Brexpiprazole: a new dopamine D2 receptor partial agonist for the treatment of schizophrenia and major depressive disorder

Abstract Second-generation antipsychotics are common candidates for the adjunctive treatment of major depressive disorder and for the treatment of schizophrenia. However, unmet needs remain in the treatment of both disorders. Considering schizophrenia, antipsychotics are the most common treatment and have demonstrated good efficacy. Still, side effects of these treatments are commonly reported and may impact adherence to the medication and functioning in patients with schizophrenia. Regarding major depressive disorder, despite the availability of several classes of antidepressants, many patients do not achieve remission. Adjunctive treatment with antipsychotics may improve clinical and functional outcomes. Compared with dopamine D2 receptor antagonism that is exhibited by most antipsychotics, partial agonism may result in improved outcomes in major depressive disorder and in schizophrenia. Aripiprazole, cariprazine, and brexpiprazole have partial agonism at the dopamine D2 receptor and could potentially overcome limitations associated with D2 antagonism. The objectives of this review were (1) to discuss the goal of treatment with second-generation antipsychotics in major depressive disorder and schizophrenia, and the clinical factors that should be considered, and (2) to examine the short- and long-term existing data on the efficacy and safety of D2 receptor partial agonists (aripiprazole, cariprazine, and brexpiprazole) in the adjunctive treatment of major depressive disorder and in the treatment of schizophrenia.

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Scale-Up Synthesis and Identification of GLYX-13, a NMDAR Glycine-Site Partial Agonist for the Treatment of Major Depressive Disorder

Molecules ◽

10.3390/molecules23050996 ◽

2018 ◽

Vol 23 (5) ◽

pp. 996 ◽

Cited By ~ 2

Author(s):

Wenchao Li ◽

Jingjian Liu ◽

Minghua Fan ◽

Zhongtang Li ◽

Yin Chen ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Partial Agonist ◽

Scale Up ◽

Glycine Site ◽

Major Depressive

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Brexpiprazole: A review of a new treatment option for schizophrenia and major depressive disorder

Mental Health Clinician ◽

10.9740/mhc.2017.09.207 ◽

2017 ◽

Vol 7 (5) ◽

pp. 207-212 ◽

Cited By ~ 10

Author(s):

Lauren A. Diefenderfer ◽

Courtney Iuppa

Keyword(s):

Clinical Trials ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Partial Agonist ◽

Adjunctive Treatment ◽

Inadequate Response ◽

Major Depressive ◽

Two Phase ◽

New Treatment

Abstract Brexpiprazole is an atypical antipsychotic that works as a partial agonist at serotonin 5-hydroxytryptamine1A and dopamine D2 receptors and an antagonist at serotonin 5-hydroxytryptamine2A. It has US Food and Drug Administration approval for monotherapy treatment of schizophrenia and adjunctive treatment to antidepressants for major depressive disorder. Two phase-3 clinical trials demonstrated efficacy and relatively fair tolerability with regard to adverse effects for each indication. Akathisia was frequently reported in the major depressive disorder trials but less so in the schizophrenia trials. Significant increases in body weight and triglycerides were seen across all studies. Brexpiprazole appears to be a viable option for treating an acute exacerbation of schizophrenia requiring hospitalization or adjunctive treatment of major depressive disorder in patients who showed an inadequate response to 1 to 3 antidepressants. Further clinical trials are warranted to determine the long-term efficacy of brexpiprazole, and comparison trials would be beneficial to establish its place in therapy.

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The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyy059 ◽

2018 ◽

Vol 21 (12) ◽

pp. 1102-1108 ◽

Cited By ~ 2

Author(s):

Richard Ågren ◽

Peter Århem ◽

Johanna Nilsson ◽

Kristoffer Sahlholm

Keyword(s):

Potassium Channel ◽

G Protein ◽

Dopamine D2 Receptor ◽

Partial Agonist ◽

D2 Receptor ◽

Channel Activation ◽

Receptor Ligand ◽

Dopamine D2

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Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis

Psychological Medicine ◽

10.1017/s0033291713002857 ◽

2013 ◽

Vol 44 (11) ◽

pp. 2255-2269 ◽

Cited By ~ 9

Author(s):

T. Kishi ◽

H. Y. Meltzer ◽

Y. Matsuda ◽

N. Iwata

Keyword(s):

Systematic Review ◽

Major Depressive Disorder ◽

Side Effects ◽

Depressive Disorder ◽

Partial Agonist ◽

Meta Analysis ◽

Gastrointestinal Symptoms ◽

Cochrane Library ◽

Number Needed To Treat ◽

Major Depressive

BackgroundA meta-analysis of the serotonin1A (5-HT1A) receptor partial agonist of the azapirone class as an anxiolytic drug for the treatment of major depressive disorder (MDD) has not previously been reported.MethodWe carried out a systematic review of the literature available in PubMed, the Cochrane Library database and PsycINFO up to 12 October 2013, and conducted a meta-analysis of randomized controlled trials (RCTs) comparing 5-HT1A agonists with placebo and RCTs of 5-HT1A agonist augmentation therapies for MDD treatment. We calculated the risk ratio (RR), number needed to treat (NNT)/number needed to harm (NNH) and 95% confidence intervals (CIs).ResultsFifteen RCTs comparing 5-HT1A agonists with placebo (total n = 2469, four studies with buspirone, seven with gepirone, three with ipsapirone and one with zalospirone) were identified. Pooled 5-HT1A agonists had significantly more responders (RR 0.74, 95% CI 0.65–083, p < 0.00001, NNT = 6, 12 trials, n = 1816) than placebo. Pooled 5-HT1A agonists were superior to placebo in discontinuation due to inefficacy (RR 0.49, p = 0.02, NNH = 16, p = 0.03, 10 trials, n = 1494) but were inferior to placebo in discontinuation due to side-effects (RR 1.88, p < 0.0001, NNH = 17, p = 0.001, 13 trials, n = 2196). However, all-cause discontinuation was similar in both groups (RR 0.99, p = 0.85, 14 trials, n = 2402). Four 5-HT1A agonist augmentation studies were identified (total n = 365, three buspirone studies and one tandospirone study). There were no statistically significant effects of 5-HT1A agonist augmentation therapies on response rate (RR 0.98, p = 0.85, four trials, n = 341). 5-HT1A agonist-related side-effects including gastrointestinal symptoms, dizziness, insomnia, palpitation, paresthesia and sweating were greater than with placebo (p < 0.00001 to p = 0.03).ConclusionsOur results suggest that 5-HT1A agonist has a more beneficial effect on MDD than placebo, but has several side-effects.

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