Asenapine

Novel psychopharmacologic agent. Displays antagonist activity at 5-HT, dopamine, noradrenalin and histamine receptor subtypes (pK_i values are 8.60, 8.40, 10.15, 9.75, 10.46, 8.84, 9.60, 9.94, 8.85, 8.90, 8.84, 9.38, 8.95, 8.93, 8.9, 9.49, 8.91,

Asenapine for the treatment of adults with an acute exacerbation of schizophrenia: results from a randomized, double-blind, fixed-dose, placebo-controlled trial with olanzapine as an active control.[Pubmed:27821210]

CNS Spectr. 2017 Aug;22(4):333-341.

OBJECTIVE: Evaluate the efficacy and safety of Asenapine 2.5 mg twice daily (bid; n=97) or 5 mg bid (n=113) versus placebo (n=101) in adults with acute exacerbation of schizophrenia. METHODS: Adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) schizophrenia diagnosis were randomized to Asenapine 2.5 mg bid, 5 mg bid, placebo, or olanzapine 15 mg once daily. The primary objective was to test superiority of Asenapine versus placebo as measured by the change from baseline to day 42 in the Positive and Negative Syndrome Scale (PANSS) total score. The key safety objective was to evaluate weight change in Asenapine versus olanzapine at day 42. RESULTS: The primary efficacy endpoint was met; the difference in least squares mean change from baseline to day 42 in PANSS total score between Asenapine 5 mg bid and placebo was -5.5 points (unadjusted 95% CI: -10.1, -1.0; multiplicity adjusted P=0.0356). Neither Asenapine 2.5 mg bid nor olanzapine 15mg were superior to placebo. Both Asenapine groups demonstrated significantly less weight gain than olanzapine at day 42. Significantly higher incidences of oral hypoesthesia and dysgeusia (combined) for Asenapine 2.5 mg bid (5.2% vs 0.0%; P=0.0217) and 5 mg bid (7.1% vs 0.0%; P=0.0033) were observed versus placebo. There were no significant differences between Asenapine and placebo for insomnia, extrapyramidal symptoms, akathisia, dizziness, or combination of somnolence/sedation/hypersomnia. CONCLUSION: This study supports previous efficacy and safety findings of Asenapine; Asenapine 5 mg bid is the lowest effective dose in adults with schizophrenia. Asenapine was associated with significantly less weight gain than olanzapine at day 42.

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model.[Pubmed:27099073]

Acta Neuropsychiatr. 2016 Dec;28(6):327-336.

OBJECTIVE: Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for Asenapine. Therefore, we compared the effects of Asenapine in the conditioned fear stress model with those of clozapine and olanzapine. METHOD: Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with Asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with Asenapine. The effects of Asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis. RESULTS: Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of Asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both Asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus. CONCLUSION: Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

Does the efficacy of asenapine in bipolar disorder increase in the presence of comorbidity with a substance use disorder? A naturalistic study.[Pubmed:28255436]

Ther Adv Psychopharmacol. 2017 Feb;7(2):67-77.

BACKGROUND: Asenapine is a second-generation antipsychotic approved in Europe for treating moderate-to-severe manic episodes in adults affected by type I bipolar disorder (BD-I). We aimed to compare its efficacy in psychiatric inpatients with BD-I, with or without substance use disorder (SUD). METHODS: We administered flexible Asenapine doses ranging from 5-20 mg/day to 119 voluntarily hospitalized patients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) BD-I diagnosis, with or without SUD. Patients were assessed with clinician-rated questionnaires [i.e. Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Global Assessment of Functioning (GAF)]. Assessments were carried out at baseline (T0, prior to treatment), and 3 (T1), 7 (T2), 15 (T3), and 30 days (T4) after starting treatment for all clinical scales and at T0 and T4 for the GAF. RESULTS: Patients improved on all scales (p < 0.001) across all timepoints, as shown both by paired-sample comparisons and by applying a repeated-measures, generalized linear model (GLM). Patients without comorbid SUD showed greater reductions in BPRS scores at T2 and T3, greater reduction in YMRS scores at T3, and lower HARS scores at all timepoints. HDRS scores did not differ between the two groups at any timepoint. However, the reduction in HARS scores in the comorbid group was stronger than in the BD-I only group, albeit not significantly. Side effects were few and mild-to-moderate. CONCLUSIONS: The open-label design and the relatively short observation period may expose to both type I and type II statistical errors (false positive and false negatives). Asenapine showed effectiveness and safety in hospitalized BD-I patients. Its effect was stronger in patients without comorbid SUD.

Asenapine for the Control of Physical Aggression: A Prospective Naturalist Pilot Study.[Pubmed:28138201]

Psychopharmacol Bull. 2017 Jan 26;47(1):27-32.

It has been previously purported that higher relative affinity to the dopamine D4 receptor compared to D2 (i.e., D4/D2 affinity ratio > 1) may underlie unique antiaggression potency. Asenapine is a newer antipsychotic that also has D4/D2 affinity ratio > 1. It has demonstrated efficacy in reducing acute agitation in a placebo-controlled study. We performed a prospective naturalistic, pilot, proof of concept study on an inpatient psychiatric unit. Among patients with aggression at time of admission (>/= 12 on Refined Aggression Questionnaire [RAQ], or >/= 2 on Modified Overt Aggression Scale [MOAS]), Asenapine treatment was associated with a significant reduction in total aggression as measured by the MOAS (-14.7 +/- 11.59 vs. -5.4 +/- 10.12, P = 0.045), and particularly physical aggression (-8.0 +/- 5.06 vs. -0.78 +/- 2.40, P < 0.0001) compared to treatment that did not include Asenapine. These data suggest that Asenapine may be useful in the targeted treatment of aggression, and provide some support for the D4/D2 affinity ratio hypothesis.

Asenapine.[Pubmed:19876039]

Nat Rev Drug Discov. 2009 Nov;8(11):843-4.

In August 2009, Asenapine (Saphris; Schering-Plough) was approved by the US FDA for the acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults.

Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.[Pubmed:18308814]

J Psychopharmacol. 2009 Jan;23(1):65-73.

Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of Asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, Asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKiAsenapine had a higher affinity for 5-HT2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT6, alpha2B and D3 receptors, suggesting stronger engagement of these targets at therapeutic doses. Asenapine behaved as a potent antagonist (pKB) at 5-HT1A (7.4), 5-HT1B (8.1), 5-HT2A (9.0), 5-HT2B (9.3), 5-HT2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2 (9.1), D3 (9.1), alpha2A (7.3), alpha2B (8.3), alpha2C (6.8) and H1 (8.4) receptors. These functional effects differed from those of risperidone (pKB<5 for 5-HT6) and olanzapine (pKB<5 for 5-HT1A and alpha2). Our results indicate that Asenapine has a unique human receptor signature, with binding affinity and antagonistic properties that differ appreciably from those of antipsychotic drugs.

Asenapine maleate is a 5-HT (1A, 1B, 2A, 2B, 2C, 5A, 6, 7) and D2 antagonist with Ki values of 0.03-4.0 nM, 1.3nM, respectively, and an antipsychotic.

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