lurasidone-hydrochloride and asenapine

Medicinal chemistry is continually developing and testing new drugs and drug candidates to satisfactorily address the needs of patients suffering from schizophrenia. In the last few years, some significant additions have been made to the list of widely available atypical antipsychotics. In particular, iloperidone, asenapine and lurasidone have been approved by the USA's Food and Drug Administration in 2009-10. In this paper, the most notable metabolic characteristics of these new drugs are addressed, with particular attention to their potential for pharmacokinetic interactions, and to the respective advantages and disadvantages in this regard. Moreover, current perspectives on the therapeutic drug monitoring (TDM) of the considered drugs are discussed. Since TDM is most valuable when it allows the personalisation and optimisation of therapeutic practices, it is even more interesting in the case of novel drugs, such as those discussed here, whose real impact in terms of side and toxic effects on very large populations is still unknown. Some analytical notes, related to TDM application, are included for each drug.

Topics: Animals; Antipsychotic Agents; Dibenzocycloheptenes; Drug Approval; Drug Design; Drug Monitoring; Heterocyclic Compounds, 4 or More Rings; Humans; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; United States; United States Food and Drug Administration

Akathisia is a troubling side effect that leads to non-adherence with antipsychotic regimens. Second generation antipsychotics (SGAs) tend to cause less akathisia than older agents but the risk still exists and rates vary between agents. Little is known about the incidence of akathisia among the newer SGAs. The purpose of this study was to conduct a meta-analysis of akathisia incidence rates for three of the newer SGAs: aripiprazole, asenapine, and lurasidone. Data were drawn from published and unpublished clinical trials comparing the drug of interest to either placebo or another SGA in adults with schizophrenia. Twenty-four studies (11 aripiprazole, 5 asenapine, and 8 lurasidone) provided incidence rates for akathisia and related nervous system events. Data showed that the relative risk (RR) of akathisia was double that of controls, with lurasidone having the highest individual RR at 2.7 [CI: 2-3.6]. Sensitivity analysis changed the RR of akathisia to less than 10%. The RR of akathisia was still elevated (1.75 [1.4-2.1]) when these drugs were compared only to actives (older SGAs). Agitation and anxiety RRs were also higher with the newer SGAs as compared to the older SGAs. Previous theory suggests antagonism of serotonin (5-HT)2A receptors may decrease akathisia risk. Expectations were that aripiprazole, asenapine and lurasidone would have a low incidence of akathisia, as all display strong antagonism at 5-HT2A. However, in this study all three had a significantly higher risk of akathisia compared to placebo or other SGAs. This suggests the pathophysiology of akathisia involves other receptors and is multifactorial.

Topics: Akathisia, Drug-Induced; Animals; Antipsychotic Agents; Aripiprazole; Dibenzocycloheptenes; Heterocyclic Compounds, 4 or More Rings; Humans; Incidence; Lurasidone Hydrochloride; Schizophrenia

Insufficient treatment of psychosis often manifests as violent and aggressive behaviors that are dangerous to the patient and others, and that warrant treatment strategies which are not considered first-line, evidence-based practices. Such treatment strategies include both antipsychotic polypharmacy (simultaneous use of 2 antipsychotics) and high-dose antipsychotic monotherapy. Here we discuss the hypothesized neurobiological substrates of various types of violence and aggression, as well as providing arguments for the use of antipsychotic polypharmacy and high-dose monotherapy to target dysfunctional neurocircuitry in the subpopulation of patients that is treatment-resistant, violent, and aggressive. In this review, we focus primarily on the data supporting the use of second-generation, atypical antipsychotics both at high doses and in combination with other antipsychotics.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Brain; Clozapine; Dibenzocycloheptenes; Drug Therapy, Combination; Heterocyclic Compounds, 4 or More Rings; Humans; Impulsive Behavior; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Polypharmacy; Psychotic Disorders; Quetiapine Fumarate; Receptors, Dopamine D2; Risperidone; Thiazoles; Violence

The management of schizophrenia has seen significant strides over the last few decades, due to the increasing availability of a number of antipsychotics. Yet, the diminished efficacy in relation to the negative and cognitive symptoms of schizophrenia, and the disturbing adverse reactions associated with the current antipsychotics, reflect the need for better molecules targeting unexplored pathways.. To review the salient features of the recently approved antipsychotics; namely, iloperidone, asenapine, lurasidone and blonanserin.. We discuss the advantages, limitations and place in modern pharmacotherapy of each of these drugs. In addition, we briefly highlight the new targets that are being explored.. Promising strategies include modulation of the glutamatergic and GABAergic pathways, as well as cholinergic systems.. Although regulatory bodies have approved only a handful of antipsychotics in recent years, the wide spectrum of targets that are being explored could eventually bring out antipsychotics with improved efficacy and acceptability, as well as the potential to revolutionize psychiatric practice.

Topics: Antipsychotic Agents; Dibenzocycloheptenes; Drug Discovery; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperazines; Piperidines; Schizophrenia; Thiazoles

This article reviews the pharmacological profile and published efficacy and tolerability/safety data of iloperidone, asenapine and lurasidone, the most recent atypical antipsychotics to be approved in the USA for the treatment of schizophrenia. All three agents are similar in terms of overall efficacy and low propensity for clinically significant weight gain or adverse changes in glycemic or lipid profile. However, these agents differ from one another in terms of formulations, pharmacokinetics, and dosing and nonmetabolic adverse effect profile. For each drug, comparative and real-world effectiveness studies are lacking, as are effectiveness and safety data in elderly, young and pregnant/nursing patients. As such, the exact place of iloperidone, asenapine and lurasidone within the broader antipsychotic armamentarium is currently difficult to establish.

Topics: Antipsychotic Agents; Dibenzocycloheptenes; Drug Approval; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; Thiazoles

Three newer atypical antipsychotic drugs were FDA-approved in 2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The three drugs are indicated for the treatment of acute schizophrenia. Asenapine is also approved for treatment of manic or mixed episodes associated with bipolar I disorder, for the maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.. This review compares and contrasts the current preclinical, clinical, safety and tolerability profiles of the three newer drugs, as reported in published preclinical and clinical studies, product labels, poster presentations and press releases.. Preclinical studies have reported that the three drugs have variable affinities for a wide range of neurotransmitter receptors, and are active in animal models predictive of antipsychotic activity. Asenapine is the first antipsychotic to be administered sublingually, whereas iloperidone requires titration to minimize orthostatic hypotension. Asenapine and lurasidone are associated with dose-related akathisia, whereas iloperidone is not. The three drugs appear to have relatively benign metabolic profiles. The availability of the three novel antipsychotics should provide additional options for improved treatment of schizophrenia and other psychotic disorders.

Topics: Adult; Animals; Antipsychotic Agents; Bipolar Disorder; Dibenzocycloheptenes; Drug Approval; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; Thiazoles; United States; United States Food and Drug Administration

The introduction of second-generation antipsychotics (SGAs) over the past 2 decades generated considerable optimism that better antipsychotic treatments for schizophrenia and bipolar disorder were possible. SGAs offer several tolerability benefits over first-generation antipsychotics (FGAs), particularly with respect to extrapyramidal symptoms. However, SGAs can induce serious metabolic dysregulations, especially in drug-naive, first-episode, and child and adolescent populations, with olanzapine and clozapine having the highest propensity to cause these abnormalities. In this context, newer SGAs were developed to further improve the adverse effect burden of available agents. However, until now, the metabolic risk profile of the newly approved SGAs - asenapine, iloperidone, lurasidone and paliperidone (paliperidone extended release and paliperidone palmitate) - has not been compared.. The objective of this systematic review and exploratory meta-analysis was to assess the effects of asenapine, iloperidone, lurasidone and paliperidone on body weight and other metabolic parameters (cholesterol, triglycerides and glucose), as this information is relevant to guide clinical decision making.. A systematic literature search (1966-March 2012), using the Cochrane Central Register of Controlled Trials and MEDLINE, CINAHL and EMBASE databases, was conducted for randomized, placebo-controlled and head-to-head clinical trials of asenapine, iloperidone, lurasidone and paliperidone. Published and unpublished data on changes in body weight and glucose and lipid metabolism parameters were extracted. For placebo-controlled, short-term (≤12 weeks) and longer-term (>12 weeks) trials with available data on ≥7% weight increase compared with pre-treatment weight, or mean weight change with standard deviation, a formal meta-analysis was performed, estimating the pooled effect size (represented as relative risk [RR], numbers-needed-to-harm [NNH] and weighted mean difference [WMD]). An exploratory meta-analysis was also performed for the other metabolic variables (cholesterol, triglycerides and glucose). Data from active- and placebo-controlled studies were used for a pooled comparison of simple mean changes in weight, cholesterol, triglyceride and glucose levels.. Fifty-six trials (n = 21 691) in schizophrenia (N = 49, n = 19 299) or bipolar disorder (N = 7, n = 2392) were identified (asenapine: N = 9, iloperidone: N = 11, lurasidone: N = 8, paliperidone: N = 28). Most of the trials (64.3%) were of ≤12 weeks' duration. In the short-term trials, compared with placebo, a ≥7% weight increase was statistically significantly (p < 0.05) most prevalent for asenapine (5 trials, n = 1360, RR = 4.09, 95% confidence interval [CI] 2.25, 7.43, NNH = 17), followed by iloperidone (4 trials, n = 1931, RR = 3.13, 95% CI 2.08, 4.70, NNH = 11) and paliperidone (12 trials, n = 4087, RR = 2.17, 95% CI 1.64, 2.86, NNH = 20). The effect of lurasidone on body weight (6 trials, n = 1793, RR = 1.42, 95% CI 0.87, 2.29) was not statistically significant. Short-term weight gain was statistically significantly (p < 0.001) greater than placebo with iloperidone (1 trial, n = 300, +2.50 kg, 95% CI 1.92, 3.08), paliperidone (15 trials, n = 3552, +1.24 kg, 95% CI 0.91, 1.57), asenapine (3 trials, n = 751, +1.16 kg, 95% CI 0.83, 1.49), as well as with lurasidone (5 trials, n = 999, +0.49 kg, 95% CI 0.17, 0.81, p < 0.01). Sufficient meta-analysable, longer-term, weight change data were only available for asenapine and paliperidone, showing statistically significantly (p < 0.001) greater weight gain versus placebo for both drugs (asenapine, 3 trials, n = 311, +1.30 kg, 95% CI 0.62, 1.98; paliperidone, 6 trials, n = 1174, +0.50 kg, 95% CI 0.22, 0.78). Although statistically significant, in general, no clinically meaningful differences were observed between the four newly approved SGAs and placebo regarding the mean change from baseline to endpoint in cholesterol levels in short-term trials, with the exception of iloperidone for total cholesterol (1 trial, n = 300, +11.60 mg/dL, 95% CI 4.98, 18.22, p ≤ 0.001), high-density cholesterol (1 trial, n = 300, +3.6 mg/dL, 95% CI 1.58, 5.62, p < 0.001) and low-density cholesterol (1 trial, n = 300, +10.30 mg/dL, 95% CI 4.94, 15.66, p < 0.001) and with the exception of lurasidone for high-density cholesterol (5 trials, n = 1004, +1.50 mg/dL, 95% CI 0.56, 2.44, p < 0.01). Asenapine increased total cholesterol statistically significantly (p < 0.05) during longer-term treatment (1 trial, n = 194, +6.53 mg/dL, 95% CI 1.17, 11.89). Regarding triglycerides, only short-term (3 trials, n = 1152, +1.78 mg/dL, 95% CI 0.40, 3.17, p < 0.01) and longer-term treatment with paliperidone (4 trials, n = 791, -0.20 mg/dL, 95% CI -. While preliminary data suggest the lowest weight gain potential with lurasidone and potentially relevant short-term metabolic effects for asenapine and iloperidone, data are still too sparse to comprehensively evaluate the metabolic safety of the newly approved SGAs. Therefore, there is a clear need for further controlled studies to evaluate whether these agents are less problematic regarding treatment-emergent weight gain and metabolic disturbances than other currently available antipsychotics.

Topics: Antipsychotic Agents; Bipolar Disorder; Blood Glucose; Dibenzocycloheptenes; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lipid Metabolism; Lurasidone Hydrochloride; Paliperidone Palmitate; Piperidines; Pyrimidines; Randomized Controlled Trials as Topic; Schizophrenia; Thiazoles; Weight Gain

Three new second-generation antipsychotics were approved by the US Food and Drug Administration in 2009 and 2010: iloperidone, asenapine, and lurasidone. All 3 agents are approved for the treatment of acute schizophrenia in adults, and asenapine is also approved for the maintenance treatment of schizophrenia and as a monotherapy or as an adjunct to lithium or valproate for the treatment of bipolar manic or mixed episodes. The expectation is that these new agents will be less problematic regarding treatment-emergent weight gain and metabolic disturbances, which unfortunately can occur with several other second-generation antipsychotics. Asenapine is a sublingual preparation, in contrast to iloperidone and lurasidone, which are swallowed. Iloperidone and asenapine are dosed twice daily, in contrast to lurasidone, which is dosed once daily with food. Both asenapine and lurasidone can be initiated at a dose that is possibly therapeutic, but iloperidone requires 4 days of titration to reach its recommended target dose range. Although both asenapine and lurasidone can be associated with dose-related treatment-emergent akathisia, iloperidone is essentially free of extrapyramidal adverse effects or akathisia throughout its recommended dose range. Sedation and/or somnolence have been reported with each medication. They are the most common adverse events associated with asenapine treatment, and are clearly dose-related for lurasidone. In contrast, no therapeutic dose response for iloperidone, asenapine, or lurasidone is clearly evident from short-term clinical trials. Longer-term and naturalistic studies will be helpful in evaluating these agents and their role in the psychiatric armamentarium.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Dibenzocycloheptenes; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; Thiazoles

Many psychoactive compounds have been developed to have more beneficial clinical efficacy than conventional drugs by adding agonistic action at 5-HT. The [. The specific binding was stimulated by brexpiprazole in rat hippocampus, human hippocampus, and human prefrontal cortex. Aripiprazole also behaved as an agonist in the same brain regions. Interestingly, its potency was much higher in rat hippocampal membranes than in human brain membranes, indicating the possibility of species differences. Although vortioxetine was an efficacious stimulator at high concentrations, its potency was undeterminable because of a lack of saturability. In addition to 5-HT. Our previous studies have raised the concept of a psychoactive drug group with a common pharmacological mechanism of action, i.e., 5-HT

Topics: Animals; Aripiprazole; Brain; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Lurasidone Hydrochloride; Psychotropic Drugs; Rats; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin Receptor Agonists; Vortioxetine

Antipsychotics are often used in combination with other psychotropic drugs to treat a variety of psychiatric disorders, as well as in combination with other drugs taken by patients with co-morbidities. When these drugs are combined, the potential for drug-drug interaction increases, leading to side-effects, in addition to the predicted increase in effectiveness. The present study aimed at examining the effects of the three atypical neuroleptics asenapine, lurasidone and iloperidone on cytochrome P450 (CYP) expression in the human liver. The study was carried out on cryopreserved human hepatocytes. The hepatotoxicity of the tested drugs was assessed after exposure to the neuroleptics (LDH cytotoxicity assay). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). Parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Asenapine significantly decreased the mRNA level and activity of CYP1A2, while iloperidone potently diminished the mRNA level and activity of CYP3A4 in the cultures of human hepatocytes. Lurasidone did not affect the expression and activity of any of the investigated human CYP enzymes. The presented findings may have clinical implications for the prediction of potential drug-drug interactions involving the asenapine-induced inhibition of metabolism of CYP1A2 substrates (e.g. caffeine, theophylline, melatonin, tricyclic antidepressants, phenacetin, propranolol) and iloperidone-induced inhibition of CYP3A4 substrates (e.g. antidepressants, benzodiazepines, atorvastatin, macrolide antibiotics, calcium channel antagonists).

Topics: Antipsychotic Agents; Cell Survival; Cells, Cultured; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dibenzocycloheptenes; Drug Interactions; Hepatocytes; Heterocyclic Compounds, 4 or More Rings; Humans; Isoxazoles; L-Lactate Dehydrogenase; Lurasidone Hydrochloride; Piperidines; RNA, Messenger

Asenapine, iloperidone and lurasidone are relatively new atypical antipsychotics. There is limited information on toxicity on pediatric exposures to these drugs. The objective of this study was to compare toxicity associated with asenapine, iloperidone and lurasidone exposures in young children.. A retrospective study of U.S. National Poison Data System from 2010 to 2015 of single substance exposures to asenapine, iloperidone or lurasidone in children <6 years of age that were followed to known outcome was performed.. There were 95 asenapine, 64 iloperidone and 124 lurasidone cases that met inclusion criteria. Reason was exploratory for 96% of cases. Drowsiness/lethargy occurred most frequently with iloperidone (45%) and least often with lurasidone (8%). Two iloperidone cases had respiratory depression. For asenapine, iloperidone and lurasidone, respectively, management sites were on-site non-health care facility (non-HCF) (32%, 16%, 26%), treated/discharged from emergency department (ED) (46%, 47%, 63%), admitted to noncritical care (9%, 14%, 10%) and admitted to critical care (10%, 22%, 2%). Clinical effect duration was 8 h or less for the majority of non-HCF cases (80%) and for children treated/discharged from the ED (72%). For asenapine, iloperidone and lurasidone, coded outcomes were no effect (50%, 41%, 81%), minor effect (43%, 39%, 17%), moderate (6%, 19%, 2%) and major (0, 2%, 0).. These findings suggest that in children under 6 years of age, lurasidone exposures were least serious and iloperidone exposures were most serious based on clinical effects, management sites and coded outcomes. Observation of symptomatic children in the ED for 8 h should be sufficient to make triage decisions based on persistence or resolution of clinical effects.

Topics: Antipsychotic Agents; Child, Preschool; Dibenzocycloheptenes; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Infant; Isoxazoles; Lurasidone Hydrochloride; Male; Piperidines; Poison Control Centers; Retrospective Studies; United States

This article briefly reviews the novel atypical second-generation antipsychotic drugs iloperidone (Fanapt®), asenapine (Saphris®), and lurasidone (Latuda®), all of which have been approved by the U.S. Food and Drug Administration since 2009. Each is indicated for the treatment of schizophrenia, and asenapine has an additional indication for bipolar disorder. Very little information is available on their use in other disorders, pediatric and geriatric patients, and during pregnancy and breastfeeding. Their overall efficacy is no different than other antipsychotic drugs, but they do have different side effect profiles. Because of their unique pharmacologies and different tolerability profiles, they may be a more effective alternative for patients who do not respond to or cannot tolerate other antipsychotic drugs.

Topics: Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Child; Clinical Trials as Topic; Dibenzocycloheptenes; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Male; Piperidines; Pregnancy; Schizophrenia; Thiazoles; Treatment Outcome

Topics: Antipsychotic Agents; Cyclooxygenase 2 Inhibitors; Dibenzocycloheptenes; Evidence-Based Medicine; Heterocyclic Compounds, 4 or More Rings; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoindoles; Isoxazoles; Lactones; Lurasidone Hydrochloride; Piperidines; Psychotic Disorders; Pyridines; Serotonin Receptor Agonists; Sulfones; Thiazoles