Brexpiprazole – Psychopharmacology | Mechanism of Action | Clinical Application

WHAT IS A PARTIAL DOPAMINE AGONIST AND HOW DOES IT DIFFER FROM DOPAMINE ANTAGONISTS?

A Simplified Guide to Oral Antipsychotic Medications – Mechanism of Action, Side Effects, and Need to Know Points

• Typical and atypical antipsychotics act on dopamine D₂ receptors; however, atypical antipsychotics also act on serotonin 5-HT_2A receptors. The Dopamine Hypothesis of Schizophrenia – Advances in Neurobiology and Clinical Application
• Antagonism of dopaminergic pathways can result in adverse events such as extrapyramidal symptoms, hyperprolactinemia, and worsening negative and cognitive symptoms.
• Treatment-emergent adverse events contribute to poor treatment adherence and reduce a patient’s functioning and quality of life. [Barnes, 2011]
• The most common side-effects associated with second-generation antipsychotics are weight gain, metabolic-related disorders, sedation, and sexual-related adverse effects. [Leucht et al., 2013]

Partial Dopamine Agonist

A partial dopamine agonist is a medication that binds to the dopamine receptor but possesses less intrinsic activity than the endogenous full agonist dopamine (DA), i.e. qualitatively acts like DA but quantitatively produces a response that is smaller than that produced by dopamine.

Depending on DA levels, it can act as either a functional antagonist or agonist, which provides benefits in treating schizophrenia. [Kikuchi et al., 2021]

Functional antagonist:

• In the presence of excess DA transmission, it can reduce this transmission to lower levels, levels corresponding to its intrinsic activity.
• Functional antagonism in the mesolimbic dopamine pathway addressing the excessive dopamine activity causes positive symptoms.

Functional agonist:

• In the presence of low DA levels, it can increase DA neurotransmission again to the level of its intrinsic activity.
• Functional agonist activity in the mesocortical pathway, addressing the reduced dopamine activity, is associated with adverse symptoms and cognitive impairment.

A partial dopamine agonist can be considered to be a dopamine modulator adjusting dopamine levels depending on whether they are too high or low (the dimmer switch effect or Goldilocks effect)

Partial agonists

The Goldilocks effect

The Dimmer Switch Effect 

Partial agonists may be particularly useful in preventing D2 receptor upregulation that occurs with long-term administration of D2 antagonists, increasing the risk of DA supersensitivity psychosis.[Nair et al., 2022]

The potential clinical consequence of DA supersensitivity psychosis is that antipsychotic medication may progressively lose effectiveness in treating schizophrenia, necessitating increasingly higher antipsychotic doses over time, with an increased side-effect burden.

There are suggestions that DA supersensitivity psychosis may progress to treatment-resistant schizophrenia (TRS).

PHARMACOLOGY AND MECHANISM OF ACTION OF BREXPIPRAZOLE

The development of Brexpiprazole was spurred by the hypothesis that:

Adding a more potent effect on the serotonin system to a Dopamine system stabiliser (DSS) such as Aripiprazole would lead to an improved tolerability profile minimising the side effects that occur in the initial phase of Aripiprazole treatment (e.g. akathisia).

The drug discovery process thus focused on

Increasing the 5-HT2A receptor antagonism:

• Reduce insomnia and other sleep disturbances, as  5-HT2A receptor antagonists can ameliorate insomnia by enhancing slow-wave sleep during the night. (Mirtazapine is a 5-HT2A antagonist and improves slow wave sleep)
• Minimise akathisia. (Mirtazapine is evidence-based in the treatment of akathisia via 5-HT2A antagonism. SSRIs on the other hand are associated with akathisia through activation of the 5-HT2A receptor)

Increasing 5-HT1A agonist activity: 

• It may improve symptoms of depression and anxiety. (5-HT1A agonist activity at postsynaptic receptors increases dopamine in the frontal cortex).

Reducing the intrinsic activity at the D2 receptors

• Reduce akathisia and activation.

This led to the development of Brexpiprazole, characterised by almost equally high affinities for 5-HT1A,   5-HT2A and D2 receptors.

Brexpiprazole has: 

• 5-HT1A Partial agonist activity (potent)
• 5-HT2A antagonist activity (potent)
• D2 Partial agonist activity (reduced level of intrinsic activity)

Brexpiprazole is thus classified as a serotonin-dopamine activity modulator (SDAM) as it acts as a partial agonist at serotonin 5-HT1A and D2 receptors. [Maeda et al., 2014]

Brexpiprazole primarily modulates dopaminergic neurotransmission in the mesolimbic pathway (positive symptoms) and mesocortical pathway (negative symptoms)

Receptor Profile: 

• Partial agonist of dopamine D2 receptors at a lower activity level than aripiprazole.
• Partial agonist at serotonin 5-HT1A at a stronger activity level than aripiprazole.
• A potent antagonist of serotonin 5-HT2A
• Antagonist at 5-HT7 receptors
• A potent antagonist of noradrenaline alpha 1B/2C receptors.
• Moderate affinity for histamine H1 receptors and muscarinic M1 receptors as well.

HOW IS BREXPIPRAZOLE DIFFERENT FROM ARIPIPRAZOLE?

• Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia) and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity. [Hope et al., 2018]
• 5-HT1A activation may synergise with its potent 5-HT2A antagonism to increase neurite growth, which may have a role in antidepressant augmenting characteristics of brexpiprazole in depression. [Ishima et al., 2015].
• Brexpiprazole is an antagonist at both 5HT7 and noradrenergic α1b/2c receptors, which may mediate mood and cognitive effects in schizophrenia and postural hypotension with respect to α blockade.
• The lower intrinsic activity of brexpiprazole at D₂ receptors relative to aripiprazole indicates a lower likelihood of inducing side effects such as akathisia, restlessness, and insomnia; side effects considered to be associated with aripiprazole-induced stimulating activity at D2 receptors (Activating side effects).
• The more potent 5-HT2A antagonism may also be linked to a lower incidence of EPSE, as 5-HT2A antagonism increases dopamine in the striatum.
• The potency and intrinsic activity of brexpiprazole are much higher and slightly lower than buspirone (5-HT1A partial agonist).
• 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 have benefits for PTSD. (See later)
• Brexpiprazole had little or no significant effect on blood prolactin levels in schizophrenia, although aripiprazole was associated with decreased blood prolactin levels. This can be attributed to the lower intrinsic activity of brexpiprazole. [Kikuchi et al., 2021]

PHARMACOKINETICS OF BREXPIPRAZOLE

Brexpiprazole has an oral bioavailability of 95%, and the pharmacokinetics of brexpiprazole are as follows [Rexulti (package insert)]:

• Peak plasma concentration (T_max) of brexpiprazole is reached within 4 hours and has a T_1/2 of 91 hours.
• A steady-state is reached within 10 to 12 days with daily administration and is not affected by hepatic or renal impairments.
• Brexpiprazole is metabolised in the liver by CYP3A4 and CYP2D6, and the primary metabolite, DM-3411, has no apparent therapeutic effect.

Drug absorption, metabolism, and excretion are not affected by age, sex, or renal or hepatic impairments; therefore, dose adjustments are generally unnecessary. However, brexpiprazole is metabolised by CYP450 3A4 and 2D6 enzymes. Therefore, CYP2D6 status is essential, as is the presence of concomitant CYP2D6/CYP3A4 inhibitors or CYP3A4 inducers. [Diefenderfer & Luppa, 2017]

• A dose reduction of approximately 50% is recommended in patients who are classed as poor CYP2D6 metabolisers.
• Poor CYP2D6 metabolisers also currently being administered a CYP3A4 inhibitor should have their dose reduced by 75%.
• The presence of a concomitant CYP3A4 or CYP2D6 inhibitor will require brexpiprazole to be adjusted to 50% of the usual dosage.
• However, the presence of a concomitant CYP3A4 inducer will require brexpiprazole to be instead adjusted to double the usual dosage.

DOSING OF BREXPIPRAZOLE

Oral brexpiprazole was approved for adult patients with acute schizophrenia after favourable data was published in the VECTOR [Correll et al., 2015] and BEACON [Kane et al., 2015] clinical trials. From these trials, the recommended dosing information is:

• Dose initiation begins at 0.5 to 1 mg and is increased until clinical response is observed.
• Brexpiprazole can be administered with or without food.
• The minimum effective dose is 2 mg once daily, and the maximum dose for treating schizophrenia is 4 mg once daily.
• The dose range for schizophrenia is 2-4 mg.
• The recommended dose for adjunctive treatment in major depressive disorder is 2mg. The maximum dose is 4 mg.

SAFETY PROFILE OF BREXPIPRAZOLE

Brexpiprazole has a well-tolerated adverse effect profile. The BEACON trial showed that most treatment-emergent adverse events were classified as mild or moderate and that no event was observed in >5% of the patient cohort. [Kane J et al., 2015]

Adverse reactions

• The more commonly observed side effects are Akathisia, headache, somnolence, tremor, nausea, anxiety, fatigue and mild weight gain.
• No clinically-significant metabolic side effects have been reported, like with clozapine, olanzapine, and quetiapine. [De Hert et al., 2012], [Rummel-Kluge et al., 2010], [Correll et al., 2014]
• Antipsychotic Induced Weight Gain and Metabolic Dysfunction – A Review of Pathophysiology and Management Strategies
• Mild weight gain is comparable to aripiprazole administration and significantly less than with clozapine or olanzapine. [De Hert et al., 2012]
• Dopamine D₂ partial agonist-mediated adverse effects such as akathisia, insomnia, restlessness, and nausea occur at a lower rate than aripiprazole. [Kane et al., 2010]
• Brexpiprazole also has a lower incidence of akathisia compared to Cariprazine. [Citrome, 2018]
• There are lower levels of sedation due to its affinity for the histamine H1 receptor. 

Special precautions

The package insert has the following black box warnings [Rexulti (package insert)]:

• Increased mortality risk in elderly patients with dementia-related psychosis.
• In addition, elderly patients with dementia have a higher risk of cerebrovascular adverse reactions such as stroke and transient ischaemic attack.
• The neuroleptic malignant syndrome is a rare CNS-related adverse event caused by antipsychotic drugs and is characterised by hyperpyrexia, muscle rigidity, and autonomic instability.
• There is an increased risk for suicidal thoughts and behaviours in patients aged <24 years old due to brexpiprazole’s antidepressant activity. Extra vigilance is therefore advised in this patient population.
• The safety and efficacy of brexpiprazole have not been established in paediatric patients.

CLINICAL APPLICATIONS OF BREXPIPRAZOLE

Schizophrenia

• The VECTOR trial included 636 patients with schizophrenia and compared brexpiprazole (0.25 mg/day, 2 mg/day, or 4 mg/day) against a placebo. There was a clinically significant change in the Positive and Negative Syndrome Scale (PANSS) for 2 mg/day and 4 mg/day compared to placebo (p<0.0001 and p=0.0006, respectively). [Correll C et al., 2015]
• The BEACON trial included 674 patients with schizophrenia and compared brexpiprazole (1 mg/day, 2 mg/day, or 4 mg/day) against a placebo. There were only significant changes in the PANSS from baseline in the 4 mg/day group (p=0.0022). [Kane J et al., 2015]

Major depressive disorder

• The PYXIS trial included 175 patients with MDD who had an inadequate response to 1 to 3 previous antidepressant trials. Brexpiprazole (2 mg/day) was added to a standard antidepressant. There was a significant change in MADRS score from baseline to week 6 (P=0.0002) with significantly more ≥50% MADRS responders compared to placebo (23.4% vs 15.7%; p=0.0429). [Thase M et al., 2015]
• The POLARIS trial included 211 patients with MDD who had an inadequate response to 1 to 3 previous antidepressant trials. Brexpiprazole (1 mg/day or 3 mg/day) was added to a standard antidepressant. There were significant changes in the MADRS score from baseline to week 6 only in the 3 mg/day group (p=0.0079). The 1 mg/day and 3 mg/day brexpiprazole groups showed more ≥50% MADRS responders compared to placebo (23.2% and 23.0% vs 14.3%, respectively). [Thase M et al., 2015]

Bipolar Depression: 

• A pilot open-label study showed evidence for reduction of depressive symptoms and improvement of quality of life scores. [Brown et al., 2019]

Acute mania: 

SUMMARY

Brexpiprazole is a partial dopamine D₂ agonist. The data appears to support a more favourable tolerability profile than other second-generation antipsychotic drugs due to its unique mode of action.

It is evidence-based in treating Schizophrenia and as an adjunct in Major Depressive Disorder. Preliminary evidence shows benefits for bipolar disorder and PTSD.