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Brexpiprazole: A Novel Antipsychotic for Major Depressive Disorder and Schizophrenia

By: Nicollette Pacheco, Staff Editor [Graphics-focused]

Brexpiprazole (REXULTI®) is a novel atypical antipsychotic that was approved in July 2015 for the adjunctive treatment of Major Depressive Disorder (MDD) and as monotherapy in schizophrenia.1 Brexpiprazole is a serotonin-dopamine activity modulator with partial agonism at serotonergic 5HT1α and dopaminergic D2 receptors, as well as potent antagonism at 5HT2α and noradrenergic α1B and α2C receptors. D2 receptor action demonstrates lower intrinsic activity than aripiprazole, suggesting fewer adverse effects (such as akathisia). Decreased affinity for histaminic H1 receptors also suggests decreased sedation compared with other antipsychotics. The advantageous pharmacologic profile of brexpiprazole makes it a viable option in patients with schizophrenia or MDD.3

The dosing of brexpiprazole for MDD is 0.5 to 1 mg daily by mouth (initially), and it is titrated weekly to a maximum daily dose of 3 mg. In schizophrenia, brexpiprazole is initiated at 1 mg daily and titrated every 3 to 4 days to a maximum daily dose of 4 mg. Dose adjustments are required in patients who are poor CYP2D6 metabolizers, taking CYP3A4 inducers or inhibitors, have a creatinine clearance below 60 mL/min, or have moderate to severe hepatic impairment (Child-Pugh class B or C). FDA Boxed Warnings caution the use of brexpiprazole in elderly patients with dementia-related psychosis (due to increased mortality) and in patients aged 24 years and younger (due to suicidal thoughts and behaviors).2


Brexpiprazole in Schizophrenia

Schizophrenia is a severely debilitating, lifelong illness that compromises a person’s thinking, perception, emotion, and behavior. While early signs of schizophrenia may be difficult to differentiate from other psychological illnesses, early recognition and treatment is key because a delay in treatment may alter long-term outcomes and the patient’s ability to achieve remission. Pharmacologic, psychosocial, and rehabilitative treatments are often needed to reduce the risk of symptomatic exacerbations and hospitalizations.4

In a phase III clinical trial, patients diagnosed with schizophrenia who were experiencing an acute exacerbation were randomized to daily doses of brexpiprazole 0.25 mg, 2 mg, 4 mg, or placebo, and they were followed for 6 weeks. The Change in Positive and Negative Syndrome Scale (PANSS) was used to measure the primary endpoint of disease severity (by screening for both the positive and negative symptoms associated with schizophrenia). The secondary endpoint was measured by the Clinical Global Impressions (CGI) Scale, which indicated improvement in disease severity. After 6 weeks of treatment, patients who received daily doses of brexpiprazole 2 mg and 4 mg demonstrated a statistically significant reduction in the PANSS compared to the placebo group (treatment differences: -8.72 and -7.64; p<0.0001 and p=0.0006, respectively). The CGI scale also revealed statistically significant improvements in disease severity when compared to the placebo group (treatment differences: -0.33 and -0.38; p=0.0056 and p=0.0012, respectively). Moderate weight gain was observed among patients in the brexpiprazole groups (1.45 kg for the 2 mg daily group; 1.28 kg for the 4 mg daily group; 0.42 kg for the placebo group), while no clinically significant changes in lipid or glucose levels were noted.5

Brexpiprazole in Major Depressive Disorder

MDD is a chronic illness with heavy physical, social, and financial burdens. It commonly occurs in a person’s late 20s, and it can manifest as a single episode or several recurrent episodes. The risk of recurrence increases after each episode, warranting careful therapeutic management in patients who have not achieved an adequate response with previous antidepressant treatments. Patients who achieve a therapeutic response exhibit a >50% decline in various depression severity rating scales. Treatment usually involves psychotherapy, medications, and lifestyle adjustments.6

In a Phase III trial, patients who did not experience an adequate response to previous antidepressant treatments were followed for 8 weeks of open-label antidepressant treatment and then randomized to daily doses of brexpiprazole 3 mg, 1 mg, or placebo for 6 weeks. The primary endpoint was the change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6. This scale measured the severity of depressive episodes in patients with mood disorders. Secondary endpoints measured improvements in family, social, and work life. Safety endpoints were extrapyramidal symptom (EPS)-related adverse events, such as hyperkinesia, akinesia, dystonia, akathisia, and tremor. The Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Rating Scale were used to measure the severity of these symptoms. Vital signs, clinical laboratory tests, electrocardiograms, suicidal behaviors / ideations, and sexual function were additional safety endpoints in the study.

Adjunctive brexpiprazole 3 mg daily demonstrated improvements in MADRS scores compared to antidepressant monotherapy in patients who had inadequate responses to initial MDD therapy (n=203; -8.29 vs -6.33; p=0.0079). Patients receiving brexpiprazole 1 mg daily experienced moderate improvements in MADRS scores compared to patients on monotherapy, but the outcome was not statistically significant (n=211; -7.64 vs -6.33; p=0.0737). Secondary endpoints reinforced the primary outcome, demonstrating improvements in family and social lives. Brexpiprazole 1 mg and 3 mg daily doses also achieved statistical significance in their secondary endpoints. Frequently reported, treatment-emergent adverse events in the 1 mg daily group included headache (9.3%), nasopharyngitis (6.6%), and weight gain (6.6%). In the 3 mg daily group, akathisia (13.5%), headache (6.1%), somnolence (5.7%), weight gain (5.7%), and tremor (5.2%) were reported. All events were considered mild to moderate in severity. Weight gain of 1.4 kg and 1.57 kg were seen for the 1 mg daily and 3 mg daily groups, respectively, compared to 0.24 kg in the placebo group. Small increases in prolactin levels were seen in both brexpiprazole groups. No changes in vital signs or electrocardiograms were noted.3

Although not seen in clinical trials of brexpiprazole, cerebrovascular adverse events and neuroleptic malignant syndrome (NMS) have been observed in patients who take antipsychotics and antidepressants (with similar pharmacologic activity). For this reason, brexpiprazole is not recommended in elderly patients with dementia or in patients with symptoms of NMS. Metabolic changes, blood dyscrasias, orthostatic hypotension, body temperature dysregulation, and dysphagia have all been associated with antipsychotic use, and providers should monitor for these adverse events in patients who take brexpiprazole.2

Overall, many patients suffering from MDD do not respond to first-line therapies (such as selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and the norepinephrine-dopamine reuptake inhibitors). These patients are managed by changing the initial antidepressant or by adding a second-generation antipsychotic (such as aripiprazole or quetiapine). While these therapies have demonstrated efficacy in MDD and schizophrenia, tolerability limits their use in some patients. For example, aripiprazole is known to cause akathisia and quetiapine is notorious for its excessive sedation.3 Brexpiprazole is considered to be a relatively safe / efficacious option for patients with schizophrenia or patients who have an inadequate response to other MDD treatments.



  1. U.S. Food and Drug Administration. FDA approves new drug to treat schizophrenia and as an add on to an antidepressant to treat major depressive disorder 2015. Updated 07/14/2015. Accessed 03/01/2016.
  2. Rexulti (Brexpiprazole) [package insert]. Rockville, MD; Otsuka America Pharmaceutical, Inc.; Revised 08/2015.
  3. Thase ME, Youakim JM, Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015;76(9):1232-1240.
  4. Lacro JP, Farhadian S, Endow-Eyer RA. Schizophrenia. In: Alldredge BK, Corelli RL, Ernst ME et al. Applied Therapeutics: The Clinical Use of Drugs. 10th ed. Philadelphia, PA.: Lippincott Williams & Wilkins; 2013: 1921-1948.
  5. Correl CU, Skuban A, Ouyang J, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015;172(9):870-80.
  6. Finley PR, Lee KC. Mood Disorders 1: Major Depressive Disorders. In: Alldredge BK, Corelli RL, Ernst ME et al. Applied Therapeutics: The Clinical Use of Drugs. 10th ed. Philadelphia, PA.: Lippincott Williams & Wilkins; 2013: 1949-1982.
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