Psychotic illnesses such as schizophrenia and bipolar disorder are severe and debilitating psychiatric disorders. Though numerous antipsychotic drugs are available, many patients still experience poor outcomes. The treatment is limited due to adverse side effects. Cariprazine sold under the brand name Vralyar is a new antipsychotic drug with unique pharmacodynamic and pharmacokinetic properties.
Cariprazine (Vraylar®) is a new antipsychotic manufactured by Forest Laboratories (New York, NY). It was approved by the Food and Drug Administration in September 2015. The new drug application was originally submitted in 2012. However, the Food and Drug Administration required additional studies to identify the optimal dosing recommendations given the drug’s unique pharmacokinetics and dose-related adverse effects.
Vraylar is indicated for the treatment of schizophrenia and acute manic or mixed episodes associated with bipolar 1 disorder as monotherapy only. Vraylar is only contraindicated in people with hypersensitivity reaction to the drug. The package includes a standard antipsychotic black box warning for increased risk of mortality in elderly patients in case of dementia-related psychosis. Target dose recommendations vary according to indications. Vraylar is pharmacodynamically and pharmacokinetically distinct from other oral antipsychotics.
In this article, we will review schizophrenia and bipolar disorder along with Vraylar use, its mechanism of action, side effects, indications and contraindications, use in pregnancy and lactation and finally the conclusion.
It is severe debilitating mental disorder characterized by a diversified range of symptoms. These include abnormal behavior, strange speech, inability to understand reality, etc. Other symptoms such as confused and unclear thinking, fixed false believes (delusions), hearing voices that don’t exist (visual hallucinations), reduced emotional expressions and lack of motivation. These people also suffer from anxiety, depression and substance use disorder.
Both environmental and genetic factors play a role in the development of this disease. Environmental factors include the use of cannabis, certain infections, poor nutrition during pregnancy, etc. The genetic factors include common and rare genetic variants.
Diagnosis of this condition is made after the evaluation of a patient for almost three months. While making a diagnosis, doctors consider factors such as genetic predisposition, person’s living conditions, financial and relationship crisis, the culture of the patient, etc.
The approved treatment of schizophrenia is the use of various antipsychotics. It is not clear whether typical or atypical antipsychotics are better. Along with the medication, counseling, social rehabilitation and job training is also employed. Vraylar is a new medication which is now being used for the treatment and management of schizophrenia.
Bipolar disorder, also called manic depressive illness, is a debilitating mental illness that causes extreme mood swings. It can cause extreme high and extreme low mental states.
When a person becomes depressed, he feels sad or hopeless and loses interest or pleasure in most activities. When the mood shifts to mania or hypomania (less extreme than mania), he feels euphoric, full of energy or unusually irritable. These mood swings affect sleep, energy, activity, judgment, behavior and the ability of a person to think clearly.
These episodes of mood swings can occur rarely or multiple times a year. Most people will experience some emotional symptoms between episodes, while others may not experience any of the symptoms.
Depending on the symptoms, bipolar disorders are of two types. Bipolar disorder I, in which the patient had at least one manic episode that preceded or followed a major depressive or hypomanic episode. Bipolar disorder type II, in which then the patient had at least one major depressive and hypomanic episode but never had a manic episode.
Bipolar disorder is a lifelong condition, but you can manage your mood swings and other symptoms by following a treatment plan. In most cases, bipolar disorder is treated with anti-psychotic medicines along with psychological counseling. Vraylar is also used for the management of bipolar disorder.
Mechanism of Action
Vraylar or cariprazine acts as a partial agonist at dopamine D2 and D3 receptors. Both these receptors belong to the D2 family of dopamine receptors. They are the inhibitory receptors coupled to Gi transmembrane protein. Activation of these receptors results in decreased cAMP, a second messenger, in the cells. These receptors are mainly present in the brain and thus the effects of this drug are mainly central. The rationale of the use of this drug in psychiatric illnesses is to overcome the deficiency of dopamine, an inhibitory neurotransmitter. There is a deficiency of dopamine in schizophrenia and bipolar disorder.
This drug also acts as an antagonist at 5-HT2A and 5-HT2B serotonin receptors. Serotonin is an excitatory neurotransmitter which is present in excess in conditions like schizophrenia and bipolar disorder.
Vraylar also binds to histamine H1 receptors with low affinity.
Vraylar is distinct from all other anti-psychotic drugs regarding pharmacokinetic properties. It is absorbed from the GI tract into the blood. It is metabolized in the liver by hydroxylation and demethylation. It is primarily metabolized by cytochrome P450 enzymes.
Cariprazine in Vraylar is converted into two active metabolites; desmethyl cariprazine and didesmethyl-cariprazine.
Cariprazine in Vraylar and its major active metabolites are plasma protein bound to a greater extent. Only a small amount of free drug is available to be distributed to the tissues. The drug and its activated metabolites are removed from the body via renal excretion. They the body along with the urine.
Like other anti-psychotics, Vraylar is also metabolized in the liver. When taken in high doses it can cause liver injury. Liver injury mainly is due to metabolic disturbances. Liver toxicity with vraylar has been reported to be associated with increased serum aminotransferases.
Vraylar is indicated for the treatment of schizophrenia. It is also indicated for the acute treatment of major depressive episode or manic episode in patients od bipolar disorder. It is also indicated in patients with delusions, visual or auditory hallucinations or mood swings.
Patients who have not yet been diagnosed with bipolar disorder but are going through a major depressive can also be treated with this drug.
Dosing and Uses
Vraylar comes in the form of capsules in doses of 1.5 mg, 3 mg, 4.5 mg, and 6 mg.
For the treatment of schizophrenia, a single dose of 1.5 mg per day is given per oral route in adults. However, the dose may be increased to 3 mg per day.
In the case of a manic episode of bipolar disorder, the same single dose of 1.5 mg per day is given to the adult patient. Depending on response and tolerability, the dose can be increased to 3mg per day or 4.5 mg per day. However, the dose should not increase above 6mg per day.
In a major depressive episode of bipolar disorder, a single dose of 1.5 mg is started on the first day. It can be increased to 3 mg per day after 15 days. However, if side effects are noticed one or two doses can be missed. In this case, the dose should not exceed 3 mg per day.
Dosing in children are different from adults.
Vraylar causes increased mortality in elderly patients with dementia-related psychosis.
- According to black box warning, elderly patients with dementia-related psychosis if treated with antipsychotic drugs are at an increased risk of death
- This drug is not approved by the FDA for the treatment of patients with dementia-related psychosis
Suicidal thoughts and behaviors
- Studies found that antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients
- It is recommended to closely monitor all antidepressant-treated patients for clinical worsening, and for the emergence of suicidal thoughts and behaviors
- The safety and effectiveness of vraylar has not been established in pediatric patients
Studies have shown that all antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. They are also responsible for a higher incidence of stroke and TIA, including fatal stroke.
Hypersensitivity reactions are also reported with vraylar ranging from rash, pruritus, urticaria to the events suggestive of angioedema (such as swollen, tongue, lip swelling, face edema, pharyngeal edema, facial swelling).
A neuroleptic malignant syndrome is also reported with vraylar. Patients on this drug should be monitored for hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Other signs which are reported include increased CPK, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue the treatment.
Tardive dyskinesia is a potentially irreversible, involuntary, dyskinetic movement syndrome which may develop in patients treated with antipsychotics such as Vraylar.
Like other anti-psychotics, Vraylar is associated with a number of adverse side effects. These adverse effects may first appear several weeks after initiation of the treatment, as drug and metabolite levels accumulate in the body. Patients on Vraylar should be monitored for extrapyramidal symptoms or akathisia.
Leukopenia and neutropenia are also reported with the use of vraylar. Fatal cases of agranulocytosis are also reported with other atypical antipsychotics. A doctor can consider discontinuing cariprazine (Vraylar) in patients with absolute neutrophil count <1000/mm³ and follow WBC until recovery.
Vraylar can cause orthostatic hypotension and syncope. It should be used with caution in patients vulnerable to hypotension (such as elderly, dehydration, hypovolemia, concomitant antihypertensive drugs, cardiovascular or cerebrovascular disease).
This drug may also cause seizures. The risk of seizures is greatest with
history of seizures or conditions that lower seizure threshold
Cognitive and motor impairment is also seen with continuous use of Vraylar.
Body temperature dysregulation is also reported. It may disrupt the ability to reduce core body temperature. Care should be taken in patients with strenuous exercise, exposure to extreme heat, dehydration, and coadministration with anticholinergic medications
Esophageal dysmotility and aspiration have been reported with antipsychotic drug use including vraylar.
Vraylar may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. If patients have diseases, conditions, or medications that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and should be done recurrently for patients on long-term antipsychotic therapy.
Coadministration of Vraylar with a strong CYP3A4 inhibitor (an enzyme of cytochrome P450 family) such as itraconazole, ketoconazole increases the exposures of cariprazine and its major active metabolite, didesmethyl cariprazine (DDCAR), compared to the use of cariprazine alone. If Vraylar is used with inhibitors, its dose should be adjusted accordingly.
The effects of CYP3A4 inducers such as carbamazepine, rifampicin, etc. on the exposure of vraylar has not been evaluated, and the net effect is unclear.
Overdose Toxicity and Management
Overdose of vraylar is mostly suicidal. Overdose can cause worsening of the adverse side effects already mentioned in the text. One patient was reported with a suspected overdose of vraylar. He developed sedation and orthostatic hypotension. The patient was recovered the same day with proper care and management.
If elderly people overdose with vraylar, studies show that there are much greater chances of their death.
Management of overdose case includes securing the airway, breathing, and circulation of the patient. No particular antidote is available and only symptomatic treatment is applied. If proper care is taken, the patient can recover from the overdose toxicity.
Use in Pregnancy
Drugs which can easily cross placenta are not advised in case of pregnant ladies. They can enter the blood of the fetus and can cause similar effects in the baby. Vraylar can also cross the placental barrier.
Antipsychotics including Vraylar are not advised to pregnant ladies. They can cause severe harm to the baby. It has been reported that neonates exposed to the antipsychotic drugs during their third trimester of pregnancy are at the risk for extrapyramidal symptoms or withdrawal symptoms after delivery.
These complications vary in severity. Some of them are self-limiting while others require ICU support and prolonged hospitalization. Because of these adverse effects, Vraylar is never prescribed to pregnant ladies, especially in their third trimester.
Use in Lactation
If a drug is lipid-soluble and excreted in the breast milk of the mother, it indirectly goes into the body of the baby who feeds on breast milk. In this way, it can cause effects in the baby, similar to the mother. The liver enzymes are not much functional in the babies and even small doses of some drugs can cause adverse effects and can be fatal. This fact is always kept in mind while prescribing a drug to a lactating mother.
Vraylar is unknown if distributed in human breast milk or not. However, it is resent in rat milk. Thus, care should be taken while prescribing to lactating mother. The developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug should be considered and compared.
If any potential adverse effects appear in the breastfed infant from the drug or from the underlying maternal condition, always seek expert care in some tertiary care hospital.
Vraylar is a new but effective drug to be used in the acute and long term management of schizophrenia and bipolar disorders. Although it is different from other antipsychotic drugs, it has a similar tendency of adverse side effects and toxicity. Its use in pregnancy and lactation is also challenged.
It can be used in the acute management of severe manic or depressive episode, but the drug should not be started without consulting a good doctor. If the doctor has prescribed you this drug, use it as advised.
Don’t increase or decrease the dose without the advice of your doctor. Your doctor has proper knowledge of your present condition and he knows better how the drug will work in your body. Trust your doctor and follow him. You can’t become a doctor after all, although you have read an article full of knowledge.
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