Women with mental illness are 5x more likely to experience an unplanned pregnancy due to lower rates of effective contraception use; they also experience higher rates of adverse pregnancy outcomes. Education about women’s reproductive health and family planning are not routinely offered in inpatient mental health and addiction treatment settings.

Weekly women’s groups on the inpatient psychiatry unit were led by psychiatry residents who were trained and provided a script. Groups focused on structured contraception education followed by an open-discussion format.

Data collected included the percentage of women with history of contraception use, child protective service involvement, unplanned pregnancies, abortions, and percentage of women who found the group helpful. Special care was taken to discuss contraception as a tool for empowering women to make their own decisions about their contraceptive needs.

Thirteen sessions were conducted, and attendance among women on the inpatient unit was 42%. Out of the 32 patients who participated, 100% found the group beneficial and responded they would share information they learned with women outside the group. 26.4% self-identified as using contraception, 50% had unplanned pregnancy, 23.6% have had an abortion, and 26.4% have had child protective services involvement.

Dissemination of contraceptive information in these women’s groups effectively led women to consider options that were available to them and seek contraceptive methods that were appropriate to their situation. Women reported they gained a better understanding of the medical, emotional, and financial implications of unplanned pregnancies. The groups were conducted in an open-discussion format that allowed women to participate in shared experiences; in many cases, the discussions were therapeutic. Feedback from patients and unit staff was positive. Many patients requested further groups to discuss issues women face, such as domestic violence and experiences as a mother.

Conducting women’s groups on the inpatient unit is critical in view of the poor access to healthcare that vulnerable women who seek inpatient psychiatric care experience. The groups on the inpatient unit are unique because it is often the only time these women have an opportunity for crucial, gender-specific preventative healthcare. These groups should further lead to appropriate referral and follow-up with primary care or women’s clinic providers.

Ongoing efforts will be put forth to increase group attendance, to incorporate participation from unit staff, and to build this group into a resident curriculum for group therapy.

No Funding

Stimulant medications and the norepinephrine reuptake inhibitor, atomoxetine, contain warnings regarding potential for slowing of growth (weight and height) in children and recommend monitoring of growth when using these medications for pediatric ADHD. Viloxazine ER (viloxazine extended-release capsules; Qelbree®), is a nonstimulant medication, FDA-approved for ADHD in adults and children (≥6 years of age). Viloxazine ER has pharmacologic differences from other approved ADHD medications and might not affect growth in the same manner as other therapies. A safety analysis was conducted to determine viloxazine ER effects on growth and weight trajectories in pediatric ADHD patients with long-term use.

Data were evaluated from five DBPC, phase 2 and 3 clinical trials and an ongoing long-term, open-label extension (OLE) trial (NCT02736656). Viloxazine ER doses during the trials ranged from 100–400 mg/day (age 6–11 yrs) or 100–600 mg/day (age 12–17 yrs). Height and weight were evaluated pretreatment in both DB and OLE every 3 months during the OLE, and converted into percentile values and corresponding z-scores using Centers for Disease Control (CDC) normal growth curves to evaluate growth trajectories. The incidence of weight- and growth-related adverse events (AEs) terms were also evaluated.

At the time of data cut (31 July 2019), 1097 subjects had received at least one dose of viloxazine ER in the OLE (66% male, mean (SD) age 10.8 (3.06), 59% age 6–11, mean (SD) BMI 18.8 (3.42) kg/m2, height 146.7 (17.46) cm, weight 42.1 (16.01) kg. During the OLE, mean (SE) z-scores for height and weight were between -1 and 1 for all timepoints, indicating growth measures within a normal range compared with expected values. Similar results were observed when weight and height were analyzed by sex and by age categories. Growth data were available for 338 subjects at 12 months. Among these subjects, the mean (SD) change from baseline in weight-for-age z-score was -0.2 (0.5) and height-for-age z-score was -0.14 (1.1). Adverse events relevant to weight and growth in the DB trials (incidence ≥ 1%) included (viloxazine ER [100–600 mg/day] n=1117 vs. placebo n=487): decreased appetite (8.1% vs. 0.8%), nausea (5.1% vs. 2.7%), vomiting (4.7% vs. 1.4%), weight increase (0.4% vs. 1.2%) and weight decrease (1.3% vs. 0.4%), and increased appetite (0.2% vs. 1.2%). During the OLE weight-and growth-related AEs reported for ≥ 1% of subjects were: decreased appetite 5.8%, vomiting 2.7%, nausea 2.4%, weight decreased 2.3%, and weight increased 2.0%.

Over time, pediatric subjects taking viloxazine ER, on average, maintained normal weight and height relative to the CDC’s child growth charts. However, because Qelbree may affect weight, it is recommended that healthcare providers check patient weight before starting and while using viloxazine ER.

Supernus Pharmaceuticals, Inc.

Executive function deficits (EFDs) are associated with attention-deficit/hyperactivity disorder (ADHD). Viloxazine ER (viloxazine extended-release capsules; Qelbree®) is a novel, nonstimulant, FDA-approved treatment for ADHD in persons ≥6 years of age. In a Phase 3, double-blind (DB), placebo-controlled trial in adults (NCT04016779), viloxazine ER-treated subjects exhibited significant improvement in both ADHD core symptoms (inattention and hyperactivity/impulsivity) compared to placebo. In addition, improvement in EFDs was observed in subjects using the Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A, Self-report), a 75-item scale that assesses aspects of executive function (Metacognition Index [MI]) and problems with self-regulation (Behavioral Regulation Index [BRI]) and overall functioning (Global Executive Composite [GEC]). At Week 6 in DB trial, a statistically significant greater reduction (improvement) was observed in viloxazine ER-treated subjects compared to placebo in the GEC and MI, but not in the BRI. Here, preliminary results of further BRIEF-A assessments in adults during an ongoing open-label extension (OLE) safety trial (NCT04143217) are presented.

Subjects complete the BRIEF-A at baseline and at Week 6 in the DB trial, and at Week 4 and every 8 weeks thereafter in the OLE trial. Subjects rate each BRIEF-A item on a 3-point scale (1=Never, 2=Sometimes, or 3=Often) based on the last month. Raw scores for GEC, MI, and BRI (sum of 70, 40, and 30 items, respectively) were converted to a T-score (mean=50, standard deviation=10; T-score ≥ 65 considered abnormally elevated) and then to a change from (DB) baseline (CFB) T-score. The mean [±SE] CFB T-score was calculated for the GEC, MI, and BRI by study OLE visit, and the mean last on-study OLE visit was analyzed using a paired t-test.

In the OLE trial, 157 subjects received viloxazine ER (first subject dosed, 24 Jan 2020; data cut, 30 MAR 2021). The mean [±SE (n)] T-score at DB baseline between placebo and viloxazine ER groups was similar for GEC [70.9 ± 0.82 (177) and 71.0 ± 0.77 (173)], MI [73.6 ± 0.86 (178) and 74.0 ± 0.83 (173)], and BRI [63.9 ± 0.85 (177) and 63.6 ± 0.77 (174)]. The CFB T-score decreased across OLE visits in all three measures. At last on-study OLE visit, the mean [±SE (n)] CFB T-score was significantly improved for the GEC [-12.4 ± 1.23 (121); P<0.0001], the MI (-12.6 ± 1.30 (121); P<0.0001], and the BRI [-10.0 ± 1.04 (122); P<0.0001]; median viloxazine ER dose was 400 mg/day.

Following the DB trial, improvement in executive function continued during viloxazine ER treatment in adults throughout the OLE trial, including a significant improvement at subjects’ last on-study visit for overall functioning (GEC) and both indices (MI and BRI). Overall, the results suggest adults with ADHD may show improvement in executive function with viloxazine ER treatment.

Supernus Pharmaceuticals, Inc.

Currently utilized clinician-rated symptom scales for tardive dyskinesia (TD) have not kept up with the expanding spectrum of TD phenomenology. The objective of this study was to develop and test the reliability of a new instrument, the CTI.

A movement disorder neurologist devised the outline of the scale. A steering committee (four neurologists and two psychiatrists) provided revisions until consensus was reached. The resulting instrument assesses frequency of abnormal movements of the eye/eyelid/face, tongue/mouth, jaw, limb/trunk, complex movements (e.g., handwringing, self-caressing), and vocalizations. The CTI rates symptoms from 0–3 with 0 = absent, 1 = infrequent/intermittent or only present with activating maneuvers, 2 = frequent intermittent, brief periods without movements, 3 = constant or nearly constant. Functional impairments including activities of daily living (ADL), social impairment, symptom bother, and harm are rated 0–3 with 0 = patient is unaware or unaffected, 1 = symptoms mildly impact patient, 2 = symptoms moderately impact patient, 3 = symptoms severely impact patient. Following institutional review board approval, the CTI underwent inter-rater and test-retest reliability testing. Videos of patient TD examinations were obtained and reviewed by two movement disorder specialists to confirm the diagnosis of TD by consensus and the adequacy to demonstrate a TD-consistent movement. Vignettes were created to include patients’ symptom descriptions and functional, social, or occupational impairments/limitations. Four clinicians rated each video/vignette. Selected videos/vignettes were also subject to an intra-rater retest. Interrater agreement was analyzed via 2-way random-effects interclass correlation (ICC) and test-retest agreement assessment utilizing Kendall’s tau-b.

45 video/vignettes were assessed for interrater reliability, and 16 for test-retest reliability. ICCs for movement frequency were as follows: abnormal eye movement .89; abnormal tongue/mouth movement .91; abnormal jaw movement .89; abnormal limb movement .76; complex movement .87; abnormal vocalization .77; and functional impairments including harm .82; social embarrassment .88; ADLs .83; and symptom bother .92. Retests were conducted on mean (SD) 15 (3) days later with scores ranging from .66–.87.

The CTI is a new instrument with good reliability in assessing TD symptoms and functional impacts. Future validation study is warranted.

Neurocrine Biosciences

When the SARS-Cov2 virus hit the New York and New Jersey metropolitan area in Spring 2020, hospitals and hospital workers were hit hard with a new unknown pathogen that either killed people or made them very ill. There were large numbers of severely ill patients that strained resources. Hospital workers had extraordinary stress with multiple additional patients, the need to use personal protective equipment (PPE) in short supply, and faced with a pathogen that had no treatments beyond care and support initially.

We surveyed our hospital workers in late Spring 2020 to identify the main stressors and find out what measures were helpful. An online anonymous survey included questionnaires about sleep, mood, outside stressors, helpful measures, and how they coped generally. All levels of hospital workers were surveyed. Resources were provided to all respondents.

Over 240 individuals responded to the survey; most respondents were women (76%). ‘Workplace stressors’ topped the chart for 98 of our respondents. The worst workplace stressor that was cited was ‘irritable workforce,’ but ‘lack of ‘protocols’ and ‘shortage of PPE’ were also cited as stressors. ‘Other’ (not described) and ‘taking care of an ill relative’ were rated highly. Those who had ‘symptoms everyday:’ Anhedonia (loss of pleasure or interest), 13%; feeling down and hopeless, 12%; sleep disturbance, 41%; low energy, feeling tired, 29%; appetite disturbance, 26%; poor concentration and attention, 15%. Respondents told us what resources they used and what was most helpful; exercise was most frequently cited as helpful.

Various resources for formal and informal mental health support were provided to all respondents at the time of survey. Our hospital mounted its own response with support services, as did our medical school and university. A "warm line" was available through the Department of Psychiatry from late March 2020; tip sheets and online groups were widely circulated; State Department of Health provided resources. There were formal peer support sessions and workers helped each other. Medical students provided child care, shopping, and transport. We learned that extra support for workers and more frequent rest and recharge time are important. A weekly "town hall" was instituted and a weekly update about the hospital and support in healthy activities are widely circulated to employees. Those with active PTSD (some were very disturbed by the number of deceased patients) were referred to professional providers. Hospitals need to be ready to deal with epidemics and pandemics more effectively in order to mitigate stress and support workers. Being prepared, not just with equipment, but with protocols in how to proceed should another pandemic come. We learned that listening to workers is important. Workers also need to know how valued they are.

Department of Psychiatry, New Jersey Medical School

KarXT combines the M1/M4 preferring muscarinic receptor agonist xanomeline and the peripherally restricted anticholinergic trospium. In the phase 2 EMERGENT-1 study, KarXT met the primary endpoint of a significant reduction in Positive and Negative Syndrome Scale (PANSS) total score through week 5 vs placebo, improved other key secondary efficacy measures, and was generally well tolerated.

EMERGENT-2 was a phase 3, randomized, double-blind, placebo-controlled, 5-week trial of KarXT in acutely psychotic patients with schizophrenia in the inpatient setting. Eligible patients were randomized 1:1 to KarXT or matched placebo. Dosing of KarXT (mg xanomeline/mg trospium) started at 50 mg/20 mg BID and increased to a maximum of 125 mg/30 mg BID. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Key secondary endpoints included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, and PANSS negative Marder factor scores compared with placebo. Efficacy analyses were performed using the modified intent-to-treat population (patients with ≥1 dose of study medication, a baseline PANSS assessment, and ≥1 postbaseline PANSS assessment). All patients receiving ≥1 dose of study drug were included in safety analyses.

252 US patients were enrolled. KarXT demonstrated a statistically significant and clinically meaningful 9.6-point reduction from baseline to week 5 (effect size=0.61) in PANSS total score vs placebo (p<0.0001); a significant improvement in PANSS total score was demonstrated starting at week 2 (first postbaseline rating) and continued through the study end. KarXT also met key secondary endpoints. Results at week 5 included a 2.9-point reduction in PANSS positive subscale score with KarXT vs placebo (p<0.0001), a 1.8-point reduction in PANSS negative subscale score with KarXT vs placebo (p=0.0055), and a 2.2-point reduction in PANSS negative Marder factor score with KarXT vs placebo (p=0.0022). KarXT was generally well tolerated. Overall discontinuation rates were similar with KarXT (25%) and placebo (21%). The overall treatment-emergent adverse events (TEAEs) rate for KarXT and placebo was 75% and 58%, respectively. Discontinuation rates related to TEAEs were similar between KarXT (7%) and placebo (6%). Rates of serious TEAEs were similar with KarXT and placebo (2%, each group); no serious TEAEs were determined to be drug related. The most common TEAEs (≥5%) with KarXT were all mild to moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, blood pressure increases, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea. KarXT was not associated with sedation/somnolence, weight gain, and extrapyramidal symptoms.

KarXT has the potential to be the first in a new class of treatments for patients with schizophrenia and a promising alternative to postsynaptic dopamine D2 receptor antagonists.

Karuna Therapeutics, Inc.

Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we summarize ongoing clinical research characterizing the efficacy and safety of ulotaront as a member of the novel trace amine-associated receptor 1 (TAAR1) agonist class.

Summarized are results from a double-blind, placebo-controlled study to evaluate the efficacy and safety of ulotaront (50 mg or 75 mg) in an acute exacerbation of schizophrenia, and a 6-month, open-label follow-up study. Also summarized are post-hoc analyses evaluating negative symptom efficacy, and key safety and adverse event (AE) outcomes.

In the short-term study, treatment with ulotaront was associated with significant (p<0.001) endpoint improvement in the PANSS total score (effect size [ES]: 0.45), the CGI-Severity score (ES: 0.52) and the Brief Negative Symptom Scale total score (ES: 0.48). The incidence of any AE was lower on ulotaront versus placebo (45.8% vs. 50.4%), and the number needed to harm (NNH) for individual AEs on ulotaront were all >40. Ulotaront was associated with lower risk for antipsychotic class-related AEs (extrapyramidal symptoms, akathisia, somnolence, nausea/vomiting, increased weight/metabolic labs, prolactinemia). The 6-month study demonstrated further improvement, with a completion rate (67%) that was higher than reported for current dopamine D2 antipsychotics.

The emerging profile of ulotaront is characterized by significant improvement in positive and negative symptoms of schizophrenia. The safety and tolerability profile of ulotaront is markedly different with respect to antipsychotic class-related AEs. The benefit-risk profile of ulotaront, as a member of a novel TAAR1 agonist class, is distinguished from antipsychotics by lack of AEs related to D2 and serotonin 5-HT2A receptor blockade.

Sunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development & Commercialization, Inc.

Trace amine-associated receptors (TAARs) are a family of G-protein-coupled receptors (GPCRs) first identified in 2001. TAAR1 has emerged as a promising therapeutic target due to its ability to modulate monoaminergic and glutamatergic neurotransmission. Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we provide a brief review of the discovery of ulotaront and preclinical research suggesting efficacy in schizophrenia, leading to the first clinical trial of ulotaront resulting in FDA Breakthrough Therapy Designation.

Ulotaront was discovered through a target-agnostic approach optimized to identify drug candidates that demonstrate an antipsychotic-like profile in vivo but lack D2 and 5-HT2A receptor antagonism. Ulotaront was further characterized by in vitro pharmacology, electrophysiology, behavioral, and imaging studies.

Ulotaront demonstrated an antipsychotic-like profile in a high-throughput, phenotypic behavior screening platform, as well as efficacy in preclinical models of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition of acoustic startle, and subchronic PCP-induced deficits in social interaction. Although not fully elucidated, ulotaront’s mechanism of action appears to be mediated by agonism at trace amine-associated 1 (TAAR1) and 5-HT1A receptors. This was further corroborated with whole cell patch clamp recordings, demonstrating inhibition of dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) neuronal firing via 5-HT1A and TAAR1 receptors. Furthermore, ulotaront attenuated the ketamine-induced increase in striatal dopamine synthesis capacity, suggesting that it may modulate presynaptic dopamine dysfunction which is hypothesized to contribute to the pathophysiology of schizophrenia.

Preclinical studies have identified ulotaront as a TAAR1 agonist with antipsychotic-like activity. Ulotaront’s unique receptor profile led to its designation as a member of the new “-taront” class of TAAR1 agonists, distinct in pharmacology from the D2/5-HT2A class of antipsychotics. A companion poster will summarize the efficacy and safety of ulotaront based on initial clinical trials in schizophrenia.

Sunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development & Commercialization, Inc.

Solriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The wake-promoting mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to further elucidate the molecular targets activated by solriamfetol and compare them to that of known WPAs and traditional stimulants.

In vitro binding and functional studies were conducted in a panel of cell lines or membrane preparations expressing transmembrane receptors and monoamine transporters to measure the activity of solriamfetol, comparator WPAs, and traditional stimulants. Electrophysiology studies were conducted in slice preparations from mouse ventral tegmental area (VTA). Studies to measure locomotor activity and wake-promoting effects were conducted in mice.

In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity. Solriamfetol (1–10 μM) dose-dependently inhibited the firing frequency of dopaminergic VTA neurons in mouse brain slices, similar to known TAAR1 agonists; however, these effects were inhibited by a D2 antagonist, suggesting a DAT-mediated effect. Unlike traditional stimulants, solriamfetol did not increase locomotor activity in naive mice, but inhibited the increase in locomotor activity in DAT knockout mice.

Preclinical studies have identified agonist activity at the TAAR1 receptor and, possibly, lower potency agonist activity at 5-HT1A receptors as potential pharmacological targets for solriamfetol, in addition to its activity as a DAT/NET inhibitor. Given the current understanding of TAAR1 agonists as modulators of monoamine transmission with potential wake-promoting effects in multiple preclinical species, agonist activity at the hTAAR1 receptor may represent an additional pharmacological target underlying the wake-promoting effects for solriamfetol, in addition to its DNRI activity.

Axsome Therapeutics, Jazz Pharmaceuticals

Currently approved treatments for schizophrenia (antipsychotics) have demonstrated effectiveness for treating positive symptoms; however, these agents are largely ineffective in treating other domains. Negative symptoms, including avolition, alogia, blunted affect, and asociality, are difficult to treat, and often persist despite adequate control of positive symptoms. Additionally, some patients experience “predominant” (moderate-to-severe negative symptoms that have greater relative severity than co-occurring positive symptoms) or “prominent” (severity of negative symptoms [moderate-to-severe] without any reference to positive symptoms) negative symptoms. These symptoms are known to have great impact on patient social functioning and quality of life, and are associated with poorer clinical course and outcomes for patients. Here, we examined inpatient healthcare resource utilization in patients with schizophrenia experiencing predominantly negative symptoms (PNS).

De-identified data were extracted from electronic health records in the NeuroBlu Database across 25 US mental healthcare providers. Positive and negative symptom data were derived from free-text records using natural language processing. PNS was defined as the presence of three or more negative symptoms and three or fewer positive symptoms at first clinical contact following schizophrenia diagnosis. Groups were balanced for baseline demographic and clinical characteristics by minimizing the generalized Mahalanobis distance and compared using chi-square and t-tests. Treatment patterns were visualized using Sankey diagrams.

A total of 4444 patients with schizophrenia were identified and 8% were classified as PNS. A balanced cohort of 720 patients (50% PNS) was generated. Patients with PNS were more likely to be hospitalized in the 12 months following diagnosis (PNS: 76%, non-PNS: 60%, χ2: 22.5, p < 0.001) and were switched to a second-line antipsychotic after a shorter first-line treatment duration. The most frequently prescribed antipsychotics differed between groups (PNS: risperidone, aripiprazole, haloperidol; non-PNS: risperidone, olanzapine, other atypical).

This study demonstrates that negative symptoms in schizophrenia may be associated with worse illness course and higher healthcare resource utilization. There remains a need for new treatment options for patients with persistent, prominent, or predominant negative symptoms which specifically improve this historically hard-to-treat and assess symptom domain.

Sunovion Pharmaceuticals, Inc.

Tardive dyskinesia (TD) is a persistent and often disabling hyperkinetic movement disorder associated with prolonged exposure to dopamine receptor blocking agents (e.g., antipsychotics, antiemetics). The use of anticholinergics for the treatment of movement disorders including TD is a common practice, despite a lack of supportive evidence and the potential to worsen TD. Moreover, there are now FDA-approved medications specifically indicated for TD. Two virtual meetings were held with movement disorder experts from neurology and psychiatry to better understand the real-world use of anticholinergics for TD.

In November 2020, a panel of eight experts was convened to gather insights on the challenges of differentiating TD from other drug-induced movement disorders (DIMDs) and to discuss appropriate treatments for TD and other DIMDs. A follow-up meeting was held in June 2021 to consolidate these insights. Key recommendations based on the panel discussions are presented.

The panel emphasized that while anticholinergics can help with managing some DIMDs, current evidence indicates that they are not effective in TD and may even worsen symptoms. Therefore, FDA-approved vesicular monoamine transporter 2 (VMAT2) inhibitors like valbenazine were recommended by the panel as first-line TD therapies. The panel noted that TD is often grouped under the term “extrapyramidal symptoms,” which leads to difficulty in differentiating TD from other DIMDs and the inappropriate treatment of TD with anticholinergics. The panel agreed that prophylaxis with anticholinergics is only appropriate in patients at high risk of acute dystonia. However, chronic anticholinergic use should be avoided whenever possible due to potentially serious adverse effects (e.g., cognitive difficulties) and anticholinergic burden, particularly in older patients. The potential for abuse, addiction, and diversion should also be considered when prescribing anticholinergics. Abrupt anticholinergic discontinuation can result in cholinergic rebound, which is characterized by sleep disturbances, gastrointestinal problems, urinary urgency, and manifestations of DIMDs. Thus, when used appropriately (e.g., for acute dystonia), anticholinergics should be prescribed at minimally effective doses and slowly tapered for successful discontinuation.

These findings align with the current TD treatment guidelines, including the lack of evidence for anticholinergic use and recommended first-line treatment with approved VMAT2 inhibitors. Conclusions from this panel highlight educational needs across HCPs on the phenomenology of DIMDs, the inappropriate use of anticholinergics for TD, TD risks and assessment, and treatment strategies for TD.

Neurocrine Biosciences, Inc.

The value of the unpaid labor performed by caregivers is estimated to be at least $306 billion annually, nearly double the combined costs of home health care ($43 billion) and nursing home care ($115 billion). However, studies show caregivers are at risk of developing high levels of physical, emotional, and mental strain, which can negatively impact their role, quality of life, and increase medical costs.

The project aims to determine if giving informal caregivers non-pharmacological interventions such as self-guided bibliotherapy, stress reduction interventions, and improving health literacy will reduce the role strain of informal adult caregivers and improve their quality of life.

This project employed a mix-method design focusing on the role strain and quality of life of relatives and friends assisting individuals with neurocognitive or mental health disorders. The subjects engaged in weekly self-guided activities for 8 weeks, and responded to survey questions regarding demographics, depression, anxiety, and stress levels. Personal health information (PHI) was not obtained. The subjects were required to answer qualifying questions. A $5 Amazon gift card was given to participants who completed the project.

Seven people enrolled in the project, but only four participated. All participants were female. Two were African Americans, one Caucasian, and one Hispanic. All four participants completed the pre-test, demographic surveys, and intervention. However, only two completed the post-test survey. One participant completed the pre-test and post-test on the same day at the end of the project.

Descriptive statistics were employed for the data analysis due to the small sample size. A non-parametric 2-independent sample test was used because of the small sample size. The test did not show any statistical significance between the variables in the pre-and post-test DASS-21 after the intervention. Subjects reported the project intervention was “helpful.” Another participant said she could not fully engage in the interventions because of family obligations. Still, she enjoyed the resources, such as the weekly NAMI family support group meetings given by the SI. The pre-test DASS-21 mean score for N=3 was 26 and standard deviation was 15.62.

The current COVID-19 has led to an increase in mental health issues. Because of the overwhelming increase in mental health cases, many individuals with mental health problems are being turned away. The decrease in the availability of mental health providers has led to an increased need for informal caregivers. However, studies show stress from caregiving can negatively affect the health of caregivers and result in loss of work productivity. However, specialized support for caregivers is frequently limited. Brown et al. (2016) said nonpharmacological self-help interventions such as bibliotherapy, stress-reduction techniques, and health literacy training could improve caregivers’ health. Therefore, lawmakers and healthcare professionals need to come up with interventions to help caregivers.

No Funding

Medication nonadherence is a public health concern and can impact clinical trial data quality. Traditional compliance collection (pill counts, diaries) can be unreliable in central nervous system trials. As such, strategies such as adherence technologies may play a key role in trial outcomes. AiCure, a computer vision-assisted dosing mobile application (app), collects dosing data and connects patients to sites for dosing support. Phone-based computer vision algorithms confirm dosing and transfer videos for artificial intelligence and human review. Boehringer Ingelheim is partnering with AiCure on pilot trials using AiCure adherence data to improve patient retention and clinical trial data quality. Here we report initial findings.

This pilot used data from two Phase II trials on the efficacy and safety of BI 409306 in people with schizophrenia (NCT03351244) or Attenuated Psychosis Syndrome (NCT03230097). The AiCure mobile app alerted participants to dosing protocols. The dose event was visually confirmed, providing sites a real-time view of adherence and allowing for targeted outreach and intervention. Adherence data from the first 2 weeks generated quantitative, machine-learning models to predict the individual adherence over the trial. Predictive modeling explored different monitoring periods (7-, 10-, and 14-day) and adherence cutoff points (0.8, 0.7, 0.6).

Initial AiCure assessment identified 43% of participants in NCT03351244 as ≤80% compliant (definition of compliance >80% compliant). Variance in adherence rates between electronic case report forms (eCRF; 78%) and AiCure (26%) data was also observed in the highly compliant/adherent group in NCT03230097. Using the first 2 weeks of adherence data (both studies combined), a participant’s adherence predicted their average adherence for the remainder of the trial. Observation of a participant’s adherence for the latest 4 weeks predicted the probability of premature dropout from the trial. There were further correlations of lower predicted adherence with actual disposition-based dropouts.

The early adherence predictive model (0.6 adherence cutoff) identified 22%, 20%, and 19% of patients for trial NCT03351244 (total n=235) as high-risk patients (low-adherence prediction) across 7-, 10-, and 14-day monitoring periods, respectively. Of those high-risk patients, 81%, 90%, and 96%, respectively, were truly nonadherent based on actual adherence data. The 14-day monitoring period model provided the lowest false omission rate, indicative of a better performing model.

AiCure data provided insights into patient behavior and adherence patterns which would not be available via CRF. Predictive models developed with AiCure adherence data can identify and predict future poor adherers. This creates opportunities to plan interventions and mitigation strategies to improve patient adherence during trials, thereby providing test drugs the best opportunity at proving efficacy.

Boehringer Ingelheim International GmbH (NCT03351244/1289-0049 and NCT03230097/1289-0032)

Pediatric psychiatric inpatients are among the most vulnerable individuals in society. While the use of seclusion and restraint is well chronicled in the field of research in this population, there is limited literature describing the effects, meaning, and attitudes of mandating the wear of clothing in hospital settings. This research explores the phenomenon of the practice of mandatory wear of hospital-issued clothing and its meaning to patients and the awareness and attitudes of this practice among staff caring for this population. This research aims to improve understanding of the experiences of patients regarding this practice at a large, urban hospital providing care for children using a mixed methods design. A qualitative, descriptive phenomenological analysis was conducted through individual interviews with adolescent patients (N = 5) on an inpatient psychiatric unit. Additionally, a cross-sectional self-reported questionnaire examined the awareness and attitudes toward this practice among unit staff (N = 41). The patients’ attitudes toward clothing restrictions was predominantly negative, noting a lack of self-expression, feeling like a mental health patient, desires to wear ones’ personal clothing, and feelings of shame and punishment. Among the staff there was a modest correlation between age, number of years practicing as a health professional, and years practicing in a pediatric setting with feelings of a need for a change in the clothing policy to allow patients to wear their own clothing on admission. Staff age and number of years working at the institution demonstrated a modest correlation between awareness of legal statutes regarding patients’ rights to their own clothing. This research found a readiness among staff to adopt a clothing policy that would permit patients to wear their own clothing on admission, which would improve the negative experiences described among the patients in the sample.

No Funding

Flibanserin, a serotonin antagonist currently indicated for treatment of female sexual dysfunction disorder, has not heretofore been described to worsen cerebellar function. Such a case is presented.

A 60-year-old woman, 8 months prior to presentation, had an acute onset of fainting and hitting her head into a wall without loss of consciousness. She could not stand up, had left-sided weakness, and vomiting, with garbled, slow speech and severe headache. Findings in the emergency room showed a left cerebellar parenchymal hemorrhage of 3.2 x 3.1 x 2 cm with the epicenter at the dentate nucleus, extending medially towards midline into the cerebellar vermis, with surrounding perilesional edema extending into the middle cerebellar peduncle. Also, 5.2 cm of the hemorrhage extended from the petrous of the tentorium to the cerebellar vermis. Moreover, a ventral left thalamic hemorrhage with subependymal clot at the foramen of Monroe extended into the dependent portion of lateral ventricles without midline shift. Post one month of physical therapy, speech, walking, and coordination improved but she continued to have delayed speech and trouble getting up, with a wide stance.

Neurologic Examination: Cranial Nerve (CN) Examination: CN XI: Sternocleidomastoid hypertrophy, horizontal titubation. Motor examination: Drift test: L pronator drift with L abductor digiti mini sign. Gait examination: heel walking, dystonic posture of L hand. Tandem gait: unstable, wide based. Cerebellar examination: Both (B) finger-to-nose dysmetria, Left > Right. Slow rapid alternating movements (RAM) L Upper Extremity (UE). Due to absent sexual desire she started 100 mg of flibanserin nightly. Maintaining this for 5 weeks, her coordination markedly worsened with poor balance and a need for a cane to ambulate. She would stumble, with a wider gait, and found climbing stairs challenging. Physical examination displayed worse cerebellar function: prominent horizontal titubation. Finger-to-nose—dysmetria L>R. Decreased RAM, L UE. Markedly positive Holmes Rebound phenomenon, Bilateral UE. Tandem gait: unstable. A week post stopping flibanserin, gait and cerebellar examination returned to baseline.

The temporal correlation between the use of flibanserin and transient worsening of cerebellar function strongly suggests that this is the causative agent. Since serotonin is essential in cerebellar function, including its action on the cerebellar cortex and deep cerebellar nuclei, it strongly suggests that its action as a serotonin antagonist is the mechanism whereby flibanserin is causing cerebellar symptoms. In those on flibanserin, investigation to detect the presence of cerebellar dysfunction is warranted. Assessment for the presence of cerebellar dysfunction in those who are on anti-serotonin drugs, such as cyproheptadine and methysergide, may be worthwhile.

No Funding

Delusional hypergeusia has not heretofore been reported.

A 62-year-old right-handed woman described a plethora of complaints after exposure to a solvent aroma, including headaches, diffuse weakness, fatigue, hallucinated smells and tastes, burning mouth syndrome, and panic attacks. The apogee of her symptoms was that salty taste was 800% of normal, making food taste disgustingly salty. She was unable to tolerate potato chips, pizza, spaghetti sauce, Coca Cola, root beer, Sprite, 7 Up, and even bottled water. Sugar was also too sweet, 600% of normal. Foods which were unbearably sweet included cookies, sugar, and breakfast cereals. Sour and bitter were normal.

Abnormalities in Neurological Examination: Mental Status Examination: hyperverbal, loud, overly inclusive, irritable with pressured speech; disheveled, racing thoughts, and tangential. Motor Examination: Drift Test: right pronator drift with right abductor digiti mini sign. Gait Examination: heel walking with bilateral decreased arm swing. Reflexes: bilateral quadriceps femoris 3+, positive left (L) Hoffman’s reflex. Chemosensory Testing: Olfaction: Brief Smell Identification Test: 12 (normosmia). Retronasal Olfactory Testing: Retronasal Smell Index: 1 (Anosmia). Gustatory Testing: Propylthiouracil Disc Taste Test: 10 (normogeusia). Waterless Empirical Taste Test: sweet: 4, sour: 3, salty: 7, bitter: 5, brothy: 0, total: 30 (ageusia to umami, otherwise normogeusia). Neuropsychiatric Testing: Go-No-Go Test: 2/6 (abnormal).

Perhaps hypergeusia may not have been true hypergeusia but a misperception of retronasal smell associated hyperosmia with physiologic synesthesia manifested as taste. Peradventure, the perceived hypergeusia, is just one component of a generalized delusional paradigm, where many sensory perceptions are intensified. The perceived delusional hyperosmia may be intensification of the sensory misperception due to an underlying dysgeusia. This may represent a variant of the two-factor hypothesis of delusions whereby a distorted sensory perception is then misrepresented in a delusion. Dysfunction of the right hemisphere, which normally acts to censor the left, allows the delusion to manifest. While two different anatomical abnormalities (one left and one right hemisphere) have been postulated to be the foundation of such delusions, it is distinctly possible that a single lesion of the inferior parietal lobule may be sufficient for both sensory distortions to be produced as well as loss of inhibition of delusional interpretation of distorted sensation of the frontal lobe by the right parietal lobe, yclept the sensorialist hypothesis. In those who present with hypergeusia, search for delusional origin is warranted and in those who present with delusions, query as to perceived hypergeusia may be revealing.

No Funding

Episodes of acute agitation can occur in individuals who suffer from schizophrenia or bipolar disorder and these can be a significant challenge for patients and for those who provide care to them. Sublingual dexmedetomidine is a selective alpha2-adrenergic receptor agonist that was recently approved by the US Food and Drug Administration for the treatment of agitation in adults with schizophrenia or bipolar disorder. The sublingual form of dexmedetomidine does not undergo first-pass hepatic metabolism, thus resulting in greater absorption than when ingested. In two Phase 3 studies of adults with schizophrenia or bipolar disorder, sublingual dexmedetomidine significantly reduced acute agitation at 2 hours, as measured by the five-item Positive and Negative Syndrome Scale-Excited Component (PEC). When initially appraising the potential utility of a new medication, number needed to treat (NNT) and needed to harm (NNH) can be helpful to assess the size of the treatment effect and, hence, clinical relevance.

Calculation of NNT and NNH through post hoc analysis of Phase 3 data.

Post hoc analysis of data were performed on data from two double-blind, randomized, placebo-controlled studies of sublingual dexmedetomidine in adults with schizophrenia or bipolar disorder experiencing acute agitation. Patients were randomized to a single dose of sublingual dexmedetomidine 180 μg, 120 μg, or placebo. The primary endpoint was mean change from baseline in the PEC total score. A therapeutic response was defined as a ≥40% reduction from baseline in PEC total score at 2 hours. NNT was calculated for PEC response rate for sublingual dexmedetomidine versus placebo. NNH was calculated using the incidence of adverse events for sublingual dexmedetomidine versus placebo. Likelihood to be helped or harmed (LHH) was calculated as the ratio of NNH to NNT.

NNT (95% CI) was 3 (2, 3) for 180 mcg and 3 (3, 4) for 120 ug in patients with schizophrenia and 3 (2, 3) for 180 mcg and 4 (3, 6) for 120 ug in patients with bipolar disorder. NNH was greater than 10 for all AEs except somnolence, where NNH was 7 (5, 10) for all doses pooled from both studies. LLH values were greater than 1 for efficacy versus applicable tolerability outcomes in all cases.

This post hoc analysis demonstrated favorable NNT and NNH values for sublingual dexmedetomidine. In all instances therapeutic response was encountered more frequently than any adverse event. These values compare favorably to similar analyses for other approved agents for the treatment of agitation associated with schizophrenia or bipolar disorder, including intramuscular and inhaled formulations.

BioXcel Therapeutics, Inc.

Schizophrenia affects individuals, families, and systems, with treatment primarily being antipsychotic medications. Long-acting injectable (LAI) antipsychotics are increasingly being used. This study sought to identify predictors of antipsychotic choice, in terms of formulation (LAI vs oral) and class (FGA vs SGA), and clinical outcomes.

123 patients who received LAI antipsychotics were diagnosis-matched to patients who received oral antipsychotics. Sociodemographic and clinical factors were extracted from the medical record, including indicators of illness severity. Groups were compared with Chi-Square and t-tests, and logistic regression models were used to identify independent predictors of antipsychotic choice.

Patients that received LAIs had longer admissions, more complex discharges, and greater illness severity; however, there were no differences in readmission rates. Independent predictors of LAIs included younger age, being single, and longer admission. Patients who received FGA LAIs were more likely to use substances and be undomiciled compared to SGA LAIs, with the only predictor being older age. Oral FGAs were more likely than oral SGAs to be prescribed to older and female patients, as well as those with co-occurring substance use, complex discharges, and longer admissions.

Illness severity and duration of illness appear to drive choice of LAI vs. oral antipsychotic medication and FGA vs. SGA. While LAIs were prescribed to patients with greater illness severity, readmission rates were equivalent to those receiving oral medication, supporting the use of LAI in patients with greater illness severity. Rationales for prescribing LAIs to younger patients and FGAs to older patients are discussed.

No Funding

Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Three valbenazine capsule strengths (40 mg, 60 mg, 80 mg) are approved for the once-daily treatment of TD. However, some patients with TD, especially in elderly populations, have trouble swallowing due to orolingual movements. This study was conducted to evaluate two different dissolution methods for valbenazine: whole intact capsules versus crushed capsule contents.

Samples were prepared using two commercial lots (Lot-A, Lot-B) for two doses (40 mg, 80 mg), with six replicate samples per lot and dose. The whole capsules were weighed, put into a sinker, and added to a dissolution bath containing 900 mL of 0.1N HCl at 37±0.5° Celsius. Testing on the crushed capsule contents commenced after opening the capsules, weighing and crushing the contents, and transferring the contents to the dissolution bath. Samples were collected (at 10, 15, 20, 30, 45, and 60 min) with a paddle speed of 50 rpm and analyzed using high performance liquid chromatography. Standards were prepared at nominal concentrations of 0.044 mg/mL (for 40 mg) and 0.089 mg/mL (for 80 mg).

Capsules were opened easily by manual manipulation, and contents were crushed easily between spoons. Very rapid (>85% in 15 min) and complete drug release was observed in all samples, independent of capsule strength (40 mg, 80 mg) or preparation (whole intact capsule or crushed capsule contents). For 40-mg capsules, average percent release at first and last collection timepoints were as follows (whole vs crushed): 10 min (98.4% vs 98.6% [A], 93.7% vs 97.6% [B]); 60 min (102.3% vs 100.5% [A], 100.9% vs 100.6% [B]). Results for 80-mg capsules were as follows: 10 min (98.2% vs 99.6% [A], 99.4% vs 97.9% [B]); 60 min (102.0% vs 101.6% [A], 103.2% vs 100.9% [B]).

Crushing the capsule contents did not impact the in vitro dissolution performance of valbenazine. Many patients with TD, particularly elderly patients, have difficulty swallowing and may benefit from alternative delivery methods for valbenazine, especially if other TD medications cannot be crushed. More research is needed to better understand if and how crushing the capsule contents of valbenazine affects their stability when mixed with food or delivered through a feeding tube.

Neurocrine Biosciences, Inc.

Chronic insomnia (CI) often co-occurs with depression and anxiety, and treatment may positively impact mood. This ongoing study collected real-world data on changes in insomnia, depression, and anxiety symptoms among adults with CI treated with a prescription digital therapeutic (PDT) delivering cognitive-behavioral therapy for insomnia (CBT-I; Somryst®, previously SHUTi).

This prospective, single-arm, pragmatic clinical study enrolled adults (≥18 years) in the US with CI and mobile device access. The PDT consists of six core modules completed over 6–9 weeks. In this interim analysis, participants completed the Insomnia Severity Index (ISI), 8-item Patient Health Questionnaire (PHQ-8), and Generalized Anxiety Disorder-7 scale (GAD-7) and other self-reported outcomes—at screening (baseline/prior to Core 1), end of treatment (Day 63), and 6-month follow-up (Day 243).

Mean ISI scores decreased (p<0.0001) from baseline (n=991) to post-treatment (n=777;18.8 vs 11.3) and to Day 243 (n=193; 18.8 vs 12.1). Mean GAD-7 scores improved from baseline to Day 63 (n=744; p<0.0001, Cohen’s d = 0.48) and to Day 243 (n=186; p<0.0001, d = 0.45). Similarly, PHQ-8 scores improved from baseline to Day 63 (n=747; p<0.001, d = 0.76) and to Day 243 (n=186; p<0.0001, d = 0.60). These patterns persisted across baseline anxiety and depressive severity levels among people with any baseline depressive or anxiety symptoms (all p<0.05 for depression, all p<0.0001 for anxiety), with large effect sizes observed for severe anxiety (d=1.43 Day 63, d=1.55 Day 243) and for moderate to severe depression (d range = 0.96-1.51).

In this study, treatment with digital CBT-I was associated with significant reductions in ISI, anxiety, and depression at posttreatment and at 6 months. The largest observed decreases in GAD-7 and PHQ-8 scores were among people with more severe baseline mood symptoms.

Pear Therapeutics (US), Inc.