Bottles of 3mg and 4.5 Vraylar (Cariprazine) capsules showing 3mg capsules below
Cariprazine was approved for medical use in the United States in September 2015.[11] It was approved as ageneric medication in 2022,[12] but is covered by patents until 2029.[13] Cariprazine was approved by the TGA for use in Australia in 2020.[14] As of 2025, the cost of Cariprazine is generally around $50.00USD,[15] $30.60AUD[16] on the PBS and £80.36 in the UK when on the NHS.[17]
Cariprazine consistently improved clinical severity across a spectrum of patients with bipolar disorder or schizophrenia - effectively reducing psychosis, anxiety, manic and depressive symptoms.[20][21][22] In Australia, the United Kingdom, and the European Union it is approved only for treatingschizophrenia.[4][6][23]
Side effects may first appear several weeks after starting cariprazine.[5] 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."[5]
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.[27]
The smaller the Ki value, the more strongly the drug binds to the site. IA=intrinsic activity.
Unlike many antipsychotics that are D2 and 5-HT2Areceptor antagonists, cariprazine is a D2 and D3partial 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.[31] 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 theventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act ondorsal striatum dopamine receptors.[32] Cariprazine also acts on5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).[32][33] 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 awater labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted.[32] 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.[33] 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]
Mechanism of cariprazine action as antagonist or agonist.
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 ofthis class are sometimes used to treat akathisia), as well as a lack of a balanced dopaminergic(D2)/serotonergic(5-HT2A) ratio(compared to the second generation antipsychotics serving a more nuanced profile in this regard)[clarify].[34][35][36] 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.[37][38]
Partialagonists are drugs that bind to and activate specific receptors, but they produce a weaker response than fullagonists, 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 likedopamine. 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 theEC50 value, which is the concentration needed to produce half of its maximum possible effect. Drugs likearipiprazole, cariprazine, andbrexpiprazole are examples of partial agonists used as antipsychotics. They help stabilize mood and reduce psychotic symptoms by balancing dopamine activity in the brain.[39][40][41][42][circular reference]
Cariprazine has high oralbioavailability and can cross theblood brain barrier easily in humans because it is lipophilic.[43] In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).[26]
Cariprazine is metabolized primarily by thecytochrome P450 3A4 isoenzyme (CYP3A4), with some minor metabolism byCYP2D6. Cariprazine does not induce the production of CYP3A4 or CYP1A2 in the liver, and weakly, competitively inhibits CYP2D6 and CYP3A4.[18]
Cariprazine is also potentially useful as anadd-on therapy inmajor depressive disorder.[45] It is being developed jointly byAbbVie andGedeon 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 USFood 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]
^Kiss B, Horváth A, Némethy Z, Schmidt E, Laszlovszky I, Bugovics G, et al. (April 2010). "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.333 (1):328–340.doi:10.1124/jpet.109.160432.PMID20093397.S2CID42933132.
^abcCitrome L (February 2013). "Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability".Expert Opinion on Drug Metabolism & Toxicology.9 (2):193–206.doi:10.1517/17425255.2013.759211.PMID23320989.S2CID36750662.
^Veselinović T, Paulzen M, Gründer G (November 2013). "Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression".Expert Review of Neurotherapeutics.13 (11):1141–1159.doi:10.1586/14737175.2013.853448.PMID24175719.S2CID23557344.
^abNewman-Tancredi A, Kleven MS (August 2011). "Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties".Psychopharmacology.216 (4):451–473.doi:10.1007/s00213-011-2247-y.PMID21394633.S2CID5835943.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.Archived from the original on 22 May 2021. Retrieved14 August 2017.
^abcGyertyán I, Kiss B, Sághy K, Laszy J, Szabó G, Szabados T, et al. (November 2011). "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.59 (6):925–935.doi:10.1016/j.neuint.2011.07.002.PMID21767587.S2CID140205658.
^Ribeiro ELA, Vieira MEB (2018). "Efficacy and safety of aripiprazole for the treatment of schizophrenia: An overview of systematic reviews".European Journal of Clinical Pharmacology.74 (10):1215–1233.doi:10.1007/s00228-018-2498-1.PMID29905899.
^Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, et al. (2002). "Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors".The Journal of Pharmacology and Experimental Therapeutics.302 (1):381–389.doi:10.1124/jpet.102.033175.PMID12065741.
^abGründer G (July 2010). "Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression".Current Opinion in Investigational Drugs.11 (7):823–832.PMID20571978.
