Preliminary evidence suggests that a ketogenic diet may be effective for bipolar disorder.

To assess the impact of a ketogenic diet in bipolar disorder on clinical, metabolic and magnetic resonance spectroscopy outcomes.

Euthymic individuals with bipolar disorder (N = 27) were recruited to a 6- to 8-week single-arm open pilot study of a modified ketogenic diet. Clinical, metabolic and MRS measures were assessed before and after the intervention.

Of 27 recruited participants, 26 began and 20 completed the ketogenic diet. For participants completing the intervention, mean body weight fell by 4.2 kg (P < 0.001), mean body mass index fell by 1.5 kg/m2 (P < 0.001) and mean systolic blood pressure fell by 7.4 mmHg (P < 0.041). The euthymic participants had average baseline and follow-up assessments consistent with them being in the euthymic range with no statistically significant changes in Affective Lability Scale-18, Beck Depression Inventory and Young Mania Rating Scale. In participants providing reliable daily ecological momentary assessment data (n = 14), there was a positive correlation between daily ketone levels and self-rated mood (r = 0.21, P < 0.001) and energy (r = 0.19 P < 0.001), and an inverse correlation between ketone levels and both impulsivity (r = −0.30, P < 0.001) and anxiety (r = −0.19, P < 0.001). From the MRS measurements, brain glutamate plus glutamine concentration decreased by 11.6% in the anterior cingulate cortex (P = 0.025) and fell by 13.6% in the posterior cingulate cortex (P = <0.001).

These findings suggest that a ketogenic diet may be clinically useful in bipolar disorder, for both mental health and metabolic outcomes. Replication and randomised controlled trials are now warranted.

In RISE, TV46000 once monthly (q1m) or once every 2 months (q2m) significantly extended time to impending schizophrenia relapse. The current study (SHINE, NCT03893825) evaluated the long-term safety, tolerability, and effect of TV46000.

Patients completing RISE without relapse (rollover) or newly recruited (de novo) were eligible. The de novo and placebo rollover cohorts were randomized 1:1 to q1m or q2m for ≤56 weeks; the TV46000 rollover cohort continued assigned regimen. Exploratory efficacy endpoints included time to impending relapse and patient centered outcomes (PCOs) including Schizophrenia Quality of Life Scale (SQLS).

334 patients were randomized and received TV46000 q1m (n=172) or q2m (n=162), for 202.3 patient-years [PY] of TV-46000 treatment. Treatment-emergent adverse events (AEs) reported for ≥5% of patients were: overall–injection site pain (event rate/100 PY, n [%]; 23.23, 16 [5%]); de novo (n=109)–injection site pain (56.10, 11 [10%]), injection site nodule (16.03, 6 [6%]), blood creatine phosphokinase increased (16.03, 8 [7%]), urinary tract infection (10.69, 7 [6%]); placebo rollover (n=53)–tremor (18.50, 5 [9%]); TV46000 rollover (n=172)–headache (7.97, n=8 [5%]). Serious AEs reported for ≥2 patients were worsening schizophrenia and hyperglycemia. Kaplan– Meier estimates for remaining relapse-free at week 56 were 0.98 (2% risk; q1m) and 0.88 (12%; q2m). SQLS improved for q1m (least-squares mean change [SE], − 2.16 [0.98]) and q2m (− 0.43 [0.98]); other PCOs (5Level EuroQoL 5Dimensions Questionnaire, Personal and Social Performance Scale, Drug Attitudes Inventory 10-item version) remained stable.

TV-46000 had a favorable long-term benefit–risk profile in patients with schizophrenia.

Teva Branded Pharmaceutical Products R&D Inc.

Study Registration Number: NCT03893825

Exposure to second-generation antipsychotics (SGAs) carries a risk of type 2 diabetes, but questions remain about the diabetogenic effects of SGAs.

To assess the diabetes risk associated with two frequently used SGAs.

This was a retrospective cohort study of adults with schizophrenia, bipolar I disorder or severe major depressive disorder (MDD) exposed during 2008–2013 to continuous monotherapy with aripiprazole or olanzapine for up to 24 months, with no pre-period exposure to other antipsychotics. Newly diagnosed type 2 diabetes was quantified with targeted minimum loss-based estimation; risk was summarised as the restricted mean survival time (RMST), the average number of diabetes-free months. Sensitivity analyses were used to evaluate potential confounding by indication.

Aripiprazole-treated patients had fewer diabetes-free months compared with olanzapine-treated patients. RMSTs were longer in olanzapine-treated patients, by 0.25 months [95% CI: 0.14, 0.36], 0.16 months [0.02, 0.31] and 0.22 months [0.01, 0.44] among patients with schizophrenia, bipolar I disorder and severe MDD, respectively. Although some sensitivity analyses suggest a risk of unobserved confounding, E-values indicate that this risk is not severe.

Using robust methods and accounting for exposure duration effects, we found a slightly higher risk of type 2 diabetes associated with aripiprazole compared with olanzapine monotherapy regardless of diagnosis. If this result was subject to unmeasured selection despite our methods, it would suggest clinician success in identifying olanzapine candidates with low diabetes risk. Confirmatory research is needed, but this insight suggests a potentially larger role for olanzapine in the treatment of well-selected patients, particularly for those with schizophrenia, given the drug's effectiveness advantage among them.

During the COVID-19 pandemic, research organizations accelerated adoption of technologies that enable remote participation. Now, there’s a pressing need to evaluate current decentralization practices and develop appropriate research, education, and operations infrastructure. The purpose of this study was to examine current adoption of decentralization technologies in a sample of clinical research studies conducted by academic research organizations (AROs).

The setting was three data coordinating centers in the U.S. These centers initiated coordination of 44 clinical research studies during or after 2020, with national recruitment and enrollment, and entailing coordination between one and one hundred sites. We determined the decentralization technologies used in these studies.

We obtained data for 44/44 (100%) trials coordinated by the three centers. Three technologies have been adopted across nearly all studies (98–100%): eIRB, eSource, and Clinical Trial Management Systems. Commonly used technologies included e-Signature (32/44, 73%), Online Payments Portals (26/44, 59%), ePROs (23/44, 53%), Interactive Response Technology (22/44, 50%), Telemedicine (19/44, 43%), and eConsent (18/44, 41%). Wearables (7/44,16%) and Online Recruitment Portals (5/44,11%) were less common. Rarely utilized technologies included Direct-to-Patient Portals (1/44, 2%) and Home Health Nurse Portals (1/44, 2%).

All studies incorporated some type of decentralization technology, with more extensive adoption than found in previous research. However, adoption may be strongly influenced by institution-specific IT and informatics infrastructure and support. There are inherent needs, responsibilities, and challenges when incorporating decentralization technology into a research study, and AROs must ensure that infrastructure and informatics staff are adequate.

Identification of paediatric coronary artery abnormalities is challenging. We studied whether coronary artery CT angiography can be performed safely and reliably in children.

Retrospective analysis of consecutive coronary CT angiography scans was performed for image quality and estimated radiation dose. Both factors were assessed for correlation with electrocardiographic-gating technique that was protocoled on a case-by-case basis, radiation exposure parameters, image noise artefact parameters, heart rate, and heart rate variability.

Sixty scans were evaluated, of which 96.5% were diagnostic for main left and right coronaries and 91.3% were considered diagnostic for complete coronary arteries. Subjective image quality correlated significantly with lower heart rate, increasing patient age, and higher signal-to-noise ratio. Estimated radiation dose only correlated significantly with choice of electrocardiographic-gating technique with median doses as follows: 2.42 mSv for electrocardiographic-gating triggered high-pitch spiral technique, 5.37 mSv for prospectively triggered axial sequential technique, 3.92 mSv for retrospectively gated technique, and 5.64 mSv for studies which required multiple runs. Two scans were excluded for injection failure and one for protocol outside the study scope. Five non-diagnostic cases were attributed to breathing motion, scanning prior to peak contrast enhancement, or scan acquisition during the incorrect portion of the R-R interval.

Diagnostic-quality coronary CT angiography can be performed reliably with a low estimated radiation exposure by tailoring each scan protocol to the patient’s body habitus and heart rate. We propose coronary CT angiography is a safe and effective diagnostic modality for coronary artery abnormalities in children.

Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date.

To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder.

Euthymic individuals with bipolar disorder were recruited to a 6–8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198.

Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6–8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication).

The recruitment and retention of euthymic individuals with bipolar disorder to a 6–8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.

Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is known about the drugs' mortality risk or whether serious mental illness (SMI) diagnosis or race/ethnicity modify these effects.

Authors created a retrospective cohort of non-elderly adults with SMI initiating monotherapy with an SGA (olanzapine, quetiapine, risperidone, and ziprasidone, aripiprazole) or haloperidol during 2008–2013. Three-year diabetes incidence or all-cause death risk differences were estimated between each drug and aripiprazole, the comparator, as well as effects within SMI diagnosis and race/ethnicity. Sensitivity analyses evaluated potential confounding by indication.

38 762 adults, 65% White and 55% with schizophrenia, initiated monotherapy, with haloperidol least (6%) and quetiapine most (26·5%) frequent. Three-year mortality was 5% and diabetes incidence 9.3%. Compared with aripiprazole, haloperidol and olanzapine reduced diabetes risk by 1.9 (95% CI 1.2–2.6) percentage points, or a 18.6 percentage point reduction relative to aripiprazole users' unadjusted risk (10.2%), with risperidone having a smaller advantage. Relative to aripiprazole users' unadjusted risk (3.4%), all antipsychotics increased mortality risk by 1.1–2.2 percentage points, representing 32.4–64.7 percentage point increases. Findings within diagnosis and race/ethnicity were generally consistent with overall findings. Only quetiapine's higher mortality risk held in sensitivity analyses.

Haloperidol's, olanzapine's, and risperidone's lower diabetes risks relative to aripiprazole were not robust in sensitivity analyses but quetiapine's higher mortality risk proved robust. Findings expand the evidence on antipsychotics' risks, suggesting a need for caution in the use of quetiapine among individuals with SMI.

There is a paucity of data on the obstetrical outcomes of Canadian pregnant patients with epilepsy, which may differ from the average Canadian pregnancy and from other populations of pregnant patients with epilepsy.

Pregnant patients with epilepsy were identified from a prospectively collected database of patients seen at the maternal-fetal medicine obstetrics program of Mount Sinai Hospital (Toronto, Canada) between January 1, 2014, and November 20, 2020. Pregnancy, delivery, and neonatal outcome data were retrieved from this database and described using 95% binomial confidence intervals. Comparisons of obstetrical outcomes over the same period among the Canadian population average, obtained from publicly available national health data, were done using one-proportion Z-tests for nominal variables and one-sample t-tests for continuous variables.

In total, 282 pregnancies, from 224 patients, were included, which resulted in 274 live births. Mean maternal age was 32.8 years (s.d. = 4.6; population average [μ] = 30.9; p < 0.01), and 53% were primiparous (CI95% = 49%–61%; μ = 43%; p < 0.01). The observed rates of obstetrical complications were gestational hypertension 9% (CI95%=6%–13%; μ=7%; p=0.19), gestational diabetes 5% (CI95% = 3%–8%; μ = 9%; p = 0.02), cesarean section 44% (CI95% = 38%–50%; μ = 28%; p < 0.01), postpartum hemorrhage 5% (CI95% = 3%–8%; μ = 0.5%; p < 0.01), stillbirth 1% (CI95% = 0%–2%; μ=1%; p > 0.99), and prematurity 9% (CI95% = 6%–13%; μ = 8%; p = 0.44).

In this cohort of Canadian pregnant patients with epilepsy from an urban tertiary care center, observed rates of obstetrical complications were rare and no higher than in the Canadian population over the same period, with the exception of cesarean section and postpartum hemorrhage. Future prospective studies that include primary care and rural settings are needed to increase the generalizability of those results.

Web-based dietary interventions could support healthy eating. The Advice, Ideas and Motivation for My Eating (Aim4Me) trial investigated the impact of three levels of personalised web-based dietary feedback on diet quality in young adults. Secondary aims were to investigate participant retention, engagement and satisfaction.

Randomised controlled trial.

Web-based intervention for young adults living in Australia.

18–24-year-olds recruited across Australia were randomised to Group 1 (control: brief diet quality feedback), Group 2 (comprehensive feedback on nutritional adequacy + website nutrition resources) or Group 3 (30-min dietitian consultation + Group 2 elements). Australian Recommended Food Score (ARFS) was the primary outcome. The ARFS subscales and percentage energy from nutrient-rich foods (secondary outcomes) were analysed at 3, 6 and 12 months using generalised linear mixed models. Engagement was measured with usage statistics and satisfaction with a process evaluation questionnaire.

Participants (n 1005, 85 % female, mean age 21·7 ± 2·0 years) were randomised to Group 1 (n 343), Group 2 (n 325) and Group 3 (n 337). Overall, 32 (3 %), 88 (9 %) and 141 (14 %) participants were retained at 3, 6 and 12 months, respectively. Only fifty-two participants (15 % of Group 3) completed the dietitian consultation. No significant group-by-time interactions were observed (P > 0·05). The proportion of participants who visited the thirteen website pages ranged from 0·6 % to 75 %. Half (Group 2 = 53 %, Group 3 = 52 %) of participants who completed the process evaluation (Group 2, n 111; Group 3, n 90) were satisfied with the programme.

Recruiting and retaining young adults in web-based dietary interventions are challenging. Future research should consider ways to optimise these interventions, including co-design methods.

To assess experience, physical infrastructure, and capabilities of high-level isolation units (HLIUs) planning to participate in a 2018 global HLIU workshop hosted by the US National Emerging Special Pathogens Training and Education Center (NETEC).

An electronic survey elicited information on general HLIU organization, operating costs, staffing models, and infection control protocols of select global units.

The survey was distributed to site representatives of 22 HLIUs located in the United States, Europe, and Asia; 19 (86%) responded.

Data were coded and analyzed using descriptive statistics.

The mean annual reported budget for the 19 responding units was US$484,615. Most (89%) had treated a suspected or confirmed case of a high-consequence infectious disease. Reported composition of trained teams included a broad range of clinical and nonclinical roles. The mean number of HLIU beds was 6.37 (median, 4; range, 2–20) for adults and 4.23 (median, 2; range, 1–10) for children; however, capacity was dependent on pathogen.

Responding HLIUs represent some of the most experienced HLIUs in the world. Variation in reported unit infrastructure, capabilities, and procedures demonstrate the variety of HLIU approaches. A number of technical questions unique to HLIUs remain unanswered related to physical design, infection prevention and control procedures, and staffing and training. These key areas represent potential focal points for future evidence and practice guidelines. These data are important considerations for hospitals considering the design and development of HLIUs, and there is a need for continued global HLIU collaboration to define best practices.

Current treatments for schizophrenia are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides =150mg/dL, high density lipoprotein cholesterol (HDL) <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) =130mmHg or diastolic BP =85mmHg, fasting glucose =100mg/dL. Patients with MetSy have an elevated risk of developing type II diabetes and increased mortality due to cardiovascular disease. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA approved for the treatment of schizophrenia. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials. This post hoc analysis of 2 randomized, double-blind, placebo-controlled studies of patients with an acute exacerbation of schizophrenia compared rates of MetSy with lumateperone and risperidone. Data from an open-label long-term trial of lumateperone were also evaluated.

The incidence and shift in MetSy were analyzed in data pooled from 2 short-term (4 or 6 week) placebo- and active-controlled (risperidone 4mg) studies of lumateperone 42mg (Studies 005 and 302). The pooled lumateperone data were compared with data for risperidone. Data from an open-label 1-year trial (Study 303) evaluated MetSy in patients with stable schizophrenia switched from prior antipsychotic (PA) treatment to lumateperone 42mg.

In the acute studies (n=256 lumateperone 42mg, n=255 risperidone 4mg), rates of MetSy were similar between groups at baseline (16% lumateperone, 19% risperidone). At the end of treatment (EOT), MetSy was less common with lumateperone than with risperidone (13% vs 25%). More lumateperone patients (46%) compared with risperidone (25%) patients improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. Conversely, more patients on risperidone than on lumateperone developed MetSy during treatment (13% vs 5%). Differences in MetSy conversion rates were driven by changes in triglycerides and glucose. In the long-term study (n=602 lumateperone 42mg), 33% of patients had MetSy at PA baseline. Thirty-six percent of patients (36%) with MetSy at PA baseline improved to no longer meeting criteria at EOT. Fewer than half that percentage shifted from not meeting MetSy criteria to having MetSy (15%).

In this post hoc analysis, lumateperone 42mg patients had reduced rates of MetSy compared with risperidone patients. In the long-term study, patients with MetSy on PA switched to lumateperone 42mg had a reduction in the risk of MetSy. These results suggest that lumateperone 42mg is a promising new treatment for schizophrenia with a favorable metabolic profile.

Intra-Cellular Therapies, Inc.