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Clinical Trials with Multiple Objectives
Published in Alex Dmitrienko, Erik Pulkstenis, Clinical Trial Optimization Using R, 2017
The clinical trial example used in this case study is based on a Phase III trial that was conducted to evaluate the efficacy and safety of brexpiprazole, a novel treatment for schizophrenia (Correll et al., 2015). The patient population in the case study will include patients with schizophrenia who experience an acute exacerbation. The patients will be treated for 6 weeks and will be randomly assigned to a low dose of the experimental treatment (Dose L), high dose of the experimental treatment (Dose H) or placebo. An unbalanced design with a 1:2:2 randomization scheme will be employed in the trial. The use of unequal randomization helps provide more information on the treatment’s safety profile and facilitates patient enrollment since patients are more likely to be allocated to an active treatment.
The Management of Treatment-Resistant Depression
Published in Dr. Ather Muneer, Mood Disorders, 2018
This drug, structurally related to aripiprazole, is a serotonin-dopamine activity modulator. In July 2015 it received FDA approval for schizophrenia and augmentation therapy of MDD. It shows partial agonism at the D2 receptor and possibly functional selectivity at this site. Compared to aripiprazole, brexpiprazole has lower intrinsic activity at the D2R, but exhibits 10-fold higher affinity at the 5-HT1A receptor where it acts as a partial agonist. Two recently published phase III trials investigated the potential of brexpiprazole as an augmentation agent in TRD. The two identically designed studies included subjects who had inadequate response to one to three standard antidepressants (AD) for their current depressive episode. All patients entered a prospective eight-week phase of open-label antidepressant therapy and those who failed to sufficiently respond were randomized to AD + brexpiprazole or AD + placebo and followed in a double-blind fashion for a total of six weeks. The primary outcome measure was change in Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to week 6. In the first study brexpiprazole 3 mg/day was superior to placebo on MADRS total score (-8.29 versus -6.33; p = 0.0079), but brexpiprazole 1 mg/day failed to separate from placebo (-7.64 versus -6.33; p = 0.0737). In the second study, brexpiprazole 2 mg/day showed superior efficacy over placebo in changes from baseline to week 6 on MADRS total scores (-8.36 versus -5.15; p = 0.0002). Further, the active agent was also better than placebo on the Sheehan Disability Scale (-1.35 versus -0.89; p = 0.0349). The most common treatment-related adverse events were weight gain (brexpiprazole, 8%; placebo, 3.1%) and akathisia (7.4% versus 1.0%). Taken as a whole, brexpiprazole in addition to standard antidepressants was safe and well tolerated in the two phase III RCTs.14
Pharmacological strategies for sexual recovery in men undergoing antipsychotic treatment
Published in Expert Opinion on Pharmacotherapy, 2022
Tommaso B. Jannini, Andrea Sansone, Rodolfo Rossi, Giorgio Di Lorenzo, Massimiliano Toscano, Alberto Siracusano, Emmanuele A. Jannini
In conclusion, to date, the best pharmacological strategy for sexual recovery in men undergoing antipsychotic treatment is represented by the TGAs aripiprazole, with considerable evidence from RCTs and open-label studies supporting this choice, and, although more clinical data are needed, brexpiprazole, whose promise is to be equally effective, but with an even lower amount of general side effects. This could be done either by choosing them as the first-line treatment, by switching them, or by administering them in augmentation. We think it could be helpful to add brexpiprazole to the list of drugs useful for an advantageous shift. Because of its efficacy and tolerability profile, it is our strong opinion that this task will be even more easily reached shifting to the more recent kid in the block of antipsychotics.
Efficacy and safety of cariprazine in the treatment of bipolar disorder
Published in Expert Opinion on Pharmacotherapy, 2019
Gayatri Saraf, Jairo Vinícius Pinto, Lakshmi N. Yatham
Aripiprazole has been approved by the US-FDA for the treatment of acute manic and mixed episodes associated with BD, and as a maintenance treatment in BD [25]. Brexpiprazole, which is structurally very similar to aripiprazole has been approved by the United States Food and Drugs Administration (FDA) for the treatment of schizophrenia and as an adjunctive to antidepressants in major depressive disorder [26]. Though both aripiprazole and brexpiprazole are partial agonists at D2 receptors and are, therefore, similar to cariprazine, cariprazine has a greater selectivity for D3 receptors. Two recent clinical trials did not support the efficacy of brexpiprazole in the treatment of acute mania. Lurasidone was approved by the FDA in 2013 for the treatment of bipolar depression. It combines good efficacy for acute bipolar depression with overall good safety and a favorable metabolic profile. It, however, can cause akathisia [27]. Further, it has not been studied for the treatment of acute mania, and the only maintenance trial of lurasidone adjunctive therapy did not support the efficacy [28].
Brexpiprazole for treatment-resistant major depressive disorder
Published in Expert Opinion on Pharmacotherapy, 2019
Michele Fornaro, Andrea Fusco, Annalisa Anastasia, Carlo Ignazio Cattaneo, Domenico De Berardis
The FDA-approved starting dose of brexpiprazole as an adjunctive treatment for MDD is 0.5 or 1 mg once daily; the target dosage is 2 mg, taken orally with or without food. The maximum recommended daily dosage is 3 mg, however for patients with moderate to severe hepatic impairment (Child-Pugh score≥7) or patients with moderate to severe renal impairment (creatine clearance<60mL/min) the maximum recommended dosage is 2 mg/day. Comparably, the dose range of brexpiprazole approved for the treatment of schizophrenia is 1–4 mg/day. Regardless of the diagnostic target, it is advisable to begin brexpiprazole at an intermediate dose and build the dose rapidly over 3–7 days. In case of the switch from another SGAs, clinical experience has shown that asenapine, quetiapine, and olanzapine should be tapered off slowly over 3–4 weeks, to allow patients to readapt to the withdrawal of blocking cholinergic, α1, and histaminergic receptors. Clozapine should always be tapered off slowly, over four weeks or more[28]. Benzodiazepines or anticholinergic medication can be administered during cross-titration to help alleviate side effects such as insomnia, agitation, and psychosis[29].