Vraylar (Cariprazine) Approved For Schizophrenia & Bipolar Disorder

Vraylar (Cariprazine) was approved by the FDA on September 17, 2015 for the treatment of schizophrenia and mania associated with bipolar disorder.  In clinical trials, the drug was referenced as “RGH-188” – containing Cariprazine as the primary active ingredient.  The drug had completed Phase III clinical trials in 2012, and was pending FDA approval for several years prior to its recent 2015 approval.

While the drug shares commonalities with many already-approved atypical antipsychotics, it also has several mechanistic differences.  Like other antipsychotics, it modulates the neurotransmission of dopamine at various receptors (e.g. D2 receptors) to prevent positive symptoms of schizophrenia and manic symptoms of bipolar disorder.  Unlike many older antipsychotics, it acts primarily upon D3 receptors and is capable of ameliorating negative symptoms of schizophrenia when dopamine levels plummet.

Vraylar is the second atypical antipsychotic after Rexulti (Brexpiprazole) to get FDA approval in 2015.  Rights to its manufacturing are owned by Gedeon Richter and Actavis.  Though the drug is new, its side effect profile isn’t fully understood, and long-term effects remain unknown – it appears to be a promising new agent for those who don’t sufficiently respond to existing options.

How Vraylar (Cariprazine) Works (Mechanism of Action)

Vraylar’s mechanism of action differs from other atypical antipsychotics in that it primarily affects the D3 receptor as a partial agonist.  Targeting the D3 receptor has been speculated to aid in modulation of dysfunctional transmission of dopamine, while reducing likelihood of certain side effects.  Specifically, the likelihood of extrapyramidal effects may be slightly decreased when targeting D3 receptor sites due to their location within the ventral striatum (as opposed to the dorsal striatum).

• D3 receptor partial agonist
• D2 receptor partial agonist
• 5-HT2B inverse agonist
• 5-HT1A partial agonist

Like other atypical antipsychotics, Vraylar still significantly affects the D2 receptor as a partial agonist – but to a lesser extent than the D3 receptor.  From a dopaminergic perspective, Vraylar is unique in that when an individual has high dopamine levels, the drug acts as an antagonist – inhibiting excess D3 and D2 receptor stimulation.  On the other hand, when an individual has low dopamine levels, the drug acts as an agonist by actively stimulating the D3 and D2 receptors.

The drugs antagonist effects on D3 and D2 receptors minimize likelihood of positive symptoms (hallucinations, delusions, etc.) and bipolar mania, whereas its agonist effects minimize probability of negative symptoms (blunted affect, psychomotor slowing, etc.) and depression.  As a result of its broad spectrum of dopaminergic capabilities, a greater range of symptoms can be treated.  In addition to Vraylar’s primarily dopaminergic effect, the drug also acts upon serotonin receptors.

Serotonergically, the drug targets 5-HT2B receptors as an inverse agonist – meaning it stimulates these receptors to generate the opposite effect of a traditional agonist.  Vraylar also acts as a 5-HT1A partial agonist – which is thought to improve mood.  Other receptors affected by Vraylar include: 5-HT2A (inverse agonist), 5-HT2C (inverse agonist), 5-HT7 (antagonist), and H1 (inverse agonist).

It is also important to note that the drug appears to occupy dopamine receptors based on the administered dosage.  Monkey studies demonstrate that when administered at low doses, Vraylar may only occupy 5% of D2 and D3 receptors, whereas at high doses it can occupy over 90% of these receptors.  While both low and high doses can be effective for symptom management, it is apparent that higher doses may elicit greater therapeutic effects for certain individuals due to increased receptor occupancy.

• Source: https://www.ncbi.nlm.nih.gov/pubmed/23320989
• Source: https://www.ncbi.nlm.nih.gov/pubmed/21767587
• Source: https://www.ncbi.nlm.nih.gov/pubmed/21625907
• Source: https://www.ncbi.nlm.nih.gov/pubmed/21767587

Potential Benefits of Vraylar (Cariprazine)

There appear to be several benefits associated with using Vraylar for the treatment of schizophrenia and/or bipolar disorder.  The biggest benefit to be derived from the drug is the modulation of dopamine and unique targeting of the D3 receptor (which may reduce some side effects).  Additionally, the drug can treat a wide range of symptoms and improve outcomes among those with low or high levels of endogenous dopamine; it seems to modulate imbalances.

• Adjunct: Vraylar is currently being investigated as an antidepressant augmentation strategy. Like most antipsychotics, it will likely be used as an adjuvant option for those who fail to get symptomatic relief from a first-line antidepressant such as an SSRI.  It may be a particularly beneficial option for those with depression caused by low dopamine due to the fact that it agonizes D2 and D3 receptors.  Furthermore, it may also be prescribed along with a mood stabilizer among those with bipolar disorder for synergistic symptomatic relief.
• Efficacy: It is apparent that Vraylar is a clinically effective option for the treatment of schizophrenia and bipolar disorder. The drug has undergone rigorous preclinical and clinical testing and was found to be safe, well-tolerated, and effective throughout all stages of trials.  Though it remains unclear as to how effective Vraylar is compared to other atypical antipsychotics, some speculate that it may exhibit greater efficacy due to its unique mechanism of action.
• Mechanism of action: For those with dopaminergic dysfunction, a major potential advantage associated with Vraylar is its ability to modulate dopamine. If you have high dopamine, administration of Vraylar acts as an antagonist, minimizing excess stimulation at D3 and D2 receptor sites.  If you have low dopamine, administration of Vraylar acts as an agonist, increasing stimulation at D3 and D2 receptor sites.  Its ability to detect endogenous dopamine levels and correct imbalances is thought to provide significant benefit.
• Multi-purpose: Unlike many antipsychotics and psychiatric medications, Vraylar is considered a multi-purpose medication in that it was approved by the FDA to treat both bipolar disorder and schizophrenia. Since it is also under investigation for the treatment of depression, it is important to consider that it may be effective for the treatment of a third psychiatric condition.  The fact that it is a multi-purpose agent is advantageous in that it may provide significant benefit to those who struggle with multiple simultaneous mental illnesses (e.g. schizophrenia and major depression).
• Pro-cognitive: Preliminary evidence from clinical trials suggests that Vraylar may enhance cognitive function.  This means that the drug may ameliorate the highly-problematic cognitive symptoms of schizophrenia.  Although it is unclear as to how Vraylar improves cognition, its pro-cognitive effect could be due to its ability to modulate dopamine.  An excess (high) or deficient (low) amount of dopamine is known to disrupt cognitive processes.
• Side effects: Though Vraylar will likely share a similar side effect profile to other atypical antipsychotics (due to dopaminergic effects), its unique high affinity for the D3 receptor (in the ventral striatum) may minimize the intensity of certain extrapyramidal effects.  It should also be considered that its affinity for the D3 receptor may improve tolerability for certain individuals.

Vraylar (Cariprazine) Clinical Trials: Schizophrenia & Bipolar Disorder

Vraylar (Cariprazine) has been tested extensively in both preclinical and clinical trials for the treatment of schizophrenia and bipolar disorder.  It appears to be effective for treating both acute mania and mixed episodes (associated with bipolar 1 disorder) and a spectrum of symptoms associated with schizophrenia.  Included below is a general synopsis of the published clinical trials investigating Cariprazine.

2015:  Schizophrenia Trial

Results from a Phase III clinical trial assessing the efficacy and safety of cariprazine were published in 2015.  Individuals that were formally diagnosed with schizophrenia were assigned to receive either cariprazine (3 mg/d to 6 mg/d), cariprazine (6 mg/d to 9 mg/d), or a placebo over the course of 6 weeks.  Prior to the administration of cariprazine (or placebo), the participants were assessed with the PANSS (Positive and Negative Syndrome Scale) and the CGI-S (Clinical Global Impressions Severity).

A total of 147 individuals had received the placebo, 151 individuals received the cariprazine between 3 mg/d and 6 mg/d, and 148 individuals received cariprazine 6 mg/d to 9 mg/d.  Following 6 weeks of treatment, the individuals were reassessed with the PANSS and CGI-S.  Results indicated that those receiving the cariprazine experienced significant symptomatic improvement compared to those receiving the placebo.

Researchers reported that the cariprazine was considered well-tolerated and effective for the treatment of schizophrenia.  There was no significant differences between the group receiving cariprazine (3 mg/d to 6 mg/d) and the group receiving cariprazine (6 mg/d to 9 mg/d).

• Source: http://www.ncbi.nlm.nih.gov/pubmed/26075487

2015: Bipolar I Disorder Trial

A study was published in 2015 documenting the efficacy, safety, and tolerability of both low and high dose cariprazine among those experiencing either acute mania or mixed episodes associated with type 1 bipolar disorder.  Participants in the study were assigned at random to receive either: a placebo, cariprazine (3 mg/d to 6 mg/d), or cariprazine (6 mg/d to 12 mg/d) for a total of 3 weeks.  At baseline, patients were assessed with the YMRS (Young Mania Rating Scale) and CGI-S (Clinical Global Impressions Severity).

Following 3 weeks of treatment, participants were reassessed with the YMRS and CGI-S to determine changes in symptom severity.  Results indicated that both groups taking cariprazine improved significantly compared to a placebo – regardless of the dosing.  Though more side effects were experienced with cariprazine than the placebo – the drug was considered well-tolerated.

Researchers concluded that administration of low dose cariprazine (3 mg/d to 6 mg/d) and high dose cariprazine (6 mg/d to 12 mg/d) are effective for the treatment of acute mania and mixed episodes among those with bipolar disorder.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25562205

2014: Acute Exacerbation Schizophrenia

Results from a clinical trial published in 2014 documented the efficacy and safety of cariprazine among those with acute schizophrenia.  This was a fixed-dose, double-blind, placebo-controlled study in which participants were assigned to receive either: a placebo, cariprazine at various doses (1.5 mg, 3 mg, 4.5 mg), or risperidone (4 mg).  At pre-treatment baseline, participants were assessed for symptomatic severity with the PANSS and CGI-S.

Following 6 weeks of treatment, patients were reassessed with both the PANSS and CGI-S to determine whether symptoms had improved.  Results indicated that those receiving the cariprazine (regardless of dose) and risperidone experienced clinically significant symptomatic improvement compared to individuals receiving the placebo.  Since cariprazine was well-tolerated, this provides evidence that cariprazine is safe and effective among those with acute schizophrenia.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/24412468

Note: There are more clinical trials that just the few published above. These are some of the larger, more substantial trials that document its safety and efficacy.  To get a better understanding of cariprazine, search the NCBI database.

Potential Drawbacks of Vraylar (Cariprazine)

When any new drug is approved, the general media and consumers automatically assume that it’s a utopian option compared to previously approved drugs.  Although Vraylar may possess a unique mechanism of action, there is no reason to believe that it has superior efficacy or less side effects than other options.  Those taking the drug will need to be aware of adverse reactions, potential long-term effects, and discontinuation symptoms.

• Black box warning: Like all potent psychiatric drugs, it is likely that a black box warning will be attached to Vraylar. Any drug that is potent enough to treat symptoms of mania and schizophrenia is also potent enough to have detrimental effects in a subset of users.  For this reason, it is important to be aware of the possibility that Vraylar could increase depression and suicidality in certain individuals.
• Dangers: Since this is a relatively new drug, the potential dangers associated with its use haven’t been fully elucidated. It could be relatively safe, but we could also end up seeing a lawyer commercial in a decade recruiting past-users for a lawsuit for those that were victim to adverse effects.  All current-market antipsychotics should be considered dangerous psychiatric drugs due to the fact that their usage is associated with brain volume loss, weight gain, and creation of new health problems (e.g. Type 2 diabetes).
• Efficacy: Though the drug was effective in clinical trials for the treatment of schizophrenia and bipolar disorder, it is unclear as to how its efficacy stacks up compared to other options. It is clearly more effective than a placebo, but is it any more effective than other, better-understood options? We don’t know.  Furthermore, it is important to consider that from an individual perspective – this drug may not work at all.  A percentage of users are likely to derive no benefit and/or feel worse from using this drug.
• Side effects: Many people think that newer drugs always seem to have better side effect profiles. Although the targeting of the D3 receptor was thought to reduce the likelihood of extrapyramidal symptoms – they are still common with this drug.  Other side effects associated with Vraylar include: anxiety, constipation, dizziness, insomnia, nausea, sedation, and vomiting.
• Unknown long-term effects: Due to the fact that Vraylar is just hitting the market, we won’t fully understand its long-term effects for awhile. Unless some mad scientists figure out a way to accurately simulate the long-term effects of a new drug, the first users will serve as guinea pigs.  Although Vraylar could have favorable long-term effects to other antipsychotics, it also could have more deleterious long-term effects; an important possibility to consider.
• Withdrawal symptoms: All new drugs are marketed brilliantly and the creators attempt to persuade users that they won’t have any significant withdrawal symptoms. Any drug that elicits a broad spectrum of potent effects on dopaminergic and serotonergic systems will have troubling withdrawal symptoms.  It is likely that the discontinuation symptoms associated with Vraylar will be as significant as those experienced when quitting any other antipsychotic.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23320989

Would you try Vraylar (Cariprazine) for schizophrenia or bipolar disorder?

I’ve written about Cariprazine as a new schizophrenia medication, as well as a new bipolar medication.  Personally I think the drug has a lot of promise in that it modulates the neurotransmission of dopamine, eliciting both antagonist effects and agonist effects based on detected endogenous levels of dopamine.  In other words, the drug isn’t just automatically antagonizing or agonizing receptors for everybody – its effects are unique to the user’s neurotransmission.

Most antipsychotics do not attempt to modulate neurotransmission, rather they act a certain way regardless of endogenous dopamine levels.  Vraylar is now the third FDA approved antipsychotic that acts as a dopamine receptor partial agonist (the other two include: Abilify and Rexulti).  Vraylar differs from both Abilify and Rexulti though in that it is highly selective for the D3 receptor – which may offer some advantages.

Assuming you understand that Vraylar’s basic mechanism of action, would you consider using it to treat schizophrenia and bipolar disorder?  Do you believe that the drug will turn out to be any safer and/or more effective than other antipsychotics?  Share your thoughts on Vraylar in the comments section below.

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