Showing papers by "ACADIA Pharmaceuticals Inc. published in 2021"

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies

Abstract: Objective: To evaluate response to esketamine nasal spray plus an oral antidepressant (ESK + AD) at day 28 in patients with major depressive disorder (DSM-5) and treatment-resistant depression (TRD) who did not meet response criteria within the first week of treatment. Methods: The current study is a pooled post hoc analysis of two phase 3, double-blind, active-controlled studies, conducted between August 2015 and February 2018, comparing ESK + AD with an oral antidepressant plus placebo (AD + PBO). Early treatment response was defined as a ≥ 50% decrease in Montgomery-Asberg Depression Rating Scale total score at day 2 or days 2 and 8. Response rates at day 28 were determined among those not meeting early response criteria. Results: 518 patients in the analysis had day 28 observations (ESK + AD, n = 310; AD + PBO, n = 208). A greater percentage of patients treated with ESK + AD versus AD + PBO met response criteria beginning at day 2 (17.3% [55/318] vs 9.4% [19/203]) and at all subsequent timepoints, including day 28 (58.7% [182/310] vs 45.2% [94/208]). In day 2 nonresponders, 54.9% vs 44.3% (ESK + AD vs AD + PBO, respectively) achieved response at day 28 (P < .01). Similarly, among day 2 and 8 nonresponders, 52.1% vs 42.4% achieved response by day 28 (P = .01). In nonresponders at day 2 and at days 2 and 8, the odds ratio for a response at day 28 was 1.61 (95% CI, 1.09-2.40) with ESK + AD versus 1.56 (95% CI, 1.04-2.35) with AD + PBO. Conclusions: Patients with TRD without a demonstrated response within the first week of treatment may still derive benefit from a full 4-week induction course of esketamine nasal spray. Trial Registration: ClinicalTrials.gov identifiers NCT02417064 and NCT02418585.

Pimavanserin, a 5HT 2A receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer’s disease

Abstract: Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT2A -Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT2A -R knock-out mice. The Aβ-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.

Association of Dementia-related Psychosis with Long-term Care Use and Death.

Abstract: Objective To determine the association of dementia-related psychosis (DRP) with death and use of long-term care (LTC); we hypothesized that DRP would be associated with increased risk of death and use of LTC in patients with dementia. Methods A retrospective cohort study was performed. Medicare claims from 2008 to 2016 were used to define cohorts of patients with dementia and DRP. Outcomes were LTC, defined as nursing home stays of >100 consecutive days, and death. Patients with DRP were directly matched to patients with dementia without psychosis by age, sex, race, number of comorbid conditions, and dementia index year. Association of DRP with outcomes was evaluated using a Cox proportional hazard regression model. Results We identified 256,408 patients with dementia. Within 2 years after the dementia index date, 13.9% of patients developed DRP and 31.9% had died. Corresponding estimates at 5 years were 25.5% and 64.0%. Mean age differed little between those who developed DRP (83.8 ± 7.9 years) and those who did not (83.1 ± 8.7 years). Patients with DRP were slightly more likely to be female (71.0% vs 68.3%) and white (85.7% vs 82.0%). Within 2 years of developing DRP, 16.1% entered LTC and 52.0% died; corresponding percentages for patients without DRP were 8.4% and 30.0%, respectively. In the matched cohort, DRP was associated with greater risk of LTC (hazard ratio [HR] 2.36, 2.29–2.44) and death (HR 2.06, 2.02–2.10). Conclusions DRP was associated with a more than doubling in the risk of death and a nearly 2.5-fold increase in risk of the need for LTC.

Burden of illness among patients with dementia-related psychosis.

Abstract: BACKGROUND: More than 5.6 million Americans suffer from dementia, and that number is expected to double by 2060. This comes at a considerable burden to the health care system with costs estimated at $157-$215 billion in 2010. Depending on dementia type and disease progression, approximately 20%-70% of patients experience dementia-related psychosis (DRP), characterized by hallucinations and/or delusions resulting in worse clinical outcomes and greater caregiver burden compared with patients without DRP. OBJECTIVE: To compare real-world clinical events, health care resource utilization (HCRU), and health care costs among matched cohorts of DRP versus dementia-only patients. METHODS: This retrospective database analysis examined commercial and Medicare Advantage with Part D enrollees aged ≥ 40 years with evidence of DRP and dementia from January 1, 2010, through March 31, 2017. The first observed indicator of psychosis (≥ 2 diagnoses and/or antipsychotic pharmacy fills) co-occurring with or following evidence of dementia (≥ 2 diagnoses and/or dementia medication pharmacy fills) was the index date among patients with DRP. DRP patients were propensity score matched 1:1 to patients with dementia only based on demographics, comorbidities, dementia type, dementia severity, and pre-index all-cause HCRU. Continuous health plan enrollment ≥ 12 months before evidence of dementia through the index date and ≥ 12 months following the index date was required. Outcomes included clinical events, HCRU, and health care costs. RESULTS: A significantly higher percentage of DRP patients had ≥1 diagnosis for behavioral health conditions in the pre-index period compared with dementia-only patients (depression: 32.4% vs. 22.8%; anxiety: 19.1% vs. 11.5%; and insomnia: 9.0% vs. 6.3%; P < 0.001 for all comparisons). Diagnoses of post-index clinical events were significantly more likely among DRP patients compared with dementia-only patients including falls/fractures (28.3% vs. 14.1%), neurologic effects (17.7% vs. 12.9%), sedation (15.0% vs. 2.4%), cardiovascular effects (7.0% vs. 4.1%), and extrapyramidal reactions (3.2% vs. 1.7%; P < 0.001 for all comparisons). Higher percentages of DRP patients had an all-cause outpatient visit (80.2% vs. 68.9%), emergency visit (65.0% vs. 36.6%), or inpatient stay (47.2% vs. 20.0%) during the post-index period (P < 0.001 for all comparisons). The proportions of DRP patients with a post-index dementia-related office visit, outpatient visit, emergency visit, or inpatient stay was 48%, 147%, 339%, and 286% higher, respectively, compared with patients with dementia only. Compared with patients with dementia only, patients with DRP had significantly higher mean total post-index all-cause costs ($21,657 vs. $12,026; P < 0.001) and dementia-related costs ($11,852 vs. $3,013; P < 0.001). CONCLUSIONS: Patients with DRP were more likely to have diagnoses for behavioral health conditions, experience clinical events, and have higher mean all-cause and dementia-related HCRU and costs compared with patients with dementia only. These results reflect the unmet need of patients with DRP and an urgency for new treatment options to reduce substantial clinical and economic burden in this population. DISCLOSURES: This study was funded by Acadia Pharmaceuticals, which participated in the study design, interpretation of study results, and critical review of the manuscript. Abler, Skoog, and Rashid were employees of Acadia Pharmaceuticals at the time this study was conducted. Frazer and Halpern were employees of Optum at the time this study was conducted and were funded by Acadia Pharmaceuticals to conduct the study.

Falls and Fractures in Patients with Parkinson's Disease-Related Psychosis Treated with Pimavanserin vs Atypical Antipsychotics: A Cohort Study.

Abstract: BACKGROUND Parkinson's disease-related psychosis increases patients' risk of falls. Pimavanserin is an atypical antipsychotic approved in the USA in 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease-related psychosis. OBJECTIVE We aimed to compare the risk of falls/fractures among patients with Parkinson's disease-related psychosis treated with pimavanserin vs other atypical antipsychotics. PATIENTS AND METHODS We identified a cohort of patients with Parkinson's disease-related psychosis aged ≥ 40 years initiating either pimavanserin or a comparator antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) in US commercial insurance and supplementary Medicare claims (2015-2019). Comparators were propensity score matched 2:1 with pimavanserin initiators; incidence rates of falls/fractures were compared using incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS We identified 112 eligible pimavanserin initiators and 982 comparators. Pimavanserin initiators were younger and had fewer severe comorbidities, indicators of impairment, and healthcare encounters, though they had higher Parkinson's disease medication use. The crude incidence rates [cases/100 person-years] (95% CI) for composite falls/fractures were 17.8 (7.7-35.0) for pimavanserin and 40.8 (35.0-47.4) for comparators. Matching retained 108 pimavanserin initiators and 216 comparators-all characteristics were well balanced after matching-with a matched IRR (pimavanserin vs comparator) of 0.71 (95% CI 0.27-1.67). Sensitivity analysis IRR estimates were consistently below 1.00, with a sensitivity analysis not requiring a diagnosis of psychosis resulting in an IRR estimate of 0.55 (95% CI 0.34-0.86). CONCLUSIONS The results of this study do not suggest an increase in the risk of falls or fractures associated with pimavanserin compared with other antipsychotics in patients with Parkinson's disease-related psychosis. Sensitivity analyses suggest a decreased risk.

Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy.

Abstract: Psychosis occurs across a wide variety of dementias with differing etiologies, including Alzheimer's dementia, Parkinson's dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia. Pimavanserin, a selective serotonin 5-HT2A receptor (5-HT2AR) inverse agonist, has shown promising results in clinical trials by reducing the frequency and/or severity of hallucinations and delusions and the risk of relapse of these symptoms in patients with dementia-related psychosis. A literature review was conducted to identify mechanisms that explain the role of 5-HT2ARs in both the etiology and treatment of dementia-related psychosis. This review revealed that most pathological changes commonly associated with neurodegenerative diseases cause one or more of the following events to occur: reduced synaptic contact of gamma aminobutyric acid (GABA)-ergic interneurons with glutamatergic pyramidal cells, reduced cortical innervation from subcortical structures, and altered 5-HT2AR expression levels. Each of these events promotes increased pyramidal cell hyperexcitability and disruption of excitatory/inhibitory balance, facilitating emergence of psychotic behaviors. The brain regions affected by these pathological changes largely coincide with areas expressing high levels of 5-HT2ARs. At the cellular level, 5-HT2ARs are most highly expressed on cortical glutamatergic pyramidal cells, where they regulate pyramidal cell excitability. The common effects of different neurodegenerative diseases on pyramidal cell excitability together with the close anatomical and functional connection of 5-HT2ARs to pyramidal cell excitability may explain why suppressing 5-HT2AR activity could be an effective strategy to treat dementia-related psychosis.

Increased risk of falls and fractures in patients with psychosis and Parkinson disease.

Abstract: Objective Evaluate whether the risk of falls and fractures differs between patients with Parkinson disease with psychosis (PDP) and patients with Parkinson disease (PD) without psychosis at similar disease stages. Methods Patients with PD without psychosis were identified in the Medicare claims databases (2008-2018) and followed from the first PD diagnosis date during the study period. Patients with a subsequent diagnosis of psychosis were included in the PDP group. Patients with PDP and PD without psychosis were propensity score-matched based on characteristics within blocks of time since cohort entry. The incidence rates (IRs), expressed per 100 person-years, and 95% confidence intervals (CIs) of falls and fractures were evaluated as composite and separate outcomes. Incidence rate ratios (IRRs) were used to compare patients with PDP and PD without psychosis in the matched cohort. Results 154,306 patients had PD without psychosis and no falls or fractures before cohort entry; the IR for falls and fractures was 11.41 events (95% CI, 11.29-11.53). 12,127 patients (7.8%) had a subsequent PDP diagnosis. PDP patients had a higher prevalence of most comorbidities and risk factors for falls and fractures than those without psychosis. The crude IR for falls and fractures among PDP patients was 29.03 events (95% CI, 28.27-29.81). PD without psychosis and PDP groups had more falls than fractures. After matching, 24,144 PD patients without psychosis (15.6%) and 12,077 PDP patients (99.6%) were retained. Matched PDP patients had a higher incidence of falls and fractures than PD patients without psychosis (IRR = 1.44; 95% CI, 1.39-1.49). The higher increased rate was noted separately for falls (IRR = 1.48; 95% CI, 1.43-1.54) and any fractures (IRR = 1.17; 95% CI, 1.08-1.27) as well as within specific types of fracture, including pelvis and hip fractures. Conclusions Our findings suggest a modest but consistently higher increased risk of falls and fractures in PDP patients compared with PD patients without psychosis.

Symptoms and Treatment Needs of People with Dementia-Related Psychosis: A Mixed-Methods Study of the Patient Experience.

Abstract: This study describes the person-centered experience and impact of symptoms and the treatment needs of dementia-related psychosis (DRP) from a patient and care partner perspective.Qualitative interv...

A 3-way Cross-over Study of Pregabalin, Placebo, and the Histamine 3 Receptor Inverse Agonist AZD5213 in Combination With Pregabalin in Patients With Painful Diabetic Neuropathy and Good Pain-reporting Ability.

Abstract: OBJECTIVES In this study, patients with painful diabetic neuropathy were trained using an experimental pain paradigm in an attempt to enroll a subset of patients who are "pain connoisseurs" and therefore more able to discriminate between active and placebo treatments. METHODS AZD5213, a novel histamine H3 receptor inverse agonist+pregabalin, pregabalin, and placebo were then tested in a 3-period cross-over. RESULTS The study did not provide any evidence of clinical efficacy for AZD5213 when combined with pregabalin in the treatment of painful diabetic neuropathy. DISCUSSION The training of study patients in pain reporting and subsequent enrichment with good pain reporters also did not enable the robust detection of the efficacy of pregabalin relative to placebo in a small sample size. Further work is required before recommending the use of "connoisseur" patients in future neuropathic pain studies.

Real-World Medication Treatment Patterns for Long-Term Care Residents with Dementia-Related Psychosis.

Abstract: Objectives: This study evaluated treatment patterns and factors associated with medication treatment changes in residents with dementia-related psychosis in a long-term care (LTC) setting. Methods:...

Treatment Patterns With Antipsychotics in Long-Term Care Patients With Parkinson’s Disease Psychosis:

Abstract: This study assessed treatment change patterns in Parkinson's disease psychosis (PDP) residents receiving antipsychotic (AP) therapies in U.S. long-term care (LTC) facilities. Residents with PDP in LTC between 01/01/13 and 06/30/16 were identified with ≥1 claim of psychosis, hallucinations, or delusions after PD diagnosis. Treatment patterns were evaluated during the 12 months post index. We identified 864 PDP residents: 408 (47.2%) on AP therapy and 456 (52.8%) on no AP therapy. A total of 335 residents (82.1%) continued, 13 (3.2%) discontinued, 11 (2.7%) switched, and 49 (12.0%) augmented (used ≥2 APs) their index AP therapy. Based on the multivariate regression analysis, younger age, male gender, anemia, anxiolytic use or anxiety, sedatives/hypnotic use, bladder disorders including urinary tract infections, coronary conditions, diabetes, hypertension, and dementia were associated with a higher likelihood of treatment change. Understanding the factors associated with treatment change may inform ways to improve management of PDP in the U.S. LTC setting.

Lewy Body Dementia Association's Industry Advisory Council: proceedings of the second annual meeting.

Abstract: In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council's goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.

Comparative Efficacy, Safety, Tolerability, and Effectiveness of Antipsychotics in The Treatment of Dementia-Related Psychosis (DRP): A Systematic Literature Review

Abstract: To evaluate the comparative efficacy, safety, tolerability, and effectiveness of atypical antipsychotics (AAPs) for the treatment of dementia related psychosis (DRP) in older adults. In this systematic literature review (SLR), we qualitatively synthesized evidence on the comparative efficacy (based on neuropsychiatric inventory), tolerability (weight gain), and safety (cerebrovascular adverse events [CVAE], cardiovascular events, mortality, somnolence, extrapyramidal symptoms [EPS]) of AAPs used to treat DRP. We also assessed effectiveness based on all-cause discontinuations and discontinuations due to lack of efficacy or adverse events (AE). Published articles from through March 2021 from PubMed, EMBASE, PsycINFO, and Cochrane databases evaluated. We included double-blind, active-comparator/placebo-controlled randomized trials, open-label trials, and observational studies. This qualitative synthesis included 51 eligible studies with sample size of 13,334 and mean age of 79.36 years. Risperidone, olanzapine, quetiapine, and aripiprazole demonstrated numerically small improvement in psychotic symptoms among patients with DRP. Somnolence was the most reported AE for all the AAPs, with weight gain and tardive dyskinesia more common with olanzapine and risperidone, respectively. These AAPs are associated with falls, EPS, cognitive declines, CVAE, and mortality. Aripiprazole and olanzapine had lower odds of discontinuation due to lack of efficacy, with olanzapine having greater discontinuation odds due to AEs. This SLR demonstrated that AAPs used off-label to treat DRP are associated with small numerical symptom improvement but with a high risk of AEs, including cognitive decline and potentially higher mortality. These results underscore the need for new treatments with a favorable benefit-risk profile for treating DRP.

Palatability and Swallowability of Pimavanserin When Mixed with Selected Food Vehicles: An Exploratory Open-Label Crossover Study.

Abstract: Dysphagia (difficulty swallowing) affects up to 13% of persons 65 years and older and 51% of older persons in nursing homes and can contribute to reduced adherence to oral medications. This was an exploratory, single-center, open-label, randomized, crossover study in healthy older adult participants. Primary objectives were evaluation of palatability (taste) and swallowability of the contents of pimavanserin 34 mg capsules mixed with selected soft foods or a liquid nutritional supplement. Secondary objectives included evaluation of additional palatability endpoints and ease of capsule manipulation for mixing. A total of 18 healthy, older adult participants (mean age 65 years) were included. Mean participant ratings for all food vehicles were “moderately like” to “neither like nor dislike” for palatability and “very easy” to “somewhat easy” for swallowability. Capsule manipulation to allow sprinkling of contents was rated “very easy” or “somewhat easy” by most participants. There were five treatment-emergent adverse events, all mild; two were deemed related to study treatment. The palatability and swallowability of pimavanserin was considered acceptable when administered with certain soft foods or a liquid nutritional supplement by the study participants.

Pimavanserin Promotes Trophic Factor Release and Protects Cultured Primary Dopaminergic Neurons Exposed to MPP+ in a GDNF-Dependent Manner.

Abstract: Neurodegeneration and impaired neural development are a common feature of many neuropsychiatric disorders. Second-generation antipsychotics (SGAs) and certain atypical antidepressants display neuroprotective effects. Though these drugs interact with many molecular targets, a common shared attribute is high antagonist potency at 5-HT2A receptors. Pimavanserin is a selective 5-HT2A inverse agonist/antagonist that was recently FDA approved for treating hallucinations and delusions associated with Parkinson's disease. Unlike SGAs, pimavanserin lacks activity at other targets like dopamine, histamine, muscarinic, and adrenergic receptors. To investigate whether selective 5-HT2A inverse agonists have neuroprotective properties, pimavanserin and another selective 5-HT2A inverse agonist, M100907, were applied to primary cultures of dopaminergic neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Both pimavanserin and M100907 protected dopaminergic neurons against MPP+-induced cell death. The neuroprotective effects of pimavanserin required signaling through the extracellular signal-regulated kinase 1/2 pathway, restored mitochondrial function, and reduced oxidative stress. Further investigation showed that pimavanserin promotes the release of brain-derived neurotrophic factor and glial-derived neurotrophic factor (GDNF) and that the neuroprotective effects of pimavanserin were blocked by antibodies to GDNF but not by anti-tyrosine receptor kinase B receptor antibodies. Thus, pimavanserin induces release of neurotrophic factors and protects dopaminergic neurons against MPP+ toxicity in a GDNF-dependent manner.