Alkermes (Ireland)

Background: Mismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a pre-attentive stage of auditory information processing closely linked to N-methyl-D-aspartate receptors (NMDAR). Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia and is increasingly used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude which, in turn, might reflect reduced function of NMDAR-mediated neurotransmission. Nonetheless, there is growing evidence showing MMN amplitude either having high variability or, paradoxically, moving in the opposite direction after ketamine in different individuals. Methods: In here, we analyzed results from three independent ERP studies to test the hypothesis of a cross-over interaction (″disordinal″ drug effect) between the duration-deviant MMN at baseline (without ketamine) and the direction and magnitude of the ketamine effect. To rule out regression to the mean (RTM), a statistical phenomenon that may also partially explain this cross-over interaction, we separately estimated RTM using a drug-free test-retest study. Results: Our results are the first to statistically demonstrate the existence of a disordinal drug response to ketamine, where the direction and magnitude of ketamine-induced changes in MMN amplitude can be predicted by baseline MMN amplitude. Conclusions: These new insights may contribute to novel precision medicine approaches to treatment of CNS disorders.

Abstract Introduction Narcolepsy is a chronic neurological disorder that causes debilitating daytime sleepiness among other symptoms. This study compared clinical and humanistic outcomes between those with and without narcolepsy to characterize the extent of disease burden. Methods This study was a retrospective, cross-sectional analysis of 2021/2023 US National Health and Wellness Survey data. The narcolepsy cohort included those who reported a physician diagnosis of narcolepsy. Propensity-score matching (1:3) adjusted for demographic/health characteristics between those with and without narcolepsy (controls). Chi-square tests and t-tests compared comorbidities, symptoms of depression and anxiety, and health-related quality of life (HRQoL) between groups. Results Before matching, respondents with narcolepsy (n=335; female=56%; mean age, 45.5 years; White=68%) and without narcolepsy (n=141,072; female=55%; mean age, 47.8 years; White=72%) were included. Additionally, the narcolepsy cohort had higher mean [SD] body mass index (30.1 [8.4] vs 27.6 [7.1], p<.001) and were more likely to have obesity (44% vs 28%, p<.001) and be current smokers (25% vs 17%, p<.001) than those without narcolepsy. After matching, the narcolepsy cohort reported more frequent physician-diagnosed psychiatric comorbidities vs controls, including depression (58% vs 32%, p<.001), anxiety (54% vs 33%, p<.001), and ADHD (20% vs 6%, p<.001). The narcolepsy cohort had higher reporting of moderate-to-severe depression symptoms via Patient Health Questionnaire-9 (52% vs 33%, p<.001) and moderate-to-severe anxiety via Generalized Anxiety Disorder Questionnaire-7 (41% vs 26%, p<.001). On the Brief Resilience Scale, more respondents with narcolepsy reported low resiliency scale score vs controls (43% vs 28%, p<.001). Compared with controls, the narcolepsy cohort scored lower on HRQoL measures, including mean [SD] mental health composite (32.8 [11.3] vs 40.6 [12.6], p<.001) and physical health composite (35.7 [11.4] vs 42.9 [11.6], p<.001) scores of the RAND 36-Item Health Survey. The narcolepsy cohort reported greater impairment of daily activities vs controls (51% vs 34%, p<.001). Conclusion Narcolepsy is associated with broad clinical and humanistic burden. Those with narcolepsy had more frequent psychiatric comorbidities, more severe depression and anxiety symptoms, less self-reported resiliency, and lower HRQoL. Future strategies should focus on comprehensive management that prioritizes mental health, while investigating new treatments that may improve HRQoL for narcolepsy patients. Support (if any) Alkermes, Inc.

To present the results from a randomized, double-blind, phase 1b study assessing the safety, tolerability, and pharmacodynamics of ALKS 2680 in patients with narcolepsy type 1 (NT1).

Qualitative research methods can be used to obtain a deeper understanding of patient experience by collecting information in the patients' own words about their encounters, perspectives, and feelings. In this study, patients with schizophrenia were interviewed to capture their voice and to complement the quantitative data typically obtained in clinical trials. Semi-structured exit interviews were conducted with 41 patients who completed or prematurely discontinued from a phase 3, open-label trial (NCT02873208). The interview guide included open-ended questions on current and prior disease burden, symptoms, quality of life, and treatment experiences. Steps taken to reduce interview stress and secure the validity of data included interviewer sensitivity training specific to mental health conditions and schizophrenia, use of in-person interviews whenever possible and use of videoconferencing for remote interviews to promote trust and comfort, and working closely with clinical site staff to identify patient eligibility and willingness to participate. Transcripts based on audio recordings were content coded and analyzed using thematic analysis; a post-hoc quantitative content analysis was conducted. Patients reported that the symptoms of schizophrenia negatively impacted their work, relationships, self-esteem, emotional health, and daily activities. Most patients had positive experiences with medications that alleviated hallucinations, depression, and anxiety. However, side effects of medications were associated with negative impacts on physical, emotional, behavioral, and cognitive health. Lack of energy/drowsiness, weight gain, mood changes, and involuntary movements were the most common side effects reported with the use of antipsychotic medications. Patients reported unmet treatment needs related to better symptom control and to improved social and physical functioning. Collection of qualitative information within a schizophrenia clinical development process provides value and insights into patients' views on burden of illness, experiences with previous medications, and experiences following participation in a clinical trial and can inform design for future studies.

Research has indicated a rise in the prevalence of depression and anxiety among adolescents over the past three decades. However, the factors underpinning increases in mental health difficulties remain poorly understood. This study examines psychological, social and environmental risk and protective factors that may explain changes in depression and anxiety among adolescents. Data were taken from two nationally representative My World Surveys of adolescents aged 12-19 years in 2012 (N = 5,490) and 2019 (N = 9,844). Survey data on depression and anxiety and a range of potential risk (e.g., alcohol use, psychotic symptoms) and protective factors (e.g., resilience, self-esteem) were assessed at both time points. Multiple group analyses assessed whether the predictive ability of risk/protective factors changed from wave 1 to wave 2. Results showed that the prevalence of depression and anxiety increased significantly between 2012 and 2019, particularly among females. Predictors accounted for between 37% and 61%of the variance in outcomes across waves. While some risk/protective factors were consistent predictors of depression and anxiety at both waves (e.g., bullying, discrimination, optimism), reporting female genderand having higher formal help-seeking tendencies more strongly predicted anxiety at wave 2, while lower self-esteem andlowerresilience(personalcompetence)strongly predicted both depression and anxiety at wave 2. Findings highlight the need to prioritize adolescent mental health service provision, especially in females. Self-esteem and resilience are potentially important targets for supporting adolescent mental health. Further research is required to understand the causal factors associated with increases in anxiety and depression.