Rexulti (Brexpiprazole) is a drug that was approved July 10, 2015 for the treatment of schizophrenia and as an adjunctive option for major depressive disorder. In clinical trials it was referred to as the chemical “OPC-34712” and is being marketed as a superior successor to Abilify (Aripiprazole) due to the fact that Abilify’s patent expired in 2014. Rexulti was developed as a result of a partnership between pharmaceutical companies Otsuka and Lundbeck.
In 2011, Otsuka and Lundbeck announced that they were joining forces to develop and commercialize up to 5 new products in the psychiatry field. The first of their contributions was the newly approved Rexulti (OPC-34712). Otsuka developed OPC-34712 and Lundbeck paid them $200 million as a preliminary payment.
Total payments to Otsuka from Lundbeck for acquisition of OPC-34712 are estimated to reach $1.8 billion. It is believed that the newly introduced Rexulti will be highly profitable for both companies. In addition, it is marketed as providing superior efficacy to other antipsychotics with less side effects; whether these preliminary marketing claims are legitimate remains unknown.
- Source: http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=622993
How Rexulti (Brexpiprazole) Works (Mechanism of Action)
Rexulti is classified as a serotonin-dopamine activity modulator (SDAM). It functions primarily as a D2 dopamine receptor partial agonist. Despite its primary effects as a D2 receptor partial agonist, it has an affinity for serotonin and norepinephrine receptors. Research has noted that it has a high binding affinity for serotonergic receptors 5-HT1A (as a partial agonist) and 5-HT2A (as an antagonist).
- D2 receptor partial agonist
- 5-HT1A partial agonist
- 5-HT2A antagonist
It also acts as an antagonist at the Alpha-1B and Alpha-2C adrenergic receptors. Mechanistic studies suggested that Rexulti also acted upon other Alpha-1A and Alpha-1D noradrenergic receptors, as well as D3 dopaminergic receptors, and H1 histamine receptors. Other serotonergic receptors affected by Rexulti included 5-HT2B and 5-HT7.
Rexulti also had a low affinity for M1 muscarinic acetylcholine receptors. In rodent research, this drug elicited most potent action on D2 receptors, 5-HT2A receptors, and 5-HT1A receptors. Administration of Rexulti to rats resulted in decreased extracellular dopamine levels in the nucleus accumbens, with simultaneous increases of dopamine metabolites in the prefrontal cortex.
Compared to its predecessor Abilify, this drug has less potent effects on D2 receptors and greater effect on serotonergic 5-HT1A and 5-HT2A receptors. It appears as though the antipsychotic Rexulti elicits a unique mechanism of action as a serotonin-dopamine activity modulator (SDAM), possibly resulting in fewer side effects than many existing antipsychotics.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24947465
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24947464
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23363735
Potential Advantages of Rexulti (Brexpiprazole)
There are many potential advantages to be attained with using Rexulti (Brexpiprazole) over previous antipsychotics. Perhaps the most obvious advantage is the fact that it elicits less effect on D2 receptors compared to other antipsychotics, resulting in less unfavorable side effects stemming from dopaminergic alterations.
- Adjunct: Rexulti has been granted FDA approval for the treatment of major depressive disorder as an adjunct. In other words, when Rexulti is prescribed along with a first-line antidepressant (e.g. an SSRI), it results in increased efficacy. While using an antipsychotic as an antidepressant augmentation strategy should be considered a last-resort, Rexulti may have less side effects than other antipsychotics (when used as an adjunct).
- Efficacy: It has been speculated that Rexulti was engineered to provide enhanced efficacy for the treatment of schizophrenia. It has proven to be a highly-effective drug in clinical trials, and thus has been approved by the FDA. Due to the fact that Rexulti was recently approved (2015), it remains unclear as to whether it offers superior efficacy for the treatment of schizophrenia (or depression when used as an adjunct) compared to current-market options.
- Mechanism of action: Rexulti is the first drug to hit the market under the classification of a “SDAM” (serotonin-dopamine activity modulator). It elicits significant effects on serotonergic receptors (5-HT1A and 5-HT2A) as well as the D2 dopaminergic receptors (a prominent target for most antipsychotic agents). Its unique mechanism of action as a “SDAM” may provide benefit to those with refractory cases of schizophrenia and/or those who have poor responses to existing treatments.
- Multi-Purpose: Rexulti has been granted FDA approval for the treatment of schizophrenia, but it was also approved as an adjunct for major depressive disorder. It was investigated for the treatment of ADHD (attention-deficit/hyperactivity disorder) as well, but failed to meet clinical endpoints. It appears to treat symptoms of schizophrenia, improve mood, enhance cognitive function, and reduce certain symptoms of Alzheimer’s – making it a multi-faceted pharmaceutical agent.
- Pro-cognitive effect: While it has been noted in rodent studies that Rexulti lowers dopamine in the nucleus accumbens region, it is thought to increase dopaminergic metabolites in the prefrontal cortex. Preliminary evidence suggests that Rexulti may ameliorate cognitive symptoms of schizophrenia and enhance cognitive function among those with schizophrenia-induced deficits. This may be an improvement over previous medications that tend to impair cognitive function over time.
- Side effect profile: Due to the fact that this drug is a less potent D2 partial agonist than Abilify, it is thought to be less likely to trigger a variety of side effects associated with antipsychotics including: akathisia, insomnia, and restlessness. In addition, the likelihood of cognitive deficits during treatment are thought be decreased due to the fact that it has minimal effects on H1 and M1 receptors. There is a low risk of extrapyramidal side effects associated with Rexulti compared to other antipsychotics. (Read more: “Rexulti Side Effects“).
- Social recognition: It appears that administration of Rexulti may improve deficits in social recognition associated with schizophrenia and possibly major depression. Studies conducted in mice discovered that Rexulti had significant positive effects on social recognition, whereas other antipsychotics (Risperdal and Zyprexa) had no such effects.
- Tolerability: It is thought that Rexulti is likely to offer superior tolerability compared to older medications. While not everyone will respond well to Rexulti, the fact that certain side effects such as akathisia, insomnia, and restlessness are less likely may respond in greater tolerability for a majority. Any improvement in antipsychotic tolerability is welcomed due to the fact that it may increase treatment adherence rates.
Clinical Trials of Rexulti (Brexpiprazole): Schizophrenia & Major Depression
Rexulti was enrolled in several clinical trials gauging its safety, efficacy, and tolerability for the treatment of various conditions including: schizophrenia, major depressive disorder (as an adjunct), and ADHD. Clinical trial results suggest that Rexulti was highly effective for the treatment of schizophrenia and major depressive disorder (when used as an adjunct). Clinical trials for its usage to treat ADHD were discontinued, likely due to lack of efficacy.
2015: Rexulti was tested in a 6-week multicenter, placebo-controlled, double-blind study to determine efficacy, safety, and tolerability. This study was considered Phase 3 of clinical trials, and involved administration of Rexulti (1 mg, 2 mg, or 4 mg) or a placebo. Baseline measures of symptomatic severity were collected with the PANSS (Positive and Negative Syndrome Scale) and secondary assessments were taken with the CGI-S (Clinical Global Impressions Severity).
Results demonstrated that administration of Rexulti (4 mg) significantly improved PANNS scores compared to the placebo. Lower doses of Rexulti (1 mg and 2 mg) were also significantly superior to a placebo, but not as significant as the 4 mg dosage. Some side effects were reported, but the drug was considered well-tolerated and safe for the treatment of adult schizophrenia.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25682550
2015: Another double-blind, placebo-controlled, randomized, and multicenter design was constructed to evaluate the safety and efficacy of Rexulti for the treatment of schizophrenia. Adults with schizophrenia were assigned (at random) to receive Rexulti (0.25 mg, 2 mg, 4 mg) or a placebo over the course of 6 weeks. Baseline measures were recorded with the PANSS (Positive and Negative Syndrome Scale) and CGI-S (Clinical Global Impressions Severity).
Results indicated that Rexulti (2 mg and 4 mg) were significantly superior to a placebo for the treatment of schizophrenia. This was evidenced by significant reductions in PANSS scores and severity of CGI. Researchers concluded that Rexulti was well-tolerated and effective for adults with schizophrenia at dosages of 2 mg and 4 mg per day.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25882325
2015: Researchers reviewed data from registration trials to determine the clinical efficacy of Rexulti for the treatment of schizophrenia and major depressive disorder (as an adjunct). It was noted that Rexulti had been assessed in two Phase 3 trials for schizophrenia, as well as two Phase 3 trials for major depression (as an adjunct). Researchers documented that individuals with acute schizophrenia responded 45.5% of the time to Rexulti and only 31% to a placebo.
It was also noted that symptomatic relapse was significantly less likely among those taking Rexulti (13.5%) compared to individuals administered a placebo (38.5%). Evidence from clinical trials suggests that Rexulti is effective at dosages between 2 mg and 4 mg for the treatment of schizophrenia, and at 2 mg (as an adjunct) for major depressive disorder. Further research is necessary to elucidate its efficacy compared to other medications.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26250067
Note: The trials investigating Rexulti’s efficacy for the treatment of schizophrenia involved a total of 1,310 participants (divided into two 6-week trials). The trials investigating Rexulti’s efficacy for the treatment of major depression involved a total of 1,046 participants (divided into two 6-week trials).
Why wasn’t Rexulti approved for the treatment of ADHD?
Rexulti (Brexpiprazole) was originally investigated in adults for the treatment of ADHD when administered as an adjunct to a psychostimulant medication. Initial preclinical trials suggested efficacy for improving cognitive function, and it had been noted as effective in Phase I trials. However, results were thought to be unsatisfactory in Phase II clinical trials, resulting in discontinued investigation as a therapeutic agent for ADHD.
While it may successfully ameliorate cognitive deficits associated with schizophrenia, its ability to modulate dopamine may not be as applicable to those with ADHD. It may prove useful for improving attention among those with schizophrenia and/or major depression – but its efficacy should not be considered clinically significant. It is clearly not as effective as other, proven ADHD medications.
- Source: https://clinicaltrials.gov/ct2/show/NCT01074294
How Rexulti (Brexpiprazole) is similar to other antipsychotics
Despite the fact that there is often preliminary excitement and hype associated with the approval of a new pharmaceutical agent, no drug should be considered a utopian option. Despite preliminary evidence that Rexulti may have less side effects than other antipsychotics, it is still a new drug that hasn’t been tested over a long-term in a real-world population.
- Black box warning: Like other psychiatric drugs, Rexulti has a “black box warning,” meaning it is associated with an increased risk of death when used for off-label conditions. This black box warning means that like other antipsychotics, it may provoke suicidal thinking and/or urges in certain individuals. Therefore usage of Rexulti needs to be monitored by a medical professional as it may alter thinking, behavior, and/or have adverse health effects.
- Dangers: Any antipsychotic and/or medications that have a complex effect on neurochemistry may pose dangers. Rexulti is a new medication, meaning it hasn’t been around long enough for experts to fully decipher any potential adverse effects it may have on a person’s health. Although it is new, it is still an antipsychotic and should be considered a dangerous psychiatric drug.
- Side effects: Despite the fact that it may have fewer side effects than older antipsychotics, Rexulti is not devoid of side effects. Those taking Rexulti were found to experience moderate weight gain (after 6 weeks), headaches, insomnia, akathisia, and agitation. (Read more: “Rexulti & Weight Gain“). Rexulti is being touted as producing less akathisia, restlessness, and insomnia than other agents, but it is important to be skeptical of this marketing due to the fact that clinical trials reported all of these side effects. (Additional information: “Rexulti Side Effects“).
- Unknown long-term effects: The long-term effects associated with Rexulti usage are unknown. Due to its less significant influence on D2 receptors as a partial agonist compared to Abilify, it may have some long-term advantages. That said, many antipsychotics cause brain volume loss when administered over a long-term. Rexulti’s safety profile when administered over the span of several years is unclear.
- Withdrawal symptoms: Like all antipsychotics, Rexulti will likely have severe withdrawal symptoms. These symptoms will be subject to individual variation, but will be downplayed by the manufacturers of the drug in order to boost sales. It can be assumed that the discontinuation effects of Rexulti are likely as severe as many other antipsychotic agents. (Read more: “Rexulti withdrawal symptoms“).
How does Rexulti compare to Abilify?
Both Rexulti and Abilify attenuate symptoms of schizophrenia via action as D2 dopamine receptor partial agonists. Individuals with schizophrenia are thought to have dysfunctional neurotransmission of dopamine. Many antipsychotic drugs act as D2 receptor antagonists, meaning they bind to a receptor, and inhibit stimulation associated with excess dopamine.
In other words, individuals with high dopamine benefit from D2 receptor antagonists due to the fact that they reduce dopamine to a normal range in areas of the brain that are misfiring. This antagonist activity helps reduce many of the positive symptoms of schizophrenia such as hallucinations and delusions. However, excess antagonism of these dopaminergic receptors may exacerbate certain negative symptoms of schizophrenia such as avolition due to excessively low dopamine.
Rexulti and Abilify are common in that they modulate dopaminergic activity as partial D2 receptor agonists. This is thought to normalize neurotransmission of dopamine in the brains of those with schizophrenia, without leading to excess negative symptoms and side effects that may be associated with full antagonism. In addition, both drugs elicit significant effects on 5-HT1A serotonergic receptors as partial agonists and 5-HT2A serotonergic receptors as antagonists.
Their mechanisms of action are extremely common, hence many consider Rexulti to be a new (possibly improved) format of Abilify as a result of Abilify’s patent expiry. However, the key differences between these drugs is that Rexulti elicits greater action on the 5-HT1A and 5-HT2A receptors than Abilify, whereas Abilify elicits greater action on the D2 receptor than Rexulti. Abilify affects neurotransmission of dopamine to a greater extent than Rexulti, while Rexulti modulates serotonin more significantly.
Rexulti may have a slightly favorable side effect profile compared to Abilify as well. Research has suggested that Rexulti improves and/or preserves cognitive function significantly more than Abilify. It is thought that Rexulti’s balanced mechanism on 5-HT1A, 5-HT2A and D2 receptors (serotonin-dopamine activity modulation) is responsible for yielding a pro-cognitive response.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25225185
Would you try Rexulti (Brexpiprazole) for schizophrenia or major depression?
Feel free to leave a comment below mentioning whether you would try Rexulti (Brexpiprazole) for the treatment of schizophrenia. Do you think that Rexulti will demonstrate equal or greater efficacy compared to its predecessor Abilify (Aripiprazole)? Preliminary data suggests that the side effect profile may be a slight improvement over older medications.
In addition, it has a unique mechanism of action as a serotonin-dopamine activity modulator, acting as a D2 receptor partial agonist. Its unique mechanism of action may be able to provide relief to individuals with schizophrenia and/or refractory depression that never attained significant therapeutic benefit from older drugs. While Rexulti should not be expected to be a utopian antipsychotic, it may be an improvement over past options and serve as a much-needed new treatment option for those with schizophrenia.