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 Table of Contents  
Year : 2022  |  Volume : 10  |  Issue : 3  |  Page : 121-123

Cariprazine: A complete solution for full-spectrum bipolar I disorder?

Department of Psychiatry, Murshidabad Medical College & Hospital, Kolkata, West Bengal, India

Date of Submission19-Nov-2021
Date of Decision23-Dec-2021
Date of Acceptance21-Jan-2022
Date of Web Publication21-Feb-2023

Correspondence Address:
Ranjan Bhattacharyya
Department of Psychiatry, Murshidabad Medical College & Hospital, 29, Anandasree, Garia, Kolkata 700084, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/DYPJ.DYPJ_61_21

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Cariprazine is a partial agonist of dopamine and serotonin with high affinity for D3 receptor. There is excess endogenous dopamine both in schizophrenia and bipolar disorder. Cariprazine binds to D3/D2 receptor as antagonist and agonist in schizophrenia and bipolar depression, respectively. Thus, the dopamine pathway inhibited and stimulated in the respective cases. The United States Food and Drug Administration (USFDA) approval now covers the full-spectrum Bipolar I disorder, yet to hit the Indian market.

Keywords: Artial dopamine agonist, bipolar disorder, cariprazine, schizophrenia

How to cite this article:
Bhattacharyya R. Cariprazine: A complete solution for full-spectrum bipolar I disorder?. D Y Patil J Health Sci 2022;10:121-3

How to cite this URL:
Bhattacharyya R. Cariprazine: A complete solution for full-spectrum bipolar I disorder?. D Y Patil J Health Sci [serial online] 2022 [cited 2023 Mar 23];10:121-3. Available from: http://www.dypatiljhs.com/text.asp?2022/10/3/121/370124

  Introduction Top

Cariprazine is recommended by the United States Food and Drug Administration (USFDA) for acute treatment of mania and mixed episodes associated with Bipolar I disorder and the treatment of schizophrenia in adults in 2015. It has also been approved now in the treatment of depressive episode of Bipolar 1 disorder in adults. It is available in Europe in the brand name Reagila and in the rest of the world it is available in the name Vrarylar.[1]

  Mechanism of Action Top

Cariprazine is a dopamine D3/D2 and 5HT1A partial agonist. It is a partial agonist to the 5HT1A receptor and an inverse agonist to the 5HT2C receptor. It is an antagonist to 5HT2A, 2B, and 5HT7 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.[2] Cariprazine’s high selectivity toward D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs. 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.[3],[4]

The chemical structure of cariprazine is depicted in [Figure 1].
Figure 1: Chemical structure of cariprazine

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  Pharmacokinetics Top

It has high oral bioavailability and as it is lipophilic, it can cross blood–brain barrier easily. It is primarily metabolized through Cyp 3A4 pathway and to a minor extent through Cyp 2D6 and 1A2 pathways. Of two equipotent metabolites, desmethylcariprazine and didesmethylcariprazine, didesmethylcariprazine has a half-life of 1–3 weeks. Strong CYP3A4 inhibitors increase the concentration of cariprazine. The common adverse reactions are extrapyramidal syndrome (EPS), akathisia, vomiting, dyspepsia, somnolence, and restlessness.[5],[6] It is a novel antipsychotic with unique pharmacodynamic and pharmacokinetic properties. Pros and cons of cariprazine from the prescriber’s point of view are summarized in [Table 1].
Table 1: Advantages and disadvantages of the cariprazine

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  Clinical Trials Top

The molecule got its extended indication following three clinical trials. The primary indication was change in the MADRS scale after 6 weeks of treatment. The three doses of cariprazine have been studied. The trials found that the patients treated with 1.5 mg/d dose experienced significant improvement, whereas one trial found a similar response for 3 mg/d dose. FDA recommended 1.5 and 3 mg/d dose for depressive illness and 3–6 mg/d dose in a manic and mixed episode. The three clinical trials RGH-MD-53, RGH-MD-54, and RGH-MD-56 have been evaluated.[7],[8] The result of the first one is not available and the other two are summarized in [Table 2].
Table 2: Clinical trials prior approval

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The most prevalent adverse effects are akathisia, insomnia, and weight gain. It does not prolong corrected QT interval.[9],[10] The details of these adverse effects as per the manufacture’s guideline are given in [Table 3].
Table 3: Adverse effects as per prescriber’s guideline

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  Special Populations Top

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. Lactation studies have not been conducted to assess the presence of cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Safety and effectiveness in pediatric patients have not been established. It is not recommended for the treatment of behavior disorders in older adults with dementia due to high mortality associated with use of atypical antipsychotic drug and aggravation of behavioral symptoms in this age group. Also in geriatric population, renal, hepatic, and cardiac functions need to be monitored. The dose adjustment is not required in mild-to-moderate renal (CrCl> 30 mL/min) or hepatic impairment (Child Pugh scoring 6–9). The dose adjustment is necessary for severe renal impairment (CrCl<30 mL/min) and in severe hepatic impairment (Child Pugh’s score is 10–15).[11],[12],[13],[14] Patients should be counseled before prescribing few practical information as mentioned in [Table 4].
Table 4: Special precautions before prescribing cariprazine

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  Conclusion Top

Cariprazine has now been approved by USFDA for full spectrum manic, mixed, and depressive episodes. One should be cautious about the use of this molecule in the elderly because of the increased risk of mortality in elderly with dementia-related psychosis. It is contraindicated in patients with known hypersensitivity like development of rash, pruritus, urticarial, and angioedema. Increased risks of CVA, NMS, EPS, and TD are there. The development of metabolic syndrome, leukopenia, neutropenia, agranulocytosis, orthostatic hypotension, syncope, falls, seizures, cognitive impairment, esophageal dysmotility, dysregulation of body temperature, and dysphagia can occur.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Seeman P, Kapur S Schizophrenia: More dopamine, more D2 receptors. Proc Natl Acad Sci USA 2000;97:7673-5.  Back to cited text no. 1
Gyertyán I, Kiss B, Sághy K, Laszy J, Szabó G, Szabados T, et al. 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. Neurochem Int 2011;59:925-35.  Back to cited text no. 2
Citrome L The ABC’s of dopamine receptor partial agonists - aripiprazole, brexpiprazole and cariprazine: The 15-min challenge to sort these agents out. Int J Clin Pract 2015;69:1211-20.  Back to cited text no. 3
Durgam S, Cutler AJ, Lu K, Migliore R, Ruth A, Laszlovszky I, et al. Cariprazine in acute exacerbation of schizophrenia: A fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry 2015;76:e1574-82.  Back to cited text no. 4
Durgam S, Starace A, Li D, Migliore R, Ruth A, Németh G, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: A phase Ii, randomized clinical trial. Schizophr Res 2014;152:450-7.  Back to cited text no. 5
Kane JM, Zukin S, Wang Y, Lu K, Ruth A, Nagy K, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: Results from an international, phase Iii clinical trial. J Clin Psychopharmacol 2015;35:367-73.  Back to cited text no. 6
Sachs GS, Greenberg WM, Starace A, Lu K, Ruth A, Laszlovszky I, et al. Cariprazine in the treatment of acute mania in bipolar I disorder: A double-blind, placebo-controlled, phase Iii trial. J Affect Disord 2015;174:296-302.  Back to cited text no. 7
Dibben CR, Khandaker GM, Underwood BR, O’Loughlin C, Keep C, Mann L, et al. First-generation antipsychotics: Not gone but forgotten. Bjpsych Bull 2016;40:93-6.  Back to cited text no. 8
Durgam S, Litman RE, Papadakis K, Li D, Németh G, Laszlovszky I Cariprazine in the treatment of schizophrenia: A proof-of-concept trial. Int Clin Psychopharmacol 2016;31:61-8.  Back to cited text no. 9
Girgis RR, Slifstein M, D’Souza D, Lee Y, Periclou A, Ghahramani P, et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using Pet with the D3/D2 receptor ligand [(11)C]-(+)-Phno. Psychopharmacology (Berl) 2016;233:3503-12.  Back to cited text no. 10
Calabrese JR, Keck PE Jr, Starace A, Lu K, Ruth A, Laszlovszky I, et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: A double-blind, placebo-controlled study. J Clin Psychiatry 2015;76: 284-92.  Back to cited text no. 11
Lao KS, He Y, Wong IC, Besag FM, Chan EW Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: A systematic review with meta-analysis of randomized controlled trials. Cns Drugs 2016;30:1043-54.  Back to cited text no. 12
Durgam S, Earley W, Guo H, Li D, Németh G, Laszlovszky I, et al. Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: A randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. J Clin Psychiatry 2016;77:371-8.  Back to cited text no. 13
Durgam S, Earley W, Li R, Li D, Lu K, Laszlovszky I, et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. Schizophr Res 2016;176:264-71.  Back to cited text no. 14


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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