reduce accuracy due to respondent fatigue. Using data from a sample of adults enrolled in a psychotherapy randomized trial in Thailand and a cross-sectional sample of adolescents in Zambia, we leveraged Item Response Theory (IRT) methods to create brief, psychometrically sound, mental health measures.

We used graded-response models to refine scales by identifying and removing poor performing items that were not well correlated with the underlying trait, and by identifying well-performing items at varying levels of a latent trait to assist in screening or monitoring purposes.

In Thailand, the original 17-item depression scale was shortened to seven items and the 30-item Posttraumatic Stress Scale (PTS) was shortened to 10. In Zambia, the Child Posttraumatic Stress Scale (CPSS) was shortened from 17 items to six. Shortened scales in both settings retained the strength of their psychometric properties. When examining longitudinal intervention effects in Thailand, effect sizes were comparable in magnitude for the shortened and standard versions.

Using Item Response Theory (IRT) we created shortened valid measures that can be used to help guide clinical decisions and function as longitudinal research tools. The results of this analysis demonstrate the reliability and validity of shortened scales in each of the two settings and an approach that can be generalized more broadly to help improve screening, monitoring, and evaluation of mental health and psychosocial programs globally.

The concept of endoscopic diagnosis and procedures on the nasal cavity had been investigated for several decades in Europe in the early part of the twentieth century. It was Prof Walter Messerklinger and his assistant, Heinz Stammberger, with US colleague, David Kennedy, who brought the science and technique of functional endoscopic sinus surgery to the wider world.

The author, an English-speaking surgeon, was present at this movement from the commencement of its propagation, and has recorded the remarkable ascendency of this technique throughout the world.

The technique revolutionised the diagnosis and management of intranasal, sinus and intracranial conditions.