New atypical antipsychotic approved


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New Drug

A new atypical antipsychotic, brexpiprazole (Rexulti—Otsuka), has received FDA approval as an adjunct treatment to antidepressants for major depressive disorder (MDD) and for the treatment of schizophrenia. According to the National Alliance on Mental Illness, approximately 6.7% of American adults−about 14.8 million people—live with MDD, and approximately 1.1% of American adults—about 2.4 million people—live with schizophrenia. Therefore, there is a real need for effective treatments for these conditions.


Brexpiprazole’s effects are believed to be mediated via a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors and antagonist activity at serotonin 5-HT2A receptors. Its use has been evaluated in numerous studies for MDD and schizophrenia, with four Phase III trials supporting its approval. 


Efficacy, safety data 


As adjunctive therapy for MDD, the efficacy of brexpiprazole was evaluated in two, 6-week, placebo-controlled trials of adult patients with MDD who failed to reach an adequate response with antidepressants. The primary endpoint for both studies was change from baseline to Week 6 in the MADRS (Montgomery–Asberg Depression Rating Scale). At randomization, the mean MADRS total score was 27 and treatment with brexpiprazole 2 mg/d and 3 mg/d in combination with an antidepressant was superior to placebo plus an antidepressant in improvements in the MADRS across both studies. The mean baseline MADRS score decreased from 27 at randomization by 8.36 (2 mg) and 8.29 (3 mg) in the brexpiprazole groups compared with reductions of 5.15 and 6.33 in the placebo groups in the respective studies; the 1-mg dose was not superior to placebo. 


For schizophrenia, the efficacy of brexpiprazole was also evaluated in two, 6-week, Phase III, randomized, placebo-controlled clinical trials. When given at an adequate dose for 6 weeks, use of brexpiprazole demonstrated statistically significant efficacy compared with placebo for the primary endpoint of PANSS (Positive and Negative Syndrome Scale). In one trial, change from baseline in PANSS total score for brexpiprazole at both 2 mg/d and 4 mg/d (−20.73 and −19.65) was superior to placebo (−12.01); in a second trial, the change from baseline in PANSS total score at a dose of 4 mg/d (−20.00 vs. −13.53, respectively) was superior to placebo. 


The most common adverse reactions were an increase in weight in both the MDD and schizophrenia trials and akathisia in the MDD trials.



Patient counseling


Give patients the Medication Guide and educate them on the need to dose titrate the drug when initiating therapy and on potential adverse events. Patients should understand the signs of neuroleptic malignant syndrome and tardive dyskinesia and to contact their provider if these reactions occur. In addition, inform patients that various lab tests may be needed to monitor them for low blood counts and/or changes in blood glucose or lipid levels. Also educate patients that brexpiprazole may make them feel drowsy and tips on how to avoid getting over-heated or dehydrated such as not over-exercising, staying out of the sun, and drinking plenty of water.


Brexpiprazole (Rexulti)


Manufacturer: Otsuka


Drug class: Atypical antipsychotic


Indication: As an adjunct to antidepressants for the management of major depressive disorder (MDD) and for the treatment of schizophrenia


Dosage: For MDD, a starting dose of 0.5 mg/d or 1 mg/d, taken once daily with or without food, is recommended with dose titrations occurring at weekly intervals based on response and tolerability to a target dose of 2 mg/d. The maximum dose for MDD is 3 mg/d.


  • For schizophrenia, a starting dose of 1 mg/d, taken once daily with or without food on days 1 to 4, is recommended with dose titrations to 2 mg/d on days 5 through 7, then 4 mg on day 8 and beyond based on response and tolerability. The maximum dose for schizophrenia is 4 mg/d.

  • For patients with moderate to severe hepatic impairment (i.e., Child–Pugh score ≥ 7) and for those with moderate, severe, or end-stage renal impairment (i.e., creatinine clearance < 60 mL/min), the maximum recommended dose for MDD is 2 mg/d and for schizophrenia is 3 mg/d.

  • Dosage adjustments are also listed in the label for patients who are known cytochrome P450 2D6 poor metabolizers, and in patients taking concurrent medications that interact with brexpiprazole. 


Of note: Brexpiprazole has a boxed warning for increased mortality in older patients with dementia-related psychosis and an increased risk of suicidal thoughts and behaviors in patients aged 24 years and younger. 


  • The drug is contraindicated in those with a known hypersensitivity to the drug or to any of its components.

  • Other warnings and precautions listed in the label include the potential for cerebrovascular adverse reactions, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes (e.g., hyperglycemia, dyslipidemia, weight gain), leukopenia, neutropenia, agranulocytosis, orthostatic hypotension and syncope, seizures, body temperature dysregulation, dysphagia, and potential for cognitive and motor impairment.
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