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Cariprazine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter,[6] which is used in the treatment of schizophrenia and bipolar disorder.[7] It is also prescribed as an add-on treatment for bipolar depression[8] and major depressive disorder. Cariprazine acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. It is a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors.[9] It is taken by mouth. The most prevalent side effects include nausea, mild sedation, fatigue, diabetes regardless of weight changes, and dizziness. At higher dosages, there is an increased risk for restlessness, insomnia, and tremors.

Cariprazine was approved for medical use in the US in September 2015.[10] It was approved as a generic medication in 2022,[11] but is covered by patents until 2029.[12] Cariprazine was approved by the Therapeutic Goods Administration (TGA) for use in Australia in 2020.[13] As of 2025, the cost of Cariprazine is generally around US$50,[14] $30.60AUD[15] on the PBS and £80.36 in the UK when on the National Health Service (NHS).[16]

Medical uses

Cariprazine is used to treat patients with schizophrenia, schizoaffective disorder and manic, depressive,[17] or mixed episodes associated with bipolar I disorder. In the US, it is approved for schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and treatment of depressive episodes associated with bipolar I disorder (bipolar depression).[18][19] In Australia, the UK, and the European Union, cariprazine is approved only for treating schizophrenia.[4][5][20]

Cariprazine consistently improved clinical severity across a spectrum of patients with bipolar disorder or schizophrenia, effectively reducing psychosis, anxiety, manic and depressive symptoms.[21][22][23]

Side effects

Side effects may first appear several weeks after starting cariprazine. Cariprazine does not appear to impact prolactin levels, and unlike many other antipsychotics, does not increase the QT interval on the electrocardiogram (ECG). In short term clinical trials, extrapyramidal effects, sedation, akathisia, nausea, headache, dizziness, vomiting, insomnia, anxiety, and constipation were observed. One review characterized the frequency of these events as "not greatly different from that seen in patient treated with placebo"[24] but a second called the incidence of movement-related disorders "rather high".[25][26]

Regarding these side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time."[27]

Because cariprazine and its active metabolites have long half-lives, many healthcare professionals monitor for adverse effects up to several weeks after starting cariprazine. A longer monitoring period is also indicated for dosage changes, whether they represent an increase or a decrease, because elimination may take several weeks.[28]

Pharmacology

Pharmacodynamics

Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist. It also has a higher affinity for D3 receptors. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia.[32] Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine's high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3 receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors.[33] Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).[33][34] In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted.[33] This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.

Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity.[24] In monkey studies, the administration of increasing doses of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94% occupied, while at the lowest dose (1 μg/kg), receptors were 5% occupied.[34] Dopamine D2 and D3 receptor occupancy in humans has been summarized as, "In healthy volunteers, single-dose cariprazine of 0.5 mg occupied up to 12% of striatal D2/D3 receptors, while striatal D2/D3 occupancy after multiple dosing up to cariprazine 1.0 mg/d ranged from 63 to 79% [39]. In an open-label, fixed-dose, 2-week trial in eight males with schizophrenia, PET scans of dorsal striatal regions (caudate nucleus and putamen) and ventral striatum (nucleus accumbens) showed maximum occupancy (‡ 90%) at a 3-mg target dose of cariprazine following 14 d of treatment [40,41]. After 14 d of cariprazine 1.5 mg/d, receptor occupancy was 69% in the caudate nucleus, 69% in the nucleus accumbens, and 75% in the putamen".[24]

Cariprazine, as well as other third generation antipsychotics, possesses a lower chance of exacerbating extrapyramidal symptoms. However the ability to induce akathasia remains relatively high. This may be mediated through a lack of anticholinergic effects (as agents of this class are sometimes used to treat akathisia), as well as a lack of a balanced dopaminergic(D2)/serotonergic(5-HT2A) ratio .[35][36][37] Moreover, partial agonists, through their limited response triggering, ironically often have the tendency to occupy near all targeted receptors at relatively low dosages of the drug. An extreme example is aripiprazole with an average occupancy of 70% (D2) at a 2 mg dose, well below its usual antipsychotic dosage (the often cited threshold of occupancy for an antipsychotic effect is 70%). This could be another reason for akathasia from partial agonists.[38][39]

Partial agonists are drugs that bind to and activate specific receptors, but they produce a weaker response than full agonists, even when all receptors are occupied. In neuronal signaling pharmacology, their activity is often described using two models: one considers how much of the drug binds to postsynaptic receptors, which can block stronger agonists from activating the receptor, while the other looks at how the drug can activate receptors by itself, but only to a limited extent compared to a full agonist. Partial agonists can act as both weak activators and blockers, depending on the presence of natural neurotransmitters like dopamine. When natural dopamine levels are high, partial agonists compete for the same receptors, reducing excessive signaling. When dopamine levels are low, partial agonists provide some activation, but not as much as dopamine or a full agonist would. The effectiveness of a partial agonist is often measured by the EC50 value, which is the concentration needed to produce half of its maximum possible effect. Drugs like aripiprazole, cariprazine, and brexpiprazole are examples of partial agonists used as antipsychotics. They help stabilize mood and reduce psychotic symptoms by balancing dopamine activity in the brain.[40][41][42]

Pharmacokinetics

Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic. In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).[26]

Cariprazine is metabolized primarily by the cytochrome P450 3A4 isoenzyme (CYP3A4), with some minor metabolism by CYP2D6. Cariprazine does not induce the production of CYP3A4 or CYP1A2 in the liver, and weakly, competitively inhibits CYP2D6 and CYP3A4.[18]

Research

Positive Phase III study results were published for schizophrenia and mania in early 2012, and for bipolar disorder I depression from a Phase II trial in 2015.[43][44]

Cariprazine is also potentially useful as an add-on therapy in major depressive disorder.[45] It is being developed jointly by AbbVie and Gedeon Richter Plc, with AbbVie responsible for commercialization in the US, Canada, Japan, Taiwan and certain Latin American countries (including Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru and Venezuela). In February 2022, AbbVie requested approval by the US Food and Drug Administration (FDA) for adjunctive treatment for major depressive disorder.[46] Approval was granted by the FDA in December 2022 for cariprazine to be used as an adjunctive treatment for major depressive disorder.[47]

References

  1. AusPAR: Cariprazine hydrochloride tga.gov.au, Therapeutic Goods Administration, 21 June 2022, retrieved 18 April 2023^
  2. Vraylar Product information health-products.canada.ca, Health Canada, 25 April 2012, retrieved 29 June 2022^
  3. Summary Basis of Decision - Vraylar hpr-rps.hers.ca, Health Canada, 26 August 2022, retrieved 29 September 2022^
  4. Reagila 1.5 mg hard capsules - Summary of Product Characteristics (SmPC) medicines.org.uk, 9 August 2018, retrieved 20 October 2020^
  5. Reagila ema.europa.eu, European Medicines Agency, 18 September 2017, retrieved 20 October 2020^
  6. Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety Advances in Therapy, July 2021^
  7. Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors Bioorganic & Medicinal Chemistry Letters, May 2012^
  8. Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study The American Journal of Psychiatry, June 2019^
  9. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile The Journal of Pharmacology and Experimental Therapeutics, April 2010^
  10. FDA approves new drug to treat schizophrenia and bipolar disorder fda.gov, Food and Drug Administration, 17 September 2015, retrieved 16 December 2019^
  11. 2022 First Generic Drug Approvals fda.gov, Food and Drug Administration, 3 March 2023, retrieved 30 June 2023^
  12. Generic Vraylar Availability Drugs.com, 9 March 2023, retrieved 26 March 2023^
  13. Reagila tga.gov.au, Therapeutic Drug Association Australia, 11 November 2020, retrieved 20 May 2025^
  14. Generic Vraylar Prices (Cariprazine) - U.S. & International PharmacyChecker.com, 2 June 2025, retrieved 2025-06-02^
  15. Pharmaceutical Benefits: Fees, Patient Contributions and Safety Net Thresholds pbs.gov.au, Pharmaceutical Benefits Scheme, 1 January 2025, retrieved 2 June 2025^
  16. Amendments to the Drug Tariff nhsbsa.nhs.uk, NHS Business Services Authority, 1 December 2020, retrieved 2 June 2025^
  17. Healthcare resource utilization and costs of using cariprazine as the first versus subsequent adjunctive therapy for major depressive disorder Journal of Medical Economics, 2025, retrieved 2025-10-31^
  18. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability Expert Opinion on Drug Metabolism & Toxicology, February 2013^
  19. Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials Frontiers in Psychiatry, 2021^
  20. Cariprazine hydrochloride for schizophrenia Australian Prescriber, October 2021^
  21. Efficacy of cariprazine in bipolar I depression across patient characteristics: a post hoc analysis of pooled randomized, placebo-controlled studies International Clinical Psychopharmacology, March 2021^
  22. Cariprazine as a Treatment Option for Depressive Episodes Associated with Bipolar 1 Disorder in Adults: An Evidence-Based Review of Recent Data Drug Design, Development and Therapy, 2021^
  23. Efficacy of Cariprazine in the Psychosis Spectrum: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials in Schizophrenia and Bipolar Disorder CNS Drugs, December 2024^
  24. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy Advances in Therapy, February 2013^
  25. Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression Expert Review of Neurotherapeutics, November 2013^
  26. Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties Psychopharmacology, August 2011^
  27. Vraylar- cariprazine capsule, gelatin coated Vraylar- cariprazine kit DailyMed, 18 May 2019, retrieved 20 October 2020^
  28. Prescriber's Guide: Stahl's Essential Psychopharmacology Cambridge University Press, 2020, retrieved 11 October 2022^
  29. PDSP Ki Database Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill and the United States National Institute of Mental Health, retrieved 14 August 2017^
  30. Involvement of 5-HT1A and 5-HT2A Receptors but Not α 2-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo Molecular Pharmacology, December 2018^
  31. Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy? Frontiers in Psychiatry, 25 January 2022^
  32. Schizophrenia: more dopamine, more D2 receptors Proceedings of the National Academy of Sciences of the United States of America, July 2000^
  33. Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents Neurochemistry International, November 2011^
  34. Occupancy of dopamine D₂ and D₃ and serotonin 5-HT₁A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography Psychopharmacology, December 2011^
  35. Pharmacological management of antipsychotic-induced akathisia: an update and treatment algorithm. BJPsych Advances, September 2015^
  36. Cariprazine and akathisia, restlessness, and extrapyramidal symptoms in patients with bipolar depression Journal of Affective Disorders, June 2021^
  37. Risperidone Pharmacotherapy, 1994^
  38. Full agonists, partial agonists and inverse agonists DerangedPhysiology.com, retrieved 21 February 2023^
  39. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride Neuropsychopharmacology, August 2002^
  40. Efficacy and safety of aripiprazole for the treatment of schizophrenia: An overview of systematic reviews European Journal of Clinical Pharmacology, 2018^
  41. Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity Current Neuropharmacology, 2017^
  42. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors The Journal of Pharmacology and Experimental Therapeutics, 2002^
  43. An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression The American Journal of Psychiatry, March 2016^
  44. Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression Current Opinion in Investigational Drugs, July 2010^
  45. Safety and Efficacy of Cariprazine As Adjunctive Therapy In Major Depressive Disorder ClinicalTrials.gov, U.S. National Library of Medicine, retrieved 6 December 2018^
  46. AbbVie Submits Supplemental New Drug Application to U.S. FDA for cariprazine (major depressive disorder) for the Adjunctive Treatment of Major Depressive Disorder AbbVie, retrieved 11 October 2022^
  47. U.S. FDA Approves Vraylar (cariprazine) as an Adjunctive Treatment for Major Depressive Disorder AbbVie, 16 December 2022, retrieved 3 January 2023^