reSET-O® is an FDA-authorized prescription digital therapeutic (PDT) for opioid use disorder (OUD) providing cognitive behavioral therapy as an adjunct to buprenorphine therapy. This analysis describes differences in inpatient hospitalization rates over a 2-year period between patients treated with the PDT and those who were not.

A real-world claims analysis using the HealthVerity Private Source 20 database compared inpatient hospitalization rates (including intensive care unit stays and rehospitalizations) in patients who filled a reSET-O prescription (“cases”) to patients not filling their prescription (“controls”). Index date was date of reSET-O initiation for cases, and prescription date for controls, from January 1, 2019 to June 30, 2020. Pre- and post-index incidence rates of HCRU were compared with the incidence rate ratio (IRR) using a repeated-measures negative binomial model, adjusted for age, sex, region, payer type, Charlson comorbidity index (CCI) score, and number of similar services in the 12 months pre-index with an offset for number of days in the 12-month post-index period. Adjusted differences in inpatient hospitalizations in cases vs. controls were evaluated at 3-month intervals beginning at 12 months pre-index through 12 months post-index, using a difference in differences (DID) approach.

In this analysis, 901 cases (median age 36 years, 62.4% female, 73.9% Medicaid recipients, 95% treated with buprenorphine in the post-index period) were compared with 978 controls (median age 38 years, 55.1% female, 65.4% Medicaid recipients, 95% treated with buprenorphine in the post-index period). Incidence rate ratios of inpatient stays trended lower in later pre-post comparison periods among cases (IRRs 0.80, 0.95, 0.87, and 0.75 at 3-, 6-, 9-, and 12 months pre-post, respectively), and trended higher in later pre-post periods in controls (IRRs 0.93, 0.83, 0.86, 0.88 at 3-, 6-, 9-, and 12-month intervals respectively). The DID for controls vs. cases during the 12-month post interval compared to the 12-month pre-index rates, represented a 44% lower incidence of inpatient hospitalizations vs. controls between the first and last quarters of observation.

This difference in difference analysis showed a lower 12-month pre-post incidence rate ratio of inpatient hospitalizations for patients using reSET-O vs. controls, and a 24-month change in quarterly inpatient hospitalizations in reSET-O patients that was almost half that of controls.

Pear Therapeutics (US), Inc.

This analysis examined the impact of a digital therapeutic for treating chronic insomnia (currently marketed as Somryst®, at the time called Sleep Healthy Using The internet [SHUTi]) on healthcare resource use (HCRU) by comparing patients treated with the digital cognitive behavioral therapy for insomnia (dCBTi) to patients not treated with dCBTi, but with insomnia medications.

A retrospective observational study using health claims data was conducted in two cohorts across the United States: patients who registered for dCBTi (cases) between June 1, 2016 and October 31, 2018 (index date) vs. patients who did not register for dCBTi but initiated a second prescription for an insomnia medication in the same time period (controls). Observation period was 16–24 months. No other inclusion/exclusion criteria were used. Control patients were matched using a nearest neighbor within-caliper matching without replacement approach. Incidence rates for HCRU encounter type were calculated using a negative binomial model for both cohorts. Costs were estimated by multiplying HCRU by published average costs for each medical resource.

Evaluated were 248 cases (median age 56.5 years, 57.3% female, 52.4% treated with sleep-related medications) and 248 matched controls (median age 55.0 years, 56.0% female, 100.0% treated with sleep-related medications). Over the course of 24 months post-initiation, cases had significantly lower incidences of inpatient stays (55% lower, IRR: 0.45; 95% CI: 0.28–0.73; P=0.001), significantly fewer emergency department (ED) visits without inpatient admission (59% lower; IRR: 0.41; 95% CI: 0.27–0.63; P<0.001), and significantly fewer hospital outpatient visits (36% lower; IRR: 0.64; 95% CI: 0.49–0.82; P<0.001). There was also a trend for fewer ambulatory surgical center visits (23% lower; IRR: 0.77; 95% CI: 0.52–1.14; P=0.197) and fewer office visits (7% lower; IRR: 0.93; 95% CI: 0.81–1.07; P=0.302) with the use of SHUTi. Use of sleep medications was more than four times greater in controls vs. cases, with 9.6 (95% CI: 7.88–11.76) and 2.4 (95% CI: 1.91–2.95) prescriptions/patient, respectively (P<0.001). All-cause per-patient HCRU costs were $8,202 lower over 24 months for cases vs. controls, driven primarily by a lower incidence of hospitalizations (-$4,996 per patient) and hospital outpatient visits (-$2,003 per patient).

Patients with chronic insomnia who used a digital CBTi treatment had significant and durable real-world reductions in hospital inpatient stays, ED visits, hospital outpatient visits, and office visits compared to matched controls treated with medications.

Pear Therapeutics (US), Inc.

Cognitive impairment is a major determinant of poor functional outcome in schizophrenia and there are currently no available pharmacotherapies. Deficits in glutamatergic signaling play a key role in the neuropathology of cognitive symptoms. Iclepertin (BI 425809), an inhibitor of glycine transporter-1, enhances glutamatergic signaling by increasing synaptic levels of the N-methyl-D-aspartate receptor co-agonist, glycine. A 12-week, Phase II trial (NCT02832037) in 509 patients with schizophrenia demonstrated that iclepertin was well tolerated and significantly improved cognition. The Phase III CONNEX program aims to confirm the efficacy, safety, and tolerability of iclepertin in improving cognition and functioning in a larger cohort of patients.

CONNEX consists of three replicate randomized, double-blind, placebo-controlled parallel-group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) currently stable on antipsychotic treatment. Each trial aims to recruit ~586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug; ≥35 days on current dose prior to treatment), who have functional impairment in day-to-day activities, and interact ≥1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological, or other disorders, or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centers across 32 countries in Asia, North and South America, and Europe, and randomized 1:1 to receive either oral iclepertin 10 mg (n=293), or placebo (n=293) once daily over 26 weeks. The primary efficacy endpoint is change from baseline (CfB) in the MATRICS Consensus Cognitive Battery overall composite T-score. Key secondary efficacy endpoints are CfB in Schizophrenia Cognition Rating Scale total score and CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety and tolerability data will be collected in an open-label safety extension study (CONNEX-X).

The studies are currently recruiting (first patients enrolled Aug–Sept 2021), with completion expected in Q2 2024. Here we present an overview of the current study status, including any information relating to screening failures, and the experience of collecting these data as part of a large multi-country, multi-center study.

To date, most large, industry-sponsored studies testing various compounds to address cognitive function have failed to show proof-of-clinical concept. Demonstration of efficacy of iclepertin in improving cognition in this Phase III program would provide important insight into the role of glutamate in cognitive symptoms that may also have relevance for other cognitive disorders. Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia.

Boehringer Ingelheim International GmbH (1346-0011, NCT04846868; 1346-0012, NCT04846881; 1346-0013, NCT04860830)

There are currently no approved pharmacotherapies to treat cognitive impairment associated with schizophrenia (CIAS). Iclepertin (BI 425809) is a novel glycine transporter-1 inhibitor under development for treatment of CIAS. A previous study demonstrated pro-cognitive effects of iclepertin in patients with schizophrenia; however, concurrent cognitive stimulation could in theory enhance any pro-cognitive pharmacological effects on neuroplasticity. We present preliminary demographics and baseline data from a trial exploring the efficacy of iclepertin together with at-home computerized cognitive training (CCT).

This is an ongoing Phase II, double-blind, placebo-controlled, parallel-group trial in patients with schizophrenia on stable antipsychotic therapy across ~58 centers in 6 countries. Patients aged 18–50 years, compliant with CCT during the run-in period (completing ≥2 hours/week for 2 weeks), were randomized (1:1) to receive once-daily iclepertin 10 mg or placebo together with CCT for 12 weeks. Thereafter, minimum compliance for at-home CCT is 1 hour/week, with a target of ~30 hours across 3–5 sessions totaling 2.5 hours/week. Patients have been stratified to balance potential effects of age (18–40; 41–50 years). Primary endpoint is change from baseline (CfB) in neurocognitive composite T-score of the MATRICS Consensus Cognitive Battery (MCCB) at Week 12. Secondary endpoints include CfB in the Schizophrenia Cognition Rating Scale (SCoRS) total score, MCCB overall composite T-score, and Positive and Negative Syndrome Scale (PANSS) total scores. Novel exploratory endpoints include the Virtual Reality Functional Capacity Assessment Tool to assess daily functioning and the Balloon Effort Task to assess motivation in cognitive performance.

Of the planned sample of 200 randomized patients, the overall treated population currently includes 183: 67% (n=122) are male; mean (standard deviation [SD]) age and time since first diagnosis are 38.2 (7.9) years and 13.5 (8.5) years. Overall, 49% (n=89) are White and 43% (n=79) are Black or African American; 80% (n=147) are from North America, 15% (n=28) from Europe, and 4% (n=8) from Australia/New Zealand. Mean (SD) baseline MCCB neurocognitive composite and overall T-scores (n=178) are 33.7 (11.9) and 32.5 (12.6). Mean (SD) baseline SCoRS total score (n=167) is 35.2 (8.7). Mean (SD) baseline PANSS total and negative symptom scale scores (n=183) are 64.7 (14.6) and 17.3 (5.4). Median (Q1, Q3) CCT compliance over the on-treatment period for patients who have completed or discontinued early is 2.00 (1.21, 2.51) hours/week.

This trial is, to our knowledge, the largest of its kind combining daily pharmacotherapy for CIAS with at-home CCT. It will indicate whether iclepertin together with concurrent cognitive stimulation provides enhanced cognitive benefit, and whether any improvements in neurocognition can translate into improved measures of daily functioning in patients.

Boehringer Ingelheim International GmbH (NCT03859973/1346-0038)

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is often associated with numerous medical and psychiatric comorbidities. Patients with OSA experience a variety of symptoms that can be burdensome and affect their quality of life and satisfaction with care. Excessive daytime sleepiness (EDS) is a common symptom of OSA, and can persist despite primary airway therapy (e.g., positive airway pressure [PAP]). This analysis aimed to characterize common comorbidities, as well as symptoms present at OSA diagnosis and their burden in a real-world population of participants with OSA.

US residents (≥18 years of age, self-reported clinician diagnosis of OSA [from 1/1/2015 to 3/31/2020]) completed a survey in Evidation Health’s Achievement app that assessed self-reported sleepiness (Epworth Sleepiness Scale [ESS]), self-reported PAP usage, self-reported physician-diagnosed comorbidities, and information on their symptoms at time of OSA diagnosis. Self-reported PAP use was categorized as nonuse (no PAP use), nonadherent (<4 h/night or <5 d/wk), intermediate (4–6 h/night, ≥5 d/wk), or highly adherent (≥6 h/night, ≥5 d/wk). EDS was defined as ESS score >10. All data were summarized descriptively.

In total, 2289 participants completed the survey (50.3% female; 82.5% White; mean ± standard deviation [SD] age, 44.8 ± 11.1 years; mean ± SD age at OSA diagnosis, 40.7 ± 11.4 years; mean ± SD body mass index, 35.4 ± 8.7 kg/m2); 42.5% had EDS. Among the total population, 30.6% were PAP non-users, 6.7% were nonadherent, 9.8% were intermediate adherent, and 52.9% were highly adherent. Across the study population, the most common self-reported physician-diagnosed comorbidities were anxiety (44%) and depression (42%) followed by hypertension (39%), dyslipidemia (26%), and asthma (21%). Among the symptoms participants reported having had at the time of OSA diagnosis, the most common were EDS (79%), fatigue (79%), snoring (75%), and awakening with a dry mouth or sore throat (63%). Concentration/Memory problems (48%) and mood changes (46%) were also common. In the overall population, the symptoms present at the time of OSA diagnosis that were most likely to be highly burdensome were fatigue (53%), EDS (46%), snoring (35%), difficulty concentrating/memory issues (31%), and mood changes (25%).

These real-world survey data identify anxiety and depression as the most frequently reported comorbidities in a population of participants with OSA, each affecting over 40% of participants. In addition to classic OSA symptoms (e.g., EDS, fatigue, snoring, and awakening with dry mouth/sore throat), concentration/memory problems and mood changes were also common at the time of OSA diagnosis and were among the presenting symptoms most frequently reported as highly burdensome, along with fatigue, EDS, and snoring.

Axsome Therapeutics and Jazz Pharmaceuticals

Obstructive sleep apnea (OSA) is a sleep disorder that is highly comorbid with psychiatric disorders, including depression and anxiety. Excessive daytime sleepiness (EDS) is common in psychiatric disorders and OSA. In participants with OSA, EDS can persist despite use of positive airway pressure (PAP) therapy. This analysis of real-world data aimed to describe EDS and its relationship with PAP use in participants with and without depression.

US residents (≥18 years of age, self-reported physician diagnosis of OSA [from 1/1/2015 to 3/31/2020]) completed a survey in Evidation Health’s Achievement app assessing subjective levels of sleepiness (Epworth Sleepiness Scale [ESS]) and self-reported PAP usage, categorized as nonuse (no PAP use), nonadherent (<4 h/night or <5 d/wk), intermediate (4-6 h/night, ≥5 d/wk), or highly adherent (≥6 h/night, ≥5 d/wk). ESS score >10 defined EDS. A linear model assessed relationships between PAP use and ESS score. P-values are uncontrolled for multiplicity (nominal).

In total, 2289 participants (EDS, n=972; no EDS, n=1317) completed the survey (50.3% female; 82.5% White; mean±standard deviation [SD] age, 44.8 ± 11.1 years). Anxiety and depression were the most common comorbidities and were more common in participants with EDS (49% and 49%, respectively) than those without EDS (41% and 37%, respectively). Overall, EDS was more common among participants with comorbid depression (49%) than those without (38%), even among highly adherent PAP users (46% vs 30%, respectively). In a linear model (PAP users only), an additional 1 h/night of PAP use was associated with lower ESS scores in the subgroup of participants without depression (n=928; estimate [SE], −0.42 [0.09]; P<0.05), but not in the subgroup with depression (n=661; estimate [SE], −0.15 [0.10]; P>0.05). In a sensitivity analysis that excluded participants using medications that cause sleepiness, PAP use was associated with lower ESS scores regardless of depression status; however, EDS remained more common in participants with comorbid depression (46%) than in those without (36%).

In this real-world population of participants with OSA, those with EDS were more likely to have comorbid anxiety or depression. EDS was more common in participants with comorbid depression than those without, even with highly adherent PAP use. PAP use was associated with lower ESS scores in participants without comorbid depression, but not in those with comorbid depression; the use of medications that cause sleepiness may contribute to but does not fully explain this phenomenon.

Axsome Therapeutics and Jazz Pharmaceuticals

Genetics, environment, and lifestyle each contribute to human behaviors. We have developed a direct-to-consumer genetic assay (Mental Health Map) that allows users to explore their genetic behavioral predispositions and potential interventions that may positively influence mental health and wellness. Based on preliminary consumer feedback suggesting increased desire to take action on their mental health and wellness, we initiated a pilot study to assess several measures of mental health and self-care in individuals both before and after reviewing their Mental Health Map.

This was a virtual case series in adults who purchased a Mental Health Map. Subjects served as their own control based on survey responses leading up to genetic testing and up to 7 weeks after an introductory coaching session. Coaching included a demonstration of how to navigate the interactive online report, discussion of key results, and provision of additional external resources as appropriate. The co-primary measures were changes in quality of life as measured by WHO-5, report of initiating a discussion or seeking mental health care with a health care provider, report of initiating and sustaining positive lifestyle changes, and subjective improvements in stress management, sleep quality, mood, focus, and social interactions. Secondary measures were changes in GAD-7 and PHQ-9.

Twenty-seven individuals completed the study. Average WHO-5 at baseline was 41.2 which numerically increased to 48.3 at week 7, suggesting improved quality of life, but this effect was not statistically significant. 42.3% of individuals were in treatment with a mental health provider at the time of survey. Of those not in treatment, 33.3% were actively seeking professional mental healthcare prompted by the coaching session. At week 6, 87% of survey respondents (n=15) asserted that they continued to make lifestyle changes that improved stress; 74% made changes to improve mood and 80% made changes that improved their habits. Percentage of respondents who reported lifestyle changes to improve sleep, focus, and social interactions were all less than 70%. In secondary outcomes, average GAD-7 at baseline was 8.9 and decreased to 6.7 at week 7, while PHQ-9 averaged 10.3 at baseline and decreased to 7.5 at week 7. Neither of the secondary outcome measures achieved a statistically significant difference.

Despite the small patient population, this pilot study provides proof-of-concept that Mental Health Map and the accompanying coaching session encourages participants to make positive lifestyle changes and prompts pursuit of a healthcare professional. We also saw numerical trends toward modest improvements in quality of life, anxiety, and depression symptoms, although these differences were not statistically significant, and may require larger sample sizes.

Genomind

Bipolar disorder (BP) is a chronic and recurrent psychiatric disorder characterized by manic/hypomanic and depressive episodes with or without mixed features. Despite high levels of functional disability associated with BP, internal and external stigma can create barriers to successful recovery. This retrospective, observational social listening study was conducted to understand how stigma-related terms correlated with discussion of therapeutic interventions and psychosocial domains associated with functional recovery in unprompted, online conversations by self-identified bipolar disorder patients.

A comprehensive search was performed for publicly available, online conversations posted on forums, blogs, message boards, and the social media platforms Facebook and YouTube between 1/1/2019 and 9/30/2021. Digital interactions of anonymous self-identified BP-diagnosed patients were analyzed to identify associations between common themes and sentiments related to BP and stigma. An index value (baseline=100) was calculated based on the expected correlation between the rate that a stigma-related concept was used in BP conversation versus general online conversation. An index value >100 indicated higher correlation than statistically expected; index values <100 indicated lower correlation than expected.

A total of 257,964 conversations from 30,710 patients with BP were identified for analysis (mean, 8.4 BP-I posts per individual/year). The most prevalent stigma-related terms in patient conversations were guilt (6.9%), frustrated/discouraged (1.8%), shame (1.1%), and exhaustion (1.1%). Stigma-related terms over-indexed in conversations attributed to bipolar patients (e.g., guilt=708, denial=563, embarrassment=480); stigma-related terms were also over-indexed in relapse-related conversations (e.g., stressed=184, shame=141, and frustrated/discouraged=124). Social/familial topics (47.2%) were discussed as often as medical/psychological interventions (48.7%) and medication (42.8%). Medical intervention-related conversations were not highly correlated with stigma, except in areas of insurance/disability. Stigma-related terms were over-indexed in conversations related to social/familial relationships (e.g., isolation/loneliness=134, guilt=132), and jobs/school (e.g., embarrassment=190, stigma=184, overwhelmed=154, shame=142, isolation/loneliness=140).

These analyses describe the pattern by which stigma appears in patient perceptions of psychosocial and medical/therapeutic domains. Stigma significantly associates with psychosocial domains related to functional recovery, but not with patient perceptions of therapeutic interventions. Thus, stigma may act as a barrier between symptomatic remission and functional recovery. The patient-provider therapeutic alliance represents a trusted channel and an opportunity through which patients should be supported in overcoming stigma-related barriers to functional recovery.

AbbVie

Approved therapeutics for bipolar depression are associated with a range of undesirable side effects. Lumateperone (LUMA), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. The efficacy of LUMA in bipolar depression was previously established in two Phase 3 trials, as monotherapy (NCT03249376) and as adjunctive to lithium or valproate (NCT02600507).

A recent Phase 3 multi-center trial, Study 401 (NCT02600494) investigated the efficacy and safety of LUMA in bipolar depression and comprised a 6-week, randomized, double-blind, placebo-controlled period and a 6-month open-label extension (OLE) period. Here, we report the results of the OLE period, examining long-term safety.

Patients, aged 18–75 years, with a clinical diagnosis of bipolar I or II disorder who were experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and a Clinical Global Impression Scale-Bipolar Version, Severity [CGI-BP-S] score ≥4) were eligible for Study 401. Patients who completed the double-blind study were eligible for direct rollover into the OLE or were re-screened if completing the double-blind period prior to the initiation of the OLE. During the OLE, LUMA 42 mg was administered once-daily in the evening for 25 weeks.

The primary objective was safety and tolerability of LUMA as measured by incidences of adverse events (AEs) and changes in laboratory parameters, cardiometabolic measurements, electrocardiogram (ECG), and vital signs. The secondary objective was improvement/maintenance of symptoms of depression as measured MADRS and CGI-BP-S Total scores.

A total of 127 patients were enrolled in the OLE, with 74 (58.3%) completing the study. Treatment-emergent AEs (TEAEs) occurred in 73 patients (57.5%) with 54 (42.5%) experiencing a drug-related TEAE. TEAEs that occurred in ≥5% of patients were headache, dry mouth, dizziness, nausea, somnolence, anxiety, and irritability. Most TEAEs were mild or moderate in severity. Extrapyramidal-symptom-related TEAEs were rare. Most patients who had normal metabolic laboratory values at baseline remained normal during the treatment period. Mean changes in blood pressure, pulse rate, ECG, and body morphology were minimal. Symptoms of depression improved as measured by the mean change from baseline to Day 175 in MADRS Total score (−8.9) and CGI-BP-S Total score (−2.3).

In patients with bipolar depression, long-term LUMA treatment was generally well tolerated with low risk of extrapyramidal symptoms, weight gain, and cardiometabolic effects. These data further support the safety, tolerability, and effectiveness of LUMA in patients with bipolar depression.

Intra-Cellular Therapies, Inc.

The Doctor Dolittle delusion, of animals conversing with the sufferer, has not heretofore been reported to occur with heroin intoxication.

This 23-year-old right-handed single male used heroin daily since the age of 19. For 2 years prior to presentation, 1 hour after injecting at least one bag of heroin IV, he developed hallucinations of animals talking to him. The voices would occur simultaneously with moving their mouths. Dogs would bark, cats would meow, and birds would squawk his name. Insects would engage him in friendly conversation. Different pitches of voice were produced from each animal; birds were high-pitched; squirrels, insects, and cats were lower-pitched; dogs were medium-pitched. As his intoxication resolved, the hallucinations also evaporated.

Mental Status Examination: Oriented x 1, able to recall five digits forwards and three digits backwards. Able to remember none of four objects in 3 minutes without reinforcement and three with reinforcement. Able to spell the word “world” forwards but not backwards.

The hallucination of animals talking, coincident with their mouths moving, articulating the words, associated with intoxication with high doses of heroin, with resolution with elimination of heroin, suggests opioid intoxication is the causative factor. The mechanism of zoopsia in Parkinson’s disease has been attributed to dysfunction of the inferior longitudinal and inferior fronto-occipital fasciculi which relay visual information from the occipital cortex to the temporal and the orbitofrontal cortices. Heroin may have induced cortical inhibition, disinhibiting such pathways and thus facilitating these hallucinations. The simultaneous congruent auditory and visual hallucinations suggests a central origin of these, controlling both the auditory and visual system, such as the left superior and middle temporal gyrus, or possibly the cerebellar vermis. What is unique about the current description is that multiple animal and insect species were involved, and that the pitch of their voice was species specific (high-pitched in birds, and low-pitched in rodents and insects). The pitch may reflect the individual’s personal hedonics towards the type of animal or the individual’s interpretations of mass media’s representation of these animals (i.e., cartoons of Looney Toons high-pitched Tweety Bird or Disney’s low-pitched Jiminy Cricket). While it is possibly due to the opioids themselves, heroin is frequently adulterated with fillers which may contain hallucinogenic properties, any of which may have been the pathogenic factor. Autophobia, or the need for social contact, may be the nidus motivating such communicative anthropomorphism. Query as to the presence of such Doctor Dolittle hallucinations in those with heroin or other intoxicants may be revealing.

No Funding

Electroconvulsive therapy (ECT) continues to be one of the most effective treatments for severe and treatment-resistant major depression. Although there are no absolute contraindications to performing ECT, the risks and benefits need to be assessed in all patients. We present a patient with a history of paroxysmal nocturnal hemoglobinuria (PNH) with significant thrombocytopenia, who completed an index course of six ECT sessions without complication. Currently, there are only two published case reports which describe the use of ECT in patients with thrombocytopenia.

AD is a 37-year-old female with a history significant for MDD, GAD, panic disorder, PNH, and Budd Chiari, who presented to ED for suicidal ideation. Initial labs showed pancytopenia (Hb 4.56 mg/dl, Absolute Neutrophil 0.7 x 103/mL). Given her history of multiple failed SSRIs, ECT was proposed to treat her depression. Anesthesia delayed her initial pre-operative assessment due to concerns regarding her platelet count and risk of bleeding. They recommended transfusion with a preprocedural platelet count goal of 50 x 103/mL. Psychiatry recommended a platelet goal of 20 x 103/mL given previous ECT literature. Patient underwent six ECT sessions without complications. Her platelets ranged from 24–40 x 103/mL and she did not require preprocedural platelet transfusion.

Due to a lack of published literature, there are no formal guidelines for performing ECT in thrombocytopenic patients. The first case report details a 64-year-old female who underwent 12 ECT sessions without complication, while her platelet count ranged from 7–38 x 103/mL. The most recent case report describes a 74-year-old male who underwent nine ECT treatments without complications. The authors decided to transfuse prophylactically if pre-procedure platelet count was less than 20 x 103/mL. The patient underwent nine treatments, requiring eight transfusions. CT head did not show any signs of hemorrhage or structural changes. The authors remarked it is unclear whether the transfusions were necessary.

Even though ECT has been in use for over 80 years, there is still much that is unknown about this treatment modality. This case highlights the lack of absolute contraindications to performing ECT. However, the lack of literature and studies regarding platelet goals in thrombocytopenic patients for ECT delayed patient care in this specific case. We add a third case report in a thrombocytopenic patient who underwent ECT without complications with a pre-procedure transfusion criterion if platelet count was less than 20 x 103/mL. More research needs to be conducted to determine risk and cut-off limits for platelet transfusion prior to performing ECT in thrombocytopenic patients.

No funding

Viloxazine ER (viloxazine extended-release capsules (Qelbree®) is a novel, nonstimulant, FDA-approved treatment for attention-deficit/hyperactivity disorder (ADHD) in adults and children ≥6 years of age. Viloxazine ER inhibits cytochrome P450-1A2, the enzyme responsible for caffeine metabolism. In a Phase 1 study, the peak exposure (Cmax) of caffeine was unchanged, while the systemic total exposure (AUC) was shown to increase ~5-fold following coadministration of caffeine (200mg) with viloxazine ER (900 mg/day x 4 days) compared to caffeine alone. Except for insomnia (44.4%), and possibly dizziness (8.3%), the incidence of adverse events (AEs) was not notably higher following coadministration vs. either caffeine or viloxazine ER alone. The objective of this analysis was to evaluate the impact of caffeine consumption on the incidence of AEs in adults with ADHD treated with viloxazine ER.

Data were analyzed from the Phase 3, double-blind (DB), placebo-controlled trial (NCT04016779) and ensuing (ongoing) open-label extension (OLE) safety trial (NCT04143217) supporting the viloxazine ER indication for adults with ADHD. Participants reported caffeine intake during the past week at each study visit.

Correlation was assessed between viloxazine ER dose (mg/day) and weekly total caffeine consumption (mg) and between ADHD Investigator Symptom Rating Scale (AISRS) Total score and caffeine consumption. Fifteen AE preferred terms, known to be associated with caffeine consumption, were evaluated. For viloxazine ER-treated subjects (200–600 mg/day) who experienced a potentially caffeine-associated AE, the probability the AE occurred as a function of viloxazine ER dose and caffeine consumption during the DB or OLE trials was estimated using a logistic regression model for AEs with an incidence ≥5%.

Of 372 enrolled subjects ~85% reported caffeine use during the DB trial; mean caffeine use was 1034 mg/week for the placebo group and 859 mg/week for the viloxazine ER group. There was no correlation between viloxazine ER dose and caffeine consumption (p=0.73), nor between AISRS total score and caffeine consumption (p=0.908). Of subjects reporting caffeine use, 44 (DB placebo), 79 (DB viloxazine ER), and 33 (OLE viloxazine ER) reported any of the pre-identified caffeine- associated AEs and were included in the regression analysis. For these subjects, insomnia-related AEs, fatigue, nausea, headache-related AEs, decreased appetite, and somnolence-related AEs occurred in ≥5% of viloxazine ER-treated subjects. Based on the regression analysis, caffeine consumption significantly increased the probability of experiencing insomnia-related AEs only (p=0.02).

This analysis suggests using caffeine concomitantly with viloxazine ER does not increase the likelihood of experiencing caffeine-related AEs except for insomnia. Still patients should be aware of the potential for viloxazine ER to augment caffeine exposure.

Supernus Pharmaceuticals, Inc.

Most ADHD treatments are thought to be effective due to augmentation of dopamine (DA) and norepinephrine (NE). Our prior preclinical studies found that the ADHD treatment, viloxazine, may augment serotonin (5-HT) in addition to NE and DA; however, it was unclear if these effects occurred at clinically relevant concentrations. To further understand these potential 5-HT effects, we conducted a series of experiments with two objectives: 1) Can we confirm and better elucidate the previously observed serotonergic effects of viloxazine and determine if they occur at clinically relevant concentrations? 2) Are these effects observed in species with close physiology to humans?

Objective 1: The affinity of viloxazine for human isoforms of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors was assessed via cell-based binding assays. Viloxazine agonism of 5-HT2C and antagonism at 5-HT7 was elucidated with IP1, Ca2+, β-arrestin, internalization, and cAMP assays in cells expressing human receptor isoforms. A microdialysis study was conducted in rats to determine the relationship between viloxazine concentrations in the interstitial fluid (ISF) and changes in NE, DA, 5-HT, and their metabolite concentrations in the prefrontal cortex (PFC). Objective 2: A PET imaging study using a 5-HT2A/2C radioligand agonist, [11C]CIMBI-36, is being conducted in non-human primates (NHPs) to evaluate if viloxazine binds these receptors and/or increases 5-HT release.

Animal research was approved by animal care and use committees. Animals were cared for according to international standards.

Objective 1: Cell-based assays to measure viloxazine affinity for NET, 5-HT2B, 5-HT2C, and 5-HT7 found Ki values of 0.14, 0.65, 0.84, 1.90 μM respectively. These values were lower than therapeutically relevant rat ISF concentrations (3.5 ± 1.6 μM) approximating pediatric ADHD patients unbound plasma concentrations (2.1-3.3 μM), indicating receptor recruitment. Binding affinity and functional activity assays found viloxazine had negligible activity for 5-HT2A and SERT at therapeutic concentrations. Viloxazine 5-HT2C agonism activated Gq-protein signaling (EC50=1.6 μM, Ca2+ assay), but not β-arrestin or internalization pathways (EC50 values >150 μM). Viloxazine 5-HT7 antagonism decreased Gs-protein signaling (IC50 =6.7 μM). The microdialysis study found that at therapeutically relevant ISF concentrations, 5-HT levels were significantly increased over baseline; no changes were seen in the 5-HIAA metabolite, indicating 5-HT increase is not due to 5-HT reuptake inhibition. Objective 2: PET imaging studies are ongoing.

To date, our experiments to further elucidate the potential 5-HT effects of viloxazine have shown that the previously observed effects of viloxazine on 5-HT receptors and its augmentation of 5-HT in rat PFC occur at clinically relevant concentrations. Further exploration is needed to ascertain if these effects occur in NHPs and are relevant to ADHD.

Supernus Pharmaceuticals, Inc.

Lumateperone (LUMA) is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. An open-label study (Study 303) evaluated the safety and tolerability of LUMA in outpatients with stable schizophrenia who switched from previous antipsychotic (AP) treatment. This post hoc analysis of Study 303 investigated the safety and tolerability of LUMA stratified by previous AP in patients who switched to LUMA treatment for 6 weeks.

Adult outpatients (≥18 years) with stable schizophrenia were switched from previous AP to LUMA 42 mg once daily for 6 weeks followed by switching to another approved AP for 2 weeks follow-up. Post hoc analyses were stratified by most common previous AP: risperidone or paliperidone (RIS/PAL); quetiapine (QET); aripiprazole or brexpiprazole (ARI/BRE); olanzapine (OLA). Safety analyses included adverse events (AE), vital signs, and laboratory tests. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions-Severity (CGI-S) scale.

The safety population comprised 301 patients, of which 235 (78.1%) were previously treated with RIS/PAL (n=95), QET (n=60), ARI/BRE (n=43), or OLA (n=37). Rates of treatment-emergent AEs (TEAEs) while on LUMA were similar between previous AP groups (44.2%-55.8%). TEAEs with incidences of ≥5% in any AP group were dry mouth, somnolence, sedation, headache, diarrhea, cough, and insomnia. Most TEAEs were mild or moderate in severity for all groups. Rates of serious TEAEs were low and similar between groups (0%–7.0%).

Statistically significant (P<.05) decreases from baseline were observed in the OLA group that switched to LUMA in total cholesterol and low-density lipoprotein cholesterol with significant decreases thereafter on LUMA. Statistically significant decreases in prolactin levels were observed in both the RIS/PAL (P<.0001) and OLA (P<.05) groups. Patients switched from RIS/PAL to LUMA showed significant (P<.05) decreases for body mass index, waist circumference, and weight. At follow-up, 2 weeks after patients switched back from LUMA to another AP, none of the decreases in laboratory parameters or body morphology observed while on LUMA maintained significance.

Those switching from QET had significant improvements from baseline at Day 42 in PANSS Total score (mean change from baseline −3.47; 95% confidence interval [CI] −5.27, −1.68; P<.001) and CGI-S Total score (mean change from baseline −0.24; 95% CI, −0.38, −0.10; P<.01).

In outpatients with stable schizophrenia, LUMA 42 mg treatment was well tolerated in patients switching from a variety of previous APs. Patients switching from RIS/PAL or OLA to LUMA had significant improvements in cardiometabolic and prolactin parameters. These data further support the favorable safety, tolerability, and efficacy of LUMA in patients with schizophrenia.

Intra-Cellular Therapies, Inc.

Sleep is an important behavioral biomarker for patients with serious mental illness (SMI). The ability to accurately quantify sleep in a real-world setting could thus provide insight into patient well-being. In this study, patients in a sleep lab wore a patch that is part of a digital medicine system (aripiprazole with sensor (AS)) designed to provide objective records of medication ingestion. The patch provided accelerometer and electrocardiogram (ECG) data; polysomnography (PSG) data was collected to be used as the gold standard for sleep stage classification. The accelerometer and ECG data were used to build machine learning classification models to distinguish periods of wake from periods of sleep. To optimize these models for a real-world environment, different data sampling paradigms and methodologies were explored, and resultant model performances were analyzed.

Data was collected for a total of 220 nights, across 73 unique subjects—42 subjects had a diagnosed SMI (schizophrenia, bipolar disorder I, or major depressive disorder) and 31 subjects were healthy volunteers. PSG data, which provides a sleep stage designation at 30-second intervals, was combined into 5-minute windows, labeled as either “Sleep” or “Wake” based on which class comprised the majority of the 30-second intervals within the window. Accelerometer and ECG features were derived for each 5-minute window. Models were trained with three learning methodologies: a light gradient boosting machine (LGBM), a conditional random field (CRF), and a long short-term memory (LSTM) network. Model performance was tested with the full complement of accelerometer and ECG data, as well as down-sampled subsets of data. Additionally, ECG data from the PSG system was incorporated to test the effect of other ECG sampling strategies.

CRF models produced the best classification performance (AUC = 0.91) with the full patch dataset. Down-sampling to include less than half of the accelerometer data did begin to degrade the specificity of the model. Down-sampling to include less frequent ECG collection did not have a significant effect on model performance; however, changing the sampling paradigm to continuous ECG collection from a block sampling paradigm did lead to more robust classification of when a patient was awake.

Accurately recording sleep in a logistically simple way can provide insights into the well-being of SMI patients. Combining these insights with the objective medication ingestion records provided by AS would be of great value to SMI patients, as well as their caregivers and physicians. This research explores what amount of sensor data is required to accurately quantify sleep and some of the machine learning strategies that can ameliorate data limitations, providing guidance for the optimization of digital device design.

Otsuka Pharmaceutical Development & Commercialization, Inc.

Most FDA-approved ADHD treatments increase norepinephrine (NE) and dopamine (DA); however, our prior preclinical studies of the non-stimulant ADHD treatment viloxazine ER (Qelbree®) demonstrated that viloxazine also increases serotonin (5-HT). A prior microdialysis study showed increases in NE, DA, and 5-HT in the rat prefrontal cortex (PFC); however, the 50 mg/kg dose resulted in supratherapeutic plasma concentrations. Viloxazine is a moderate affinity selective NE reuptake inhibitor, structurally different than traditional SSRI antidepressants. Viloxazine has negligible activity at the serotonin reuptake transporter (SERT), suggesting viloxazine has a different mechanism of 5-HT PFC elevation than SSRIs. The current microdialysis study was undertaken to further characterize if viloxazine affects 5-HT and its 5-HIAA metabolite at therapeutically relevant plasma concentrations. Results are compared to similar microdialysis studies of SSRIs.

Rats were implanted with I-shaped microdialysis probes connected to a microperfusion pump, delivering artificial cerebrospinal fluid, in the PFC. After a 2-hour baseline period, viloxazine (1, 3, 10, or 30 mg/kg) was administered (ip). Dialysate samples were collected from the interstitial fluid (ISF) of the PFC before and after dosing. LC-MS/MS was used to determine the dialysate concentrations of viloxazine and viloxazine-induced changes in NE, 5-HT, and their respective metabolites, DHPG and 5-HIAA. Viloxazine plasma concentrations were also measured.

Animal research was approved by the Institutional Animal Care and Use Committee and conducted in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals.

Viloxazine administration resulted in significant dose-dependent increases in ISF NE levels and corresponding decreases in DHPG (NE metabolite) at all doses tested, reflecting viloxazine’s activity as a NET inhibitor. Viloxazine treatment also resulted in a dose-dependent elevation of ISF 5-HT levels in the PFC. Of the doses tested, 30 mg/kg was found to be clinically relevant as it induced ISF concentrations approximating unbound plasma concentrations in pediatric ADHD patients. At this dose, 5-HT levels were significantly increased over baseline and higher than vehicle levels. Coincident changes in 5-HIAA concentrations were not observed, reaffirming viloxazine’s lack of activity as a SERT inhibitor.

Viloxazine induced dose-dependent increases in NE and 5-HT in the PFC, a critical target region for ADHD therapies. At clinically relevant viloxazine plasma concentrations, 5-HT was increased in the PFC. Unlike SSRIs, which correspondingly decrease the 5-HT metabolite in the PFC (indicating serotonin reuptake inhibition), viloxazine did not affect 5-HIAA levels. Thus, viloxazine increases cortical 5-HT levels by a different mechanism than SSRIs. Whether 5-HT effects aid in viloxazine therapeutic efficacy in ADHD is yet unknown.

Supernus Pharmaceuticals, Inc.

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months, intended for the treatment of schizophrenia and maintenance monotherapy treatment of bipolar I disorder (BP-I). This 32-week trial evaluated the safety, tolerability, and pharmacokinetic profile of multiple-dose gluteal administration of Ari 2MRTU 960 in clinically stable adult patients with a diagnosis of schizophrenia or BP-I, versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the treatment of schizophrenia and maintenance monotherapy treatment of BP-I).

This was an open-label, multiple-dose, randomized, parallel-arm trial conducted at 16 sites in the US. Eligible patients (N=266) were randomized to receive Ari 2MRTU 960 every 56±2 days (n=132; 4 injections in total) or AOM 400 every 28±2 days (n=134; 8 injections in total). Safety and tolerability were evaluated throughout the study; assessments included adverse event reporting, patient reporting of injection site pain, and monitoring of extrapyramidal symptoms.

In the Ari 2MRTU group, 102 patients (77.3%) completed the study; in the AOM 400 group, 92 patients (68.7%) completed the study. The overall incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 and AOM 400 (71.2% versus 70.9%, respectively). The most frequently reported TEAEs were increased weight (22.7% for Ari 2MRTU 960 versus 20.9% for AOM 400) and injection site pain (18.2% for Ari 2MRTU 960 versus 9.0% for AOM 400), none of which were assessed as serious or severe by the investigators. All injection site pain events in the Ari 2MRTU 960 group were assessed as mild or moderate in severity; most (15.9%) coincided with the first injection and resolved within 5 days. Extrapyramidal symptom scores remained unchanged in both treatment groups.

Multiple-dose administration of Ari 2MRTU 960 was generally well tolerated in patients with schizophrenia or BP-I and did not show any new safety concerns.

Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark)

In patients with bipolar disorder, depression symptoms are associated with greater reduction in function and quality of life than hypomania/mania symptoms. Lumateperone (LUMA), is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder.

In a recent phase 3 clinical trial (Study 404, NCT03249376) in people with bipolar depression, LUMA 42 mg monotherapy significantly improved symptoms of depression compared with placebo (PBO). This analysis of Study 404 investigated the effects of LUMA on functional disability and quality of life as measured using the secondary outcome measure, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF).

Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4) were randomized to LUMA 42 mg or PBO orally, once daily in the evening for 6 weeks. The primary endpoint was the change from baseline to Day 43 in MADRS Total score, analyzed using a mixed-effects model for repeated measures (MMRM) approach in the intent-to-treat population (ITT). This post hoc analysis evaluated the mean change from baseline to Day 43 in the Q-LES-Q-SF individual item scores using an analysis of covariance with last observation carried forward (ANCOVA-LOCF) in the ITT. Categorical shifts in individual items were also analyzed.

The ITT comprised 376 patients (LUMA 42 mg, 188; PBO, 188). Patients in the LUMA 42 mg group had significantly greater improvement on MADRS Total score change from baseline to Day 43 compared with PBO (least squares mean difference vs PBO [LSMD], −4.585; 95% CI, −6.344 to −2.826; effect size vs PBO [ES], −0.56; P<.0001). LUMA 42 mg treatment significantly improved Q-LES-Q-SF Total score from baseline to Day 43 compared with PBO (LSMD, 2.9; 95% CI, 1.15 to 4.59; P=.001).

The Q-LES-Q-SF items with the lowest mean scores at baseline in both groups were mood, leisure time activities, and sexual drive, interest, and/or performance. By Day 43, LUMA 42 mg treatment significantly improved 8 of the 14 items in the Q-LES-Q-SF (P<0.05). Overall life satisfaction also significantly improved with LUMA treatment (P=.0016). The largest improvements with LUMA 42 mg compared with PBO (ES>0.3,) were seen for the ability to function in daily life, family relationships, household activities, leisure time activities, and mood (all LSMD=0.3; all P<.01).

In patients with bipolar depression, treatment with LUMA 42 mg compared with PBO significantly improved patient quality of life and functional impairment. These results support LUMA 42 mg as treatment of MDEs associated with bipolar I or bipolar II disorder in adults.

Intra-Cellular Therapies, Inc.

While seen in patients with bipolar disorder due to NMS, antipsychotic side effects, or substance use, rhabdomyolysis resulting from behaviors seen in mania has not been reported in recent literature. We present a case of a patient with rhabdomyolysis due to exertion during a manic episode.

A 29-year-old male with a history of bipolar disorder type 1 was brought to the ED in June 2022 after he was found on the roof of a local theater sharing excerpts from a book he had written. Temperatures outside were 100–102 Fahrenheit. On presentation, the patient had rapid, pressured speech and demonstrated flight of ideas. He was religiously preoccupied. He had been previously admitted to Psychiatric Emergency Services in April 2022 for mania and was discharged with lithium and lamotrigine. He had been titrating these medications with his outpatient psychiatrist.

The patient’s labs showed an elevated creatinine of 1.49, up from his baseline of 1.09. Further workup revealed an elevated CK of 3,538. Additional abnormalities included an AST of 70, calcium of 10.6, total bilirubin of 1.6, and WBC of 15.5. He was afebrile, oriented, and had no obvious signs of infection. The patient received 2 liters of Lactated Ringers (LR) and was admitted to Internal Medicine. Later, he was agitated overnight and received 10mg olanzapine and 2mg lorazepam. Lithium level following fluid resuscitation was 0.6.

On interview the next day, the patient described working on a creative religious piece that he wanted to share with others, leading to him climbing on the roof. He had been hyper-focused on this work, with 1–4 hours of sleep nightly. He also had been frequently doing gymnastics, walking long distances, and climbing other buildings. He endorsed diffuse muscle pain, but this was not reproducible on exam.

150mL/hr of LR was started, and PO fluid intake was encouraged. He agreed to resume his medications and was started on lithium 900mg and lamotrigine 50mg. His CK continued to downtrend. WBC count decreased and was 12.9 at discharge. Lamotrigine was titrated up to home dose of 100mg. His mania improved, and he was ultimately discharged home with outpatient follow-up.

Rhabdomyolysis results from the release of toxic cellular compounds from muscle fibers. Complications include acute renal failure, hyperkalemia, and compartment syndrome. Causes include substance use, medications, trauma, seizures, ischemia, overexertion, and dehydration. Recently reported cases of mania-associated rhabdomyolysis involve iatrogenic causes, such as neuromuscular malignant syndrome (NMS) and non-NMS antipsychotic side effects.Other causes include high-risk drug use during mania. Rhabdomyolysis due to behavioral manifestations of mania have been documented more rarely in older reports, similarly, addressing excessive exercise and dehydration. Therefore, our case represents a reminder of the medical sequalae resulting from actions undertaken during acute mania. This highlights the importance of implementing effective treatment to prevent such episodes.

No Funding

Accurate assessment of disability associated with Parkinson’s Disease Psychosis (PDP) is essential and has been poorly studied. Patients often have poor insight on impact of PDP on daily function. This phase 4 study is the first to evaluate the impact of pimavanserin on activities of daily living (ADL) in PDP patients.

Eligible PDP patients entered a 16-week single-arm, open-label study of oral pimavanserin (34 mg) taken once daily. Primary endpoint (modified Functional Status Questionnaire [mFSQ]) and secondary endpoints (MDS-UPDRS I & II; Schwab and England ADL; CGI-S, CGI-I, and PGI-I) were measured as change from baseline to Week 16 using mixed-effects model for repeated measures (MMRM) and least-squares means (LSM).

29 patients were treated with pimavanserin, of which 24 (82.8%) completed the study. Treated patients demonstrated significant improvements in LSM (SE) mFSQ score change from baseline to Week 12 (11.5 [2.44]) and Week 16 (14.0 [2.50]; both p<0.0001). Significant improvements (p<0.05) were also observed for all secondary outcomes at Week 16 (MDS-UPDRS Part I: -6.3 [0.97]; MDS-UPDRS Part II: -2.6 [0.98]; CGI-S: -1.5 [0.25]; CGI-I: 1.9 [0.17]; PGI-I: 2.0 [0.22], except for Schwab and England ADL. No new safety signals were observed.

Functional outcomes and psychosis measures improved in PDP patients treated with pimavanserin, with safety findings consistent with previous studies. Our findings highlight the positive effect of pimavanserin in improving ADLs in patients with PDP.

Acadia Pharmaceuticals Inc.