Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania

Abstract

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). Methods: ST studies were three-week randomized, double-blind, flexible dose (2–4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2–4 mg/day) study for patients completing the ST studies. Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (−1.74, 2.03), p = 0.8797; study 081: −1.62 (−3.56, 0.32), p = 0.1011. OL study patients ( n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

Effects of Atypical Antipsychotics, Clozapine, Quetiapine and Brexpiprazole on Astroglial Transmission Associated with Connexin43

“…Contrary to monoamine transporter inhibiting antidepressants, the effects of mood-stabilizing antipsychotics on astroglial transmission associated with Cx43 have remained to be clarified [ 9 , 43 , 44 ]. To explore the novel mood-stabilizing mechanisms, the present study determined the effects of mood-stabilizing antipsychotics, CLZ, QTP and BPZ [ 54 , 55 , 56 , 57 ] on Cx43 expression and Cx43 containing hemichannel using primary cultured rat cortical astrocytes. The results in this study, are summarized in Table 1 .…”

“…CLZ is established the sole approval antipsychotic agent for the treatment of antipsychotics-resistant schizophrenia and one of the most effective antipsychotics [ 74 ]. Another meta-analysis study reported that CLZ, BPZ and QTP therapies for the management of acute phase of bipolar disorder and bipolar depression were efficacious [ 54 , 55 , 56 , 57 , 75 , 76 ]. Taken together with clinical findings, the present results suggest the candidate mechanisms that enhanced functional astroglial Cx43 is, at least partially, involved in the mood-stabilizing antipsychotic actions of CLZ, QTP and BPZ.…”

“…However, the effects of mood-stabilizing atypical antipsychotics on Cx43 expression and astroglial hemichannel activity has remained to be clarified. Therefore, based on our hypothesis, to explore the mechanisms of effects of mood-stabilizing antipsychotics, the present study determined the concentration-dependent effects of acute and subchronic administrations of CLZ, quetiapine (QTP) and brexpiprazole (BPZ) [ 54 , 55 , 56 , 57 ] on astroglial Cx43 expression and l -glutamate release through astroglial hemichannel using cortical primary cultured astrocytes. Additionally, combination of mood-stabilizer, VPA with mood-stabilizing antipsychotics is considered to be the first line medication for the treatment of various phases of bipolar disorder [ 54 , 58 , 59 , 60 , 61 ].…”

Reducing Addiction in Bipolar Disorder via Hacking the Dopaminergic System

“…While cariprazine proved to be efficacious in both bipolar mania and bipolar depression ( 49 ) [3–6 mg in bipolar mania ( 50 ) and 1.5–3 mg in bipolar depression ( 51 )], studies of aripiprazole confirmed efficacy in bipolar mania only ( 52 ). Brexpiprazole studies in bipolar mania were unsuccessful ( 53 ), and, following a positive pilot trial ( 54 ), a RCT in bipolar depression is ongoing ( 55 ). Human PET studies with cariprazine ( 56 , 57 ), aripiprazole ( 58 ), and brexpiprazole ( 58 ) have pointed to the difference potentially explaining these findings: while all three compounds were able to occupy the D 2 receptors in the brain, only cariprazine was able to sufficiently occupy the D 3 receptors as well [( 59 ); Figure 1 ].…”

The Journal of Psychopharmacology: La Plus ça change. . .

“…The primary analyses did not show a statistically significant difference between brexpiprazole and placebo. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than patients with excellent insight (predominantly US patients) (Vieta et al, 2021). Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severely ill enough (especially regarding insight), and that the dose/titration schedule is optimal.…”