:Cariprazine

Cariprazine is used to treat patients with schizophrenia, schizoaffective disorder and manic, depressive, or mixed episodes associated with bipolar I disorder. In the United States 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).{{cite journal | vauthors = Citrome L | title = Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 9 | issue = 2 | pages = 193–206 | date = February 2013 | pmid = 23320989 | doi = 10.1517/17425255.2013.759211 | s2cid = 36750662 }}{{cite journal | vauthors = Do A, Keramatian K, Schaffer A, Yatham L | title = Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials | journal = Frontiers in Psychiatry | volume = 12 | pages = 769897 | date = 2021 | pmid = 34970166 | pmc = 8712443 | doi = 10.3389/fpsyt.2021.769897 | title-link = doi | doi-access = free }}

Cariprazine consistently improved clinical severity across a spectrum of patients with bipolar disorder or schizophrenia - effectively reducing psychosis, anxiety, manic and depressive symptoms.{{cite journal | vauthors = Patel M, Jain R, Tohen M, Maletic V, Earley WR, Yatham LN | title = Efficacy of cariprazine in bipolar I depression across patient characteristics: a post hoc analysis of pooled randomized, placebo-controlled studies | journal = International Clinical Psychopharmacology | volume = 36 | issue = 2 | pages = 76–83 | date = March 2021 | pmid = 33230026 | pmc = 7846289 | doi = 10.1097/YIC.0000000000000344 }}{{cite journal | vauthors = Tohen M | title = Cariprazine as a Treatment Option for Depressive Episodes Associated with Bipolar 1 Disorder in Adults: An Evidence-Based Review of Recent Data | journal = Drug Design, Development and Therapy | volume = 15 | pages = 2005–2012 | date = 2021 | pmid = 34012253 | pmc = 8126799 | doi = 10.2147/DDDT.S240860 | doi-access = free }}{{cite journal | vauthors = Tarchi L, Bugini S, Dani C, Cassioli E, Rossi E, Lucarelli S, Ricca V, Caini S, Castellini G | display-authors = 6 | title = Efficacy of Cariprazine in the Psychosis Spectrum: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials in Schizophrenia and Bipolar Disorder | journal = CNS Drugs | volume = 38 | issue = 12 | pages = 961–971 | date = December 2024 | pmid = 39382790 | pmc = 11543740 | doi = 10.1007/s40263-024-01125-9 }} In Australia, the United Kingdom, and the European Union it is approved only for treating schizophrenia.{{cite journal | vauthors = | title = Cariprazine hydrochloride for schizophrenia | journal = Australian Prescriber | volume = 44 | issue = 5 | pages = 170–171 | date = October 2021 | pmid = 34728883 | pmc = 8542486 | doi = 10.18773/austprescr.2021.047 }}

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"{{cite journal | vauthors = Citrome L | title = Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy | journal = Advances in Therapy | volume = 30 | issue = 2 | pages = 114–126 | date = February 2013 | pmid = 23361833 | doi = 10.1007/s12325-013-0006-7 | title-link = doi | doi-access = free }} but a second called the incidence of movement-related disorders "rather high".{{cite journal | vauthors = Veselinović T, Paulzen M, Gründer G | title = Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression | journal = Expert Review of Neurotherapeutics | volume = 13 | issue = 11 | pages = 1141–1159 | date = November 2013 | pmid = 24175719 | doi = 10.1586/14737175.2013.853448 | s2cid = 23557344 }}{{cite journal | vauthors = Newman-Tancredi A, Kleven MS | title = Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties | journal = Psychopharmacology | volume = 216 | issue = 4 | pages = 451–473 | date = August 2011 | pmid = 21394633 | doi = 10.1007/s00213-011-2247-y | s2cid = 5835943 }}

Regarding these side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time. "Cariprazine blocks the effects of THC.{{cite web | title=Vraylar- cariprazine capsule, gelatin coated Vraylar- cariprazine kit | website=DailyMed | date=18 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4b5f7c65-aa2d-452a-b3db-bc85c06ff12f | access-date=20 October 2020 | archive-date=24 October 2020 | archive-url=https://web.archive.org/web/20201024131022/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4b5f7c65-aa2d-452a-b3db-bc85c06ff12f | url-status=live }}

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.{{cite book |chapter=Cariprazine |date=2020 |chapter-url=https://www.cambridge.org/core/books/prescribers-guide/cariprazine/F5A7E531908E0A04808881D91C06A124 |title=Prescriber's Guide: Stahl's Essential Psychopharmacology |pages=137–146 |veditors=Stahl SM |edition=7th |place=Cambridge |publisher=Cambridge University Press |doi=10.1017/9781108921275.024 |isbn=978-1-108-92601-0 |access-date=11 October 2022 |archive-date=18 May 2024 |archive-url=https://web.archive.org/web/20240518060306/https://www.cambridge.org/core/books/abs/prescribers-guide/cariprazine/F5A7E531908E0A04808881D91C06A124 |url-status=live }}

{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}

Unlike many antipsychotics that are D₂ and 5-HT_2A 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.{{cite journal | vauthors = Seeman P, Kapur S | title = Schizophrenia: more dopamine, more D2 receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 14 | pages = 7673–7675 | date = July 2000 | pmid = 10884398 | pmc = 33999 | doi = 10.1073/pnas.97.14.7673 | title-link = doi | doi-access = free | bibcode = 2000PNAS...97.7673S }} 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.{{cite journal | vauthors = Gyertyán I, Kiss B, Sághy K, Laszy J, Szabó G, Szabados T, Gémesi LI, Pásztor G, Zájer-Balázs M, Kapás M, Csongor EÁ, Domány G, Tihanyi K, Szombathelyi Z | title = 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 | journal = Neurochemistry International | volume = 59 | issue = 6 | pages = 925–935 | date = November 2011 | pmid = 21767587 | doi = 10.1016/j.neuint.2011.07.002 | s2cid = 140205658 }} Cariprazine also acts on 5-HT_1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).{{cite journal | vauthors = Seneca N, Finnema SJ, Laszlovszky I, Kiss B, Horváth A, Pásztor G, Kapás M, Gyertyán I, Farkas S, Innis RB, Halldin C, Gulyás B | title = 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 | journal = Psychopharmacology | volume = 218 | issue = 3 | pages = 579–587 | date = December 2011 | pmid = 21625907 | pmc = 3210913 | doi = 10.1007/s00213-011-2343-z }} 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. 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. 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. 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".

File:Cariprazine mechanism.png

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-HT_2A) ratio {{clarify span|text=(compared to the second generation antipsychotics serving a more nuanced profile in this regard)|date=January 2024}}.{{cite journal | vauthors = Jethwa KD | title = Pharmacological management of antipsychotic-induced akathisia: an update and treatment algorithm. | journal = BJPsych Advances | date = September 2015 | volume = 21 | issue = 5 | pages = 342–344 | doi = 10.1192/apt.bp.114.013797 | s2cid = 146670706 | doi-access = free }}{{cite journal | vauthors = Citrome L, Yatham LN, Patel MD, Barabássy Á, Hankinson A, Earley WR | title = Cariprazine and akathisia, restlessness, and extrapyramidal symptoms in patients with bipolar depression | journal = Journal of Affective Disorders | volume = 288 | issue = | pages = 191–198 | date = June 2021 | pmid = 33915374 | doi = 10.1016/j.jad.2021.03.076 | s2cid = 233462432 | url = | doi-access = free }}{{cite journal | vauthors = Cohen LJ | title = Risperidone | journal = Pharmacotherapy | volume = 14 | issue = 3 | pages = 253–65 | date = 1994 | pmid = 7524043 | doi = 10.1002/j.1875-9114.1994.tb02819.x }} 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.{{cite web | url=https://derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacodynamics/Chapter%20417/full-agonists-partial-agonists-and-inverse-agonists | title=Full agonists, partial agonists and inverse agonists | Deranged Physiology | access-date=21 February 2023 | archive-date=14 February 2023 | archive-url=https://web.archive.org/web/20230214080128/https://derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacodynamics/Chapter%20417/full-agonists-partial-agonists-and-inverse-agonists | url-status=live }}{{cite journal | vauthors = Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF | title = 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 | journal = Neuropsychopharmacology | volume = 27 | issue = 2 | pages = 248–259 | date = August 2002 | pmid = 12093598 | doi = 10.1016/S0893-133X(02)00304-4 | s2cid = 26101524 | doi-access = free }}

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..{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/29905899/ | pmid=29905899 | date=2018 | author1=Ribeiro ELA | author2=Vieira MEB | title=Efficacy and safety of aripiprazole for the treatment of schizophrenia: An overview of systematic reviews | journal=European Journal of Clinical Pharmacology | volume=74 | issue=10 | pages=1215–1233 | doi=10.1007/s00228-018-2498-1 }}{{cite journal | pmid=28412910 | date=2017 | title=Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity | journal=Current Neuropharmacology | volume=15 | issue=8 | pages=1192–1207 | doi=10.2174/1570159X15666170413115754 | pmc=5725548 | vauthors = Tuplin EW, Holahan MR }}{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/12065741/ | pmid=12065741 | date=2002 | title=Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=302 | issue=1 | pages=381–389 | doi=10.1124/jpet.102.033175 | vauthors = Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB }}{{cite web | url=https://en.m.wikipedia.org/wiki/Partial_agonist | title=Partial agonist }}{{Circular reference|date=February 2025}}

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).

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.

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.{{cite journal | vauthors = Durgam S, Earley W, Lipschitz A, Guo H, Laszlovszky I, Németh G, Vieta E, Calabrese JR, Yatham LN | title = An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression | journal = The American Journal of Psychiatry | volume = 173 | issue = 3 | pages = 271–281 | date = March 2016 | pmid = 26541814 | doi = 10.1176/appi.ajp.2015.15020164 | title-link = doi | doi-access = free }}{{cite journal | vauthors = Gründer G | title = Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression | journal = Current Opinion in Investigational Drugs | volume = 11 | issue = 7 | pages = 823–832 | date = July 2010 | pmid = 20571978 }}

Cariprazine is also potentially useful as an add-on therapy in major depressive disorder.{{cite web |title=Safety and Efficacy of Cariprazine As Adjunctive Therapy In Major Depressive Disorder |url=https://clinicaltrials.gov/ct2/show/NCT00854100 |url-status=live |archive-url=https://web.archive.org/web/20181206102336/https://clinicaltrials.gov/ct2/show/NCT00854100 |archive-date=6 December 2018 |access-date=6 December 2018 |website=ClinicalTrials.gov |publisher=U.S. National Library of Medicine}} 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.{{Cite press release |title=AbbVie Submits Supplemental New Drug Application to U.S. FDA for cariprazine (major depressive disorder) for the Adjunctive Treatment of Major Depressive Disorder |url=https://news.abbvie.com/news/press-releases/abbvie-submits-supplemental-new-drug-application-to-us-fda-for-cariprazine-vraylar-for-adjunctive-treatment-major-depressive-disorder.htm |access-date=11 October 2022 |website=AbbVie |archive-date=16 October 2022 |archive-url=https://web.archive.org/web/20221016005559/https://news.abbvie.com/news/press-releases/abbvie-submits-supplemental-new-drug-application-to-us-fda-for-cariprazine-vraylar-for-adjunctive-treatment-major-depressive-disorder.htm |url-status=live }} Approval was granted by the FDA in December 2022 for cariprazine to be used as an adjunctive treatment for major depressive disorder.{{cite press release | title=U.S. FDA Approves Vraylar (cariprazine) as an Adjunctive Treatment for Major Depressive Disorder | publisher=AbbVie | via=PR Newswire | date=16 December 2022 | url=https://www.prnewswire.com/news-releases/us-fda-approves-vraylar-cariprazine-as-an-adjunctive-treatment-for-major-depressive-disorder-301705552.html | access-date=3 January 2023 | archive-date=4 January 2023 | archive-url=https://web.archive.org/web/20230104005727/https://www.prnewswire.com/news-releases/us-fda-approves-vraylar-cariprazine-as-an-adjunctive-treatment-for-major-depressive-disorder-301705552.html | url-status=live }}

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