Pixelated vision or visual snow has been associated with schizophrenia (Silverstein 2011). The impact of viewing a 3D motion picture on such a visualphenomenon has not heretofore been described.

Case Study: A 28 year old right handed single male three years prior to presentation noticed that all his vision was pixelated. The pixelated vision is panoramic, involving the entire visual field. The pixels are characterized by 10,000 flat white and gray dots measuring 1mm x 1mm. No changes in color, shape, or size were noted in high and low intensity light. White, dark, gray, or multicolored backgrounds had no effect on his vision. The visual distortions are not impacted by head movements, emotions, degree of tiredness, driving, or his hedonic perception of the object being visualized. The pixels were noted to disappear upon closure of both eyes but persisted during monocular vision with either eye. These visual hallucinations were sporadic during the first year and became continuous over the following two years. Two weeks after onset ofpixelated vision he developed auditory hallucinations and hyperacusis. These increased in intensity and frequency to 500-600 times per day. He denied palinopsia, migraines, tinnitus, and photophobia. These hallucinations persisted despite treatment with aripiprazole, paliperidone, lurasidone, olanzapine, clozapine, ziprasidone, benztropine, bupropion, lamotrigine, modafinil, trazodone, atomoxetine, and amphetamine.

Abnormalities in Examination: Hypoverbal, blunted affect, impaired concentration, preoccupied with racing thoughts. Admitted to actively having auditory and visualhallucinations, without suicidal or homicidal ideations. Memory testing: Able to recall 2 out of 4 objects in 3 minutes and 3 out of 4 with reinforcement. Similarities interpreted concretely. Visual Acuity: 20/20 OU. Retinal examination: Normal. Intraocular Pressure: 19 mm OD, 20 mm OS (normal). Automotive Perimetry Testing: Normal. Cover/Uncover: Normal. Near Convergence: 3 inches (normal). Lens or filtered prism have no effect on visual snow. MRI of his brain, EEG, BAER, liver function tests, CBC, vitamin B12, folate, and thyroid function tests were normal. MRA: mild hypoplasia of distal right vertebral artery.

Visual snow has been anecdotally described as static, continuous, and independent of the specific visual environment (McKendrick, 2017). However, thepersistence of visual snow in the presence of 3D movies has never been reported. The visual snow paralleled auditory hallucinations and hyperacusis in frequency and intensity, which suggests there may be generalized hyperexcitability of the brain inducing both auditory and visual hallucinations. Agents that reduce cortical hyperexcitability (i.e., anticonvulsants, anxiolytics) may have efficacy. Treatment with these agents has been described (Ghannam, 2017), warrants further investigation.

No funding.

The Dextroamphetamine Transdermal System (d-ATS) was developed as an alternative to oral amphetamine (AMP) formulations for ADHD. In a pivotal study, d-ATS met primary and secondary efficacy endpoints for ADHD in children and adolescents. Study subjects wore d-ATS for 9 hours, and an improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham scale (SKAMP) total score was observed from 2 through 12 hours after application. Patients with ADHD may need varying durations of treatment for symptoms from day to day. This analysis describes the exposure-response (E-R) relationship for d-ATS and explores possible outcomes for wear times ≤9 hours under varying assumptions.

A population pharmacokinetic (PK) model was developed to describe AMP disposition following d-ATS administration. This model was used to construct a population pharmacokinetic/pharmacodynamic (PK/PD) model from SKAMP total score data from two pediatric clinical studies to characterize onset and duration of effect after d-ATS administration. The integrated PK/PD model was used to describe the d-ATS E-R relationship and simulate the potential onset and duration of effect of d-ATS in response to various removal times (when <9 hours) by utilizing SKAMP scores as the efficacy measure. Subject-level AMP PK and SKAMP profiles were simulated for d-ATS removal at 4–9 hours post-application under different assumptions for AMP absorption after early patch removal. Modifications were made to the original population PK model to simulate patch removal.

Data from 81 children and 41 adolescents, 6–17 years old, were included. The model provided a reasonable description of the SKAMP score over time, showing an initial decline ~2 hours after patch application. In approximately 50% of children and adolescents, the maximum decline in SKAMP scores was observed within the first 4 hours after patch application. Earlier simulated d-ATS removal times were associated with reduced systemic exposure and earlier return to near-baseline scores across the range of assumptions tested.

Under different assumptions, the graphs changed modestly but not dramatically. For example, with moderate/conservative assumptions, following a 9-hour wear time, SKAMP scores returned to within 90% of baseline value in ~49% of subjects by 12 hours and ~80% of subjects by 16 hours. Following a 4-hour wear time, percentages were ~74% by 12 hours and ~95% by 16 hours.

Simulation results suggest that the duration of d-ATS efficacy may be related to wear time, which can be adjusted according to treatment needs, consistent with published observations for another transdermal stimulant. The d-ATS patch provides the ability to control medication exposure by shortening wear time, allowing treatment duration to be individualized and optimized in ADHD patients who have varying schedules and needs.

Noven Pharmaceuticals, Inc.

A combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) has been approved in the United States for the treatment of adults with schizophrenia or adults with bipolar I disorder. In a phase 3 study in adults with schizophrenia (ENLIGHTEN-2), OLZ/SAM treatment was associated with significantly less weight gain compared with olanzapine. Prespecified subgroup analyses explored the consistency of the weight mitigation effect of OLZ/SAM vs olanzapine across demographic subgroups in ENLIGHTEN-2.

The multicenter, randomized, double-blind ENLIGHTEN-2 study (NCT02694328) included outpatients aged 18–55 years with a diagnosis of schizophrenia based on DSM-5 criteria, a body mass index (BMI) of 18 to 30 kg/m2, and stable body weight (self-reported change ≤5% for ≥3 months before study entry). Patients were randomized 1:1 to receive OLZ/SAM or olanzapine for 24 weeks. Co-primary endpoints (previously reported) were percent change in body weight and proportion of patients with at least 10% weight gain from baseline at week 24. Prespecified exploratory subgroup analyses by sex, age, self-reported race, and baseline BMI were conducted.

At week 24, treatment with OLZ/SAM resulted in numerically less percent weight gain than with olanzapine across all subgroups evaluated. The proportion of patients with at least 10% weight gain was smaller in each subgroup treated with OLZ/SAM vs olanzapine.

In these exploratory subgroup analyses from the ENLIGHTEN-2 study, weight-mitigating effects of OLZ/SAM vs olanzapine were observed consistently across patient subgroups and were in line with results from the overall study population.

There are no established treatment guidelines for tardive dyskinesia (TD) based on movement severity. The 12-week ARM-TD and AIM-TD studies in TD patients with baseline Abnormal Involuntary Movement Scale (AIMS) total score (items 1–7) ≥6 showed clinically significant improvements in AIMS score with deutetrabenazine versus placebo. Patients who completed these studies were eligible for the open-label extension (OLE) trial. This post-hoc analysis evaluated deutetrabenazine in TD patients with severe movements.

Subgroups were defined by upper quartile of baseline total AIMS score (local rating). Endpoints were: change and percent change from baseline in AIMS score, and percent of patients achieving ≥50% AIMS reduction from baseline.

337 patients were analyzed. The upper quartile of baseline total AIMS score was 14. Subgroups were defined as >14 and ≤14 at baseline, respectively (n=64 vs 273); data are presented at Week 145 (n=40 vs 120). Mean treatment duration was 880.5 and 760.8 days. Mean±SE daily doses were 41.1±1.6mg and 38.9±1.0mg. Mean±SE change from baseline in AIMS score was –11.0±0.8 versus –5.1±0.3; percent change from baseline was –60.1%±3.6% versus –55.9%±3.0%. More patients with AIMS score >14 had ≥50% AIMS reduction (73% vs 65%). Less patients discontinued (38% vs 51%); reasons included withdrawal by subject (16% vs 25%), adverse event (3% vs 11%), and lost to follow-up (6% vs 7%). Withdrawal due to lack of efficacy was uncommon (5% vs 2%).

Patients with baseline total AIMS score >14 had clinically meaningful reductions in AIMS score, suggesting deutetrabenazine has long-term benefit in these patients.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel