Brexpiprazole has a low risk of dopamine D₂ receptor sensitization and inhibits rebound phenomena related to D₂ and serotonin 5‐HT_2A receptors in rats

Abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: Long-term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D 2 receptor sensitization. We evaluated the effects of brexpiprazole on D 2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D 2 receptors in rats subchronically dosed with another atypical antipsychotic. Methods:The maximum D 2 receptor density (B max ) and apomorphine (a D 2 receptor agonist)-induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for B max , 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphineinduced hyperlocomotion and (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI: a 5-HT 2A receptor agonist)-induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days. Results: Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED 50 of antiapomorphine-induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the B max and apomorphine-induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine-induced hyperlocomotion and also DOI-induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine-induced hyperlocomotion. Conclusion: Brexpiprazole has a low risk of D 2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D 2 and 5-HT 2A receptors after a repeated administration of risperidone. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Amada N, Akazawa H, Ohgi Y, et al. Brexpiprazole has a low risk of dopamine D 2 receptor sensitization and inhibits rebound phenomena related to D 2 and serotonin 5-HT 2A receptors in rats.

Effect of Switching to Brexpiprazole on Plasma Homovanillic Acid Levels and Antipsychotic-Related Side Effects in Patients with Schizophrenia or Schizoaffective Disorder

“…Murray et al raised several issues about the long-term prophylactic use of antipsychotics, including effects of antipsychotics on physical health, antipsychotic-induced dopamine receptor supersensitivity, and treatment-resistant schizophrenia. 21 Together with previous studies indicating that it seems that dopamine partial agonists do not induce D2 receptor supersensitivity, 22 , 23 our results of significant effects on prolactin, EPS, and metabolic side effects suggest that switching to BPZ is a useful long-term treatment strategy for patients with SGAs-associated side effects in real-world settings.…”

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

“…This indicates the need of searching for novel antidopaminergic agents. Brexpiprazole, for instance, exhibits low risk of D2 receptor sensitization, is well-tolerated, and has low side effects in patients with schizophrenia Moreover, it may have a lower risk for producing rebound symptoms associated with D2 receptor and 5-HT 2A receptor sensitization when switching from other antipsychotics such as risperidone [ 52 , 53 ]. The most recently approved, first-in-class antipsychotic—lumateperone—combines the synergy of the drug’s affinity for 5-HT 2A receptors at low doses, dose-dependent presynaptic D2 receptors agonism, postsynaptic D2 antagonism, and selectivity to mesolimbic and mesocortical areas for a wide range of symptoms associated with schizophrenia [ 54 ].…”

Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine

“…11 25-27 Finally, according to animal studies, a dopamine partial agonist is likely to be effective for DSP. 28 29 However, they may exacerbate psychotic symptoms in cases where DSP has already developed. 30 This would explain why brexpiprazole, which is a dopamine partial agonist, was ineffective in our case.…”