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Rexulti: A Unique Treatment Approach

Rexulti (Brexpiprazole)

Rexulti (Brexpiprazole) is a unique medication with many indications. This medication was initially approved by the U.S. Food and Drug Administration (FDA) in July 2015 for Schizophrenia and treatment-resistant Major Depressive Disorder. This medication has an uncommon mechanism of action that makes it useful in treating difficult symptomatology. Rexulti is part of the atypical antipsychotic class of medications; it works as a serotonin-dopamine activity modulator. This medication can be taken in addition to a Selective Serotonin Reuptake Inhibitor/Selective Norepinephrine Reuptake Inhibitor (antidepressants) as adjunctive therapy.

Current Indications:

FDA approved for Schizophrenia and Treatment Resistant Major Depressive Disorder (MDD)

Off-label use indications: Acute mania/mixed episode, psychotic disorders, Bipolar maintenance, Bipolar depression, Behavioral disturbance in dementia, Post Traumatic Stress Disorder (PTSD), disorders causing impulse control difficulties, behavioral disturbances in children and adolescents

Mechanism of Action:

Rexulti works by modulating both serotonin and dopamine; it acts as a partial agonist at the 5-HT1A and dopamine D2 receptors at similar potency. A partial agonist medication is a drug that binds to a given receptor but only at partial efficacy. It also works as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. An antagonist has no effect on receptor activity. This partial agonism specificity to selective serotonin and dopamine receptors aids in making this medication very diverse. This medication is primarily metabolized by CYP450 2D6 and 34A pathways (Stahl, 2021).

How Rexulti works to improve symptoms:

  • Partial agonist at 5HT1A receptor benefits mood, anxiety, and improves cognition.

  • Blocking of Serotonin 2A receptor causes dopamine release in specific areas which limits the motor side effects of Rexulti.

  • Blockade of alpha 1B receptors can reduce physical arousal symptoms in PTSD and reduce agitation

  • Blockade of alpha 2C may assist in antidepressant actions

  • Blocks serotonin 7 receptors causing improved mood, cognition, and negative symptoms in schizophrenia, bipolar disorder and MDD

(Stahl, 2021)

Rexulti and PTSD

By acting on the dopamine D2 receptor, ​​preliminary studies have shown Rexulti can alter the maladaptive fear memory by reversing the PTSD-like fear memory to a normal fear memory. It also reduces hyperactivation of activities in the brain present with PTSD (Park et al., 2022)

Rexulti can show improvements in symptoms within 1 week but full effect can take several weeks.

4-6 weeks of adequate dosing trial is needed to evaluate symptom management.

Tests needed before initiation of Rexulti:

Weight, body mass index, waist circumference, blood pressure, Hemoglobin A1C, fasting glucose, and fasting lipid panel. Tell your provider if you or a family member have a significant history of diabetes, obesity, high cholesterol, high blood pressure, or heart disease.

Typical dosing of Rexulti:


2-4mg once daily

Initial dosing begins at 1mg daily for days 1-4; increase to 2mg daily for days 5-7; increase to 4mg once daily on day 8; maximum dose is 4mg daily

Treatment-Resistant Major Depressive Disorder:

2mg once daily

Initial dosing should begin at 0.5-1mg daily; increasing weekly as needed up to 2mg daily, maximum is 3mg daily

Dosage forms: Tablet 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg


Possible side effects of Rexulti include: dizziness, hypotension, nausea, vomiting, sedation, headache, potential weight gain, and akathisia.

Potential serious side effects include Neuroleptic Malignant Syndrome (NMS) may cause hyperreflexia, muscle rigidity, delirium, and autonomic instability, elevated CPK, myoglobinuria, and acute renal failure.

How this medication differs from Abilify:

Rexulti (Brexpiprazole) differs from Abilify (Aripiprazole) in its mechanism of action. Specifically, Rexulti has more selective binding and affinity properties than Abilify. This may be an indicator for the increased efficacy and tolerability in Rexulti compared to Abilify.

More information on Rexulti indications:

Diagnosing Schizophrenia

Schizophrenia is an illness that causes thoughts that are not based in reality (delusions), having experiences that are not actually happening (hallucinations) such as seeing things that are not there or hearing voices, disorganized thoughts that can affect the way in which someone talks, and may affect the way people move their bodies (abnormal motor behavior). Schizophrenia can have both positive and negative symptoms. Positive symptoms can be thought of as added aspects that should not be present, such as hallucinations or delusions. Negative symptoms are the lack of things that should be present such as the ability to express emotions or motivation. To diagnose schizophrenia, two or more symptoms of the following must be present: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms. These symptoms must be present most of the time, for at least 6 months and decrease functioning in one or more areas of life, such as career, personal relationships, or self =-care. For diagnosis, these impairments must not be due to a medical condition or related to effects of a drug, either prescription or recreational use (American Psychiatric Association [APA], 2013; APA, “schizophrenia”).

Schizophrenia is typically treated with typical and atypical antipsychotics.

Goal of treatment in Schizophrenia: reduction of positive symptoms, improve negative symptoms, reduce aggression, and improve cognition.

Diagnosing Depression

Depression affects the way a person feels, thinks and acts. It is a feeling of sadness and inability to enjoy things that previously were enjoyable for 2 weeks or more (APA, 2013). To diagnose depression, one must have either depressed mood or loss of interest or pleasure (anhedonia), as well as 4 additional symptoms. The other symptoms in addition to the two listed are significant unexpected weight loss or weight gain, changes in sleep, changes in the way you move your body that is noticeable to others, fatigue or loss of energy, feelings of worthlessness or excessive guilt, difficulty concentrating or making decisions, or thought of death or suicidal ideation (American Psychiatric Association [APA], 2013; APA, “What is depression”).

MDD is treated with SSRI, SNRI, Tricyclic Antidepressants, and Monoamine oxidase inhibitors.

Goal of treatment in MDD: complete remission of current symptoms and prevention of relapses.

Diagnosing PTSD

PTSD may occur after someone experiences or witnesses a traumatic event (APA, 2013). Someone with PTSD has memories of the traumatic event, which can recur through nightmares or flashbacks. They may feel sadness or anger, and distant from others. To diagnose PTSD, patient must be 6 years old or older, have exposure to actual or threatened death, serious injury or sexual violence. One or more of the following intrusion symptoms associated with the traumatic event; recurrent involuntary intrusive distressing memories of the event, recurrent distressing dreams of the event, flashbacks of the event and feeling like it is actually happening again in the present moment, distress related to something that symbolizes or represents some aspect of the event, or physiological reaction to the symbolization or representation. Persistent avoidance of the distressing memory or external, distressing reminders of the event. Changes in thoughts and mood related to the events such as inability to remember certain aspects, exaggerated negative beliefs, distorted cognitions about the event, negative emotional state, diminished interest or participation in significant activities, feeling distant from others, or inability to experience positive emotions. There must also be changes in arousal or reactivity related to the event, these disturbances must be present for 1 month or more, cause significant distress in important areas of functioning (social, occupational), and these impairments must not be due to a medical condition or related to effects of a drug, either prescription or recreational use. (APA, 2013; APA, “What is posttraumatic stress disorder (PTSD))


American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

Arlington, VA: American Psychiatric Publishing.

American Psychological Association. (n.d.) Schizophrenia.


American Psychological Association. (n.d.) What is depression?


American Psychological Association. (n.d.) What is posttraumatic stress disorder (PTSD)?

Eaves, S., & Rey, J. A. (2016). Brexpiprazole (Rexulti): A New Monotherapy for Schizophrenia and Adjunctive

Therapy for Major Depressive Disorder. P & T : a peer-reviewed journal for formulary management, 41(7),


Park, H.R.; Cai, M.; Yang, E.J.(2022). Neurogenic interventions for fear memory via modulation of the

hippocampal function and neural circuits. International Journal of Molecular Sciences 23, 3582.

Stahl, S. (2021). Stahl's essential psychopharmacology: Prescriber's guide (7th ed.). Cambridge, United Kingdom: Cambridge University Press.

Thase, M. E., Weiller, E., Zhang P., Weiss, Mcintyre, R. S. (2019) Adjunctive brexpiprazole in patients with major

depressive disorder and anxiety symptoms: post hoc analyses of three placebo-controlled studies.

Neuropsychiatric Disease and Treatment. 15 37–4


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