The dopamine D4/D2 receptor antagonist affinity ratio as a predictor of anti-aggression medication efficacy

El‐Mallakh, Rif S.; McKenzie, Courtney

doi:10.1016/j.mehy.2012.10.014

Cited by 15 publications

(12 citation statements)

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“…The theoretical basis for the rapid action of sublingual asenapine in the treatment of agitation is based on sublingual asenapine's pharmacokinetic profile, with a Tmax estimated to occur in 30–90 min after administration . Moreover, asenapine has a slightly higher binding affinity for dopamine D4 receptors (Ki 1.1 n m ) vs. dopamine D2 receptors (Ki 1.3 n m ), and the dopamine D4/D2 receptor antagonist affinity ratio may predict antiaggression efficacy, and has been proposed as a possible explanation for clozapine's anti‐aggression medication efficacy .…”

Section: Discussionmentioning

confidence: 99%

A single‐dose, randomized, double‐blind, placebo‐controlled trial of sublingual asenapine for acute agitation

Pratts

Citrome

Grant

et al. 2014

Acta Psychiatr Scand

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Section: Discussionmentioning

confidence: 99%

A single‐dose, randomized, double‐blind, placebo‐controlled trial of sublingual asenapine for acute agitation

Pratts

Citrome

Grant

et al. 2014

Acta Psychiatr Scand

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“…Recently approved by the US Food and Drug Administration for the treatment of schizophrenia and BD, asenapine presents a peculiar receptor binding profile with a 5-HT 2A : D2 affinity ratio similar to other SGA, but a higher affinity for serotonergic, α 1,2 adrenergic receptors ( Weber and McCormack, 2009 ; Timpe and Chopra, 2010 ). Together with clozapine, asenapine is the unique antipsychotic presenting a D4/D2 affinity ratio of more than 1 that has been purported to confer an antiaggression effect ( El-Mallakh and McKenzie, 2013 ). This latter hypothesis was proposed in the light of the proven superiority of clozapine – in both open and randomized trials ( Frogley et al , 2012 ) – over other antipsychotic comparators.…”

Section: Introductionmentioning

confidence: 99%

Asenapine in the management of impulsivity and aggressiveness in bipolar disorder and comorbid borderline personality disorder

Aguglia

Mineo

Rodolico

et al. 2018

International Clinical Psychopharmacology

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Borderline personality disorder (BPD) often co-occurres with bipolar disorder (BD). Impulsivity and aggressiveness represent core shared features and their pharmacological management is mainly based on mood stabilizers and antipsychotics, although scarce evidence is available for this context of comorbidity. The aim of the present study was to evaluate the role of Asenapine as an adjunctive drug for reducing aggressiveness and impulsivity in a sample of Italian BD type I outpatients with or without a comorbid BPD. This was an observational 12-week open-label uncontrolled clinical study carried out from April to October 2014 in two psychiatric clinics in Sicily. Each patient was treated with asenapine at two dose options, 5 mg (twice daily) or 10 mg (twice daily), and concomitant ongoing medications were not discontinued. We measured impulsivity using the Barratt Impulsiveness Scale (BIS) and aggressiveness using the Aggressive Questionnaire (AQ). For the analysis of our outcomes, patients were divided into two groups: with or without comorbid BPD. Adjunctive therapy was associated with a significant decrease of BIS and AQ overall scores in the entire bipolar sample. Yet, there was no significant difference in BIS and AQ reductions between subgroups. Using a regression model, we observed that concomitant BPD played a negative role on the Hostility subscale and overall AQ score variations; otherwise, borderline co-diagnosis was related positively to the reduction of physical aggression. According to our post-hoc analysis, global aggressiveness scores are less prone to decrease in patients with a dual diagnosis, whereas physical aggressiveness appears to be more responsive to the add-on therapy in patients with comorbidity.

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“…It has been proposed that greater antagonist affinity at D 4 receptors compared to D 2 receptors (ie, D 4 /D 2 affinity ratio >1) may confer antiaggression effects and may explain why some medications display greater efficacy for these behaviors. 30 Asenapine has slightly higher binding affinity with D 4 receptors than D 2 receptors, 31 and this D 4 /D 2 ratio may therefore be involved in the antiaggression and antihostility effects seen in these analyses. 18 , 30 In addition to dopamine receptor affinity, the high affinity of asenapine for 5-HT 2A receptors may play a role in antiaggressive efficacy.…”

Section: Discussionmentioning

confidence: 86%

“… 30 Asenapine has slightly higher binding affinity with D 4 receptors than D 2 receptors, 31 and this D 4 /D 2 ratio may therefore be involved in the antiaggression and antihostility effects seen in these analyses. 18 , 30 In addition to dopamine receptor affinity, the high affinity of asenapine for 5-HT 2A receptors may play a role in antiaggressive efficacy. 31 Previous studies have shown that antagonism at 5-HT 2A receptors reduces aggressive behavior in preclinical models 32 as well as in patients with neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 86%

Effects of asenapine on agitation and hostility in adults with acute manic or mixed episodes associated with bipolar I disorder

Citrome¹,

Landbloom²,

Chang

et al. 2017

NDT

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BackgroundBipolar disorder is associated with an increased risk of aggression. However, effective management of hostility and/or agitation symptoms may prevent patients from becoming violent. This analysis investigated the efficacy of the antipsychotic asenapine on hostility and agitation in patients with bipolar I disorder.MethodsData were pooled from three randomized, double-blind, placebo-controlled, Phase III trials of asenapine in adults with manic or mixed episodes of bipolar I disorder (NCT00159744, NCT00159796, and NCT00764478). Post hoc analyses assessed the changes from baseline to day 21 on the Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS) hostility-related item scores in asenapine- or placebo-treated patients with at least minimal or mild symptom severity and on the PANSS-excited component (PANSS-EC) total score in agitated patients. Changes were adjusted for improvements in overall mania symptoms to investigate direct effects on hostility.ResultsSignificantly greater changes in favor of asenapine versus placebo were observed in YMRS hostility-related item scores (irritability: least squares mean difference [95% confidence interval] =−0.5 [−0.87, −0.22], P=0.001; disruptive–aggressive behavior: −0.7 [−0.99, −0.37], P<0.0001), PANSS hostility item score (−0.2 [−0.44, −0.04]; P=0.0181), and PANSS-EC total score (−1.4 [−2.4, −0.4]; P=0.0055). Changes in the YMRS disruptive–aggressive behavior score and the sum of the hostility-related items remained significant after adjusting for improvements in other YMRS item scores.ConclusionAsenapine significantly reduced hostility and agitation in patients with bipolar I disorder; improvement was at least partially independent of overall improvement on mania symptoms.

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The dopamine D4/D2 receptor antagonist affinity ratio as a predictor of anti-aggression medication efficacy

Cited by 15 publications

References 50 publications

A single‐dose, randomized, double‐blind, placebo‐controlled trial of sublingual asenapine for acute agitation

A single‐dose, randomized, double‐blind, placebo‐controlled trial of sublingual asenapine for acute agitation

Asenapine in the management of impulsivity and aggressiveness in bipolar disorder and comorbid borderline personality disorder

Effects of asenapine on agitation and hostility in adults with acute manic or mixed episodes associated with bipolar I disorder

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