Trial of Pimavanserin in Dementia-Related Psychosis.

BACKGROUND: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Pimavanserin Exposure-Response Analyses in Patients With Schizophrenia: Results From the Phase 2 ADVANCE Study.

PURPOSE/BACKGROUND: Pimavanserin is a selective serotonin 5-HT 2A receptor inverse agonist/antagonist being investigated in patients with negative symptoms of schizophrenia. This analysis aimed to characterize exposure-response relationships of pimavanserin in this population. METHODS/PROCEDURES: Exposure-response models were developed using data from ADVANCE. Patients with negative symptoms of schizophrenia receiving background antipsychotics were randomized to pimavanserin 20 mg (adjusted to 34 or 10 mg between weeks 2-8 based on efficacy or tolerability) or placebo for 26 weeks. Time-varying pimavanserin exposure measures were predicted for each patient using a population pharmacokinetic model and individual empiric Bayesian parameter estimates. Response measures were the Negative Symptom Assessment 16 (NSA-16, primary end point), Personal and Social Performance scale, negative symptoms component of the Clinical Global Impression of Schizophrenia-Severity Scale, and adverse events. FINDINGS/RESULTS: A higher pimavanserin exposure was associated with greater improvement in NSA-16 score. For a median area under the pimavanserin plasma concentration-time curve from time 0 to 24 hours of 1465 ng × h/mL for the 34-mg dose, the model predicted a 10.5-point reduction in NSA-16 score. This exposure-response relationship with NSA-16 scores was not influenced by covariates. Similar results were observed with Personal and Social Performance and Clinical Global Impression of Schizophrenia-Severity, but not to the extent as NSA-16. There was no significant exposure-response relationship with anxiety, headache, insomnia, or somnolence. IMPLICATIONS/CONCLUSIONS: Increasing pimavanserin plasma concentration was associated with improved NSA-16 scores (primary end point) in patients with negative symptoms of schizophrenia. No exposure-response relationship with select adverse events was observed.

Improvement of sexual functioning during treatment of MDD with adjunctive pimavanserin: A secondary analysis.

BACKGROUND: Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study. METHODS: Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined. RESULTS: Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo. CONCLUSIONS: Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction.

Evaluation of the efficacy of pimavanserin in the treatment of agitation and aggression in patients with Alzheimer's disease psychosis: A post hoc analysis.

OBJECTIVES: Patients with Alzheimer's disease psychosis (ADP) commonly experience concomitant agitation and aggression. We investigated whether a reduction in ADP following pimavanserin treatment conferred a reduction in associated agitation and aggression. METHODS: ACP-103-019 was a 12-week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of pimavanserin (34 mg) in reducing psychotic symptoms in patients with ADP. The primary endpoint was change from baseline in Neuropsychiatric Inventory-Nursing Home Version-Psychosis Score (NPI-NH-PS) at week six. A post hoc analysis examined whether there was a greater reduction in agitation and aggression (NPI-NH domain C [agitation/aggression] and Cohen-Mansfield Agitation Inventory-Short Form [CMAI-SF]) in pimavanserin-treated patients who experienced a reduction of hallucinations and delusions (psychosis responders defined as ≥50% reduction from baseline in NPI-NH-PS, week six) when compared with those who did not (nonresponders). RESULTS: Pimavanserin-treated patients with ≥50% response in psychotic symptoms (n = 44) showed a greater improvement in agitation and aggression symptoms on the NPI-NH domain C (week six, least squares mean [LSM] difference = -3.64, t = -4.69, P < .0001) and the CMAI-SF (week six, LSM difference = -3.71, t = -2.01, P = .0483) than nonresponders (n = 32). Differences between psychosis responders and nonresponders were also observed in patients with more severe agitation and aggression at baseline on the NPI-NH domain C (responders, n = 26; nonresponders, n = 13; week six, LSM difference = -3.03, t = -2.44, P = .019). CONCLUSIONS: Patients with ADP, who show improvement in psychotic symptoms after pimavanserin treatment, also experience an improvement in concomitant agitation and aggression.

Sparse Analyzer Tool for Biomedical Signals.

The virtual (software) instrument with a statistical analyzer for testing algorithms for biomedical signals' recovery in compressive sensing (CS) scenario is presented. Various CS reconstruction algorithms are implemented with the aim to be applicable for different types of biomedical signals and different applications with under-sampled data. Incomplete sampling/sensing can be considered as a sort of signal damage, where missing data can occur as a result of noise or the incomplete signal acquisition procedure. Many approaches for recovering the missing signal parts have been developed, depending on the signal nature. Here, several approaches and their applications are presented for medical signals and images. The possibility to analyze results using different statistical parameters is provided, with the aim to choose the most suitable approach for a specific application. The instrument provides manifold possibilities such as fitting different parameters for the considered signal and testing the efficiency under different percentages of missing data. The reconstruction accuracy is measured by the mean square error (MSE) between original and reconstructed signal. Computational time is important from the aspect of power requirements, thus enabling the selection of a suitable algorithm. The instrument contains its own signal database, but there is also the possibility to load any external data for analysis.

On Consensus-Based Distributed Blind Calibration of Sensor Networks.

This paper deals with recently proposed algorithms for real-time distributed blind macro-calibration of sensor networks based on consensus (synchronization). The algorithms are completely decentralized and do not require a fusion center. The goal is to consolidate all of the existing results on the subject, present them in a unified way, and provide additional important analysis of theoretical and practical issues that one can encounter when designing and applying the methodology. We first present the basic algorithm which estimates local calibration parameters by enforcing asymptotic consensus, in the mean-square sense and with probability one (w.p.1), on calibrated sensor gains and calibrated sensor offsets. For the more realistic case in which additive measurement noise, communication dropouts and additive communication noise are present, two algorithm modifications are discussed: one that uses a simple compensation term, and a more robust one based on an instrumental variable. The modified algorithms also achieve asymptotic agreement for calibrated sensor gains and offsets, in the mean-square sense and w.p.1. The convergence rate can be determined in terms of an upper bound on the mean-square error. The case when the communications between nodes is completely asynchronous, which is of substantial importance for real-world applications, is also presented. Suggestions for design of a priori adjustable weights are given. We also present the results for the case in which the underlying sensor network has a subset of (precalibrated) reference sensors with fixed calibration parameters. Wide applicability and efficacy of these algorithms are illustrated on several simulation examples. Finally, important open questions and future research directions are discussed.

Multifractal-based nuclei segmentation in fish images.

The method for nuclei segmentation in fluorescence in-situ hybridization (FISH) images, based on the inverse multifractal analysis (IMFA) is proposed. From the blue channel of the FISH image in RGB format, the matrix of Holder exponents, with one-by-one correspondence with the image pixels, is determined first. The following semi-automatic procedure is proposed: initial nuclei segmentation is performed automatically from the matrix of Holder exponents by applying predefined hard thresholding; then the user evaluates the result and is able to refine the segmentation by changing the threshold, if necessary. After successful nuclei segmentation, the HER2 (human epidermal growth factor receptor 2) scoring can be determined in usual way: by counting red and green dots within segmented nuclei, and finding their ratio. The IMFA segmentation method is tested over 100 clinical cases, evaluated by skilled pathologist. Testing results show that the new method has advantages compared to already reported methods.

Goethite dissolution by acidophilic bacteria.

Previous studies have reported the role of some species of acidophilic bacteria in accelerating the dissolution of goethite under aerobic and anaerobic conditions. This has relevance for environments impacted by acid mine drainage and for the potential bioleaching of limonitic laterite ores. In this study, natural well-characterized goethite mineral samples and synthetic goethite were used in aerobic and anaerobic laboratory batch culture incubation experiments with ferric iron-reducing, acidophilic bacteria, including the lithoautotrophic species Acidithiobacillus (At.) thiooxidans, At. ferrooxidans, and At. caldus, as well as two strains of the organoheterotrophic species Acidiphilium cryptum. All bacteria remained alive throughout the experiments and efficiently reduced soluble ferric iron in solution in positive control assays. However, goethite dissolution was low to negligible in all experimental assays with natural goethite, while some dissolution occurred with synthetic goethite in agreement with previous publications. The results indicate that ferric iron-reducing microbial activity at low pH is less relevant for goethite dissolution than the oxidation of elemental sulfur to sulfuric acid. Microbial ferric iron reduction enhances but does not initiate goethite dissolution in very acidic liquors.

Comparison of bioleaching of a sulfidic copper ore (chalcopyrite) in column percolators and in stirred-tank bioreactors including microbial community analysis.

Chalcopyrite is the most abundant Cu-sulfide and economically the most important copper mineral in the world. It is known to be recalcitrant in hydrometallurgical processing and therefore chalcopyrite bioleaching has been thoroughly studied for improvement of processing. In this study, the microbial diversity in 22 samples from the Sarcheshmeh copper mine in Iran was investigated via 16S rRNA gene sequencing. In total, 1063 species were recognized after metagenomic analysis including the ferrous iron- and sulfur-oxidizing acidophilic genera Acidithiobacillus, Leptospirillum, Sulfobacillus and Ferroplasma. Mesophilic as well as moderately thermophilic acidophilic ferrous iron- and sulfur-oxidizing microorganisms were enriched from these samples and bioleaching was studied in shake flask experiments using a chalcopyrite-containing ore sample from the same mine. These enrichment cultures were further used as inoculum for bioleaching experiments in percolation columns for simulating heap bioleaching. Addition of 100 mM NaCl to the bioleaching medium was assessed to improve the dissolution rate of chalcopyrite. For comparison, bioleaching in stirred tank reactors with a defined microbial consortium was carried out as well. While just maximal 32% copper could be extracted in the flask bioleaching experiments, 73% and 76% of copper recovery was recorded after 30 and 10 days bioleaching in columns and bioreactors, respectively. Based on the results, both, the application of moderately thermophilic acidophilic bacteria in stirred tank bioreactors, and natural enrichment cultures of mesoacidophiles, with addition of 100 mM NaCl in column percolators with agglomerated ore allowed for a robust chalcopyrite dissolution and copper recovery from Sarcheshmeh copper ore via bioleaching.

Pimavanserin for psychosis in Parkinson's disease dementia: Subgroup analysis of the HARMONY Trial.

INTRODUCTION: Pimavanserin is FDA-approved to treat Parkinson's disease (PD) psychosis. We analyzed the effect of pimavanserin on psychosis in the PD dementia (PDD) subgroup from the phase 3 HARMONY trial. METHODS: This subgroup analysis included PDD patients enrolled in an international, multicenter, randomized discontinuation study of pimavanserin for dementia-related psychosis. PDD patients with moderate-to-severe psychosis, age 50-90 years, received pimavanserin 34 mg/day for 12 weeks (open-label period). Those with a sustained psychosis response to pimavanserin at weeks 8 and 12 were randomized during the double-blind period to continue pimavanserin or receive placebo. Primary efficacy endpoint was time to psychosis relapse as measured by the SAPS-H + D and CGI-I. Safety was assessed, as were effects on motor symptoms and cognitive abilities using the ESRS-A and MMSE. RESULTS: 392 patients were enrolled in HARMONY (mean age: 72.6 years; 38.8 % female): 59 had PDD; 49/59 remained on pimavanserin during the open-label period (safety analysis set), and 36/49 were randomized to pimavanserin (n = 16) or placebo (n = 20) in the double-blind phase (intent-to-treat analysis set). Risk of psychosis relapse was lower with pimavanserin 34 mg compared with placebo in the double-blind phase (HR = 0.052; 95 % CI 0.016-0.166; 1-sided nominal p < 0.001). During the open-label period, 46.9 % experienced a treatment-emergent adverse event; event incidence was similar across arms in the double-blind period. Pimavanserin did not adversely affect motor or cognitive function in either treatment phase. CONCLUSIONS: Pimavanserin significantly reduced risk of psychosis relapse in patients with PDD, was well tolerated, and did not worsen motor or cognitive function.

Exposure-response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder.

In the 10-week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34 mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD-17) total score (primary endpoint) and Sheehan Disability Scale (SDS) score (secondary endpoint) versus placebo. This analysis characterized the exposure-response (E-R) relationships of pimavanserin in this CLARITY patient population. Exposure measures were estimated for each patient based on population-pharmacokinetic empirical Bayesian estimates. E-R models were developed to describe exposure-efficacy (HAMD-17, SDS, and Clinical Global Impression-Improvement [CGI-I] scale) and exposure-safety relationships (Karolinska Sleepiness Scale [KSS], Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI], and adverse events [AEs] of headache, sedation, and somnolence) relationships. For the primary efficacy endpoint (HAMD-17 scores), a sigmoid maximum-effect model described the time course of response, and a linear function of pimavanserin exposure was statistically significant. HAMD-17 scores decreased steadily over time following placebo and pimavanserin treatment; separation from placebo increased as peak pimavanserin plasma concentration (Cmax ) increased. At median pimavanserin Cmax (34-mg dose), the reduction from baseline in HAMD-17 scores was -11.1 and -13.5 at weeks 5 and 10, respectively. Relative to placebo, the model predicted comparable reductions in HAMD-17 scores at weeks 5 and 10. Similar improvements in favor of pimavanserin were detected with SDS, CGI-I, MGH-SFI, and KSS scores. No E-R relationship was found for AEs. E-R modeling predicted a relationship between higher pimavanserin exposure and improvement in HAMD-17 score and improvement across multiple secondary efficacy endpoints.

Pimavanserin for negative symptoms of schizophrenia: results from the ADVANCE phase 2 randomised, placebo-controlled trial in North America and Europe.

BACKGROUND: Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, on negative symptoms of schizophrenia. METHODS: The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18-55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete. FINDINGS: Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean -10·4 [SE 0·67]) versus placebo (least squares mean -8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]). INTERPRETATION: Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect. FUNDING: Acadia Pharmaceuticals.

Erratum to: HARMONY Study: Pimavanserin Significantly Prolongs Time to Relapse of Dementia-Related Psychosis.

[This corrects the article DOI: 10.1093/geroni/igaa057.530.].

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients.

INTRODUCTION: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. METHODS: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. RESULTS: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Blinded SAPS-PD Assessment After 10 Weeks of Pimavanserin Treatment for Parkinson's Disease Psychosis.

BACKGROUND: Parkinson's disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP. OBJECTIVE: Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study. METHODS: Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales. RESULTS: Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was - 3.4 (6.3); p < 0.0001. Mean change from Core Study baseline to OLE Week 4 for SAPS-PD was similar among prior pimavanserin- and placebo-treated patients (-6.9 vs. -6.3). Improvement was similar with CGI-I, CGI-S, CBS, and SAPS-H + D in patients previously treated with placebo. Adverse events occurred in 92 (53.8%) patients during the 4-week OLE. CONCLUSION: Improvements at OLE Week 4 from pretreatment baseline were similar with placebo and pimavanserin in the Core Study. The beneficial effects observed with pimavanserin in the 6-week Core Study were maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks.

Effect of pimavanserin on anxious depression in patients with major depression and an inadequate response to previous therapy: secondary analysis of the clarity study.

In a post hoc analysis, the effect of pimavanserin on anxious depression was determined from CLARITY, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy. Patients were randomized in a 3:1 ratio to placebo or pimavanserin 34 mg daily added to ongoing antidepressant therapy. At 5 weeks, placebo nonresponders were rerandomized to placebo or pimavanserin for an additional 5 weeks. Mean change from baseline to week 5 for the Hamilton depression rating scale (HAMD) anxiety/somatization (AS) factor was examined for all patients and those with a score ≥7 at baseline. Least squares (LS) mean [standard error (SE)] difference between placebo and pimavanserin for the AS factor score was -1.5 (0.41) [95% confidence interval (CI) -2.4 to -0.7; P = 0.0003; effect size: 0.634]. Among patients with an AS factor score ≥7 at baseline, LS mean (SE) difference was -2.2 (0.66) (95% CI -3.5 to -0.9; P = 0.0013; effect size: 0.781). Response rates (≥50% reduction in HAMD-17 from baseline) were 22.4 and 55.2% (P = 0.0012) and remission rates (HAMD-17 total score <7) were 5.3 and 24.1% (P = 0.0047), respectively, with placebo and pimavanserin among patients with a baseline AS factor score ≥7. Among patients with anxious major depressive disorder at baseline, adjunctive pimavanserin was associated with a significant improvement.

Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis.

INTRODUCTION: Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin. METHODS: This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS). RESULTS: Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years). CONCLUSIONS: Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

Effect of adjunctive pimavanserin on suicidal ideation in patients with major depression: Analysis of the CLARITY study.

BACKGROUND: Up to 15% of patients with major depressive disorder (MDD) attempt suicide and up to 2% complete suicide. This was a post-hoc analysis aimed to evaluate the risk of suicide ideation and behavior associated with adjunctive pimavanserin treatment in adults with MDD. METHODS: CLARITY was a randomized, double-blind, placebo-controlled study in patients with MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). For this post-hoc analysis, the primary endpoint was mean change from baseline for HAMD item 3 (suicide). The incidence of suicidal ideation or behavior was also assessed from the Columbia-Suicide Severity Rating Scale (C-SSRS) and reports of adverse events. RESULTS: During Stage 1, LS mean change for HAMD Item 3 was reduced from baseline at each week with pimavanserin with a significant difference between pimavanserin and placebo at Week 3 (p=0.012, effect size: 0.431). At any post-baseline assessment, suicidal ideation on the C-SSRS was reported in 28 (18.1%) of patients with placebo and 9 (17.3%) with pimavanserin during Stage 1 and in 7 (20.7%) with placebo and 4 (13.8%) with pimavanserin during Stage 2. No events of suicidal behavior were observed with either placebo or pimavanserin. LIMITATIONS: The post hoc nature, exclusion of patients with any history of suicide from the primary study, and the small number of patients who demonstrated evidence of suicidal ideation. CONCLUSIONS: Adjunctive pimavanserin was not associated with an increase in suicidal ideation in patients with MDD. Further study is needed to verify these results.

Effect of Adjunctive Pimavanserin on Sleep/Wakefulness in Patients With Major Depressive Disorder: Secondary Analysis From CLARITY.

OBJECTIVE: This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. METHODS: For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS17) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS17 insomnia factor score and KSS score, correlation between the HDRS17 insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6. RESULTS: At baseline, HDRS17 insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo. CONCLUSIONS: Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03018340.

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients With Major Depressive Disorder and an Inadequate Response to Therapy (CLARITY).

OBJECTIVE: Pimavanserin is a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist. This phase 2 study examined the efficacy and safety of pimavanserin as adjunctive therapy in patients with major depressive disorder (MDD). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5-defined MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Using a 2-stage sequential parallel-comparison design, patients were initially randomized in a 3:1 ratio to placebo or pimavanserin added to ongoing SSRI or SNRI therapy; at 5 weeks, placebo nonresponders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage in 17-item Hamilton Depression Rating Scale (HDRS-17) total score and Sheehan Disability Scale (SDS) score. RESULTS: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled Sequential Parallel Comparison Design analyses of Stages 1 and 2, the least squares (LS) mean (SE) difference for the HDRS-17 total score was -1.7 (0.85) (P = .039) and for the SDS score was -0.8 (0.29) (P = .004). At week 5 of Stage 1, LS mean (SE) difference for pimavanserin versus placebo was significant for changes on the HDRS-17 (-4.0 [1.09], P = .0003) and SDS (-1.2 [0.40], P = .0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (P < .05) occurred at 1 week. The most common adverse events with pimavanserin were dry mouth, nausea, and headache. CONCLUSIONS: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI. Tolerability was consistent with previous experience. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03018340.