Treatment Of Schizophrenia In Adults Research Articles

Exposure-Response Modeling in Adults and Adolescents With Schizophrenia to Support the Extrapolation of Brexpiprazole Efficacy to Adolescents.

In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence-based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady-state concentration)-response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure-response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease-drug-dropout models were developed using patient-level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure-response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure-response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13-17 years with schizophrenia.

Physiologically-Based Pharmacokinetic Modeling and In Vitro–In Vivo Correlation of TV-46000 (Risperidone LAI): Prediction from Dog to Human

The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in adults. Following sc injection, the copolymers together with risperidone precipitate to form a sc depot under the skin to deliver therapeutic levels of risperidone over a prolonged period of either 1 month or 2 months, depending upon the dose. This work presents the strategy and the results of the physiologically-based pharmacokinetic (PBPK) modeling and establishing of in vitro–in vivo correlation (IVIVC) for the prediction of TV-46000 pharmacokinetic profile in humans, using in vitro release, intravenous (iv), and sc single-dose pharmacokinetic data in beagle dogs. The resulting simulated TV-46000 PK profile in humans showed that the shape of the predicted risperidone and its active metabolite 9-OH-risperidone PK profiles was different from the observed one, thus suggesting that the TV-46000 release profile was species-dependent and cannot be directly extrapolated from dog to human. In conclusion, while level A IVIVC cannot be claimed, this work combining PBPK and IVIVC modeling represents an interesting alternative approach for complex injectable formulations where classical methods are not applicable.

A Long-Term Safety and Tolerability Study of TV-46000 for Subcutaneous Use in Patients with Schizophrenia: A Phase 3, Randomized, Double-Blinded Clinical Trial.

TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. In the phase 3, randomized, double-blind RIsperidone Subcutaneous Extended-release (RISE) study, TV-46000 once monthly (q1m) and once every 2months (q2m) significantly prolonged time to impending relapse compared with placebo [5.0-fold (q1m) and 2.7-fold (q2m)]. This phase 3, randomized, double-blind Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) study was designed to evaluate the long-term safety, tolerability, and exposure of TV-46000 in schizophrenia. Patients who completed RISE without relapse (rollover) or who were newly recruited (de novo) were eligible for the SHINE study. Patients were initially stabilized on oral risperidone for 12 weeks (completed in RISE for rollover, or in SHINE for de novo). Patients in the de novo cohort and patients who received placebo in RISE were randomized 1:1 in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Primary endpoint for SHINE was frequency of reported adverse events (AEs); event rates [ER; events per 100 patient-years (PYs)] were calculated for each AE by patients upon general questioning. Overall, 336patients were randomized in SHINE [TV-46000 q1m, n = 174; TV-46000 q2m, n = 162; of these, de novo, n = 109 and rollover, n = 227 (n = 172 patients were treated and n = 55 received placebo)]. A total of 334 patientswere evaluated for safety [q1m, n = 172 (PY = 97.8); q2m, n = 162 (PY = 104.5)]. Proportions of patients (ER) with ≥ 1 AE and ≥ 1 treatment-related AE were 37% (180.0) and 21% (84.9) for TV-46000 q1m and 46% (157.9) and 20% (70.8) for TV-46000 q2m, respectively. Frequent treatment-related AEs [≥ 3% of patients in either group; proportion of patients (ER)] were injection site pain [q1m, 5% (24.5); q2m, 4% (22.0)] and injection site nodule [q1m, 2% (9.2); q2m, 6%(12.4)]. The proportions of patients with serious AEs was 5% for TV-46000 q1m and 7% for TV-46000 q2m; serious AEs reported for ≥ 2 patients overall were worsening schizophrenia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]. Ofthreereported deaths, none were related to treatment. Overall, eight patients discontinued treatment because of AEs. Similar or somewhat lower rates of AEs were reported for patients who rolled over from TV-46000 treatment compared with those who had no prior TV-46000 treatment (de novo and placebo rollover). Most AEs related to injection site reactions were mild; no patient had a severe reaction. Results from this long-term safety study add to the favorable safety profiles of TV-46000 q1m and q2m, consistent with other formulations of risperidone and previous studies with TV-46000. ClinicalTrials.gov, NCT03893825; 27 March 2019.

Metabolic profiling of lumateperone in vitro and in vivo by UPLC-Q Exactive Orbitrap HRMS, and its pharmacokinetic study in rat plasma by LC-MS/MS

Lumateperone is a novel agent approved by FDA for treatment of schizophrenia in adults. To elucidate the species differences in the of biotransformation of lumateperone and its pharmacokinetic (PK) characteristics in rats, the metabolite identification of lumateperone was carried out in rat, dog and human liver microsomes, and rat plasma after oral administration using UPLC-Q Exactive Orbitrap high-resolution mass spectrometry HRMS. Furtherly, the PK characteristics of lumateperone and its N-demethylated metabolite (M3) in rat plasma were investigated using a validated LC-MS/MS method following intravenous and oral administration. Fourteen phase I metabolites were found in liver microsomes and ten of them were observed in rat plasma. N-demethylation, carbonylation, dehydrogenation, and piperazine ring cleavage were main metabolic pathway of lumateperone. No unique metabolites were formed in human liver microsomes. After rapid absorption in rats, lumateperone was quickly metabolized and eliminated with bioavailability of less than 5%. The exposure level of M3 was about 1.5-fold higher than that of lumateperone in rat plasma. Lumatperone underwent extensive metabolism and was absorbed rapidly in rats. Metabolite M3 had equivalent or slightly higher exposure levels than lumateperone. This study provides essential PK information to facilitate further pharmacodynamic researches of lumateperone.

In brief: Three new injectable antipsychotic drugs.

Three extended-release injectable formulations of second-generation antipsychotic drugs — two of risperidone (Rykindo, Uzedy) and one of aripiprazole (Abilify Asimtufii) — have been approved by the FDA for treatment of schizophrenia in adults.

The Novel Antipsychotic Lumateperone (Iti-007) in the Treatment of Schizophrenia: A Systematic Review.

Lumateperone (also known as ITI-007 or ITI-722) represents a novel second-generation medication characterized by a favorable safety and tolerability profile. This is attributed to its notable selectivity for D2 receptors within specific regions of the brain. The U.S. Food and Drug Administration (FDA) granted approval for the treatment of schizophrenia in adults in December 2019. Additionally, it gained approval for addressing depressive episodes associated with bipolar I and II disorders in adults, either as a standalone therapy or in conjunction with lithium or valproate, in December 2021. The objective of this investigation is to systematically review the existing literature to assess the safety, tolerability, and efficacy of lumateperone in the treatment of schizophrenia. Lumateperone has demonstrated effectiveness in addressing positive, negative, and cognitive symptoms associated with schizophrenia. The evaluation of safety indicators in the reviewed studies indicates that lumateperone is deemed to be a well-tolerated and safe antipsychotic. Additional research is warranted to explore lumateperone's efficacy in managing major depressive disorders, behavioral issues in Alzheimer's disease and dementia, sleep maintenance insomnia, bipolar disorders, and personality disorders.

Population Pharmacokinetic Analysis of Brexpiprazole to Support its Indication and Dose Selection in Adolescents With Schizophrenia.

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off-label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia. Using a population PK model with brexpiprazole clearance and volume of distribution allometrically scaled by body weight, PK simulations showed comparable brexpiprazole dose-exposure between adults and adolescents aged 13-17years following oral daily doses of brexpiprazole 1-4mg, indicating that the target brexpiprazole dose of 2-4mg/day in adults with schizophrenia is also suitable for adolescents. Based on this population PK analysis, together with a safety study in adolescents, the FDA approved brexpiprazole for the treatment of schizophrenia in adolescents aged 13-17years, via extrapolation of the efficacy of brexpiprazole from adults to adolescents.

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison.

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a novel long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, developed for the treatment of schizophrenia or maintenance monotherapy treatment of bipolar I disorder in adults (indication will vary by country). Aripiprazole lauroxil 1064 mg (AL 1064) is an LAI formulation of aripiprazole lauroxil, an aripiprazole prodrug, for administration once every 2 months, indicated for the treatment of schizophrenia in adults. This analysis provides an indirect comparison of aripiprazole plasma concentrations following multiple doses of either formulation. Clinical trial data were used to determine average steady-state aripiprazole plasma concentration (Cavg,ss), maximum aripiprazole plasma concentration (Cmax), and other pharmacokinetic parameters of either formulation following four administrations (96 patients received Ari 2MRTU 960; 28 patients received AL 1064). All pharmacokinetic parameters were considered in the context of a minimum aripiprazole therapeutic concentration (Cmin) of ≥95 ng/mL. An exposure-response analysis using data from two Phase III trials of aripiprazole once-monthly (an aripiprazole monohydrate LAI, administered monthly), showed that patients with a Cmin ≥95 ng/mL are 4.41 times less likely to relapse than patients with a Cmin <95 ng/mL. A similar analysis has not been performed for AL 1064. However, consensus guidelines for therapeutic drug monitoring recommend a range of 100-350 ng/mL for aripiprazole. Following four administrations, mean (standard deviation [SD]) Cavg,ss over the 2-month dosing interval was 263 (133) ng/mL for Ari 2MRTU 960 and 140.7 (57.3) ng/mL for AL 1064. Mean (SD) Cmax during the fourth dosing interval was 342 (157) ng/mL for Ari 2MRTU 960 and 188.8 (79.8) ng/mL for AL 1064. This indirect comparison showed that, following four administrations, Ari 2MRTU 960 and AL 1064 delivered mean aripiprazole plasma concentrations that remained above the minimum therapeutic concentration of aripiprazole over the 2-month dosing interval.

Med Check: Zuranolone for Depression, Uzedy for Schizophrenia, and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Zuranolone for Depression, Uzedy for Schizophrenia, and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:25 May 2023https://doi.org/10.1176/appi.pn.2023.06.6.1Zuranolone Found to Quickly Reduce Major Depression SymptomsAdults with major depressive disorder may experience mood improvements within days of taking zuranolone (50 mg/day), a study published in May in The American Journal of Psychiatry (AJP) suggests. Zuranolone is an oral, once-daily neuroactive steroid that acts on GABA-A receptors.The phase 3 trial included patients who were between the ages of 18 and 64 years, had received a diagnosis of major depressive disorder, had been experiencing symptoms of depression for a least four weeks, and had a Hamilton Depression Rating Scale (HAM-D) score of at least 24 at screening and before they started taking the assigned study medication.The researchers randomized 534 participants to take either 14 days of treatment with zuranolone 50 mg/day or placebo in the evening. The researchers evaluated the participants 10 times over the course of the 42-day trial using such assessments as the HAM-D, the Columbia–Suicide Severity Rating Scale, the Clinical Global Impressions severity score, and more.Compared with patients who took placebo, those who took zuranolone demonstrated a statistically significant improvement in depressive symptoms at day 15. “Numerically greater improvements in depressive symptoms for zuranolone versus placebo were observed by day 3 (least squares mean change from baseline HAM-D score, −9.8 vs. −6.8), which were sustained at all visits throughout the treatment and follow-up periods of the study,” the researchers wrote.FDA Approves Uzedy for Treating SchizophreniaIn April the U.S. Food and Drug Administration (FDA) approved Uzedy (risperidone extended-release injectable suspension) for the treatment of schizophrenia in adults, Teva and MedinCell announced. Uzedy is a long-acting subcutaneous antipsychotic that may be given in one- or two-month dosing intervals.In the phase 3 RISE trial, 544 patients aged 13 to 65 years with schizophrenia were randomized to receive a subcutaneous injection of Uzedy (either once per month or once every two months) or placebo. Those who received Uzedy once per month or once every two months had a reduction of 80.0% and 62.5% in the risk to relapse compared with those who received placebo, respectively. Results were similar in the phase 3 SHINE trial, which examined the long-term safety of the drug for up to 56 weeks in 336 patients aged 13 to 65 years with schizophrenia.A companion survey of participants in the SHINE trial found that 89% of patients and 92% of health professionals rated administration of Uzedy as easy when asked how easy or difficult it was to receive or administer the medication in its current form. Further, 70% of patients reported that Uzedy provided a better injection experience than their previous long-acting injectables (LAIs).Abilify Asimtufii Approved for Schizophrenia, Bipolar I TreatmentAbilify Asimtufii (aripiprazole extended release injectable suspension) has been approved by the FDA for the treatment of schizophrenia in adults and as a monotherapy treatment of bipolar I disorder in adults, Otsuka and Lundbeck announced in April. Abilify Asimtufii is a long-acting subcutaneous atypical antipsychotic that may be given every two months.The approval was based on safety and efficacy data from trials of Abilify Maintena, which is for once monthly dosing, and on the results of a phase 1-2 study. In the phase 1-2 study, 266 adults with schizophrenia or bipolar I disorder were randomly assigned to receive either Abilify Asimtufii 960 mg every 56 days, for a total of four injections or Abilify Maintena 400 mg administered every 28 days for a total of eight injections. Treatment with Abilify Asimtufii resulted in similar aripiprazole plasma concentrations and efficacy to Abilify Maintena. ■ ISSUES NewArchived

Cariprazine (Vraylar)

CADTH recommends that Vraylar not be reimbursed by public drug plans for the treatment of schizophrenia in adults. Vraylar was discussed at the March 2022 meeting of the CADTH Canadian Drug Expert Committee (CDEC) and reconsidered at the July 2022 meeting. Based on evidence from 5 clinical trials, treatment with Vraylar improved symptoms of schizophrenia or delayed relapse compared with placebo. Vraylar also improved negative symptoms of schizophrenia compared with risperidone. Although these results were statistically significant, it is not clear whether any of these effects result in a clinically meaningful improvement in patient-identified needs. It is not clear whether cariprazine offers any clinical benefits over other treatments that are available for schizophrenia because there were no clinical trials in patients with acute schizophrenia that compared Vraylar with any other treatments. The committee did not have confidence in the results of the indirect comparative evidence because it had too many limitations. There was not enough robust evidence to show that Vraylar filled a treatment gap. This document was initially published on August 26, 2022, and subsequently revised on February 2, 2023, to provide additional details on the expert committee's deliberations and the request for reconsideration filed by the sponsor.

Lumateperone Normalizes Pathological Levels of Acute Inflammation through Important Pathways Known to Be Involved in Mood Regulation.

Lumateperone is indicated for the treatment of schizophrenia in adults and for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate (Calabrese et al., 2021). It is currently under evaluation for the treatment of major depressive disorder (www.ClinicalTrials.gov). Lumateperone acts by selectively modulating serotonin, dopamine, and glutamate neurotransmission in the brain. However, other mechanisms could be involved in the actions of lumateperone, and because of the connection between the immune system and psychiatric health, we hypothesized that lumateperone might improve symptoms of depression, at least in part, by normalizing pathologic inflammation. Here, we show that in male and female C57BL/6 mice subjected to an acute immune challenge, lumateperone reduced aberrantly elevated levels of key proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) in both brain and serum; lumateperone also reduced proinflammatory cytokines in male mice under acute behavioral stress. Further, we demonstrate that lumateperone altered key genes/pathways involved in maintaining tissue integrity and supporting blood-brain barrier function, such as claudin-5 and intercellular adhesion molecule 1. In addition, in acutely stressed male Sprague Dawley rats, lumateperone conferred anxiolytic- and antianhedonic-like properties while enhancing activity in the mammalian target of rapamycin complex 1 pathway in the PFC. Together, our preclinical findings indicate that lumateperone, in addition to its ability to modulate multiple neurotransmitter systems, could also act by reducing the impact of acute inflammatory challenges.SIGNIFICANCE STATEMENT Lumateperone is indicated in adults to treat schizophrenia and depressive episodes associated with bipolar I or II disorder, as monotherapy and adjunctive therapy with lithium or valproate. Because aberrant immune system activity is associated with increased depressive symptoms, the relationship between lumateperone and immune function was studied. Here, lumateperone reduced the levels of proinflammatory cytokines that were increased following an immune challenge or stress in mice. Additionally, lumateperone altered genes and pathways that maintain blood-brain barrier integrity, restored an index of blood-brain barrier function, reduced anxiety-like behavior in rodents, and enhanced mammalian target of rapamycin complex 1 pathway signaling in the PFC. These results highlight the anti-inflammatory actions of lumateperone and describe how lumateperone may reduce immune pathophysiology, which is associated with depressive symptoms.

Med Check: Lecanemab; ANEB-001; Azstarys; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Lecanemab; ANEB-001; Azstarys; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:27 Oct 2022https://doi.org/10.1176/appi.pn.2022.11.11.2Lecanemab May Slow Decline in Alzheimer’sLecanemab, an investigational anti-amyloid beta protofibril antibody, may slow cognitive decline in Alzheimer’s disease, Biogen Inc. and Esai Co. Ltd. announced in September. Lecanemab is being developed for the treatment of mild cognitive impairment from Alzheimer’s disease and mild or early Alzheimer’s disease with confirmed presence of amyloid pathology in the brain.In the phase 3 Clarity AD trial, 1,795 patients with early Alzheimer’s disease were randomized to receive either placebo or biweekly doses of 10 mg of lecanemab per kilogram of body weight. The primary endpoint was reduced clinical decline, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). At the end of 18 months, CDR-SB scores had declined by 27% less in patients who received lecanemab compared with those who received placebo. The CDR-SB scores were a mean 0.45 points lower for those who received lecanemab compared with those who received placebo.Last year the Food and Drug Administration (FDA) granted Breakthrough Therapy designation to lecanemab based on the results of a phase 2b clinical trial, which examined the impact of treatment with lecanemab on reducing amyloid beta and clinical decline, as measured by changes on the Alzheimer’s Disease Composite Score (ADCOMS). Breakthrough Therapy designation expedites the development and review of drugs for serious conditions.In the trial, 856 patients who had mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia were randomized to receive 2.5 mg/kg, 5 mg/kg, or 10 mg/kg of lecanemab once every two weeks; 5 mg/kg or 10 mg/kg of lecanemab once every four weeks; or placebo for 18 months. Patients who took 10 mg/kg biweekly lecanemab had a 76% probability of achieving 25% less decline on ADCOMS compared with those who took placebo. ANEB-001 May Reverse Cannabinoid IntoxicationA phase 2 trial of the investigational cannabinoid receptor agonist ANEB-001 suggests that the medication may reverse cannabinoid intoxication, Anebulo Pharmaceuticals Inc. announced in September.The trial involved approximately 60 participants, who were given 21 mg of delta-9-tetrahydrocannabinol (THC). They were then given 10 mg of ANEB-001, 30 mg of ANEB-001, or placebo.Those who received placebo reported a substantial increase in feeling high and body sway, decreased alertness, and a slightly increased heart rate from baseline. Participants who received either 10 mg or 30 mg of ANEB-001 experienced significant reductions in the visual analog scale (VAS) score for feeling high, improvement in the VAS alertness scale, and a reduction in THC-induced body sway compared with those who received placebo. Azstarys May Improve Sleep for Children with ADHDAzstarys (serdexmethylphenidate and dexmethylphenidate) may help improve sleep in children with attention-deficit/hyperactivity disorder (ADHD), Corium Inc. announced in September. Azstarys is approved for the treatment of ADHD in patients aged six years and older.In a one-year open-label study, 238 children with ADHD aged six to 12 years received Aztarys for one year. After one month of treatment with Azstarys, the children’s total average sleep disturbance score on the Children’s Sleep Habits Questionnaire (CSHQ) decreased significantly from a mean of 53.4 points to 50.5 points. Furthermore their total mean CSHQ scores remained between 48.9 to 50.1 points for up to 12 months, indicating that the improvements in their sleep were sustained.The results of the study were presented in a poster at the Psych Congress 2022 in New Orleans. FDA Reviews Two-Month Aripiprazole Injection for SchizophreniaIn September, Otsuka America Pharmaceutical Inc. and H. Lundbeck A/S announced that the FDA has accepted for review a New Drug Application (NDA) for aripiprazole two-month, long-acting injectable for the treatment of schizophrenia in adults and for maintenance monotherapy of bipolar I disorder in adults. The NDA is for a formulation designed to be administered via intramuscular injection in the gluteal muscle.The NDA is based on data from a clinical trial involving 266 patients who were randomized to receive either four 920 mg injections of aripiprazole two-month long-acting injectable or eight 400 mg injections of aripiprazole one-month depot. Plasma concentrations of aripiprazole were similar between both groups of patients, and the two-month injectable was well-tolerated and showed no safety concerns compared with the once-monthly injectable. ■ ISSUES NewArchived

Cariprazine (Vraylar)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses Cariprazine (Vraylar) 5 mg, 3 mg, 4.5 mg, and 6 mg oral capsules.&#x0D; Indication: For the treatment of schizophrenia in adults.&#x0D;

Cariprazine (Vraylar)

&#x0D; CADTH recommends that Vraylar should not be reimbursed by public drug plans for the treatment of schizophrenia in adults.&#x0D; Based on evidence from 5 clinical trials, treatment with Vraylar improved symptoms of schizophrenia or delayed relapse compared with placebo. Vraylar also improved negative symptoms of schizophrenia compared with risperidone. Although these results were statistically significant, it is not clear whether any of these effects are clinically important.&#x0D; It is not clear whether cariprazine offers any clinical benefits over other treatments that are available for schizophrenia because there were no clinical trials in patients with acute schizophrenia that compared Vraylar with any other treatments. The committee did not have confidence in the results because the indirect comparative evidence reviewed had too many limitations.&#x0D; There was not enough evidence to show that Vraylar filled a treatment gap.&#x0D;

Lumateperone-mediated effects on prefrontal glutamatergic receptor-mediated neurotransmission: A dopamine D1 receptor dependent mechanism

Lumateperone is a novel drug approved for the treatment of schizophrenia in adults and depressive episodes associated with bipolar depression in adults, as monotherapy and as adjunctive therapy with lithium or valproate treatment in the United States. Lumateperone simultaneously modulates key neurotransmitters, such as serotonin, dopamine, and glutamate, implicated in serious mental illness. In patients with schizophrenia, lumateperone was shown to improve positive symptoms along with negative and depressive symptoms, while also enhancing prosocial behavior. Moreover, in patients with bipolar I or II disorder, lumateperone improved depressive symptoms as well. To further understand the mechanisms related to lumateperone's clinical response, the aim of this study was to investigate the effect of lumateperone on dopaminergic- and glutamatergic signaling in the rat medial prefrontal cortex (mPFC). We used the conditioned avoidance response (CAR) test to determine the antipsychotic-like effect of lumateperone, electrophysiology in vitro to study lumateperone's effects on NMDA- and AMPA-induced currents in the mPFC, and the neurochemical techniques microdialysis and amperometry to measure dopamine- and glutamate release in the rat mPFC. Our results demonstrate that lumateperone; i) significantly suppressed CAR in rats, indicating an antipsychotic-like effect, ii) facilitated NMDA and AMPA receptor-mediated currents in the mPFC, in a dopamine D1-dependent manner, and iii) significantly increased dopamine and glutamate release in the rat mPFC. To the extent that these findings can be translated to humans, the ability of lumateperone to activate these pathways may contribute to its demonstrated effectiveness in safely improving symptoms related to neuropsychiatric disorder including mood alterations.

Aripiprazole lai two-injection start in a 16 year-old with Schizophrenia

IntroductionAripiprazole LAI is approved for the treatment of schizophrenia in adults. Recently, Europe and Canada approved the use of the two-injection start (TIS) regimen: two separate injections of 400 mg long-acting aripiprazole along with a single 20 mg dose of oral aripiprazole. Aripiprazole showed efficacy in the treatment of adolescents with acute schizophrenia in several controlled trials, leading to its approval for 13-17 year-old adolescents with schizophrenia by the EMA. However, the LAI formulation still remains off-label in adolescents.ObjectivesTo demonstrate the efficacy and safety of the TIS regimen of aripiprazole LAI formulation in a 16 year-old adolescent with schizophrenia.MethodsWe evaluated the symptoms of schizophrenia and general severity by means of the PANSS and CGI scales. The scales were administered at hospital admission, after 3 weeks, 5 weeks, and at 4-weeks follow-up.ResultsAt the admission the patient PANSS total score was 136, the CGI score of 7. Aripiprazole was started and up-titrated to 30 mg/day. After 3 weeks, the positive symptoms were significantly reduced; due to the persistence of negative symptoms, clozapine 100 mg/day was added. At week 5 the PANSS total score decreased to 81. Due to poor insight we proposed aripiprazole LAI with the two-injection start. One month later, global functioning and illness insight improved; PANSS score was 43, CGI score 2. There was no evidence of akathisia or other side effects.ConclusionsAripiprazole LAI showed good efficacy and tolerability in an adolescent with schizophrenia. The two-injection start regimen was a safe and viable option.DisclosureNo significant relationships.

Med Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:26 Apr 2022https://doi.org/10.1176/appi.pn.2022.05.5.35Adlarity Transdermal Patch Approved for Treatment of Alzheimer’sIn March the U.S. Food and Drug Administration (FDA) approved Adlarity (donepezil transdermal system) as a treatment for patients with mild, moderate, or severe dementia associated with Alzheimer’s disease, Corium Inc. announced. Adlarity is a once-weekly patch that continuously delivers either 5 mg or 10 mg of donepezil through the skin per day. Either the patient or a caregiver may place the patch on the patient’s back, thigh, or buttocks.The FDA approved Adlarity based on a relative bioavailability study in healthy patients that compared the transdermal system to Aricept (donepezil hydrochloride) tablets. In the study, 60 healthy volunteers received 5 mg of Adlarity per day for five weeks, after which they received either 10 mg of Adlarity or oral donepezil per day for another five weeks. At the end of the study, exposure to donepezil was similar among patients who took Adlarity and those who took oral donepezil. Adlarity is expected to be available in the early fall. Qulipta Promising for Treatment of Chronic MigraineAdults with chronic migraine who took Qulipta (atogepant) in a phase 3 trial experienced fewer monthly migraine days compared with those who took placebo, AbbVie announced in March. Qulipta is currently approved for preventing episodic migraine in adults.In the trial, more than 750 patients with at least a one-year history of chronic migraine were randomized to receive 60 mg of atogepant once a day, 30 mg of atogepant twice a day, or placebo for 12 weeks. All patients had at least 15 headache days with at least eight migraine days in the 28 days before randomization. The trial consisted of two analyses based on regulatory agency feedback in the United States and European Union.The U.S. analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.88 and 7.46 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.05 monthly migraine days. The European Union analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.75 and 7.33 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.09 monthly migraine days. Acadia Resubmits Nuplazid for Treatment of Alzheimer’s PsychosisAcadia Pharmaceuticals in March announced that the FDA has set an action date for the company’s resubmitted supplemental New Drug Application (sNDA) for Nuplazid (pimavanserin) for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis. The FDA’s Division of Psychiatry has also advised the company that it is planning to hold an advisory committee meeting in connection with its review.In April 2021 the FDA rejected pimavanserin for this indication, citing “a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.”The resubmission provides additional analyses from two previously conducted clinical studies, HARMONY and Study-019, to support the proposed indication for the drug and addresses the issues raised in the FDA’s rejection last year.Pimavanserin is currently approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Vraylar sNDA Submitted for Adjunctive Treatment of Major Depressive DisorderIn February AbbVie announced that it has submitted an sNDA for Vraylar (cariprazine) for the adjunctive treatment of major depressive disorder in patients who are receiving ongoing antidepressant therapy. Cariprazine is currently approved for the treatment of schizophrenia in adults, the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and the treatment of depressive episodes associated with bipolar I disorder in adults.In a phase 3 study of 759 adults with major depressive disorder, patients who took 1.5 mg cariprazine daily experienced a statistically significant change from baseline to week six in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with those who took placebo. In a second study, patients who took 2 mg to 4.5 mg of cariprazine per day also experienced a significant change from baseline to week eight in the MADRS total score compared with those who took placebo. In both of these studies, no new safety events were identified. ■ ISSUES NewArchived

POSA46 Cost Analysis of Lurasidone for the Treatment of Schizophrenia in Adults within the United Kingdom

An economic model was built to establish the incremental costs of lurasidone, a second-generation atypical antipsychotic, when introduced as a first-line adult schizophrenia treatment in the UK. The incremental cost of the following treatment sequences was estimated: lurasidone, cariprazine, brexpiprazole, clozapine versus cariprazine, brexpiprazole, lurasidone and clozapine. The costs of either lurasidone or cariprazine were compared as first-line options because there are currently no restrictions on treatment lines of schizophrenia therapy. A Markov model incorporating the following health states was developed: stable (receiving, or temporarily discontinued from, treatment) and relapse. Patient movement between health states was dependent on six-weekly probabilities of relapse and discontinuation due to intolerable side effects or any other reasons. All efficacy data were obtained from network meta-analyses. A six-week cycle length was used and a 3.5% discount rate was applied to costs over a five-year time horizon. Resource use and unit costs were reflective of the NHS and were obtained from published literature. Costs included treatment, outpatient, adverse events, primary and residential care. An increased mortality risk associated with schizophrenia was applied to all patients. Deterministic sensitivity analysis was undertaken to assess the uncertainty of the economic Results: The treatment sequence containing lurasidone as a first-line treatment resulted in a cost-saving of £816 per patient. First-line lurasidone was associated with increased treatment, stable health state and adverse event costs (£570, £107 and £6 per patient respectively). However, these costs were outweighed by the cost-savings within the relapse health state (savings of £1,499 per patient). Deterministic sensitivity analysis demonstrated the results were most sensitive to discontinuation rates, relapse rates and relapse residential costs. However, no variation in inputs caused first-line lurasidone to become cost-incurring. Lurasidone is a cost-saving intervention for the treatment of schizophrenia in adults when received first-line in a UK setting.

Long-term efficacy and safety of once-monthly Risperidone ISM® in the treatment of schizophrenia: Results from a 12-month open-label extension study

ObjectiveTo evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted. MethodsEligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales. ResultsAltogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed. ConclusionRisperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone.

Risperidone for Extended-Release Injectable Suspension (Perseris)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses risperidone for extended-release injectable suspension (Perseris), powder for suspension, 90 mg or 120 mg subcutaneous injection.&#x0D; Indication: Treatment of schizophrenia in adults.&#x0D;