Brexpiprazole – Mechanism of Action, Side Effects and Clinical Pearls

Brexpiprazole [7-{4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butoxy}quinolin-2(1H)-one] is a novel atypical antipsychotic that is structurally similar to the atypical antipsychotic, aripiprazole.

It has the following key psychopharmacological properties:

• Partial agonist of dopamine D2 receptors that is at a lower level of intrinsic activity than aripiprazole.
• Partial agonist at serotonin 5-HT1A that is at a stronger level of activity than aripiprazole.
• Potent antagonist of serotonin 5-HT2A receptors.
• Potent antagonist of noradrenaline alpha1B/2C receptors.
• Moderate affinity for histamine H1 receptors
• 5HT1A partial agonism and 5HT7A antagonism may be responsible for antidepressant properties.

Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.

The lower intrinsic activity of brexpiprazole at D₂ receptors relative to aripiprazole indicates a lower likelihood of inducing side effects such as akathisia, restlessness, insomnia; side effects considered to be associated with aripiprazole-induced stimulating activity at D₂ receptors (Activating side effects).

The potency and intrinsic activity of brexpiprazole are much higher and slightly lower than buspirone (5HT1A partial agonist).

In addition, brexpiprazole shows moderate affinities for histamine H₁ receptors and adrenaline α1A receptors.

Brexpiprazole also has a high affinity for α1B and α2C receptors and acts as an antagonist at both receptors. The α1B antagonism confers prazosin like effects and may explain why brexpiprazole blocks PTSD-like memory while promoting normal fear memory in an animal model. A study showed that adjunctive treatment with brexpiprazole improved treatment-resistant complex PTSD in domestic family violence victims. [O’Connor, 2020]

Brexpiprazole had little or no significant effect on blood prolactin levels in schizophrenia, although aripiprazole was associated with decreases in blood prolactin levels. This can possibly be attributed to the lower intrinsic activity of brexpiprazole. [Kikuchi et al., 2021]

Based on the differences in receptor profiles Aripiprazole is best described as a Dopamine System Stabiliser (DSS) vs Brexpiprazole as a Serotonin Dopamine Activity Modulator (SDAM). [Kikuchi et al., 2021]

Side Effects:

• Low incidence of EPSE and akathisia than aripiprazole
• H1 antagonism can be associated with mild weight gain

Pharmacokinetics: 

• Metabolised by CYP3A4 and CYP2D6.
• The terminal elimination half-life of brexpiprazole and its major metabolite, DM-3411, is 91.4 hours and 85.7 hours, respectively

Dose Range: 

• 1mg – 4mg
• Day 1 – 1 mg
• Day 5-7 – 2 mg and increase
• By day 8 – 4 mg

Important clinical pearls: 

• Switch from Olanzapine and Quetiapine should be done gradually to avoid antihistaminergic and anticholinergic rebound.
• Less akathisia than aripiprazole
• Useful as an augmentation agent to treat mixed features
• Useful as an augmentation agent to treat psychotic depression or melancholic depression with agitation 
• A long half-life reduces the immediate risk of relapse if a patient is non-compliant.

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